method for preparing a dry composition, method for reconstituting the dry composition, paste, dry co

专利摘要:
METHODS FOR PREPARING A DRY COMPOSITION AND RECONSTITUTING A DRY COMPOSITION, PASTE, DRY COMPOSITION, CONTAINER, HOMEOSTATIC KIT, AND, SYRINGE. The present description refers to a dry composition that reconstitutes without mechanical mixing to form a slurry having a soft and light consistency suitable for use in homeostasis and wound healing procedures by the addition of an aqueous medium. The description also refers to methods of preparing the dry composition, methods for reconstituting the dry composition and medical use of the composition.
公开号:BR112017007466B1
申请号:R112017007466-4
申请日:2015-10-13
公开日:2021-03-02
发明作者:Kristian Larsen；Flemming Reissig Jensen；Michael Wrang Mortensen
申请人:Ferrosan Medical Devices A/S；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] The present description refers to a method for preparing a dry composition suitable for use in homeostasis and wound healing procedures. The dry composition efficiently reconstitutes to form a paste having a soft, light consistency with the addition of an aqueous medium without mechanically mixing air in the paste. BACKGROUND OF THE INVENTION
[002] Hemostatic protein-based materials, such as collagen and gelatin, are commercially available in the form of a solid sponge or loose or unpackaged powder for use in surgical procedures. Mixing loose or unpackaged powder with a fluid, such as saline or thrombin, can form a paste or mass that is useful as a hemostatic composition for use in cases of diffuse bleeding, particularly from uneven surfaces or difficult to reach areas. achieve, depending on the mixing conditions and relative proportions of the materials.
[003] Conventional hemostatic pastes are usually prepared at the time of use by mechanical stirring and mixing of biocompatible polymer, for example, gelatin and a liquid, for example, a thrombin solution, to provide uniformity of the composition. Mixing to form a paste usually requires extensive mixing, such as kneading or transferring between two syringes.
[004] WO 03/055531 refers to a container that comprises a fixed amount of hemostatic agent in powder form, such as powdered gelatin. After adding a suitable amount of liquid, mechanical mixing inside the container can be carried out by closing the lid and shaking the container. The hemostatic paste with a consistency similar to a resulting mass can then be removed from the container and applied to a patient to promote hemostasis.
[005] Surgiflo ® (Ethicon) hemostatic matrix is a kit to produce a homeostatic gelatin paste comprising thrombin, which is prepared by transferring a gelatin-thrombin solution mixture back and forth between two syringes connected by a total of hair minus six passes. Floseal ® (Baxter) hemostatic matrix is also a kit to produce a homeostatic gelatin paste, but requires transferring the gelatin matrix-thrombin solution mixture back and forth between two syringes connected for a total of at least twenty passes. Once a substantially homogeneous paste composition is obtained, hemostatic pastes can be applied to bleed to promote homeostasis by extruding the pastes from the syringe.
[006] US 2005/0284809 relates to a method for preparing a hemostatic paste that more readily absorbs aqueous liquids, such that less mechanical force and time is required to form a hemostatic paste. US 2005/0284809 paste is prepared from particles of compressed hemostatic powder and to prepare the paste, it must be transferred between the connected syringes at least five times.
[007] WO 2011/151400 relates to a process for the preparation of a dry hemostatic composition comprising a coagulation inducing agent, such as thrombin and a biocompatible polymer, such as gelatin. The coagulation inducing agent and the biocompatible polymer are mixed to form a paste and the paste is subjected to lyophilization. The resulting dry composition is reconstituted by transferring the composition and a diluent between two syringes connected for a total of at least twenty times as previously described.
[008] The transfer between the connected syringes ensures sufficient mixing of the liquid component and the gelatin matrix component. During the passage, air is mixed into the paste, which affects the consistency of the reconstituted paste. However, mixing and manipulation procedures are time consuming, which in an operating room (OS) with bleeds is not acceptable, since the surgeon will have to abruptly interrupt his procedure while waiting for the hemostatic. The mixture can also potentially compromise the sterility of the homeostatic paste and, in some cases, it can even negatively affect the consistency of the homeostatic paste. The consistency of the paste is an important parameter both for the application of the paste and for the adhesion of the paste to the wound.
[009] WO 2013/185776 describes a dry paste composition suitable for wound healing and homeostatic use that spontaneously reconstitutes to form a fluid paste, that is, without any mixing required, by adding an aqueous medium. The dry composition is prepared by mixing a cross-linked biocompatible polymer, one or more polyols and an aqueous medium to prepare a paste and then lyophilizing the paste to obtain the dry composition.
[0010] WO 2014/202760 describes a dry composition suitable for use in wound healing and as a homeostatic that spontaneously reconstitutes to form a fluid paste, that is, without any necessary mixing, by adding an aqueous medium. The dry composition is prepared by mixing a cross-linked biocompatible polymer and an aqueous medium to prepare a paste, expanding the paste by subjecting the paste to reduced pressure, freezing the expanded paste and then drying the expanded paste and freezing to obtain the dry composition.
[0011] As previously mentioned, the consistency of paste can be important for the homeostatic effect and adhesion of the paste to the fabric. In addition, the consistency of reconstituted pastes can also be an important parameter in determining which types of surgeries are most suitable for pastes. For example, a softer paste consistency may be preferable in certain types of surgery. The surgeon's preferences also vary with regard to the consistency of the pastes, where some surgeons prefer a softer consistency than others. Thus, there is a need in the art to develop dry pulp compositions, in which the consistency of the reconstituted pulp can be more easily controlled. SUMMARY OF THE INVENTION
[0012] The present invention addresses the above problems and thus provides a dry composition which, upon the addition of an aqueous medium, forms a substantially homogeneous paste without any necessary mechanical mixing. A soft and light consistency of the reconstituted paste is controlled by the presence of an alkali and an acidic compound, which are able to react to produce a gas by moistening the dry composition. The gas produced in the reaction of the acid and the base expands within the composition being reconstituted and results in a paste having a desirable soft and light consistency without having to introduce air through mechanical mixing procedures.
[0013] The release of a gas by wetting the dry composition can be obtained in at least three alternative forms: 1. By preparing a dry composition comprising an alkaline compound and reconstitution with a liquid comprising an acidic compound. 2. For the preparation of a dry composition comprising an acidic compound and reconstitution with a liquid comprising an alkaline compound. 3. By preparing a dry composition comprising both an alkaline and an acid compound and reconstitution with an aqueous medium, for example, water.
[0014] The alkaline compound and the acidic compound are capable of reacting in the presence of an aqueous medium to release a gas.
[0015] Thus, in a first embodiment, the invention relates to a method for preparing a dry composition comprising the steps of: a) mixing a biocompatible polymer in the form of powder, an aqueous medium and an alkaline compound to obtain a paste, and b) drying the paste, in which the alkaline compound is capable of reacting with an acidic compound in an aqueous medium to release a gas.
[0016] In a second embodiment, the invention relates to a method for preparing a dry composition comprising the steps of: a) mixing a biocompatible polymer in the form of powder, an aqueous medium and an acidic compound to obtain a paste, and b) drying the paste, in which the acidic compound is able to react with an alkaline compound in an aqueous medium to release a gas.
[0017] In a third embodiment, a dry composition comprising both an alkaline and an acid compound is added: a) an acidic compound in the dry form after the paste has been dried if the dry composition already comprises an alkaline compound, or b) a compound alkaline in dry form after the paste has been dried if the dry composition already comprises an acidic compound. in which the acidic compound and the alkaline compound are capable of reacting in the presence of an aqueous medium to release a gas.
[0018] The dry composition prepared by the previous methods is efficiently reconstituted in the addition of a suitable liquid to the paste having a soft and "fluffy" consistency. The paste is formed independently of external stimuli, such as mixing or stirring of any kind.
[0019] The present description also refers to a dry composition obtained by the previous methods, methods for reconstituting the dry composition and the uses thereof
[0020] The present disclosure also refers to a paste having a desirable soft consistency and its uses. DESCRIPTION OF THE DRAWINGS
[0021] Figure 1. Average reconstitution time +/- standard deviation of lyophilized gelatin pastes comprising the different polyols of example 1. Pastes do not have an expanded vacuum prior to lyophilization. Inclusion of different polyols in the lyophilized paste composition resulted in the spontaneous reconstitution of the pastes in about 30 seconds.
[0022] Figure 2. Average reconstitution time +/- standard deviation of the freeze-dried and freeze-dried gelatin pastes of example 3. Expansion under vacuum greatly reduces the time for spontaneous reconstitution of pastes comprising mannitol.
[0023] Figures 3 to 14 represent different modalities of the method of the present description involving vacuum expansion of the pastes before drying.
[0024] Figure 3 shows two possible modalities of a syringe for use as a container before the paste is added. Concept 1 includes a standard single-use syringe and concept 2 includes a single-use syringe with a lyophilization shortcut on the syringe body. The pressure valve is closed.
[0025] Figure 4 shows the concept syringes 1 and 2 with a quantity of paste.
[0026] Figure 5 shows a syringe fitted with a lyophilization plunger comprising a shortcut (lyophilization plunger; concept 1) or a syringe comprising a shortcut in the syringe body being fitted with a standard plunger (concept 2). The shortcuts of both concept 1 and 2 allow gaseous communication between the product chamber and the outside of the container. The application of low vacuum results in the expansion of the paste, that is, the volume of the paste is greater than before the vacuum application.
[0027] Figure 6 shows the syringes of concepts 1 and 2 after the paste is frozen. Freezing results in a closed expanded paste structure.
[0028] Figure 7 shows the syringes of concepts 1 and 2 that undergo vacuum lyophilization. Lyophilization does not change the volume of the frozen paste.
[0029] Figure 8 shows the syringes of concepts 1 and 2, in which the shortcuts were closed with a removable shelf. The syringes contain the dry paste in a vacuum product chamber.
[0030] Figure 9 shows the syringes of concepts 1 and 2 after the vacuum in the freeze dryer is released. The vacuum inside the product chamber and the atmospheric pressure outside the product chamber causes the plunger to move until it comes in contact with the dry paste product.
[0031] Figure 10 shows the syringes of concepts 1 and 2 after assembling a stem and plunger edges.
[0032] Figure 11 shows the concept 1 syringe being sterilized by irradiation.
[0033] Figure 12 shows two different ways to reconstitute the dry paste. In a first mode (top), the syringe is fitted to a plastic bag that keeps the H2O sterile or saline. In a second embodiment (bottom), the syringe is fitted to a plastic container keeping H2O sterile or saline, in which the plastic container is fitted with a movable plunger.
[0034] Figure 13 shows the two modalities of figure 12 after the valve is opened. Opening the valve results in the liquid being automatically drawn into the product chamber, due to the pressure difference between the product chamber (low pressure) and the liquid container (normal pressure). The paste is spontaneously reconstituted upon contact with the liquid. Mechanical mixing is not required before using the paste.
[0035] Figure 14 represents a paste ready for use in a syringe fitted with an applicator tip.
[0036] Figure 15 shows a correlation between the pressure used for vacuum that expands a gelatin paste and the density of the final dry paste composition: The lower the pressure; lower the density of the dry composition.
[0037] Figures 16a-d show perspective views of the barrel of a currently described syringe modality.
[0038] Figures 17a-b show proximal views of two different modalities of the syringe barrel currently described.
[0039] Figures 18a-b are cross-sectional side view illustrations of the barrel of a syringe modality currently described, with the pressure valve in two different positions.
[0040] Figure 19a shows another modality of a pressure valve.
[0041] Figure 19b shows a front view of another embodiment of the pressure chamber of the syringe currently described with the pressure valve of figure 19a.
[0042] Figures 19c-d shows a front cross-sectional view of the configuration of the pressure valve of figure 19a inside the pressure chamber of figure 19b.
[0043] Figures 20a-b are illustrations of side cross-sectional views of the pressure valve of figure 19a inside the pressure chamber of figure 19.
[0044] Figures 20c-d are illustrations of perspective view of the barrel with the pressure valve and pressure chamber of figure 19.
[0045] Figure 21 shows the average reconstitution time +/- standard deviation of dry gelatin paste compositions comprising different amounts of mannitol (% by weight in wet paste) with and without vacuum expansion. Vacuum expansion has greatly reduced the spontaneous reconstitution time of dry pastes, which is further reduced by increasing concentrations of mannitol in dry pastes.
[0046] Figure 22 shows the reconstitution time +/- standard deviation of vacuum-expanded dry gelatin paste compositions with and without PEG (% by weight in wet paste). PEG decreased the reconstitution time compared to vacuum expanded compositions without PEG.
[0047] Figure 23 shows the consistency of reconstituted pastes of dry compositions comprising different concentrations of NaHCO3 (Example 7). The results show that the consistency of the pastes softens as the concentration of NaHCO3 in the dry composition increases
[0048] The drawings are only exemplary and should not be construed as limiting the scope of the invention
[0049] Definitions
[0050] "Ambient pressure" is used here interchangeably with the term "atmospheric pressure". It is the pressure in the surrounding area, that is, the pressure in the place where a process occurs.
[0051] "Bar" (unit). The bar is a non-SI pressure unit, defined as exactly equal to 100,000 Pa. It is almost equal to the atmospheric pressure on Earth, at sea level.
[0052] A "bioactive agent" means any agent, drug, compound, composition of matter or mixture that provides some pharmacological effect, often beneficial, an effect that can be demonstrated in vivo or in vitro. A bioactive agent is thus considered, whether it has an interaction with or effect on a cellular tissue in the human or animal body. As used herein, this term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect on an individual. Bioactive agents can be a protein, such as an enzyme. Other examples of bioactive agents include, but are not limited to, agents that comprise or consist of an oligosaccharide, a polysaccharide, an optionally glycosylated peptide, an optionally glycosylated polypeptide, an oligonucleotide, a polynucleotide, a lipid, a fatty acid, an fatty acid ester and secondary metabolites. It can be used either prophylactically, therapeutically, in connection with the treatment of an individual, such as a human or any other animal. The term "bioactive agent" as used herein does not include cells, such as eukaryotic or prokaryotic cells.
[0053] "Biocompatible" refers to the ability of a material to perform its intended function without causing any substantial undesirable local or systemic effects on the host.
[0054] "Biologically absorbable" or "reabsorbable" are terms that in the present context are used to describe that the materials from which said powder is made can be degraded in the body into smaller molecules having a size that allows them to be transported in the current blood. For such degradation and absorption of the referred powder materials will be gradually removed from the application site. For example, gelatin can be degraded by tissue proteolytic enzymes to smaller absorbable molecules, whereby gelatin when applied to tissues is typically absorbed within about 4 to 6 weeks and when applied to bleeding surfaces and mucous membranes, typically in 3 to 5 days.
[0055] "Carbonate salt" as used herein includes carbonate (CO32-) and bicarbonate salts (HCO3-).
[0056] "Expansion" is as defined here an increase in volume and a decrease in density. Thus, if a material is considered to be expanded, the total volume of the material is greater than before the expansion, without affecting the total weight of the material.
[0057] A "gel" is a solid, gelatinous material that can have properties ranging from soft and weak to hard and resistant. Gels are defined as a substantially diluted lattice system, which does not exhibit flow when in a steady state. By weight, gels are mostly liquid, although they behave as solids, due to a three-dimensional lattice network within the liquid. It is the reticulations of the fluid that give the gel its structure (hardness) and contribute to them being sticky (adhesion). In this way, gels are a dispersion of molecules of a liquid within a solid in which the solid is the continuous phase and the liquid is the discontinuous phase. A gel is not a paste or paste. For example, uncrosslinked gelatin particles are soluble and can form a gel upon contact with an aqueous medium such as water. A gel does not have pores that comprise expandable gas or air.
[0058] "Hemostasis" is a process that causes bleeding to decrease or cease. Hemostasis occurs when blood is present outside blood vessels or the body and represents the instinctive response for the body to stop bleeding and blood loss. During hemostasis, three steps occur in a rapid sequence. Vascular spasm is the first response, so blood vessels constrict to allow less blood to be lost. In the second step, in the formation of the platelet plug, the platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and final stage is called blood clotting or clotting. Coagulation reinforces the platelet buffer with the fibrin network that acts as a "molecular glue". In this way, a hemostatic compound is able to stimulate hemostasis.
[0059] “International Unit (UI)”. In pharmacology, the International Unit is a unit of measurement for the quantity of a substance, based on the biological activity or effect. It is abbreviated as IU, UI, or as IE. It is used to quantify vitamins, hormones, some drugs, vaccines, blood products, and similar biologically active substances.
[0060] A "paste" according to the present invention has a malleable consistency similar to a dough, such as toothpaste. The paste is a thick fluid mixture of powdered solid / powdered solid with a liquid. A paste is a substance that behaves like a solid until a sufficiently large level of charge or tension is applied, to a point where it flows like a fluid, that is, a paste is fluid. Fluid substances adapt efficiently to uneven surfaces upon application. Pastes typically consist of a suspension of granular material in a background fluid. The individual grains are placed together like sand on a beach, forming a disorderly, glassy or amorphous structure, and giving the folders their characteristic that resembles a solid. It is this “cluster” that gives pastes some of its most unusual properties; this makes the folders demonstrate fragile properties. The paste is not a gel / jelly. The “dough” is a mixture of a powdered / powdered solid fluid with a liquid (usually water). The masses behave in a certain way, like thick fluids, which flow by gravity and are capable of being pumped, if not very thick. A dough can be functionally considered to be a thin, watery paste, but a dough usually contains more water than a paste. A paste, according to the present description, has pores that are compartments comprising an expandable gas, such as air. Powder particles substantially insoluble in water, such as crosslinked gelatin particles, will form a paste upon mixing with an aqueous medium.
[0061] "Percentage". If nothing else is indicated, the percentage is percentage by weight:% w / w or% by weight.
[0062] The reasons are indicated as weight by weight (p: p).
[0063] A "reduced pressure" is a pressure below ambient pressure, that is, a pressure below that of the pressure in the surrounding area, in which a certain process occurs.
[0064] "Spontaneous". The term “spontaneous” is used to describe phenomena resulting from internal forces or causes that are independent of external agents or stimuli and that occur within a short period of time, that is, preferably within less than about 30 seconds , more preferably in less than about 20 seconds, even more preferably in less than about 10 seconds or in less than about 5 seconds, such as in less than about 3 seconds, for example, less than about 2 seconds.
[0065] “Vacuum” is defined as a region with a gas pressure less than the ambient pressure, that is, the surrounding atmospheric pressure. At sea level on Earth, the atmospheric pressure is approximately 1 bar, that is, 1000 mbar (100 kPa) at 25 ° C. The following table shows the approximate pressures at “low”, “medium” and “high” vacuum at sea level on Earth in millibar (mbar).
DETAILED DESCRIPTION OF THE INVENTION
[0066] The present description provides a dry composition which, with the addition of an adequate amount of an aqueous medium, forms a substantially homogeneous paste, which is soft and light ("fluffy" or "aerated"). The dry composition is able to reconstitute without any mechanical mixing required.
[0067] Reconstitution without mechanical mixing and a smooth consistency of the reconstituted paste can be achieved by contacting an acid and a base, which are able to react with each other to produce a gas in the presence of an aqueous medium. The acid and base are able to react with each other when the dry composition is moistened, that is, by reconstituting the dry composition.
[0068] In a preferred embodiment, the dry composition is prepared with a carbonate salt as the base. Upon addition of an aqueous medium comprising an acid, the acid reacts with the carbonate ion to create carbonic acid, which decomposes rapidly to CO2. The CO2 gas expands inside the paste, thus allowing an efficient distribution of liquid within the dry composition. The resulting paste has a desirable soft consistency.
[0069] The advantages of the dry composition and the reconstituted paste obtained by the methods of the present invention are numerous and include: • Less time is spent preparing the paste, which means that bleeding can be stopped quickly. • Less risk of compromising the sterility of the paste during preparation due to fewer handling steps. • Less risk of producing errors during the preparation of the paste. • Great consistency of paste obtained every time. • Reliable and consistent replenishment within a short period of time. • Bioactive agents, which are unstable in solution, can be added to the paste prior to drying and are thus present in the dry composition of the invention. For example, thrombin can be added to the paste before drying, thus avoiding the time-consuming and error-prone thrombin dilution steps. • Minimizes the costs of the Operating Room because the preparation of the product currently described is so simple and fast that there is no reason to pre-prepare fluid homeostats before surgery, which may not be used. • The reconstituted paste has a smooth consistency, which may be desirable in certain types of surgery.
[0070] All of the above factors lead to increased patient safety. Biocompatible polymer
[0071] The paste can be formed of a biocompatible polymer when the biocompatible polymer is in powder form and the powder particles are substantially insoluble in the aqueous medium in which they are mixed. Thus, the biocompatible polymer in powder form consists substantially of water-insoluble powder particles. Preferably, the agent is a biocompatible crosslinked polymer suitable for use in hemostasis and / or wound healing, such as a crosslinked hemostatic agent in powder form, for example, gelatin crosslinked powder. Cross-linking makes the biocompatible polymer substantially insoluble in an aqueous medium.
[0072] The biocompatible polymer in powder form consists of solid particles, porous or non-porous of a biocompatible polymer suitable for use in homeostasis and wound healing procedures.
[0073] In one embodiment, the composition of the present description comprises one or more biocompatible polymers in powder form, such as a simple biocompatible polymer or a combination of two or more biocompatible polymers.
[0074] The biocompatible polymer of the present description can be a biological or non-biological polymer. Suitable biological polymers include proteins, such as gelatin, collagen, albumin, hemoglobin, casein, fibrinogen, fibrin, fibronectin, elastin, keratin and laminin; or derivatives thereof or combinations thereof. It is particularly preferred to use gelatin or collagen, more preferably gelatin. Other suitable biological polymers include polysaccharides, such as glycosaminoglycans, starch derivatives, xylan, cellulose derivatives, cellulose derivatives, hemicellulose derivatives, agarose, alginate, chitosan and; or derivatives thereof or combinations thereof. Suitable non-biological polymers will be selected to be degradable by either of two mechanisms, that is, (1) breaking the polymeric main chain or (2) degrading the side chains that result in water solubility.
[0075] In a preferred embodiment, the biocompatible polymer is biologically absorbable. Examples of suitable biologically absorbable materials include gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, polyglycolic acid, polyacetic acid and combinations thereof. It should be understood that various forms thereof, such as linear or reticulate forms, salts, esters and the like, are also contemplated for the present description. In a preferred embodiment of the invention, the bioabsorbable material is gelatin. Gelatine is preferred since gelatine is biologically highly absorbable. In addition, gelatin is highly biocompatible, which means that it is not toxic to an animal, such as a human being, when / if it enters the bloodstream or is in prolonged contact with human tissues.
[0076] Gelatin typically originates from a porcine source, but can originate from other animal sources, such as from bovine or fish sources. Gelatin can also be made synthetically, that is, made by recombinant means.
[0077] In a preferred embodiment the biocompatible polymer is cross-linked. Cross-linking generally makes the polymer substantially insoluble in an aqueous medium. Any suitable crosslinking methods known to a person skilled in the art can be used, including chemical and physical crosslinking methods.
[0078] In one embodiment of the present description, the polymer was cross-linked by physical means, such as dry heat. Dry heat treatment is generally carried out at temperatures between 100 ° C and 250 ° C, such as about 110 ° C to about 200 ° C. In particular, the temperature can be in the range of 110 to 160 ° C, for example, in the range of 110 to 140 ° C, or in the range of 120 to 180 ° C, or in the range of 130 to 170 ° C, or in 130 to 160 ° C, or in the range 120 to 150 ° C. The time period for the crosslinking can be optimized by a person skilled in the art and is normally a period between about 10 minutes to about 12 hours, such as about 1 hour to about 10 hours, for example, between about 2 hours to about 10 hours, such as between about 4 hours to about 8 hours, for example, between about 5 hours to about 7 hours, such as about 6 hours.
[0079] In another embodiment, the polymer was cross-linked by chemical means, that is, by exposure to a chemical cross-linking agent. Examples of suitable chemical crosslinking agents include, but are not limited to, aldehydes, especially glutaraldehyde and formaldehyde, acyl azide, caboimides, hexamethylene diisocyanate, polyether oxide, 1,4-butanedioldiglycidyl ether, tannic acid, aldose sugars, for example, D-fructose, genipin and dye-mediated photo-oxidation. Specific compounds include, but are not limited to 1- (3-dimethylaminopropyl) -3-ethylcarboiimide (EDC), dithiobis (propanoic dihydrazide) (DTP), l-ethyl-3- (3-dimethylamino-propyl) - carbodiimide (EDAC).
[0080] In a preferred embodiment, the biocompatible polymer is obtained from crosslinked gelatin or collagen sponges, in particular crosslinked gelatin sponges (such as commercially available Spongostan® sponges and Surgifoam® sponges). The cross-linked sponges are micronized by methods known in the art to obtain a cross-linked biocompatible polymer in the form of powder, such as by fluidized bed, extrusion, granulation and treatment in an intensive mixer, or grinding (for example, using a hammer mill or a centrifugal mill).
[0081] Spongostan® / Surgifoam® are available from Ethicon is a cross-linked absorbable hemostatic gelatin sponge. It absorbs> 35 g of blood / g and within 4 to 6 weeks is completely absorbed in the human body.
[0082] In one embodiment, the biocompatible polymer in powder form comprises or consists of cross-linked gelatin particles obtained from a micronized porous gelatin sponge, which has been cross-linked by treatment with dry heat. Such gelatin particles will be porous.
[0083] Micronized porous gelatin sponges can be prepared by mixing an amount of soluble gelatin with an aqueous medium, in order to create a foam comprising a discontinuous gas phase, drying said foam and cross-linking the dry foam by exposure to dry heat, obtaining thus a dry cross-linked sponge. The obtained cross-linked sponge can be micronized by methods known in the art. The gelatin foam generally has a gelatin concentration of about 1% to 70% by weight, generally 3% to 20% by weight. Drying is generally carried out at about 20 ° C to about 40 ° C for about 5 to 20 hours. The dry foam is generally cross-linked by exposure to a temperature of about 110 ° C to about 200 ° C, for about 15 minutes to about 8 hours, such as about 150 ° C to about 170 ° C for about 5 to 7 hours.
[0084] In another embodiment, the biocompatible polymer comprises or consists of cross-linked gelatin particles obtained from a gelatin hydrogel. A gelatin hydrogel can be prepared by dissolving an amount of gelatin in an aqueous buffer to form a non-cross-linked hydrogel, typically with a solids content of 1% to 70% by weight, generally 3% to 10% by weight. Gelatine is cross-linked, for example, by exposure to both glutaraldehyde (eg 0.01% to 0.05% w / w, overnight at 0 DEG to 15 DEG C. in aqueous buffer), sodium periodate (for example, 0.05 M, maintained at 0 DEG C. to 15 DEG C. for 48 hours) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (“EDC”) (for example, 0.5% at 1.5% w / w, overnight at room temperature), or by exposure to about 0.3 to 3 megarads of gamma radiation or electron beam. The resulting cross-linked hydrogels can be broken up and dried to obtain a gelatin powder. Alternatively, gelatin particles can be suspended in an alcohol, preferably methyl alcohol or ethyl alcohol, in a solids content of 1% to 70% by weight, generally 3% to 10% by weight, and cross-linked upon exposure to an agent crosslinking, typically glutaraldehyde (eg 0.01% to 0.1% w / w, overnight at room temperature). When cross-linked with glutaraldehyde, cross-links are formed by means of Schiff bases that can be stabilized by subsequent reduction, for example, by treatment with sodium borohydride. After crosslinking, the resulting granules can be washed in water, and optionally washed in an alcohol and dried to obtain a gelatin powder. In one embodiment, crosslinked gelatin particles are prepared essentially in the manner described in U.S. 6,066,325. Such gelatin particles will be non-porous.
[0085] The cross-linked powder particles are in a modality less than about 1000 microns in size, that is, so that they are able to pass through a 1 x 1 mm sieve.
[0086] In one embodiment, at least 90% of the powder particles have a diameter between 1μm and 1200 μm.
[0087] In one embodiment, the average particle diameter is between 1 μm and 1000 μm, such as between 10 μm and 800 μm, for example, between 50 μm and 600 μm, such as between 100 μm and 500 μm, for example , between 200 μm and 400 μm, such as about 300 μm.
[0088] In some applications, it is desirable to have a smaller particle size, through which a softer paste can be obtained. Thus, in one embodiment, the average particle diameter is less than 100 μm, such as less than 50 μm, for example, less than 30 μm, such as less than 20 μm, for example, less than 10 μm. An example of an application where a softer paste is desirable is to control bone bleeding.
[0089] Particles of a certain size distribution can be achieved by passing a powder composition through one or more sieves with a certain mesh size and collecting the powder that passes through it and / or is maintained for a certain size. mesh. For example, powder particles with a size distribution between approximately 200 μm and 1000 μm can be obtained by collecting the powder that is able to pass through a 1 x 1 mm sieve, but is maintained through a 0.2 sieve. x 0.2 mm.
[0090] In one embodiment, the paste obtained by mixing the biocompatible polymer in powder form and the aqueous medium comprises between about 10% to about 60% of the biocompatible polymer, for example, about 10% to about 50% of the biocompatible polymer, such as about 10% to about 40% of the biocompatible polymer, for example, about 10% to about 30% of the biocompatible polymer, such as about 12% to about 25% of the biocompatible polymer, for example example, about 14% to about 25% of the biocompatible polymer, such as about 15% to about 25% of the biocompatible polymer, for example, about 16% to about 20% of the biocompatible polymer, such as about 17% to about 20% of the biocompatible polymer, for example, about 18% to about 20% of the biocompatible polymer.
[0091] In one embodiment, the paste obtained by mixing the biocompatible polymer in the form of powder and the aqueous medium comprises more than 10% of the biocompatible polymer, such as more than 15% of the biocompatible polymer, for example, more than 16% of the biocompatible polymer, such as more than 17% of the biocompatible polymer, for example, more than 18% of the biocompatible polymer, such as more than 19% of the biocompatible polymer, for example, more than 20% of the biocompatible polymer.
[0092] In one embodiment, the paste obtained by mixing the biocompatible polymer in powder form and the aqueous medium comprises less than 40% of the biocompatible polymer, such as less than 30% of the biocompatible polymer, for example, less than 25% of the biocompatible polymer, such as less than 20% of the biocompatible polymer.
[0093] In a preferred embodiment, the paste of the present description comprises between about 10% to about 30% of the biocompatible polymer, more preferably between about 15% to about 25% of the biocompatible polymer, such as about 20% of the biocompatible polymer.
[0094] After drying, the composition comprises between about 40% and 80% of the biocompatible polymer, such as between about 45% and 80% of the biocompatible polymer, for example, between about 50% and 80% of the biocompatible polymer , such as between about 55% and 80% of the biocompatible polymer.
[0095] In one embodiment, the dry composition comprises between about 40% and 80% of the biocompatible polymer, such as between about 45% and 75% of the biocompatible polymer, for example, between about 50% and 70% of the polymer biocompatible.
[0096] In one embodiment, the dry composition of the present description comprises more than about 30% of the biocompatible polymer, such as more than about 40% of the biocompatible polymer, for example, more than about 45% of the polymer biocompatible, such as more than about 50% of the biocompatible polymer, for example, more than about 55% of the biocompatible polymer, such as more than about 60% of the biocompatible polymer, for example, more than about 65 % of the biocompatible polymer, such as more than about 70% of the biocompatible polymer, for example, more than about 75% of the biocompatible polymer, such as more than about 80% of the biocompatible polymer.
[0097] In one embodiment, the dry composition of the present description comprises less than about 80% of the biocompatible polymer, such as less than about 70% of the biocompatible polymer, for example, less than about 65% of the polymer biocompatible, such as less than about 60% of the biocompatible polymer, for example, less than about 55% of the biocompatible polymer, such as less than about 50% of the biocompatible polymer. Acid-base reactions capable of forming a gas
[0098] The introduction of a gas in the reconstituted paste without mechanical mixing is obtained by the presence of an alkaline compound and an acidic compound, in which the alkaline compound and the acidic compound are capable of producing a gas in the presence of an aqueous medium.
[0099] When the dry composition of the present disclosure is reconstituted by adding an aqueous medium, a gas is produced as a result of the reaction of the acidic compound and the alkaline compound. The gas expands within the composition being reconstituted resulting in a paste having a soft and light consistency without the need to mechanically introduce air into the composition, for example, by transferring the composition between two connected syringes.
[00100] The release of a gas by wetting the dry composition can be achieved in at least three alternative forms: 1. By preparing a dry composition comprising an alkaline compound and reconstitution with an aqueous medium comprising an acidic compound. 2. By preparing a dry composition comprising an acidic compound and reconstitution with an aqueous medium comprising an alkaline compound. 3. By preparing a dry composition comprising an alkaline compound and an acidic compound and reconstitution with an aqueous medium.
[00101] For all three options, the alkaline compound and the acidic compost must be able to react with each other to produce a gas in the presence of an aqueous medium.
[00102] For the third alternative it is important that the alkaline compost and the acidic compound are not in contact with an aqueous medium before the release of gas is desired, that is, before reconstitution. The third alternative can, for example, be obtained by mixing an alkaline compound in the wet paste, drying the paste and adding an acidic compound in the dry form in the dry paste, or the reverse, mixing an acidic compound in the wet paste, drying the paste and adding an alkaline compound in the dry form in the dry paste. The alkaline compound and the acidic compound will not react in dry conditions and will only react by moistening the composition. The acidic or alkaline compound added in dry form must be at least partially soluble in water.
[00103] In one embodiment, the dry composition comprises from about 0.1% to about 10% of an alkaline compound, for example, from about 0.5% to about 8% of an alkaline compound, such as from about 1% to about 6% of an alkaline compound or from about 1% to about 5% of an alkaline compound. Optionally, the dry composition also comprises from about 0.1% to about 10% of an acidic compound, for example, from about 0.5% to about 8% of an acidic compound, such as from about 1 % to about 5% of an acidic compound, where the acidic compound is added in dry form after the paste has been dried.
[00104] In one embodiment, the dry composition comprises at least 1% of an alkaline compound, for example, at least 1.5% of an alkaline compound, such as at least 2% of an alkaline compound, for example, at least 2.5% of an alkaline compound, such as at least 3% of an alkaline compound, for example, at least 3.5% of an alkaline compound, such as at least 4% of an alkaline compound, for example, at least 4.5% of an alkaline compound, such as at least 5% of an alkaline compound. Optionally, the dry composition further comprises an acidic compound as described above.
[00105] In one embodiment, the dry composition comprises less than 10% of an alkaline compound, for example, less than 8% of an alkaline compound, such as less than 7% of an alkaline compound, for example, less than than 6% of an alkaline compound, such as less than 5% of an alkaline compound, for example, less than 4% of an alkaline compound, such as less than 3% of an alkaline compound. Optionally, the dry composition further comprises an acidic compound as described above.
[00106] In one embodiment, the dry composition comprises from about 0.1% to about 10% of an acidic compound, for example, from about 0.5% to about 8% of an acidic compound, such as from about 0.5% to about 5% of an acidic compound or from about 1% to about 5% of an acidic compound. Optionally, the dry composition also comprises from about 0.1% to about 10% of an alkaline compound, for example, from about 0.5% to about 8% of an alkaline compound, such as from about 1 % to about 5% of an alkaline compound, where the alkaline compound is added in dry form after the paste has been dried.
[00107] In one embodiment, the dry composition comprises at least 0.1% of an acidic compound, for example, at least 0.2% of an acidic compound, such as at least 0.3% of an acidic compound, per example, at least 0.4% of an acidic compound, for example, at least 0.5% of an acidic compound, such as at least 0.6% of an acidic compound, for example, at least 0.7% of an acidic compound, such as at least 0.8% of an acidic compound, for example, at least 0.9% of an acidic compound, such as at least 1.0% of an acidic compound, for example, at least 1 , 5% of an acidic compound. Optionally, the dry composition further comprises an alkaline compound as described above.
[00108] In one embodiment, the dry composition comprises less than 10% of an acidic compound, for example, less than 8% of an acidic compound, such as less than 7% of an acidic compound, for example, less than than 6% of an acidic compound, such as less than 5% of an acidic compound, for example, less than 4% of an acidic compound, such as less than 3% of an acidic compound. Optionally, the dry composition further comprises an acidic compound as described above.
[00109] In a preferred embodiment, the gas produced is carbon dioxide (CO2). One way to produce CO2 is to put a carbonate salt in contact with an acidic compound in the presence of an aqueous medium. Thus, in a preferred embodiment, the alkaline compound is a carbonate salt, more preferably a pharmaceutically acceptable carbonate salt.
[00110] Upon contact of a carbonate salt with an aqueous medium comprising an acidic compound, that is, an acidic solution, the carbonate in the dry composition will react with the acid to create the carbonic acid, which decomposes rapidly to CO2. The CO2 gas expands within the composition being reconstituted, thus ensuring a smooth and light consistency of the reconstituted paste. For example, the reaction of sodium bicarbonate (also known as sodium hydrogen carbonate or common sodium bicarbonate) and an acid produces sodium chloride and carbonic acid, which decomposes quickly into carbon dioxide and water: NaHCO3 + HCl ^ NaCl + H2CO3 H2CO3-H2O + CO2 (g)
[00111] For example, if sodium bicarbonate is brought into contact with acetic acid in an aqueous medium, the result will be sodium acetate, water and carbon dioxide: NaHCO3 + CH3COOH ^ CH3COONa + H2O + CO2 (g)
[00112] In one embodiment, the carbonate salt is selected from the group consisting of sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), potassium bicarbonate (KHCO3), potassium carbonate (K2CO3), calcium bicarbonate ( Ca (HCO3) 2), calcium carbonate (CaCO3), magnesium carbonate (MgCO3), magnesium bicarbonate (Mg (HCO3) 2), ammonium bicarbonate (NH4HCO3), ammonium carbonate ((NH4) 2CO3), bicarbonate gadolinium (Gd (HCO3) 3, gadolinium carbonate (Gd (CO3) 3, lithium bicarbonate (LiHCO3), lithium carbonate (LiCO3), rubidium bicarbonate (RbHCO3), rubidium carbonate (Rb2CO3), zinc carbonate (ZnCO3), zinc bicarbonate (Zn (HCO3) 2, iron (II) carbonate (FeCO3), iron (Fe (II) (HCO3) 2) bicarbonate, silver carbonate (Ag2CO3), silver bicarbonate (AgHCO3 ), gold carbonate Au2 (III) (CO3) 3, gold carbonate (I) (Au2CO3) and mixtures thereof.
[00113] In one embodiment, the carbonate salt cation is a metal.
[00114] In one embodiment, the cation of the carbonate salt is sodium, that is, the carbonate salt is sodium bicarbonate or sodium carbonate, preferably sodium bicarbonate.
[00115] In one embodiment, the cation of the carbonate salt is calcium, that is, the carbonate salt is calcium bicarbonate or calcium carbonate. Since calcium is a thrombin activator, the presence of calcium in the reconstituted paste can be beneficial in modalities comprising thrombin, since it can lead to greater thrombin activity.
[00116] In one embodiment, the cation of the carbonate salt is potassium, that is, the carbonate salt and potassium bicarbonate (KHCO3) or potassium carbonate (K2CO3).
[00117] In one embodiment, the carbonate salt is at least partially soluble in water. For example, the carbonate salt has a solubility in water at 20 ° C and a pressure atmosphere above about 1 g / 100 g of water, for example, at least about 5 g / 100 g of water. For example, sodium bicarbonate has a solubility of about 9.6 g / 100 g of water at 20 ° C and a pressure of 1 atmosphere. When a carbonate salt is added in dry form to a dry composition comprising an acidic compound, it is important that the carbonate salt is at least partially soluble in water to effectively come in contact with the acidic compound distributed within the dry composition when the composition it is moistened, that is, reconstituted.
[00118] In other embodiments, the carbonate salt is essentially not soluble in water. For example, calcium carbonate has a solubility of less than 0.001 g / 100 g of water at 20 ° C and at 1 pressure atmosphere and silver carbonate has a solubility of less than 0.01 g / 100 g of water at 20 ° C. ° C and a pressure of 1 atmosphere. When a dry composition is prepared with a carbonate salt essentially homogeneously distributed therein, that is, by adding the carbonate salt to the paste before drying, the carbonate salt does not have to be soluble in water.
[00119] In one embodiment, the dry composition comprises from about 0.1% to about 10% of a carbonate salt, for example, from about 0.5% to about 8% of a carbonate salt, such as from about 1% to about 6% or 1% to about 5% of a carbonate salt. Optionally, the dry composition further comprises an acidic compound in the dry form.
[00120] When a dry composition comprising a carbonate salt is brought into contact with an acidic compound in the presence of an aqueous medium, CO2 will be produced, as explained above. The dry composition comprising a carbonate salt can be reconstituted with an aqueous medium comprising an acidic compound, that is, an acidic solution (first alternative) or, if the dry composition comprising a carbonate salt is additionally added to an acidic compound in the form dried after drying, the dried composition can be reconstituted with an aqueous medium that does not comprise an acid or an alkaline compound (3rd alternative). In the latter case, an acidic solution will be formed by adding the aqueous medium, since the acid will dissolve in the aqueous medium.
[00121] In one embodiment, the dry composition comprising a carbonate salt is reconstituted by the addition of an acidic solution having a pH in the range of about 1 to about 6, such as a pH of about 1.5 to about 5, for example, a pH of about 2 to about 4. The ideal pH of the reconstitution liquid can be determined by those skilled in the art balancing the need for efficient gas development during reconstitution and the desire to have a paste reconstituted with pH as close to 7 as possible.
[00122] In one embodiment, the dry composition comprising an alkaline compound, such as a carbonate salt, is reconstituted by the addition of an acidic solution comprising between about 1% to about 10% of an acidic compound, such as about from 1% to about 8% of an acidic compound, for example, from about 1.5% to about 6% of an acidic compound, such as from about 2% to about 5% of an acidic compound, for example, from about 2% to about 4% of an acidic compound.
[00123] In one embodiment, the acid solution has a pH of about 1a to about 4, such as from about 1 to about 3, for example, from about 1.5 to about 2.5, such as about 2.
[00124] In one embodiment, the acid solution has a pH less than about 4, such as less than about 3, for example, less than about 2.5.
[00125] Preferably, the alkali and acid compounds used in the present invention are physiologically acceptable compounds. The term physiologically acceptable is used here interchangeably with the term pharmaceutically acceptable.
[00126] In one embodiment, the acidic compound in the reconstitution liquid is selected from the group consisting of acetic acid, citric acid, tartaric acid and oxalic acid.
[00127] In one embodiment, the acidic compound is acetic acid.
[00128] In one embodiment, the acidic compound is citric acid.
[00129] In one embodiment, the acidic compound is tartaric acid.
[00130] In one embodiment, the acidic compound is oxalic acid.
[00131] According to the second previous alternative, a dry composition comprising an acidic compound is prepared and said dry composition is brought into contact with the alkaline compound by reconstituting the dry composition. For example, the dry composition comprising an acidic compound can be reconstituted with an aqueous medium comprising an alkaline compound, for example, an aqueous medium comprising a carbonate salt. If the dry composition comprising an acidic compound is still added to an alkaline compound in the dry form after drying the composition, the dry composition can be reconstituted with an aqueous medium that does not comprise an acid or an alkaline compound (3rd alternative). However, it is important that the alkaline compound is at least partially soluble in water to allow the alkaline compound to effectively come into contact with the acidic compound distributed in the dry composition by moistening the composition.
[00132] In one embodiment, the dry composition comprises an acidic compound selected from the group consisting of acetic acid, citric acid, oxalic acid and tartaric acid. This composition can suitably be reconstituted by adding a solution comprising an alkaline compound, such as a carbonate salt.
[00133] In one embodiment the dry composition comprises acetic acid.
[00134] In one embodiment the dry composition comprises citric acid.
[00135] In one embodiment the dry composition comprises oxalic acid.
[00136] In one embodiment the dry composition comprises tartaric acid.
[00137] The dry composition comprising an acidic compound can be reconstituted by the addition of an alkaline solution comprising between about 1% to about 10% of an alkaline compound, such as from about 1% to about 8% of a compound alkali, for example, from about 1.5% to about 6% of an alkaline compound, such as from about 2% to about 5% of an alkaline compound, for example, from about 2% to about 4% of an alkaline compound.
[00138] In one embodiment, the alkaline solution has a pH of about 7.5 to about 9, such as from about 8 to about 9, for example, from about 8 to about 9.5.
[00139] In one embodiment, the alkaline solution has a pH greater than about 7.5, such as greater than about 7.8, for example, greater than about 8.0, such as greater than about 8, 5.
[00140] In an alternative modality, the reaction of an alkaline compound and an acidic compound causes the production of a noble gas, such as helium (He), neon (Ne) or argon (Ar).
[00141] In yet another modality, the reaction of an alkaline compound and an acidic compound causes the production of hydrogen (H2), nitrogen (N2), or oxygen (O2). Aqueous medium
[00142] An aqueous medium is used in the method of the present description to initially prepare the paste, which is subsequently dried to obtain a dry composition. An aqueous medium is also used to reconstitute the dry composition.
The aqueous medium of the present description can be any aqueous medium suitable for preparing a paste known to those skilled in the art, for example, water or saline. The water can be, for example, WFI (Water for Injection). The aqueous medium is preferably sterile and compatible with surgical use.
[00144] The aqueous medium of the present description is, in one embodiment, a saline solution.
[00145] In one embodiment, the aqueous medium is a solution of calcium chloride.
[00146] In one embodiment, the aqueous medium is water.
[00147] The aqueous medium is initially mixed with the agent in powder form in sufficient quantities to obtain a moist paste. Regarding process efficiency, it is sometimes desirable that the paste contains less water, before it dries, that is, it is thicker, than an intended paste, for example, surgical use would be such that less water would be removed in the process. drying process.
[00148] In one embodiment, the paste of the present description comprises, before drying, less than 99% water, preferably less than 95% water.
[00149] In one embodiment, the paste of the present description comprises, before drying, between about 50% to about 90% water, such as between about 55% to about 85% water, for example, between about 60% to about 80% water, as well as about 70% water.
[00150] After drying, the dry composition comprises less than about 5% water, such as less than about 3% water, preferably less than about 2% water, more preferably less than about 1.5 % water, even more preferable less than about 1% water or even less. Consequently, in one embodiment, the dry composition comprises from about 0.1 to about 5% water, such as from about 0.1% to about 2% water.
[00151] A low residual water content in the hemostatic composition, after drying is desirable, since it reduces the risk of microbial growth in the dry composition. In addition, a low residual water content is essential if the composition comprises bioactive agents that are unstable in aqueous conditions, such as, for example, thrombin. If thrombin is present in the composition of the present description, the residual water content in the dry composition is preferably less than about 3% water, more preferably less than 2% water, such as less than 1% water.
[00152] In one embodiment, the residual water content in the dry composition is about 0.5% or less. Such a low residual water content is possible with, for example, industrial freeze drying apparatus. Hydrophilic compounds
[00153] In one embodiment, the dry composition of the present description comprises one or more hydrophilic compounds. Hydrophilic compounds in general contain polar or charged functional groups, making them soluble in water. The inclusion of one or more hydrophilic compounds in the paste before drying said paste has a beneficial effect on the humidification of the paste, thus improving the reconstitution efficiency and the rate of reconstitution of the dry composition.
[00154] In one embodiment, the hydrophilic compound is a hydrophilic polymer. The hydrophilic polymer can be natural or synthetic, linear or branched, and any suitable size.
[00155] In one embodiment, the hydrophilic polymer is selected from the group consisting of Polyethyleneimine (PEI), Poly (ethylene glycol) (PEG), poly (ethylene) oxide, Poly (vinyl alcohol) (PVA), Poly (styrenesulfonate) ) (PSS), poly (acrylic) acid (PAA), Poli (allylamine) hydrochloride and poly (vinyl) acid. In one embodiment, the hydrophilic compound is poly (ethylene glycol) (PEG).
[00156] In one embodiment, the hydrophilic compound is selected from the group consisting of cetylpyridinium chloride, sodium docusate, glycine, hypromellose, hypromellose, phthalate, lecithin, phospholipids, poloxamer, polyoxyethylene alkyl esters, polyoxyethylene derivatives of castor oil , polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyvinyl alcohol, sodium lauryl sulfate, sorbitan esters (sorbitan fatty acid esters) and tricapriline.
[00157] In one embodiment, the hydrophilic compound is not a polymer.
[00158] In one embodiment, the hydrophilic compound is not a macromolecule.
[00159] In one embodiment, the hydrophilic compound has a molecular weight of less than 1,000 Da, such as less than 500 Da.
[00160] In one embodiment, the hydrophilic compound is an oligomer, such as an oligomer consisting of less than 10 monomeric subunits, for example, less than 5 monomeric subunits.
[00161] In one embodiment, the hydrophilic compound is a dimer, trimer or tetramer.
[00162] In one embodiment, the compound is a hydrophilic monomer.
[00163] In one embodiment, the hydrophilic compound comprises less than 20 carbon atoms, such as 18 C atoms or less or 12 Carbon atoms or less, such as 6 carbon atoms
[00164] In a preferred embodiment, the hydrophilic compound is a polyol. Thus, according to one embodiment, one or more polyols can be included in the paste before the expansion and drying of the paste. Polyols greatly improve the reconstitution rate of the dry pulp composition and also play a role in ensuring an optimal consistency of the reconstituted pulp.
[00165] A polyol, as defined herein, is a compound with multiple hydroxyl functional groups. Polyols as defined herein include sugars (mono-, di-, and polysaccharides) and sugar alcohols and derivatives thereof. Preferably, the polyol is not a polysaccharide.
[00166] Monosaccharides include, but are not limited to, glucose, fructose, galactose, xylose and ribose.
[00167] Disaccharides include, but are not limited to sucrose (sucrose), lactulose, lactose, maltose, trehalose and cellobiose.
[00168] Polysaccharides include, but are not limited to, starch, glycogen, cellulose and chitin.
[00169] A sugar alcohol, also known as a polyalcohol is a hydrogenated form of carbohydrates, whose carbonyl group (aldehyde or ketone, sugar reducers) has been reduced to a primary or secondary hydroxyl group (hence the alcohol). Sugar alcohols have the general formula H (HCHO) n + 1 H, while sugars have H (HCHO) n HCO. Some common sugar alcohols that can be used in the method of the present description include, but are not limited to: Glycol (2 carbons), Glycerol (3 carbons), Erythritol (4 carbons), Treitol (4 carbons), Arabitol (5 carbons) ), Xylitol (5 carbons), Ribitol (5 carbons), Mannitol (6 carbons), Sorbitol (6 carbons), Dulcitol (6 carbons), Fucitol (6 carbons), Iditol (6 carbons), Inositol (6 carbons; one cyclic sugar alcohol), Volemitol (7 carbons), Isomalt (12 carbons), Maltitol (12 carbons), Lactitol (12 carbons), Polyglycitol.
[00170] In one embodiment, the dry composition comprises a simple hydrophilic compound, such as a simple polyol.
[00171] In one embodiment, the dry composition comprises more than one hydrophilic compound, such as two, three, four, five, six or even more different hydrophilic compounds.
[00172] In a preferred embodiment, the hydrophilic compound is a polyol.
[00173] In one embodiment, the dry composition comprises two polyols, for example, mannitol and glycerol or trehalose and a glycol.
[00174] In one embodiment, the dry composition comprises one or more sugar alcohols, such as one or more sugar alcohols selected from the group consisting of Glycol, Glycerol, Erythritol, Treitol, Arabitol, Xylitol, Ribitol, Mannitol, Sorbitol, Dulcitol, Fucitol, Iditol, Inositol, volemitol, Isomalt, Maltitol, Lactitol, Polyglycitol.
[00175] In one embodiment, the dry composition comprises one or more sugar alcohols and one or more sugars, such as a sugar alcohol and a sugar.
[00176] In one embodiment, the dry composition comprises a sugar alcohol and optionally one or more additional hydrophilic compounds, such as one or more polyols, which can be either sugar alcohols or sugars.
[00177] In one embodiment, the dry composition does not comprise a sugar just like the polyol.
[00178] In one embodiment of the invention, the dry composition comprises mannitol.
[00179] In one embodiment of the invention, the dry composition comprises sorbitol.
[00180] In one embodiment of the invention, the dry composition comprises glycerol.
[00181] In one embodiment of the invention, the dry composition comprises trehalose.
[00182] In an embodiment of the invention, the dry composition comprises glycol, such as propylene glycol
[00183] In an invention embodiment, the dry composition comprises xylitol.
[00184] In one embodiment of the invention, the dry composition comprises maltitol.
[00185] In one embodiment of the invention, the dry composition comprises sorbitol.
[00186] In one embodiment, the paste according to the invention comprises, before drying, about 1% to about 40% of one or more hydrophilic compounds, for example, from about 1% to about 30% of one or more more hydrophilic compounds, such as from about 1% to about 25% of one or more hydrophilic compounds, for example, from about 1% to about 20% of one or more hydrophilic compounds, such as from about 1% to about 15% of one or more hydrophilic compounds, such as from about 1% to about 14% of one or more hydrophilic compounds, for example, from about 1% to about 13% of one or more hydrophilic compounds , such as from about 1% to about 12% of one or more hydrophilic compounds, for example, from about 1% to about 11% of one or more hydrophilic compounds, such as about 1% to about 10 % of one or more hydrophilic compounds.
[00187] In one embodiment, the paste according to the invention comprises, before drying, about 2% to about 40% of one or more hydrophilic compounds, for example, from about 2% to about 30% of one or more more hydrophilic compounds, such as from about 2% to about 25% of one or more hydrophilic compounds, for example, from about 2% to about 20% of one or more hydrophilic compounds, such as from about 2% to about 18% of one or more hydrophilic compounds, for example, from about 2% to about 17% of one or more hydrophilic compounds, such as from about 2% to about 16% of one or more hydrophilic compounds , for example, from about 2% to about 15% of one or more hydrophilic compounds, such as from about 2% to about 14% of one or more hydrophilic compounds, for example, from about 2% to about from 13% of one or more hydrophilic compounds, such as from about 2% to about 12% of one or more hydrophilic compounds, for example, from about 2% around that of 11% of one or more hydrophilic compounds, such as about 2% to about 10% of one or more hydrophilic compounds.
[00188] In one embodiment, the paste according to the invention comprises, before drying, about 3% to about 40% of one or more hydrophilic compounds, for example, from about 3% to about 30% of one or more more hydrophilic compounds, such as from about 3% to about 25% of one or more hydrophilic compounds, for example, from about 3% to about 20% of one or more hydrophilic compounds, such as from about 3% to about 18% of one or more hydrophilic compounds, for example, from about 3% to about 17% of one or more hydrophilic compounds, such as from about 3% to about 16% of one or more hydrophilic compounds , for example, from about 3% to about 15% of one or more hydrophilic compounds, such as from about 3% to about 14% of one or more hydrophilic compounds, for example, from about 3% to about from 13% of one or more hydrophilic compounds, such as from about 3% to about 12% of one or more hydrophilic compounds, for example, from about 3% around that of 11% of one or more hydrophilic compounds, such as about 3% to about 10% of one or more hydrophilic compounds.
[00189] In one embodiment, the paste according to the invention comprises, before drying, about 4% to about 40% of one or more hydrophilic compounds, for example, from about 4% to about 30% of one or more more hydrophilic compounds, such as from about 4% to about 25% of one or more hydrophilic compounds, for example, from about 4% to about 20% of one or more hydrophilic compounds, such as from about 4% to about 18% of one or more hydrophilic compounds, for example, from about 4% to about 17% of one or more hydrophilic compounds, such as from about 4% to about 16% of one or more hydrophilic compounds , for example, from about 4% to about 15% of one or more hydrophilic compounds, such as from about 4% to about 14% of one or more hydrophilic compounds, for example, from about 4% to about from 13% of one or more hydrophilic compounds, such as from about 4% to about 12% of one or more hydrophilic compounds, for example, from about 4% around that of 11% of one or more hydrophilic compounds, such as about 4% to about 10% of one or more hydrophilic compounds.
[00190] In one embodiment, the paste according to the invention comprises before drying more than about 5% of one or more hydrophilic compounds, therefore in one embodiment, the paste according to the invention comprises before drying about 5 % to about 40% of one or more hydrophilic compounds, for example, from about 5% to about 30% of one or more hydrophilic compounds, such as from about 5% to about 25% of one or more compounds hydrophilic, for example, from about 5% to about 20% of one or more hydrophilic compounds, such as from about 5% to about 18% of one or more hydrophilic compounds, for example, from about 5% to about 17% of one or more hydrophilic compounds, such as from about 5% to about 16% of one or more hydrophilic compounds, for example, from about 5% to about 15% of one or more hydrophilic compounds, such as from about 5% to about 14% of one or more hydrophilic compounds, for example, from about 5% to about 1 3% of one or more hydrophilic compounds, such as from about 5% to about 12% of one or more hydrophilic compounds, for example, from about 5% to about 11% of one or more hydrophilic compounds, such as about 5% to about 10% of one or more hydrophilic compounds.
[00191] In one embodiment, the paste according to the invention comprises, before drying, about 6% to about 40% of one or more hydrophilic compounds, for example, from about 6% to about 30% of one or more more hydrophilic compounds, such as from about 6% to about 25% of one or more hydrophilic compounds, for example, from about 6% to about 20% of one or more hydrophilic compounds, such as from about 6% to about 18% of one or more hydrophilic compounds, for example, from about 6% to about 17% of one or more hydrophilic compounds, such as from about 6% to about 16% of one or more hydrophilic compounds , for example, from about 6% to about 15% of one or more hydrophilic compounds, such as from about 6% to about 14% of one or more hydrophilic compounds, for example, from about 6% to about from 13% of one or more hydrophilic compounds, such as from about 6% to about 12% of one or more hydrophilic compounds, for example, from about 6% around that of 11% of one or more hydrophilic compounds, such as about 6% to about 10% of one or more hydrophilic compounds.
[00192] In one embodiment, the slurry according to the invention comprises, prior to drying, more than about 1% of one or more hydrophilic compounds, such as more than about 2% of one or more hydrophilic compounds, for example, more of about 3% of one or more hydrophilic compounds, such as more than about 4% of one or more hydrophilic compounds, for example, more than about 5% of one or more hydrophilic compounds, such as more than about 6 % of one or more hydrophilic compounds, for example, more than about 7% of one or more hydrophilic compounds, such as more than about 8% of one or more hydrophilic compounds, for example, more than about 9% of one or more hydrophilic compounds, such as more than about 10% of one or more hydrophilic compounds.
[00193] After drying, the dry composition comprises from about 10% to about 60% of one or more hydrophilic compounds, such as from about 10% to about 50% of one or more hydrophilic compounds, for example, from about 10% to about 50%, such as about 10% to about 45% of one or more hydrophilic compounds, for example, from about 10% to about 40%, such as about 10% to about 35% of one or more hydrophilic compounds, for example, from about 10% to about 30% of one or more hydrophilic compounds.
[00194] In one embodiment, the dry composition comprises from about 15% to about 60% of one or more hydrophilic compounds, such as from about 15% to about 50% of one or more hydrophilic compounds, for example, from about 15% to about 50%, such as from about 15% to about 45% of one or more hydrophilic compounds, for example, from about 15% to about 40%, such as from about 15 % to about 35% of one or more hydrophilic compounds, for example, from about 15% to about 30% of one or more hydrophilic compounds.
[00195] In one embodiment, the dry composition comprises from about 20% to about 60% of one or more hydrophilic compounds, such as from about 20% to about 50% of one or more hydrophilic compounds, for example, from about 20% to about 50%, such as from about 20% to about 45% of one or more hydrophilic compounds, for example, from about 20% to about 40%, such as about 20% to about 30% of one or more hydrophilic compounds.
[00196] In one embodiment, the dry composition comprises from about 25% to about 60% of one or more hydrophilic compounds, such as from about 25% to about 50% of one or more hydrophilic compounds, for example, from about 25% to about 45% of one or more hydrophilic compounds, such as from about 25% to about 40% of one or more hydrophilic compounds, for example, from about 25% to about 35% of one or more hydrophilic compounds, such as from about 25% to about 30% of one or more hydrophilic compounds.
[00197] In one embodiment, the dry composition comprises less hydrophilic compounds than the biocompatible polymer, that is, the ratio of hydrophilic compounds: biocompatible polymer is less than 1: 1, such as less than or about 0.9: 1, for example, less than or about 0.8: 1, such as less than or about 0.7: 1, for example, less than or about 0.6: 1, such as less than or about 0, 5: 1, such as less than or about 0.4: 1, for example, less than or about 0.3: 1, such as less than or about 0.2: 1, for example, less than or about 0.1: 1. The ratio of hydrophilic compounds: biocompatible polymer is the same in the paste before drying.
[00198] In one embodiment, the ratio of hydrophilic compounds: biocompatible polymer is between about 0.1: 1 and 1: 1; such as between about 0.2: 1 and 1: 1, for example, between about 0.3: 1 and 1: 1, such as between about 0.4: 1 and 1: 1. In one embodiment, the ratio of hydrophilic compounds: biocompatible polymer is between about 0.1: 1 and 0.8: 1; such as between about 0.1: 1 and 0.7: 1, for example, between about 0.1: 1 and 0.6: 1, such as between about 0.1: 1 and 0.5: 1, for example, between 0.1: 1 and 0.45: 1. Even more preferably, the ratio of hydrophilic compounds: biocompatible polymer is between about 0.15: 1 and 0.8: 1; such as between about 0.15: 1 and 0.7: 1, for example, between about 0.15: 1 and 0.6: 1, such as between about 0.15: 1 and 0.5: 1, for example, between about 0.15: 1 and 0.5: 1, such as between 0.15: 1 and 0.45: 1. In a preferred embodiment, the ratio of hydrophilic compounds: biocompatible polymer is between about 0.2: 1 and 0.8: 1; such as between about 0.2: 1 and 0.7: 1, for example, between about 0.2: 1 and 0.6: 1, such as between about 0.2: 1 and 0.5: 1, for example 0.2: 1 and 0.45: 1.
[00199] In one embodiment, the ratio of hydrophilic compounds: biocompatible polymer is between about 0.3: 1 and 0.8: 1; such as between about 0.3: 1 and 0.7: 1, for example, between about 0.3: 1 and 0.6: 1, such as between about 0.3: 1 and 0.5: 1, for example, between about 0.35: 1 and 0.5: 1, such as between about 0.35: 1 and 0.45: 1.
[00200] In one embodiment, the hydrophilic compound is not polyethylene glycol (PEG). Additional compounds
The dry composition may additionally comprise one or more of the following: DMSO (dimethyl sulfoxide), 2-Methyl-2,4-pentanediol (MPD) and / or one or more of the compounds mentioned in the table below.


[00202] In one embodiment, the dry composition comprises one or more antimicrobial agents, such as one or more antibacterial agents.
[00203] In one embodiment, the dry composition comprises benzalkonium chloride.
[00204] In one embodiment, the dry composition does not comprise an antimicrobial agent.
[00205] In one embodiment, the dry composition additionally comprises an extrusion enhancer, that is, a compound capable of facilitating extrusion of a paste from a syringe.
[00206] It has previously been demonstrated that the provision of certain extrusion enhancers, such as albumin in an appropriate amount, makes it possible to use higher concentrations of gelatin since it decreases the amount of force required to extrude the gelatin paste composition from of, for example, a syringe. The use of higher concentrations of gelatin can, in turn, improve the hemostatic properties of such products. It is necessary to supply the extrusion enhancers in appropriate quantities. The amounts are preferably high enough to obtain the extrusion effect, that is, to enable a slurry even in relatively high amounts of the biocompatible polymer, for example, cross-linked gelatin, in such a way that the hemostatic paste composition can be exactly applied by a surgeon using, for example, a syringe comprising an applicator tip; on the other hand, the amounts can be as low as to prevent negative functional properties of the hemostatic composition.
[00207] The extrusion enhancer is preferably albumin, especially human serum albumin.
[00208] In the paste before drying, the extrusion enhancer, such as albumin, is preferably present in an amount of between about 0.1% to about 10%, such as between about 0.2% to about 8%, for example, between about 0.3% to about 7%, preferably between about 0.5% to about 5%, more preferably between about 1% to about 4%.
[00209] In the dry composition, the extrusion enhancer, such as albumin, is preferably present in an amount of between about 0.3% to about 30%, such as between about 0.5% to about 25% , for example, between about 1% to about 20%, preferably between about 2% to about 15%.
[00210] In one embodiment, the extrusion enhancer is not present in the dry composition, but is instead introduced into the paste composition during reconstitution. For example, the extrusion improver may be present in the aqueous medium used for the reconstitution of the slurry, thereby obtaining a wet slurry composition comprising the extrusion improver. The concentration of the extrusion improver in the reconstituted slurry will be the same when the extrusion improver is added to the slurry before drying.
[00211] In one embodiment, the reconstituted wet paste compositions according to the present invention exhibit an average extrusion force (for example, employing the test method described in example 1 of WO 2013/060770) preferably 40 N or less below 35 N, especially preferable below 30 N or below 20 N.
[00212] Another class of extrusion enhancers according to the present description are phospholipids, such as phosphatidylcholine and -serine, or complex mixtures such as lecithins or soy oils. Bioactive agent
[00213] In one embodiment, the dry composition comprises one or more bioactive agents, that is, one or more bioactive agents are included in the paste before drying. It is essential that the bioactive agent maintains its bioactivity throughout the process and that the agent has also maintained its biological function in the final reconstituted paste. Many bioactive agents are unstable in solution, particularly enzymes and other proteins that can be degraded or otherwise lose their secondary structure when water is present.
[00214] In one embodiment, the bioactive agent is thrombin.
[00215] In one embodiment, thrombin is human thrombin.
[00216] In one embodiment, thrombin is recombinant thrombin.
[00217] Conventionally, a thrombin solution is mixed with a dry or pre-humidified gelatin powder to prepare a hemostatic paste directly at the surgical site for the necessary time of the hemostatic paste, for example, using commercially available hemostatic kits such as Floseal and Surgiflo. The thrombin solution must be prepared immediately after the preparation of the paste, since the thrombin in solution is very unstable and quickly self-degrading. The manufacture of a thrombin solution at the surgical site is time-consuming and involves a risk of making mistakes in relation to the correct thrombin dilution and quantity.
[00218] The present description allows the addition of thrombin to the paste before drying, thus resulting in a dry hemostatic composition comprising thrombin which, after reconstitution with a suitable aqueous medium, will comprise a desired amount of thrombin, without the need for delay and propensity errors in the dilution and addition of thrombin steps at the surgery site. Thrombin, which can be included in the dry composition of the present description, thus constitutes a clear advantage over conventional methods for making hemostatic pastes.
[00219] Thrombin can be included in a paste and freeze dried according to the present description, with essentially no loss of thrombin activity measured in the reconstituted paste.
[00220] Thrombin can be added to the paste of the present description before drying in an amount sufficient to guarantee efficient hemostasis of the reconstituted dry composition. In one embodiment, thrombin is added at a concentration in the range of about 100 IU / mL of paste to about 500 IU / mL of paste, such as about 150 IU / mL of paste to about 450 IU / mL of slurry, for example, about 200 IU / ml of slurry to about 400 IU / ml of slurry, such as about 250 IU / ml of slurry to about 350 IU / ml of slurry.
[00221] In one embodiment, thrombin is added to the pulp prior to drying, in a concentration in the range of about 50 IU / g of pulp to about 5000 IU / g of pulp, preferably between about 100 IU / g of pulp. pulp to about 1000 IU / g of pulp, such as between about 200 IU / g of pulp to about 800 IU / g of pulp. In such embodiments, the dry composition will comprise thrombin.
[00222] In other embodiments, the dry composition does not comprise thrombin and thrombin can be added by reconstituting the dry composition, reconstituting the dry paste composition with a liquid comprising thrombin.
[00223] One or more bioactive agents can be, for example, thrombin or thrombin in combination with fibrinogen, or thrombin and fibrinogen in combination with Factor XIII, or thrombin and fibrinogen and Factor XIII, in combination with tranexamic acid.
[00224] Thrombin is a "trypsin-like" serine protease protein that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, which ultimately results in the loss of stagnant blood. Thrombin, in turn, acts as a serine protease that converts soluble fibrinogen into insoluble fibrin chains, as well as many others that catalyze coagulation-related reactions. In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, and fibrinogen to fibrin.
A preferred bioactive agent according to the invention is thrombin. In one embodiment, thrombin is added as a prothrombin.
[00226] In one embodiment, the dry composition comprises one or more bioactive agents that stimulate bone and / or heal the tendon and / or tissue, such as one or more growth factors selected from the group consisting of matrix metalloproteinases (MMPs) ), insulin-like growth factor 1 (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and beta transformation growth factor (TGF-β).
[00227] In one embodiment, the dry composition comprises one or more bone morphogenetic proteins (BMPs). Bone morphogenetic proteins (BMPs) are a subset of the TGF-β superfamily. Bone morphogenetic proteins (BMPs) are a group of growth factors, also known as cytokines and, as metabologenes. Originally discovered for their ability to induce bone and cartilage formation, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating the architecture of tissues throughout the body.
[00228] In one embodiment, the dry composition of the present description comprises one or more metalloproteinase matrices (MMPs). MMPs are zinc-dependent endopeptidases. MMPs play a very important role in the degradation and remodeling of the extracellular matrix (ECM) during the healing process after an injury. Certain MMPs, including MMP-1, MMP-2, MMP-8, MMP-13 and MMP-14 have collagenase activity, which means that, unlike many other enzymes, they are able to break down collagen I fibrils.
[00229] These growth factors have different roles during the healing process. IGF-1 increases the production of collagen and proteoglycans during the first stage of inflammation, and PDGF is also present during the early stages after injury and promotes the synthesis of other growth factors, along with the synthesis of DNA and the proliferation of cells. The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) are known to play a role in wound healing and scar formation. VEGF is also known to promote angiogenesis and to induce endothelial cell proliferation and migration.
[00230] In one embodiment, the dry composition of the present description comprises extracellular matrix (ECM) flakes or particles. ECM is the extracellular part of animal tissue that normally provides structural support for animal cells, in addition to performing several other important functions. ECM has been shown to have very beneficial effects on healing, as it facilitates the regeneration of functional tissue.
[00231] The variety of biological agents that can be used in conjunction with the paste of the invention is wide. In general, biological agents that can be administered via the hemostatic compositions of the invention include, without limitation, anti-infective agents, such as antibiotics and antivirals; analgesics and analgesic combinations; anthelmintics; antiarthritics; anticonvulsants; antidepressants; antihistamines; anti-inflammatory agents; anti-migraine preparations; antineoplastics; antiparkinsonian drugs; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and anti-arrhythmic drugs; antihypertensive drugs; diuretics; vasodilators, including general, peripheral and cerebral coronary; central nervous system stimulants; hormones, such as estradiol and other steroids, including corticosteroids; immunosuppressants; muscle relaxants; parasympatholytic agents; psychostimulants; naturally derived or genetically modified proteins, polysaccharides, glycoproteins, or lipoproteins; oligonucleotides, antibodies, antigens, cholinergics, chemotherapeutic agents, radioactive agents, osteoinductive agents, cytostatic heparin neutralizers, procoagulants and hemostatic agents, such as prothrombin, thrombin, fibrinogen, fibrin, fibronectin, heparinase, factor X / Xa, o Factor VII / VIIa, Factor VIII / VIII a, Factor IX / IXa, Factor XI / XIa, Factor XII / XIIa, factor XIII / XIII a, tissue factor, batroxobin, ancrod, ecarina, von Willebrand factor, collagen, elastin , albumin, gelatin, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant poison, plasminogen activator inhibitor, platelet activating agents and synthetic peptides with hemostatic activity. Preparation of the paste
[00232] According to the method of the invention, the biocompatible polymer in powder form and the alkaline compound are mixed with an appropriate amount of an aqueous medium to obtain a paste, which is subsequently dried. Alternatively, the biocompatible polymer in powder form is mixed with an acidic compound in the presence of a suitable amount of an aqueous medium to obtain a paste and the paste is subsequently dried. The mixing is carried out under effective conditions to provide a substantially homogeneous paste and can be carried out in any suitable way known to a person skilled in the art, for example, by mixing the contents manually or using an electric mixer, such as a kitchen mixer , a manual mixer or an industrial mixer.
[00233] The powder particles of the biocompatible polymer are, in general, substantially insoluble in the aqueous medium, allowing a paste to form. In general, crosslinking makes polymers biocompatible, such as gelatin, insoluble in water.
[00234] Mixing the slurry in the mixing vessel introduces a substantially homogeneously dispersed discontinuous gas phase through the slurry, that is, the blended slurry will comprise bags or isolated bodies of gas, such as air.
[00235] In one embodiment, the slurry is prepared by mixing an aqueous medium, a gaseous and a quantity of powdered particles in a mixing vessel, under conditions that result in the formation of a slurry with a substantially homogeneously dispersed discontinuous gas phase through of the folder. The gas, for example, can be air, nitrogen, carbon dioxide, xenon, argon or mixtures thereof.
[00236] In a particular embodiment, the paste is prepared by the following steps: - introducing a volume of a liquid into a mixing vessel equipped with a means for mixing said liquid, - introducing a volume of a gas into said volume of liquid , although said means for mixing will operate in efficient conditions to mix said liquid and said gas together to form a foam comprising a discontinuous gas phase comprising said gas dispersed in a continuous liquid phase comprising said liquid, - introducing into the liquid said foam an amount of powdered particles of a biocompatible polymer suitable for use in hemostasis, and which is substantially insoluble in said liquid; and - mixing said foam and said powder particles together, in efficient conditions to form a substantially homogeneous paste composition comprising said discontinuous gas phase and said particles substantially homogeneously dispersed throughout said liquid phase, thus forming a paste composition.
[00237] In one embodiment, the substantially homogeneous paste composition comprises a continuous liquid phase, that is, a liquid phase that can be released when the force applied to the paste when the paste is contained in an enclosed space.
[00238] In one embodiment, the powder particles comprise pores and channels of sufficient size to maintain water by capillary forces. When a paste is prepared using such particles, water can be released from the paste, by applying force to the paste, when the paste is contained in a confined space.
[00239] The obtained paste is then transferred to a suitable container for vacuum expansion, freezing and drying the paste. Preferably, the container to which the paste is transferred is also suitable for reconstituting and applying the reconstituted paste composition, for example, to a site that requires hemostasis.
[00240] The mixing of the paste can, in general, be performed at room temperature (20-25 ° C). However, if thrombin or other sensitive agents, such as other enzymes are included in the paste, it is advisable to mix the paste at refrigerated temperatures and / or within a short period of time to prevent or decrease the proteolytic activity of thrombin, a since it is well known that thrombin is susceptible to self-degradation when wet. Consequently, when thrombin or other sensitive bioactive agents are included in the paste, the mixing of the paste is generally carried out at temperatures below room temperature, such as at about 2 ° C to about 25 ° C, for example at about 2 ° C to about 15 ° C, such as about 2 ° C to about 10 ° C, preferably about 4 ° C.
[00241] Another way or an additional way to preserve the thrombin bioactivity in the paste is to keep the thrombin time, which is in a humid state, that is, the mixing time, to a minimum. Thus, when thrombin or other proteolytic enzymes are to be included in the paste, the mixing of the paste is generally carried out within about 5 minutes to about 10 hours, such as about 5 minutes to about 5 hours, for example, about 5 minutes to about 2 hours, preferably about 5 minutes to about 1 hour, such as in about 5 minutes to about 30 minutes.
[00242] It is not essential to mix the paste at low temperatures to avoid the loss of thrombin activity, since no detectable decrease in thrombin activity was discovered when mixing the paste at room temperatures (Example 2).
[00243] The density of the wet paste is normally in the range of about 0.5 g / ml to about 1 g / ml, such as between about 0.6 g / ml to about 0.9 g / ml, for example, between about 0.7 g / ml to about 0.8 g / ml. Containers
[00244] Any suitable container known to those skilled in the art can be used for the preparation of the paste and to keep the paste of the present description during drying, such as vials, vases, tubes, trays, cartridges or syringes.
[00245] In one embodiment, the paste is prepared in a volume container, such as a mixing vessel and transferred / aliquoted in another container for drying, in which said other container is selected from an applicator, such as a syringe, a vial, a jar, a tube, a tray and a cartridge. Preferably, the other container is a medical delivery device suitable for dispersing fluid hemostatic compositions to a patient who needs them.
[00246] In one embodiment, the container containing the paste composition during drying is an applicator, such as a syringe.
[00247] A "bottle" according to the invention is a rigid, approximately cylindrical container with a wide mouth opening. Flasks may comprise a re-closure closure unit / cap applied to the mouth of the flask.
[00248] Containers may consist of any soluble material, such as plastic, glass, ceramic or metal, such as stainless steel.
[00249] Examples of suitable plastic materials include, but are not limited to, polyethylene, polypropylene, polystyrene, polyvinyl chloride, and polytetrafluoroethylene (PTFE).
[00250] In one embodiment, the paste is filled and dried in a suitable applicator to disperse fluid hemostatic compositions.
[00251] In one embodiment, the present description refers to a container comprising: a. a product chamber comprising the dry composition according to the present description, and b. a valve. In one embodiment, the container of the present description is a partial syringe assembly comprising the dry composition, as defined herein, and a valve
[00252] Preferably, the dry composition spontaneously reconstitutes to form a slurry by adding an aqueous medium to the dry composition that is present in the container.
[00253] In one embodiment, the pressure in the product chamber is less than the pressure outside the product chamber.
[00254] In one embodiment, the container comprises a diversion, allowing the communication of gases between the product chamber and the outside of the container during drying.
[00255] Gaseous communication during vacuum expansion and drying can also occur through the valve in the modalities of the present description involving vacuum expansion of the paste when the container does not include a diversion.
[00256] The dry composition of the present description can be prepared in various shapes, sizes and designs, depending on the shape of the container used. They can be, for example, in the form of plugs, discs, rods, tubes, conical cylinders, spheres, half spheres, tablets, pellets, granules or sheets.
[00257] In one embodiment, the container is a medical delivery device. Medical dispensing device
[00258] In one embodiment, the paste is placed and dried in a medical dispensing device suitable for dispersing fluid hemostatic compositions, such as a syringe. The transfer takes place before the paste dries. In embodiments of the present description involving vacuum expansion of the paste prior to drying, the transfer takes place before vacuum expansion.
[00259] In one embodiment, the medical delivery device is a disposable syringe comprising a valve. In one embodiment, the syringe comprises a shortcut freeze-drying channel, which is a gaseous communication between the syringe product chamber and the outside of the container, that is, the external environment. The shortcut can be in an open state, allowing gaseous communication between the product chamber and the outside, and a closed state. The shortcut can be located in any connection, allowing gaseous communication between the product chamber and the external environment, for example, in the syringe body or in the plunger, as shown in figure 5. If the syringe comprises a shortcut in the body of the syringe syringe (figure 5, concept 2), the syringe can be adjusted with a standard plunger.
[00260] One embodiment of the present description relates to a syringe for maintaining a lyophilized paste, such as the dry paste composition currently described, in a vacuum comprising a barrel comprising a vacuum chamber to contain the paste with a proximal end and a distal ends opened with a first fluid opening, a connector portion with a second fluid opening, and adapted to connect to a liquid receiver, and a pressure chamber that connects the connector portion and the distal end of the vacuum chamber, a pressure valve located in the pressure chamber and adapted to seal the first and / or second opening of fluids in a first position, and form a fluid passage between the first and second opening of fluids in a second position, a piston configured for be displaced axially in the vacuum chamber by means of the open proximal end and, optionally, one or more vacuum bypass channels. The syringe is preferably a disposable syringe.
[00261] During lyophilization of the paste, the vacuum that can be created in the vacuum chamber can be used to expand the paste before drying. And by keeping the paste dry in a vacuum in the vacuum chamber of the syringe, that is, at a pressure level less than the pressure of the surrounding environment, the addition of liquid through preparation and use of the paste is facilitated, due to the liquid being sucked into the vacuum chamber due to reduced pressure in the vacuum chamber.
[00262] The barrel can be provided with an edge at the proximal end of the vacuum chamber, in order to facilitate the handling of the syringe during the operation of the plunger. In addition, the internal volume of the vacuum chamber and / or the pressure chamber can advantageously be cylindrical.
[00263] The connector portion may be a connector portion of a standard type, such as a Luer lock or Luer slip connector, preferably a Luer lock or Luer slip male connector. The connector portion can be provided with a threaded portion for secure connection with a corresponding connector. This threaded portion can be provided within the connector portion, as illustrated in figures 18a, 18b, 20a and 20b.
[00264] In a syringe modality currently presented, the pressure valve comprises a groove. This groove can form the fluid passage in the second position of the pressure valve. An example is illustrated in figures 18a and 18b. In the manner also illustrated in figures 18a and 18b, the pressure valve 5 can comprise two cylindrical sections axially divided by a groove 12, and in which the vacuum formed by the groove 12 forms the fluid passage in the second position of the pressure valve 5. In this configuration the pressure valve can be symmetrical rotation along the longitudinal axis of the pressure valve, as shown in figure 18, that is, the pressure valve can be rotated inside the pressure chamber without interfering with the function of the pressure valve. pressure, that is, in the first position of the pressure valve the vacuum chamber is sealed independently of the rotational position of the pressure valve, and in the second position of the pressure valve a fluid connection is formed between the vacuum chamber and the connector portion , regardless of the rotational position of the pressure valve.
[00265] The pressure valve can be supplied in a rubberized material and / or with a rubberized surface to provide the sealing of the first and second fluid opening, in the first position of the pressure valve.
[00266] The pressure chamber is preferably located between the vacuum chamber and the second fluid opening. In addition, the pressure valve is preferably located in the pressure chamber and adapted to seal the first and second fluid opening at a first position in the pressure chamber, and to form / create a fluid passage between the first and second fluid opening in a second position in the pressure chamber, for example, the pressure valve is preferably located in the pressure chamber, for example, within the pressure chamber, both in the first and second positions. That is, preferably, the pressure valve remains inside the pressure chamber during control of the fluid passage between the first and second fluid opening.
[00267] In a currently described syringe embodiment, the pressure chamber comprises a proximal end next to the distal end of the vacuum chamber, and a distal end next to a proximal end of the connector portion. In addition, the connector portion may comprise a proximal end next to a distal end of the pressure chamber and a distal end adapted to connect to a liquid receiver. The second fluid opening can form an elongated channel through the connector portion, for example, in the manner illustrated in figures 18 and 20. As also seen in these figures, the second fluid opening may comprise a proximal end next to an end distal of the pressure chamber, and a distal end for fluid inlet and outlet. Consequently, the pressure valve can be adapted to seal a distal end of the first fluid opening and a proximal end of the second fluid opening in said first position.
[00268] Thus, in relation to the syringe currently described, the liquid for reconstitution of a dry composition in the vacuum chamber to obtain a paste can be supplied from the distal end of the syringe, through the second fluid opening in the connector portion and through the pressure chamber and in the vacuum chambers. The distribution of the reconstituted paste is also provided via the distal end of the syringe. This solution is possible due to the supply of the exclusive pressure chamber with the pressure valve located between the vacuum chamber and the distal fluid opening, through which it may be possible to control the blocking and opening of the fluid passage between the first and second fluid opening, without removing the pressure valve from the pressure chamber and also without accessing the second fluid opening. Thus, an external liquid receiver can be connected to the connector portion of the syringe, while the pressure valve is in the first position, that is, the fluid passage is blocked (sealed). Switching the pressure valve to the second position opens the fluid passage and the liquid can pass from the liquid receiver to the syringe vacuum chamber to reconstitute the dry composition. The syringe currently described is therefore safe, easy and quick to use when reconstituting a dry paste composition, such as a hemostatic paste.
[00269] In an additional embodiment of the syringe currently described, the first and second positions of the pressure valve are displaced radially with respect to the longitudinal axis of the syringe. In addition, the pressure valve may protrude from the pressure chamber in the first position of the pressure valve. In addition, the pressure valve can be aligned with the pressure chamber in the second position of the pressure valve, for example, completely incorporated in the pressure chamber. The pressure valve can be provided with a valve rim at one end of the pressure valve that protrudes from the pressure chamber. This valve rim may protrude from the pressure chamber in said first position, and the valve rim may be aligned with the pressure chamber in said second position. The valve edge can then function as a stop edge for the pressure valve, that is, the pressure valve can be configured in such a way that the valve edge protrudes from the pressure chamber in the second position of the pressure valve. pressure.
[00270] In yet another embodiment of the syringe currently described, the first and second positions of the pressure valve are rotated, for example, in the manner illustrated in figures 3-13, with the position open in figures 3-12 and the open position in figure 13. In the manner also exemplified in these figures, the pressure valve can comprise a passage channel that forms the passage of fluid in the second position of the pressure valve. In addition, the pressure valve may comprise a cylindrical section with a radial passage channel that forms the passage of fluid in the second position of the pressure valve.
[00271] In an additional mode, the pressure valve and the pressure chamber are configured in such a way that the second position of the pressure valve is a closed position. The pressure valve can be closed axially and / or rotationally in this closed position. This can assist in ensuring that once the pressure valve has been moved to the second position, it remains, thereby ensuring that the paste can be expelled from the syringe when necessary. The pressure valve and the pressure chamber can be additionally configured in such a way that the first position is a partially closed position, for example, the pressure valve cannot be removed from / out of the pressure chamber, but can only be removed. moved to the second position. This can help to ensure that the vacuum is maintained within the vacuum chamber.
[00272] In an additional embodiment of the syringe currently described, the pressure valve comprises an opening, and this opening preferably forms at least a part of the fluid passage in the second position of the pressure valve. That is, preferably, this opening extends transversely through the pressure valve, in such a way that the opening extends in the longitudinal direction of the barrel when inserted into the pressure chamber.
[00273] In an additional embodiment, the pressure valve and the pressure chamber are configured in such a way that the pressure valve is radially limited in said first position, as well as radially limited outwards with respect to the longitudinal axis of the barrel. This radial limitation can be provided by means of one or more projections on the pressure valve and / or inside the pressure chamber. For example, the pressure valve comprises one or more protrusions, preferably extending laterally, such as radial to the fluid passage. The limitation can also be provided by narrowing an inner side wall of the pressure chamber, and this narrowing can be adapted to limit a radial displacement of the pressure valve in the first position, for example, this narrowing can be adapted to match one or more protrusions of the pressure valve, such that this or these protrusions protrude from the narrowing in the first position of the pressure valve. A narrowing can be provided by means of one or more "shoulders" of an inner side wall of the pressure chamber, in the manner illustrated exemplarily in figures 19c and 19d.
[00274] In an additional embodiment, the pressure valve protrudes transversely and / or radially from the pressure chamber in said first position, and in which the pressure valve is leveled with or totally submerged in the pressure chamber in said second position. The pressure valve can be provided with an upper surface, wherein said upper surface can be flush with an upper surface of the pressure chamber in said first position. These upper surfaces can be rounded and / or combined with each other, as illustrated in figures 19 and 20.
[00275] The pressure valve and the pressure chamber can be configured in such a way that the pressure valve can be inserted from one side of the pressure chamber, as well as through only through one side of the pressure chamber, for example, by means of an opening in the pressure chamber, for example, an opening in the lower part of the pressure chamber where an upper opening of the pressure chamber can be, where by means of the pressure valve it extends in the first position.
[00276] The syringe currently described is preferably configured, in such a way that the dry paste composition can be lyophilized within the vacuum chamber. Said one or more vacuum bypass channels can be configured to provide a fluid, such as a gaseous, communication between the vacuum chamber and the surrounding atmosphere / environment, that is, the shortcut channel (s) The vacuum can (m) function as the freeze-drying shortcut channel, in the manner described here. In one embodiment, the syringe is configured in such a way that the sealable plunger engages the vacuum chamber in at least one first axial position of the plunger within the vacuum chamber, and in such a way that fluid communication is established through the plunger, in at least a second axial position of the plunger within the vacuum chamber, by means of said one or more vacuum bypass channels. That is, a vacuum can be established and the composition can be lyophilized in the second position of the plunger, whereas the vacuum in the vacuum chamber can be maintained in the first position of the plunger. However, alternatively, said one or more vacuum bypass channels are configured in such a way that a fluid communication can be provided directly between the vacuum chamber and the ambient atmosphere, regardless of the plunger position, for example, by means of a (second) pressure valve located directly in the vacuum chamber. Alternatively, said one or more vacuum bypass channels can be formed on the plunger.
[00277] Consequently, the one or more vacuum bypass channels can be configured to prevent sealing between the vacuum chamber and the plunger at a pre-defined axial position of the plunger within the vacuum chamber. Furthermore, said one or more vacuum bypass channels can be formed in the vacuum chamber. For example, said one or more vacuum bypass channels can be one or more longitudinal grooves formed on the inner surface, for example, at the proximal end of the vacuum chamber.
[00278] In a syringe modality currently described, the barrel is formed in a single fragment of material. The barrel can be advantageously suitable and / or adapted for manufacture by means of single-cycle injection molding, that is, the barrel can be advantageously manufactured by means of single-cycle injection molding. That is, the vacuum chamber, the pressure chamber and the connector portion can be integrated and / or incorporated to form a single element, for example, in the manner illustrated in figures 16-18. This can ensure that a vacuum can be established and maintained within the vacuum chamber.
[00279] However, alternatively, the vacuum chamber, the pressure chamber and the connector portion can be formed as separate elements and configured to be assembled during the manufacture of the syringe.
[00280] Additionally, the pressure chamber and the connecting portion can be formed as an element and configured to be assembled with the vacuum chamber during the manufacture of the syringe. Alternatively, the vacuum chamber and the pressure chamber can be formed as an element and configured to be assembled with the connector portion during syringe manufacture.
[00281] A barrel 1, 1 'of the syringe currently described is exemplified in figures 16-18. Barrel 1 in figure 16a is provided with a vacuum chamber, a pressure chamber 3, a connector portion 4 and an edge 8 formed in a single fragment and suitable for manufacturing by single cycle injection molding. The pressure valve 5 inserted in the pressure chamber 3 is provided with a valve rim 6. In figure 16a, the pressure valve is located in a first position, whereas in figure 16b the pressure valve has been moved to a second position. This is most clearly seen in figures 16c (first pressure valve position) and 16d (second position). In the second position of the pressure valve 5, the valve edge 6 protrudes from the pressure chamber 3.
[00282] The sectional illustrations in figure 18a and 18b show the pressure valve 5 configurations more clearly. In the first position in figure 18a, the pressure valve blocks the fluid communication between the outlet 11 of the inner volume 2 'of the chamber vacuum 2 and the outlet 7 of the connector portion 4. In the second position of the pressure valve 5, in figure 18b, a fluid communication is provided (as illustrated by the dotted line / arrow) between the neighboring regions and the internal volume 2 'of the vacuum chamber 2, by means of the pressure chamber 3 and the outlet 7 of the connector portion 4, that is, the liquid can enter the vacuum chamber 2' to mix with a dry composition, for example, to form a wet paste that can subsequently be released in a controlled manner via outlet 7, with a plunger (not shown) arranged in barrel 1, 1 '. Barrel 1 'in figure 17a does not have an edge.
[00283] As seen in figure 18, the pressure valve 5 is formed as a cylinder with a circumferential groove 12 that forms the fluid opening in the second position of the pressure valve. That is, the pressure valve 5 is formed as two hollow cylinders that are attached to each other by means of the centrally located stem 13. Although the stem 13 is located centrally in the fluid passage, the liquid entering the vacuum chamber 2 by middle of the outlet 7, and the paste that is released from the barrel 1, 1 'through the outlet 7, can easily pass through the stem 13. The pressure valve 5 as shown in figure 18 presents symmetrical rotation.
[00284] Connecting portion 4 is provided with an internal wire 10, seen more clearly in figure 18. This can help to provide a secure, firm and unadulterated connection with an external liquid container (with a connecting portion with a corresponding wire ) before suction of liquid into the vacuum chamber when the (wet) slurry is to be formed.
[00285] Vacuum bypass channels 9 are provided in figures 16-18 as grooves that extend longitudinally at the proximal end of the vacuum chamber 2. When the plunger (not shown) is arranged in barrel 1, 1 'below these channels of vacuum, the plunger connects in a sealed manner to the vacuum chamber. However, when the distal part of the plunger is leveled with the vacuum shortcut channels 9, this seal is not firm due to a fluid and, in particular air, the connection is established between the vacuum chamber 2 'and the atmosphere at around the plunger by means of vacuum bypass channels 9. That is, during the freeze-drying of paste inside the vacuum chamber 2 ', the suction applied at the proximal end of the barrel can establish a vacuum inside the pressure chamber 2' and expand thereby the dry paste. At the end of the lyophilization and expansion process, the plunger can be moved to a position after the vacuum bypass channels, thereby attaching in a sealed manner the vacuum chamber 2, and subsequently keeping the lyophilized paste in a vacuum.
[00286] Another exemplary 1 '' barrel of the currently described syringe is exemplified in figure 20 with another modality of the pressure valve 5 'and the pressure chamber 3', as illustrated in more detail in figure 19, with the figure 19a showing a closing of the pressure valve alone. This 5 'pressure valve is thin and provided in a substantially rectangular shape. An opening 17 forms the passage of fluid in the second pressure valve position within the pressure chamber 3 '. The shape on the outside of the pressure valve 5 'corresponds to the shape on the inside of the pressure chamber 3'. Figure 19b shows the pressure valve 5 'inside the pressure chamber 3' in the first position of the pressure valve 5 ', where the fluid passage is blocked and a vacuum can be maintained inside the vacuum chamber 2. In figure 19b , it is observed that the pressure valve 5 'protrudes above the pressure chamber 3', that is, it protrudes radially from the pressure chamber 3 'with respect to the longitudinal axis of the barrel 2. In figures 19c and 19d , the pressure chamber 3 'was cut transversely in such a way that the configuration of the pressure valve 5' within the pressure chamber 3 'could be observed. In figure 19c the pressure valve 5 'is in the first position, that is, extending radially from the pressure chamber 3'. The pressure valve 5 'and the pressure chamber 3' are configured in such a way that the pressure valve is radially limited in this first position by means of projections 14 on the pressure valve 5 ', which limits a narrowing 15 of the inner side wall of the pressure chamber 3 ', that is, the pressure valve 5' cannot extend further out when in the first position. This helps to ensure that the pressure valve 5 'is not accidentally removed from the pressure chamber 3', thereby making it possible to break a vacuum seal inside the vacuum chamber 2. In figure 19d, the pressure valve 5 'is on second position. The pressure valve 5 'is now completely submerged in the pressure chamber 3'. The rounded upper surface of the pressure valve 5 'corresponds to a rounded upper surface of the corresponding pressure chamber 3', such that the upper surfaces of the pressure valve 5 'and the pressure chamber 3' are aligned with each other .
[00287] Figures 20a-b shows a side cross-sectional view of the illustrations of the pressure valve 5 'inside the pressure chamber 3', with the first position of the pressure valve in figure 20a and the second position in figure 20b. As seen in figure 20a, the fluid passage 7 is blocked by the pressure valve 5 ', whereas in figure 20b the opening 17 of the pressure valve 5' establishes a fluid connection in the manner indicated by the horizontal dotted arrow in the figure 20b. Figure 20b also illustrates how the pressure valve 5 'does not protrude from the pressure chamber 3' in this second position. This helps to ensure that once the fluid passage has been established by the pressure valve 5 'in the second position, the position of the pressure valve 5' is not easily changed as it is submerged within the pressure chamber 3 '.
[00288] A dotted arrow in figure 20a indicates the opening 16, where through the pressure valve 5 'it can be inserted in the pressure chamber 3'. The 1 ’’ barrel is also suitable for molding single cycle injection. After manufacture, the 5 'pressure valve can be inserted through opening 16. The 5' pressure valve is also suitable for single-cycle injection molding. The three orifices 18 indicated in figures 19a and 20c are provided to prepare the pressure valve 5 ', suitable for injection molding. Hemostatic sheet
[00289] In one embodiment, the dry composition is in the form of a leaf, that is, a substantially flat composition.
[00290] A dry composition in the form of a sheet can be obtained by spreading the paste of the invention thinly and evenly on a surface and drying the paste to obtain a substantially flat dry sheet composition. A dry composition in the form of a leaf will, upon contact with a liquid, spontaneously reconstitute itself to form a paste. Thus, a dry composition in the form of a sheet has the advantages of both surgical sponges traditionally used in which it can cover relatively large areas, and the advantage of a paste in which it easily molds to uneven surfaces once moistened.
[00291] The dry composition in the form of a leaf is soft and flexible.
[00292] In one embodiment of the invention it relates to a dry composition in the form of a leaf for use in hemostasis and / or wound healing.
[00293] In one embodiment, the sheet is not pre-moistened before use, that is, before application to a wound. In this case, the sheet will reconstitute in situ in the open wound through contact with blood, wound exudate and / or other body fluids.
[00294] The height of the composition of the dry leaf in one embodiment, is between about 0.5 mm and about 10 mm, preferably between about 1 mm and 5 mm, more preferably between about 1 mm and 3 mm, such as about 2 mm.
[00295] The size (width and depth) of the dry leaf composition depends on the intended use of the leaf and can be selected by a person skilled in the art. The dry leaf-shaped material can, for example, be rectangular, square or circular. For example, the composition of the dry leaf can be, for example, in the form of a rectangle of approximately 5 cm x 10 cm, 2 cm x 6 cm, 6 cm x 8 cm or 8 cm x 12 cm.
[00296] The dry leaf composition can be cut to any desired shape before use. Vacuum expansion
[00297] In one embodiment of the present invention, the paste is expanded by subjecting the paste to a reduced pressure (low vacuum) before the paste is dried. The expansion results in an increase in the total volume of the paste by expansion of trapped air or other gas within interstitial pores or wet paste compartments. The expansion of a paste before drying significantly decreases the time to reconstitute the dry paste. For example, a dry gelatin paste, expanded in a vacuum being present in a medical dispensing device will reconstitute in seconds to a ready-to-use paste suitable for direct dispensing to a patient without any mechanical mixing required by adding a quantity of an aqueous medium to the medical dispensing device having the dry gelatin paste composition disposed thereon.
[00298] The vacuum expansion expands air pockets trapped within the paste and such expanded air pockets are retained in the dry composition. The presence of larger air pockets in the dry composition presumably enables wetting of the dry composition due to a greater contact surface area between the dry composition and the liquid. It also facilitates the unimpeded distribution of the liquid in the dry composition due to the formed channels.
[00299] The inventors also found that the volume of an aliquot of the paste is generally greater in the samples being aliquoted first, as opposed to the last of a single batch of paste. This is believed to be due to a partial collapse of the pulp that occurs over time, causing variations in the density of the pulp before drying. Such variations in density can lead to undesirable variations in the reconstitution time. Vacuum expansion of the pulp prior to drying is able to reduce or even eliminate such “intra-batch” variations in the pulp density and therefore leads to consistently rapid reconstitution of the dry pulps. Thus, the vacuum expansion provides a higher degree of reproducibility with respect to the reconstitution time.
[00300] The vacuum pressure is selected so that the paste expands in a sufficient degree without collapsing. Thus, the pressure should not be so low, which will result in the paste collapsing. The vacuum expansion of the paste, for example, can be carried out in a freeze dryer.
[00301] Vacuum expansion of the paste is a result of one of the universal laws of physics: the law of the ideal gas, which determines what the volume of a gas will increase through a decrease in pressure. The ideal gas law equation is: PV = nRT where P is the pressure of the gas, V is the volume of the gas, n is the amount of gas substance (in moles), T is the temperature of the gas and R is the ideal, or universal gas constant.
[00302] Submitting a wet paste to sub-atmospheric pressure results in an expansion of air or other gas in the interstitial spaces (pores) of the paste, which in turn leads to an increase in the total volume of the paste and a decrease in the density of the paste. folder. After drying the paste composition to obtain a dry paste composition, the larger pore size results in greater permeability and humidification and, thus, a higher rate of reconstitution of the dry composition. Thus, in one embodiment, the present description refers to a method for adapting the volume of the paste by adjusting the density of the paste, subjecting a wet paste to a reduced pressure.
[00303] In one embodiment, the density of the slurry is decreased by at least one factor 0.95 as a result of the vacuum expansion, such as at least one factor 0.90, for example, at least one factor 0.85, such as at least one factor 0.80, for example, at least one factor 0.75, such as at least one factor 0.70, for example, at least one factor 0.65, such as at least one factor 0, 60, for example, at least a factor of 0.55, such as at least a factor of 0.50 as a result of vacuum expansion. Preferably, the density of the slurry is decreased by at least a factor of 0.8 as a result of the vacuum expansion.
[00304] In one embodiment, the density of the paste is decreased by about a factor 0.75 as a result of the vacuum expansion.
[00305] Before the vacuum expansion of the paste, the density of the wet paste can be, for example, in the range of about 0.5 g / ml to about 1 g / ml, such as between about 0.6 g / ml to about 0.9 g / ml, for example, between about 0.7 g / ml to about 0.8 g / ml.
[00306] For example, the density of a gelatin paste before expansion is generally in the range of about 0.60 g / ml to about 0.80 g / ml, such as about 0.65 g / ml to about 0.75 g / ml, such as about 0.7 g / ml.
[00307] The density of the wet paste after the vacuum expansion is less than the density of the wet paste before the vacuum expansion. For example, the density of the wet paste after vacuum expansion can be, for example, in the range of about 0.1 g / ml to about 0.8 g / ml, more preferably between about 0.2 g / ml. ml to about 0.7 g / ml, for example, about 0.2 g / ml to about 0.6 g / ml, such as about 0.2 g / ml to about 0.5 g / ml ml.
[00308] For example, the density of a gelatin paste after expansion is generally in the range of about 0.2 g / ml to about 0.6 g / ml, more preferably between about 0.3 g / ml ml to about 0.6 g / ml, such as between about 0.4 g / ml to about 0.5 g / ml.
[00309] The volume of the paste, subjecting the paste to a reduced pressure, is approximately greater by at least about a factor 1.05, such as at least a factor 1.1, for example, at least a factor 1.2 , such as at least one factor 1.3, for example, at least one factor 1.4, such as at least one factor 1.5, for example, at least one factor 1.6, such as at least one factor 1 , 7, for example, at least a factor of 1.8, such as at least a factor of 1.9, for example, at least a factor of 2.0.
[00310] In one embodiment, the volume of the paste is greater by about a factor 1.05 to about a factor 2.0, such as about a factor 1.1 to about a factor 1.8, for example , about a factor 1.2 to about a factor 1.6 as a result of the vacuum expansion of the wet paste.
[00311] After drying, the density of the dry paste composition is further decreased to remove water. After drying the wet paste expanded in a vacuum, the density of the dry paste composition is thus, in general, in the range of about 0.1 mg / ml to about 100 mg / ml, more preferably between about 1 mg / ml to about 50 mg / ml, such as between about 5 mg / ml to about 40 mg / ml.
[00312] For example, a dry vacuum expanded composition comprising gelatin, prepared by the method of the present description, generally has a density of between about 1 mg / ml to about 40 mg / ml, such as between about 5 mg / ml to about 35 mg / ml, for example, between about 10 mg / ml to about 35 mg / ml.
[00313] In one embodiment, the density of the vacuum-expanded dry composition is in the range of about 1 mg / ml to about 40 mg / ml, more preferably between about 5 mg / ml to about 40 mg / ml, such as between about 5 mg / ml to about 38 mg / ml, for example, between about 5 mg / ml to about 36 mg / ml, such as between about 5 mg / ml to about 34 mg / ml ml, for example, between about 5 mg / ml to about 32 mg / ml, such as between about 5 mg / ml to about 30 mg / ml, for example, between about 5 mg / ml to about 28 mg / ml, such as between about 5 mg / ml to about 26 mg / ml, for example, between about 5 mg / ml to about 24 mg / ml, such as between about 5 mg / ml to about 22 mg / ml, for example, between about 5 mg / ml to about 20 mg / ml.
[00314] In one embodiment, the pulp is subjected to a reduced pressure of at least 10 mbar (1 kPa) less than the ambient pressure, for example, at least 50 mbar (5 kPa) less than the ambient pressure, such as at minus 100 mbar (10 kPa) less than the ambient pressure, for example, at least 150 mbar (15 kPa) less than the ambient pressure, such as at least 200 mbar (20 kPa) less than the ambient pressure, for example, at minus 250 mbar (25 kPa) less than ambient pressure, such as at least 300 mbar (30 kPa) less than ambient pressure, for example, at least 350 mbar (35 kPa) less than ambient pressure, such as at least 400 mbar (40 kPa) less than the ambient pressure, for example, at least 450 mbar (45 kPa) less than the pressure, such as at least 500 mbar (50 kPa) less than the ambient pressure, for example, at least 550 mbar (55 kPa) less than ambient pressure, such as at least 600 mbar (60 kPa) less than ambient pressure, for example, at least 650 mbar (65 kPa) less than the pressure, such as at least 700 mbar (70 kPa) less than the ambient pressure, for example, at least 750 mbar (75 kPa) less than the ambient pressure, such as at least 800 mbar (80 kPa) less than the ambient pressure, for example, at least 850 mbar (85 kPa) less than the ambient pressure, such as at least 900 mbar (90 kPa) less than the pressure.
[00315] The vacuum pressure is preferably selected so that the pressure is at least 50 mbar (5 kPa) less than the ambient pressure, but not more than 900 mbar (90 kPa) less than the ambient pressure, such as at least 100 mbar (10 kPa) less than ambient pressure, but not more than 800 mbar (80 kPa) less than ambient pressure.
[00316] The vacuum pressure is preferably selected, such that the pressure is not more than 1000 mbar (100 kPa) less than the ambient pressure, such as no more than 900 mbar (90 kPa) less than the ambient pressure, for example, no more than 800 mbar (80 kPa) less than the ambient pressure, just as no more than 700 mbar (70 kPa) less than the ambient pressure, for example, no more than 600 mbar (60 kPa) less than the ambient pressure, such as no more than 500 mbar (50 kPa) less than ambient pressure.
[00317] In one embodiment, the vacuum pressure is between less than 1000 mbar (100 kPa) and 100 mbar (10 kPa), such as between 950 mbar (95 kPa) and 100 mbar (10 kPa), for example, between 900 mbar (90 kPa) and 100 mbar (10 kPa), such as between 850 mbar (85 kPa) and 100 mbar (10 kPa), for example, between 800 mbar (80 kPa) and 100 mbar (10 kPa), as between 750 mbar (75 kPa) and 100 mbar (10 kPa), for example, between 700 mbar (70 kPa) and 100 mbar (10 kPa), such as between 650 mbar (65 kPa) and 100 mbar (10 kPa) , for example, between 600 mbar (60 kPa) and 100 mbar (10 kPa), such as between 550 mbar (55 kPa) and 100 mbar (10 kPa), for example, between 500 mbar (50 kPa) and 100 mbar ( 10 kPa), such as between 450 mbar (45 kPa) and 100 mbar (10 kPa), for example, between 400 mbar (40 kPa) and 100 mbar (10 kPa), such as between 350 mbar (35 kPa) and 100 mbar (10 kPa), for example, between 300 mbar (30 kPa) and 100 mbar (10 kPa), such as between 250 mbar (25 kPa) and 100 mbar (10 kPa), for example, between 200 mbar (20 kPa) ) and 100 mbar (10 kPa).
[00318] In one embodiment, the vacuum pressure is between less than 1000 mbar (100 kPa) and 200 mbar (20 kPa), such as between 1000 mbar (100 kPa) and 250 mbar (25 kPa), for example, between 1000 mbar (100 kPa) and 300 mbar (30 kPa), such as between 1000 mbar (100 kPa) and 350 mbar (35 kPa), for example, between 1000 mbar (100 kPa) and 400 mbar (40 kPa), as between 1000 mbar (100 kPa) and 450 mbar (45 kPa), for example, between 1000 mbar (100 kPa) and 500 mbar (50 kPa), such as between 1000 mbar (100 kPa) and 550 mbar (55 kPa) , for example, between 1000 mbar (100 kPa) and 600 mbar (60 kPa), such as between 1000 mbar (100 kPa) and 650 mbar (65 kPa), for example, between 1000 mbar (100 kPa) and 700 mbar ( 70 kPa), such as between 1000 mbar (100 kPa) and 750 mbar (75 kPa), for example, between 1000 mbar (100 kPa) and 800 mbar (80 kPa), such as between 1000 mbar (100 kPa) and 850 mbar (85 kPa), for example, between 1000 mbar (100 kPa) and 900 mbar (90 kPa), such as between 1000 mbar (100 kPa) and 950 mbar (95 kPa).
[00319] In a preferred embodiment, the vacuum pressure is between about 900 mbar (90 kPa) and 500 mbar (50 kPa).
[00320] The expansion rate depends on the vacuum pump and the size of the vacuum chamber, that is, how fast the pressure in the chamber can be decreased to the desired level. The low vacuum levels, according to the present description, are reached almost instantaneously, thus, the expansion of the paste occurs essentially instantly after the start of the vacuum pump.
[00321] The vacuum expansion is generally carried out at a temperature above the freezing point of the paste. In one embodiment, vacuum expansion is performed at room temperature or at temperatures below room temperature, such as at temperatures from about 0 ° C to about 25 ° C, such as at about 2 ° C to about 20 ° C, for example, about 2 ° C to about 15 ° C, such as about 2 ° C to about 10 ° C, such as about 4 ° C to about 20 ° C, for example, about 4 ° C to about 15 ° C, such as about 4 ° C to about 10 ° C. When the pulp comprises sensitive bioactive agents, such as thrombin, vacuum expansion is preferably carried out at temperatures below room temperature.
[00322] When the slurry has been expanded to a desired degree, the slurry is frozen by subjecting the slurry to a temperature below the freezing point of the slurry and / or the glass transition temperature of the slurry for a period of time sufficient for the slurry to freeze. . Freezing occurs without releasing the vacuum and freezing the pulp thus keeps the expanded pulp structure in place. Thus, additional changes in pressure from this point on will not affect the volume of the frozen paste. The freezing step is preferably carried out in a freeze dryer.
[00323] The freezing point of the paste and / or the glass transition temperature of the paste, and can be determined by those skilled in the art. The desired temperature of the frozen paste is approximately 5 ° C less than the lowest freezing point of the paste and the glass transition temperature. For example, if the freezing point of a paste is -35 ° C, the paste can be cooled to about -40 ° C. Drying the paste
[00324] According to the method currently described, the paste is dried to obtain the dry composition. The paste can be dried by any of the suitable methods known to those skilled in the art.
[00325] In a preferred embodiment, the paste is lyophilized. Any appropriate lyophilization technique and equipment known to those skilled in the art can be used.
[00326] When lyophilization is used to prepare the dry composition, expansion, freezing and drying can advantageously be carried out as a continuous process in a simple apparatus.
[00327] An additional advantage of lyophilization is that it allows the retention of a vacuum inside the container keeping the composition dry, which plays a role in the reconstitution of the dry composition.
[00328] Lyophilization (also known as freeze-drying) is a dehydration process, typically used to preserve a perishable material or make the material more suitable for transportation. Lyophilization occurs by freezing the material and then reducing the pressure of the outside medium to allow the water frozen in the material to sublime directly from the solid phase to the gas phase.
[00329] There are basically three categories of freeze-dryers: the collector-type freeze dryer, the rotary freeze-dryer and the tray-type freeze-dryer. Two components are common to all types of lyophilizers: a vacuum pump to reduce the pressure of the ambient gas in a container containing the substance to be dried and a condenser to remove the condensation moisture on a cooled surface down to -40 to -80 ° C. Collector, rotary and tray-type lyophilizers differ in the method by which the dry substance is connected to a condenser. In collector-type lyophilizers, a short, usually circular tube is used to connect multiple containers with the dry product to a condenser. The rotary and tray-type freeze-dryers have a single large reservoir for the dry substance.
[00330] Rotary freeze driers are normally used for drying granules, cubes and other substances that can be poured. The rotary dryers have a cylindrical reservoir that is rotated during drying to obtain a more uniform drying throughout the substance. Tray-type lyophilizers generally have a rectangular reservoir with shelves in which products, such as pharmaceutical solutions and tissue extracts, can be placed in trays, flasks and other containers.
[00331] Collector-type lyophilizers are normally used in the laboratory environment when drying liquid substances in small containers and when the product is going to be used in a short period of time. A collector dryer will dry the product to less than 5% moisture content. Without heat, only primary drying (removal of unbound water) can be achieved. A heater must be added for secondary drying, which will remove the bound water and produce a lower moisture content.
[00332] Tray-type freeze-dryers are generally larger than collector-type dryers and are more sophisticated. Tray-type freeze dryers are used to dry a variety of materials. A tray-type freeze dryer is used to produce the driest product for long-term storage. A tray-type freeze dryer allows the product to be frozen in place and performs both primary (removal of unbound water) and secondary (removal of bound water) lyophilization, thus producing the dryest possible final product. Tray-type freeze driers can dry products in bulk or in bottles or other containers. When drying in bottles, the freeze dryer has a closing mechanism that allows the closing to be carried out on site, sealing the bottle before being exposed to the atmosphere. This is used for long-term storage, such as vaccines.
[00333] The improvement of freeze drying techniques is being developed to expand the range of products that can be dried by freeze drying, to improve the quality of the product, and to manufacture products faster and with less work.
[00334] Since the 1930s, industrial freeze drying has been dependent on a single type of equipment: the tray-type freeze dryer. In 2005, a faster and less laborious lyophilization method was developed for bulk materials. This freeze-drying process has been shown to be able to produce free-flowing powder from a single vessel. Known as AFD [Active Lyophilization] technology, the new process used continuous motion to improve the transfer of the dough and therefore reduce processing time, while eliminating the need to transfer from trays and to drying and drying trays. small size devices upstream.
[00335] There are four stages of the complete lyophilization process: pre-treatment, freezing, primary drying and secondary drying.
[00336] Pre-treatment includes any method of treating the product before freezing. This can include product concentration, revision of the formulation (ie, adding components to increase stability and / or improve processing), decreasing a high vapor pressure of the solvent or increasing the surface area. In many cases, a product's pretreatment decision is based on theoretical knowledge of lyophilization and its requirements, or is required by cycle time or product quality considerations. Pre-treatment methods include: Freezing concentration, Solution phase concentration, Formulation to preserve the appearance of the product, Formulation to stabilize reactive products, Formulation to increase the surface area, and Decrease of high vapor pressure solvents.
[00337] In a laboratory, freezing is often performed by placing the material in a freeze-drying bottle and rotating the bottle in a bath, called a shell-type freezer, which is cooled by mechanical refrigeration, dry ice and methanol, or Liquid nitrogen. On a larger scale, freezing is usually done using a freeze-drying machine. At this stage, it is important to cool the material below its triple point, the lowest temperature at which the solid and liquid phases of the material can coexist. This ensures that, sublimation instead of fusion will occur in the following steps. Larger crystals are easier to lyophilize. To produce larger crystals, the product must be frozen slowly or can be recycled up and down. This process is called annealing. In other cases, it is best that the freezing is done quickly, in order to reduce the material below its eutectic point quickly, thus preventing the formation of ice crystals. Freezing temperatures are generally between -40 ° C and -80 ° C. The freezing phase is the most critical in the entire lyophilization process, because the product can be damaged if done poorly.
[00338] Amorphous materials do not have a eutectic point, but they do have a critical point, below which the product must be kept to prevent melting or collapse during primary and secondary drying.
[00339] During the primary drying phase, the pressure is reduced (for the range of a few millibars, or less), and sufficient heat is provided for the material so that the water is sublimated. The amount of heat required can be calculated using latent heat of sublimation of the molecules that sublimate. In this initial drying phase, approximately 95% of the water in the material is sublimated. This phase can be slow (it can last for several days in the industry), because if too much heat is added, the structure of the material can be changed.
[00340] In this phase, the pressure is controlled through the application of partial vacuum. The vacuum accelerates sublimation, making it useful as a deliberate drying process. In addition, a cold chamber condenser and / or plate condenser provides a surface (s) for re-solidifying water vapor. This condenser plays no role in keeping the material frozen; instead, it prevents water vapor from reaching the vacuum pump, which could degrade the pump's performance. Condenser temperatures are typically below - 50 ° C.
[00341] It is important to note that, in this pressure range, heat is brought mainly by conduction or radiation; the convection effect is negligible due to the low density of the air.
[00342] The water vapor pressure is the pressure at which the water vapor is saturated. At higher water pressures, it would condense. Water vapor pressure is the partial pressure of water vapor in any gas mixture saturated with water. The water vapor pressure determines the temperature and pressure required for lyophilization to occur. The water vapor pressure (mTorr = millitorr; mB = millibar) is shown in the following table:


[00343] The secondary drying phase aims to remove the unfrozen water molecules, since the ice was removed in the primary drying phase. This part of the lyophilization process is regulated by material adsorption isotherms. In this phase, the temperature is raised more than in the primary drying phase, and may even be greater than 0 ° C, to break up any physical-chemical interactions that have formed between the water molecules and the frozen material. Normally, pressure is also reduced at this stage to encourage desorption (typically in the microbar range). However, there are products that also benefit from increased pressure.
[00344] After the lyophilization process is complete, the vacuum can be broken with an inert gas, such as nitrogen, before the material is sealed.
[00345] In one embodiment, the vacuum is maintained in the product chamber to allow easy addition of liquid for reconstitution.
[00346] At the end of the operation, the final residual water content in the lyophilized product is in general very low, such as around 2% or less.
[00347] The lyophilization process transforms the paste into a dry "pie-like" composition, which with the addition of an appropriate amount of an aqueous medium, such as water, will form a paste ready to use spontaneously, that is, no mixing / mechanical reconstitution is required by said paste to form.
[00348] In an alternative embodiment of the present description which involves vacuum expansion of the pulp prior to drying, the expanded pulp is not frozen prior to drying of the pulp. Nor is the paste freeze-dried. Certainly, the low vacuum is maintained while the paste is dried, subjecting the expanded paste to a higher temperature, until the paste is dried. The highest temperature is typically in the range of about 30-200 ° C, such as about 50 ° C to about 150 ° C. External packaging
[00349] In one embodiment, the dry composition contained, for example, in a medical application device, such as the syringe described here, or another containment unit, this is contained in an external packaging so that the product is kept sterile until the use. This will allow the user to remove the outer packaging and transfer the homeostatic composition to a sterile field.
[00350] The outer packaging is usually made of a flexible, semi-rigid or rigid material and typically consists of materials, such as plastic, aluminum foil and / or laminated plastic, where the plastic can be selected from the group consisting of PET, PETG, PE, LLDPE, CPP, PA, PETP, METPET, Tyvek and optionally bonded with an adhesive, such as polyurethane, or coextruded.
[00351] In one embodiment, the outer packaging is an aluminum foil in the outer packaging.
[00352] The outer packaging preferably forms a complete moisture barrier.
[00353] The outer packaging is preferably capable of withstanding sterilization by radiation. Sterilization
[00354] The dry composition of the present invention is preferably sterile. This can be by aseptic production or by any suitable sterilization technique known in the art. Sterilization preferably occurs after the packaging step, that is, when the dry composition is contained in an outer packaging. Thus, in a preferred embodiment, sterilization is terminal sterilization.
[00355] Sterilization refers to any process that effectively kills or eliminates transmissible agents (such as fungi, bacteria, viruses, prions and spore forms, etc.). Sterilization of the dry composition can be achieved, for example, through the application of heat, chemicals, and irradiation. Thermoesterilization includes autoclaving (uses steam at high temperatures) and dry heat; radiation sterilization includes X-rays, gamma and beta rays, UV light and subatomic particles; Chemical sterilization includes the use of ethylene oxide gas, ozone, chlorine bleach, glutaraldehyde, formaldehyde, ortho-phthalaldehyde, hydrogen peroxide and peracetic acid.
[00356] In one embodiment, the dry composition is sterilized by irradiation, for example, ionizing irradiation, in order to provide the sterility of the composition. Such irradiation may include e-beam (beta irradiation) or gamma irradiation. The level of irradiation and conditions for sterilization, including the time the composition is irradiated, are those that provide sterile compositions. Sterilization conditions are similar to those currently used in the preparation of loose hemostatic powders currently available. Once having the benefit of this description, one skilled in the art will be able to readily determine the level of irradiation necessary to provide sterile compositions.
[00357] When thrombin or other sensitive bioactive agents are present in the dry product, sterilization is usually performed as terminal sterilization with about 25 kGy or less of beta or gamma irradiation.
[00358] In one embodiment, sterilization is performed with ethylene oxide.
[00359] Dry heat sterilization can typically be performed by heating the dry hemostatic composition to a temperature between 100 and 250oC, such as about 110 to about 200oC, in particular the temperature can be in the range of 110 to 160oC, for example example, in the range of 110 to 140oC, or in the range of 120 to 180 ° C, or in the range of 130 to 170oC, or in the range of 130 to 160oC, or in the range of 120 to 150oC. Thermal sterilization is not normally used when the dry composition contains thrombin, since heat treatment could disable thrombin.
[00360] In one embodiment, the dry homeostatic composition is not sterilized after packaging. When the dry homeostatic composition is manufactured using aseptic production techniques, the product is already sterile when placed in the outer packaging and no further sterilization is required. Thus, in one embodiment, the present description refers to a composition produced by aseptic techniques. Reconstitution
[00361] The present inventors have observed a dry paste composition prepared by the methods currently described efficiently reconstitutes to form a slurry having a soft consistency suitable for use in hemostatic and wound healing procedures. The dry composition reconstitutes spontaneously, that is, without any necessary mechanical mixing.
[00362] The dried composition is reconstituted by adding a suitable aqueous medium. The aqueous medium can be added by any suitable mechanism. Preferably, the aqueous medium is sterile and compatible with surgical use.
[00363] The aqueous medium is added in an amount sufficient to obtain a wet paste having a desired biocompatible polymer content. In one embodiment, the volume of liquid added to the dry composition corresponds essentially to the volume of liquid that was removed by the drying procedure. In the event that a finer paste composition is desired, more liquid can be added to the dry paste than was initially removed by the drying procedure.
[00364] Preferably, the paste is reconstituted by adding an amount of liquid to a container, such as a medical dispensing device, with the dry paste composition dispersed in it, even more preferably in the same container that kept the paste during drying.
[00365] In one embodiment, the dry composition is reconstituted by attaching a second container that contains an amount of an aqueous medium to the first container that contains the dry composition.
[00366] Preferably, the container comprising the reconstitution liquid is essentially free of air or another gas. The advantage of this is that the reconstitution is independent of how the containers are oriented in space in relation to each other.
[00367] In one embodiment, there is a vacuum inside the product chamber of the first container, that is, the pressure inside the product chamber of the first container is less than that of the surrounding environment, that is, less than the atmospheric pressure.
[00368] In one embodiment, the pressure in the second container is greater than the pressure in the first container, and the pressure difference allows the automatic flow of liquid from the second container to the first container. This can be achieved, for example, by the first container with a pressure below atmospheric pressure, while the pressure inside the second container is around the atmospheric pressure. Thus, by opening a valve that separates the two containers, the aqueous medium is automatically drawn into the product chamber of the first container due to the pressure difference. The result is a reconstituted paste, see, for example, figures 12-13.
[00369] Thus, in one embodiment, the present description refers to a method for reconstituting a dry composition that comprises the steps of: a. providing a first container comprising a product chamber containing a dry paste composition and a valve, preferably wherein the pressure in the product chamber is less than the surrounding atmospheric pressure, b. providing a second container comprising an aqueous medium, preferably wherein the pressure in the second container is greater than the pressure in the product chamber of the first container, c. bring the first container and the second container into contact, using suitable connection means, and d. open the valve.
[00370] In one embodiment, the second container is a collapsible recipient, such as a plastic bag. By attaching to the first container and opening the valve, the bag is disassembled due to the pressure difference, thus allowing the liquid to flow from the bag to the product chamber and reconstitute the paste, as shown in figures 12-13.
[00371] In another embodiment, the second container is a non-dismountable container comprising a plunger, such as a rigid or semi-rigid plastic container. By attaching to the first container and opening the valve, the plunger allows liquid to flow from the aqueous medium container to the product chamber and reconstitutes the paste without exerting pressure on the plunger, as shown in figures 12-13.
[00372] In one embodiment, a ready-to-use paste forms spontaneously with the addition of liquid to the dry composition disposed in the container in less than about 30 seconds, preferably in less than about 20 seconds, more preferably in less than about 10 seconds, even more preferably in less than about 5 seconds, such as less than about 3 seconds, for example, less than about 2 seconds. The reconstituted paste generally does not require additional mixing or other forms of manipulation before use. Thus, when the dry composition is present in a medical dispensing device, such as a syringe, it can be applied directly to a patient immediately after adding liquid, for example, for hemostatic purposes, by extruding the paste from the medical dispensing device into an open wound.
[00373] In a preferred embodiment, a ready-to-use paste forms in less than about 10 seconds, for example, in less than about 5 seconds, such as less than about 3 seconds, for example, less than about 2 seconds.
[00374] After reconstitution, the container, for example, a syringe, such as the syringe described here, can be adjusted with a suitable applicator tip to administer the paste more precisely, as illustrated in figure 14.
[00375] In one embodiment, the applicator tip is flexible or malleable and will maintain a desired configuration, chosen by the user, in such a way that it remains at an ideal angle to facilitate access and location of the exact product. Additionally, it can be cut to a desired size with a pair of dressing scissors or similar type of scissors. These features allow for an accurate and convenient application of the paste. In one embodiment, the applicator tip is essentially as described in WO 2011/047753.
[00376] In one embodiment, the reconstituted paste has a consistency in the range of about 100 gx sec to about 10,000 gx sec, such as from about 500 gx sec to about 5,000 gx sec, for example, about 1,000 gx sec to about 3,000 gx sec, such as from about 1,500 gx sec to about 2,000 gx sec.
[00377] In one embodiment, the reconstituted paste has a consistency of less than about 5,000 gx sec, for example, less than about 4,000 gx sec, such as less than about 3,000 gx sec, for example, less than about 2,000 gx sec A homeostatic paste
[00378] In one embodiment, the present description refers to a paste suitable for use in hemostatic procedures. The hemostatic paste can be obtained by the methods described here. The paste of the present invention has a desirable soft and light consistency, compared to pastes currently known in the art.
[00379] The homeostatic paste of the present disclosure comprises a biocompatible polymer and preferably has a consistency of less than 5,000 g x s.
[00380] The biocompatible polymer is generally in the form of particles substantially insoluble in water. Preferably, it is a biocompatible crosslinked polymer suitable for use in homeostasis and / or wound healing, such as crosslinked gelatin particles, as described elsewhere here.
[00381] The paste can be made using any suitable aqueous medium to prepare a paste known to a master as described herein.
[00382] In one embodiment, the consistency of the paste is less than about 4,500 g x s.
[00383] In one embodiment, the consistency of the paste is less than about 4,000 g x s.
[00384] In one embodiment, the consistency of the paste is less than about 3,500 g x s.
[00385] In one embodiment, the consistency of the paste is less than about 3,000 g x s.
[00386] In one embodiment, the consistency of the paste is less than about 2,500 g x s.
[00387] In one embodiment, the consistency of the paste is less than about 2,000 g x s.
[00388] In one embodiment, the consistency of the paste is in the range of about 100 gx to about 5,000 gxs, such as about 500 g to about 4,000 gxs, for example, from about 500 g to about 3,500 gxs, such as from about 500 gx seconds to about 3,000 gxs, for example, from about 500 gxs to about 2,500 gs, such as from about 500 gs to about 2000 gs.
[00389] In one embodiment, the consistency of the paste is in the range of about 1,000 gx to about 4,000 gxs, for example, from about 1,000 gx to about 3,500 gxs, such as from about 1,000 gx seconds to approximately 3,000 gxs, for example, from about 1,000 gxsa to about 2,500 gxs, as well as from about 1,000 gxsa to about 2,000 gxs.
[00390] The paste of the present description can further comprise one or more hydrophilic compounds as described herein. For example, the pulp may comprise a polyol as a hydrophilic compound, such as a sugar alcohol, in a concentration of at least 1%, more preferably at least 2%, such as at least 3%, for example, at least 4 %, such as at least 5%. In one embodiment, sugar alcohol is mannitol.
[00391] The paste of the present disclosure may further comprise one or more additional compounds and / or bioactive agents and / or extrusion enhancers as described herein. Preferably, the paste of the present description comprises thrombin as a bioactive agent.
[00392] In a specific embodiment, the present invention relates to a paste suitable for use in homeostasis comprising: a) a biocompatible polymer in about 10% to about 40%, b) an aqueous medium, such as water and, optionally, one or more of c) a hydrophilic compound in about 1% to about 20%, d) a bioactive agent and e) an extrusion intensifier, wherein said paste has a consistency of less than 5,000 gx s.
[00393] In one embodiment, the present description refers to a syringe comprising said paste. Medical use
[00394] The present description also refers to the use of the dry composition or paste described here to promote homeostasis and / or wound healing in an individual in need of it.
[00395] The paste of the present invention has a soft consistency, which may be preferable in certain types of surgeries. In addition, the surgeon's preferences also vary with regard to the consistency of the pastes, where some surgeons prefer a softer consistency than others. Consequently, the currently described composition and dry paste may satisfy the need for surgeons who have a preference for a softer paste consistency.
[00396] The paste of the present description can, for example, be used in a variety of surgical procedures in which bleeding control is desired. Hemostatic products in the form of paste are able to mold efficiently to uneven surfaces and are therefore useful for providing rapid hemostasis on rough or uneven surfaces where hemostatic sponges are not effective.
[00397] Hemostatic pastes currently available (for example, Floseal® and Surgiflo®) are usually prepared (that is, reconstituted) directly at the surgical site, in the time required by the medical professional, that is, doctors or nurses, by adding liquid to a container, such as a syringe, containing an amount of a biocompatible polymer. The biocompatible polymer can be pre-wetted with the liquid or be essentially dry (free flowing powder). The paste is thus often prepared in extremely stressful conditions and therefore it is essential that the process for preparing the paste is simple and quick to ensure that bleeding is contained as quickly as possible and that no mistakes are made during preparation. of the folder, in such a way that the nurse can keep the focus on the surgeon's need, instead of preparing the hemostatic. It is also important that the consistency of the paste is suitable for the particular surgical procedure, that the consistency of the product is independent of the preparation for preparation and that the consistency of the reconstituted paste is not very substantially over time (after preparation).
[00398] Due to the time spent and often complex preparation steps needed to reconstitute the currently available slurry products, they are often pre-prepared in the OR prior to surgery, if needed in surgery. Consequently, the unused product is thus often discarded because the surgeon does not use as much of the expected product. Unused product should also be disposed of if the time limit for using the reconstituted product is exceeded. This causes unnecessary high OR costs.
[00399] The preparation of the paste of the present description is simple and fast - the dry composition is reconstituted to form a diluted paste in seconds of contact with the aqueous medium. Importantly, no mechanical mixing step is necessary. Thus, there is no need to pre-prepare the paste before a surgical procedure and OR costs can be kept to a minimum.
[00400] Since the reconstitution of the dry composition of the present description is independent of the mechanical mixing, the consistency of the reconstituted paste will always be the same when the correct amount of liquid is added. This is not always the case with conventional pastes, where the consistency of the paste may depend on the force applied and the time spent mixing. The fact that mechanical mixing is not necessary also means that less time is spent preparing the paste, which in turn leads to increased patient safety, both because the hemostatic paste can be applied to the patient faster than the simple preparation method decreasing the probability of errors occurring during the preparation of the hemostatic paste.
[00401] When thrombin is comprised within the dry composition, the invention also has the advantage over conventional pastes in that it avoids the time-consuming and time-consuming dilution and addition steps of thrombin that are subject to errors that are present in current methods for prepare fluid products.
[00402] Another notable advantage of the dry composition of the present invention is that a kit consisting of a few components can be prepared compared, for example, to current hemostatic fluid product kits. All that is required to prepare a slurry composition in the OR is the dry composition in the manner described herein, comprised in a medical dispensing device, and a container comprising an aqueous medium for reconstitution. Upon connection of the two, a ready-to-use slurry containing all the necessary agents for efficient hemostasis, including thrombin, is formed spontaneously when the aqueous medium is automatically dragged into the medical dispensing device containing the dry composition. Thus, no extra syringe, bottle adapters, needles and mixing bowls are required with the product prepared according to the methods of the present description. This means that manufacturing costs can be reduced and also ensures good patient safety, since there are fewer components for the OR team to control during surgery. Needle-free preparation of the hemostat also ensures the safety of the OR team.
[00403] In one embodiment of the present description, it refers to a method to stop bleeding / promote hemostasis in an individual who needs it by applying the paste of the present description at the bleeding site.
[00404] The folder of this description can be used for any type of surgery, including general surgery, cardiothoracic surgery, vascular surgery, plastic surgery, pediatric surgery, colorectal surgery, transplant surgery, cancer surgery, trauma surgery, surgery endocrine, breast surgery, skin surgery, otolaryngology, gynecology, oral and maxillofacial surgery, dental surgery, orthopedic surgery, neurosurgery, ophthalmology, pediatric surgery, urology.
[00405] In one embodiment of the present description, it refers to a method for promoting wound healing in an individual in need of it by applying the paste of the present description to a wound.
[00406] The "wound" generally refers to lesions in the skin and / or underlying tissue (subcutaneous) initiated in different ways (for example, pressure ulcers due to prolonged bed rest and injuries caused by trauma) and with different characteristics. Wounds can be classified into one to four degrees, depending on the depth of the wound: i) Grade I: wounds limited to the epithelium; ii) Grade II: wounds that extend to the dermis; iii) Grade III: wounds that extend into the subcutaneous tissue; and iv) Grade IV (or full thickness wounds): wounds to which the bones are exposed (for example, a point of bone pressure, such as the greater trochanter or sacrum). The present description refers to the treatment of any type of wound mentioned above, using the paste of the present description.
[00407] The treatment of a wound can, in principle, result in wound healing or accelerated wound healing. Accelerated healing can be a result of, for example, administering a substance that promotes wound healing. Alternatively, wound healing can be promoted by preventing bacterial or viral infection, or by reducing the risk of such an infection, which would otherwise have prolonged the wound treatment process.
[00408] In one embodiment, the present description refers to a method for promoting the healing of bone and / or tendon in an individual in need of it by applying the paste of the present description to the injured bone / tendon.
[00409] The "subject" referred to herein may be any mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. It is preferred that mammals are of the order Carnivore, including felines (cats) and canines (dogs). Most preferably, mammals are of the order Artiodactyl, including Bovines (cows) and Swine (pigs) or of the order Perssodactyl, including Horses (horses). It is more preferably that the mammals are of the order of Primates, Ceboides, or Simoides (monkeys) or of the order Anthropoids (humans and monkeys). A particularly preferred mammal is the human.
[00410] In one embodiment, the present description refers to the dry composition described herein, for use in treating a wound, for example, to contain bleeding or to promote wound healing. A hemostatic kit
[00411] The present description further refers to a hemostatic kit comprising the dry composition of the present description and an amount of aqueous medium combined with the amount of the dry composition so that after the addition of the aqueous medium, a hemostatic paste of a suitable consistency for use as a hemostatic paste it will form without the need for mechanical mixing.
[00412] Consequently, in one embodiment, the present description refers to a hemostatic kit comprising: a. a first container comprising the dry composition obtained by the method of the present description, b. a second container comprising an aqueous medium, and c. optionally an outer packaging.
[00413] In an additional embodiment, the present description refers to a hemostatic kit comprising: a. the currently described syringe comprising a dry composition b. a container comprising an aqueous medium, and c. optionally an outer packaging.
[00414] The dry composition can be any dry composition, in particular a dry composition which, with the addition of the aqueous medium, will form a hemostatic paste of a consistency suitable for use as a hemostatic paste, as it will spontaneously form in seconds, such as a dry composition obtained by the method of the present description.
[00415] In one embodiment, the dry composition comprises thrombin.
[00416] In one embodiment, the kit additionally comprises one or more applicator tips.
[00417] The kit can optionally contain instructions for using the kit. Example 1 Materials
[00418] 50 g gelatin powder (crushed cross-linked gelatin sponges)
[00419] 200 mL of buffer
[00420] x g Polyol
[00421] 50% benzalkonium chloride (BAC)
[00422] 0.9% saline solution Equipment
[00423] Freeze dryer: Christ Alpha 1-4 LSC
[00424] Mixer: Kenwood, Major KM616 Method
[00425] Buffer solution:
[00426] Add 2.0 g ± 0.1 g BAC (50%) to a 250 ml blue lid bottle
[00427] Add 98.0 g ± 0.5 g of water to the BAC
[00428] Mix for 2 minutes using magnetic stirring, that is, it is the BAC stock solution
[00429] Add 10 g ± 0.5 g of BAC stock solution
[00430] Add water up to the 2000 mL mark
[00431] put a cork in the bottle and turn it upside down a few times
[00432] Mix by magnetic stirring for 5 ± 1 minutes Paste:
[00433] Dissolve x g of polyol in 200 ml of buffer solution while stirring in the mixer. Add 50g of gelatin powder and mix with the dissolved polyol until a homogeneous paste is obtained, approximately 5 minutes.
[00434] The resulting paste was filled in single-use plastic syringes of 10 mL (5.5 mL per syringe) comprising a freeze-drying shortcut channel and placed at -30 ° C for at least 4 hours. The frozen paste was transferred to the lyophilizer and lyophilized until dry for approximately 15 hours. At the end of the drying cycle, the freeze-drying shelves were dismantled, thereby moving the plunger and the freeze-drying shortcut channel. The pressure in the lyophilizer chamber was then brought to room pressure, leaving a vacuum in the product chamber. Reconstitution:
[00435] The dry hemostatic composition was reconstituted by placing the syringe comprising the dry composition in contact with a removable plastic bag containing water (8 mL). No mechanical mixing or stirring was used. Water was added to the dry composition using a vacuum inside the product chamber, and the composition was left intact until a paste was formed again. The vacuum inside the syringe product chamber causes the water to be automatically drawn into the syringe from the container that contains the water. Results of
[00436] The different formulations were tested in relation to the reconstitution time, that is, the time necessary for a paste suitable for hemostatic purposes to form spontaneously without mechanical agitation of any kind.
[00437] The pastes comprising different polyols were prepared, dried and reconstituted according to the previous directions. The contents of the folders are shown in the following tables.


[00438] The polyol: gelatin ratio in the dry compositions was approximately 0.4: 1.
[00439] The spontaneous reconstitution time of the pastes comprising different polyols made according to the tables above is shown in the table below and in figure 2. The experiments were repeated 5 times for each polyol.

[00440] The experiment shows that different types of polyols can be used to prepare a lyophilized gelatin paste that will spontaneously reconstitute with the addition of an aqueous medium in less than about 30 seconds. The reconstituted paste has a consistency suitable for direct use as a hemostatic paste. Example 2. Thrombin
[00441] Thrombin was included in the following paste formulation, at a theoretical concentration of 2500 IU / product. The paste was prepared at room temperature (about 20 ° C) and mixed in the manner described in example 1.
[00442] The dry paste had a spontaneous reconstitution time of about 5 seconds. The contents of the paste formulation are specified in the following table in the paste (wet) and the dry composition (dry) respectively.

[00443] The total concentration of polyol, ie mannitol and glycerol, in the paste was 13.56% and after drying 42.27%.
[00444] The polyol: gelatin ratio in the dry composition was approximately 0.75: 1.
[00445] The paste was dried by lyophilization and reconstituted in the manner described in Example 1.
[00446] Thrombin activity was measured in the reconstituted paste. The results are shown in the following table.

[00447] No loss of thrombin activity was measured in the reconstituted paste.
[00448] The results show that it is not strictly necessary to perform the mixing of the paste at low temperatures to avoid the loss of thrombin activity, since no decrease in thrombin activity was observed when the mixture was carried out at room temperature. Example 3. Vacuum expansion of pastes before freeze-drying
[00449] Gelatin pastes comprising mannitol were prepared essentially in the manner described in example 1 and aliquoted in single use 10 ml syringes, each syringe containing 4 g of the paste. The contents of the paste formulation are specified in the following table in the paste (wet) and the dry composition (dry) respectively.

[00450] The prepared pastes were either lyophilized directly in the manner described in example 1 (standard lyophilization) or subjected to a low vacuum of about 850 mbar (85 kPa), followed by a freezing step at - 40 ° C without releasing the vacuum, and finally lyophilized essentially in the manner described in example 1 (vacuum expanded lyophilization). Vacuum expansion was carried out at room temperature, that is, about 20 ° C. Upon exposure of the pastes to decreased pressure, that is, vacuum, the pastes expanded in volume almost instantly.
[00451] Prior to vacuum expansion, the density of the gelatine paste was approximately 0.7 g / mL. After vacuum expansion, the pulp density was approximately 0.5 g / mL, which corresponds to a decrease in pulp density by about a factor of 0.72 and a corresponding increase in pulp volume by about a factor. 1.4.
[00452] The lyophilized products were reconstituted essentially in the manner described in example 1, adding 5.5 ml of saline to the lyophilized product and the amount of time for the paste to completely absorb the saline was measured. The vacuum inside the syringe product chamber automatically enters the liquid. Both the vacuum and standard expanded pastes were soft and moist after reconstitution and exhibited comparable absorption capacities. The consistency of the reconstituted pastes was considered adequate for direct use on a patient. The reconstituted pastes showed a slightly whitish / yellowish color.
[00453] The reconstitution time for dry paste compositions is shown in the following table and in figure 2. The experiments were repeated 5 times (n = 5).

[00454] The inventors surprisingly observed that, subjecting the pulp to vacuum before freezing, the dry hemostatic pulp reconstituted more than seven times faster than the pulps that were not vacuum expanded. Reconstitution did not require any mechanical agitation, mixing or stirring of any kind, and a ready-to-use hemostatic paste of a consistency suitable for direct use in hemostatic procedures was formed in seconds. Example 4. Density of dry expanded vacuum paste
[00455] Gelatin pastes comprising mannitol were prepared in the manner described in examples 1 and 3. The pastes were vacuum expanded using different vacuum levels (1000 mbar (100 kPa) (in vacuum), 850 mbar (85 kPa) and 600 mbar (60 kPa)) and then frozen and lyophilized, as described in example 3.
[00456] The density of dry paste compositions is shown in the following table and in figure 15.

[00457] The dry compositions reconstitute spontaneously to form soft and moist pastes suitable for hemostatic and / or wound healing.
[00458] The results show that different pressures can be used to expand the paste before drying.
[00459] The results further show that the pressure used for expansion affects the density of the dry paste composition. In fact, there seems to be a good correlation between the pressure and the density of the dry composition with lower pressures, resulting in lower densities of the final dry paste composition. Example 5. Effect of vacuum expansion and polyol concentration
[00460] Gelatin pastes comprising different amounts of mannitol (no mannitol, average mannitol (approximately 3.9%) or high mannitol (approximately 7.4%)) were prepared essentially in the manner described in example 1, with the exception of that a Virtis Genesis 35 freeze dryer was used. The paste portions were aliquoted in single-use 10 mL syringes with a vacuum shortcut, each syringe containing 4 g of the paste. The contents of the paste formulation are specified in the following table in the paste (wet) and in the dry (dry) compositions respectively.

[00461] The prepared pastes were either lyophilized directly in the manner described in example 1 (without expansion) or expanded in vacuum by exposure to a low vacuum of about 850 mbar (85 kPa), followed by a freezing step at - 40 ° C without releasing the vacuum, and finally lyophilized essentially in the manner described in example 1 (vacuum expansion). Vacuum expansion was carried out at room temperature, that is, about 20 ° C.
[00462] The lyophilized products were reconstituted by adding 5.5 mL of saline to the lyophilized product in the syringe and the amount of time for the paste to completely absorb the saline was measured. No mechanical mixing was performed. The reconstituted pastes were soft and moist, and exhibited comparable absorption capacity. However, the consistencies of non-expanded gelatin pastes without mannitol were lower than pastes containing mannitol and / or the pastes were expanded under vacuum. The reconstituted pastes showed a slightly whitish / yellowish color.
[00463] The average reconstitution time for dry paste compositions is shown in the following table and in figure 21. Each experiment was repeated 5 times (n = 5).
* The consistency of the reconstituted pulp was evidently inferior to those containing mannitol and / or the pulps were expanded in a vacuum.
[00464] Vacuum expansion of gelatin pastes before lyophilizing greatly reduced the reconstitution time of dry gelatin paste compositions with and without mannitol. In fact, vacuum expansion was able to reduce the spontaneous reconstitution time of gelatin pastes by about a factor 3 or more. The spontaneous reconstitution time was further improved, that is, reduced, by including mannitol in the dry compositions. Mannitol also improved the consistency of the reconstituted pastes.
[00465] Gelatin pastes containing 7.4% polyethylene glycol (PEG) were also prepared in the previous way, expanded under vacuum and frozen. The contents of the paste formulation are specified in the following table in the paste (wet) and in the dry (dry) composition respectively.

[00466] The average reconstitution time for dry paste compositions comprising PEG was 8.2 +/- 2.4 seconds (n = 5). The dry and vacuum-expanded gelatin pastes containing PEG reconstituted about 1.7 times faster than the control (vacuum-expanded gelatin pastes with none of the added hydrophilic compounds), and showed superior consistency. The results are shown in figure 22.
[00467] The inventors also found that the volume of an aliquot of the paste is generally greater in the samples that are aliquoted first, as opposed to the latter, of a single batch of paste. It is known that this is due to a partial disassembly of the paste over time, causing undesirable variations in the density of the paste. Such variations in density can lead to undesirable variations in the reconstitution time. It is believed that vacuum expansion of the pulp prior to drying is able to reduce or even eliminate such differences in pulp density, which may occur between the first and last portion of the pulps that are aliquoted from a single batch pulp.
[00468] In conclusion, the results show that vacuum expansion before drying greatly improves the reconstitution rate and is capable of providing more consistent results with respect to the reconstitution time. The rate of spontaneous reconstitution can be further improved by including increasing amounts of polyols in the dry pulp compositions. In addition, the inclusion of hydrophilic compounds, such as polyols, in the dry pulp compositions also improved the consistency of the reconstituted pulps. Example 6. Effect of polyols and vacuum expansion on the consistency of reconstituted pastes containing sodium bicarbonate Materials Polyol-free paste:
[00469] 50 g of powdered gelatin (crushed Surgifoam sponges)
[00470] 200 mL of 0.005% BAC w / w in MQ water
[00471] 1% NaHCO3 Paste containing polyol:
[00472] 50 g of powdered gelatine (crushed Surgifoam sponges)
[00473] 200 mL of 0.005% BAC w / w in MQ water
[00474] 20 g of D-mannitol
[00475] 1% NaHCO3
[00476] A 2.5% citric acid solution was used to reconstitute the dry paste compositions. The pH of the solution was approximately 2. Equipment
[00477] Freeze dryer: Genesis 35
[00478] Mixer: Kenwood, Major KM616
[00479] Texture analyzer: TA.XT.plus, Stable micro systems Method Preparation of the folders
[00480] To prepare pastes without polyol, 50 g of gelatin powder were placed in a mixing vessel and 200 mL of 0.005% BAC w / w in MQ solution were added and stirred until a homogeneous paste was obtained (approximately 10 minutes of mixing in the Kenwood mixer) The resulting slurry was weighed and NaHCO3 added in resulting amount to a slurry containing 1% w / w NaHCO3. NaHCO3 was mixed in the paste for another 2 minutes.
[00481] The paste containing polyol was prepared in a similar manner to the previous procedure, except for the addition of 200 mL of 0.005% BAC w / w in MQ water having 20 g of dissolved D-Mannitol. Lyophilization
[00482] The resulting pastes were filled in freeze-dried syringes in portions of 5.5 g and the syringes were placed in the freeze dryer. Before freezing, a vacuum of approximately 450,000 Mtorr (about 600 mbar (60 kPa)) was applied to a portion of the samples. The portion of the samples that was not subjected to vacuum expansion before freezing was frozen immediately when placed in the lyophilizer. Subsequently, the samples were frozen at below -40 ° C. The samples were then dried in the lyophilizer until dry. Reconstitution
[00483] The dry pastes were reconstituted by adding 7.0 mL of 2.5% citric acid solution to each syringe. Specifically, the reconstitution liquid was added by connecting the syringe containing the dry paste with another syringe containing the citric acid solution and opening a valve, allowing communication between the two syringes. Due to the reduced pressure inside the syringe containing the dry paste, the reconstitution liquid is automatically withdrawn from the syringe containing the dry paste. All samples reconstituted spontaneously without any mechanical mixing required. The spontaneous reconstitution time of the different samples varied according to the table shown in the results section below. Texture analysis
[00484] The consistency of the reconstituted paste was tested using a texture analyzer (TA.XT.plus, Stable micro systems)
Results of
[00485] The contents of the compositions in the wet and dry state were as follows:

[00486] The consistencies were calculated as the area under the resulting curve and the results are shown in the table below. The average sample reconstitution time is also shown. All samples reconstituted spontaneously without mechanical mixing, although the reconstitution time varied between groups.

[00487] It was observed that the inclusion of NaHCO3 resulted in pastes (before drying) which on visual inspection appeared to be more dense than pastes prepared without NaHCO3. This may explain the longer reconstitution times observed compared to lyophilized pastes prepared without NaHCO3, for example, the samples of Example 5 here.
[00488] There is no significant difference in the consistency of the paste between the four groups of samples tested (+/- polyol, +/- expansion vacuum) (P = 0.3, Welch's t test). Conclusion
[00489] The consistency of the paste has not changed significantly in response to the addition of polyol or in response to exposure to vacuum expansion. A smooth uniform consistency was obtained in all four test conditions, although the reconstitution time varied depending on the inclusion of polyol and the use of vacuum expansion prior to freeze drying. Upon reconstitution, NaHCO3 in the dry compositions reacts with the acid in the reconstitution liquid and will form CO2. CO2 expands inside the paste, thus changing the consistency regardless of the presence of polyol or exposure to vacuum expansion. Example 7 - Effect of variation in sodium bicarbonate concentration on the consistency of reconstituted pastes Materials Folder containing NaHCO3:
[00490] 100 g of gelatin powder (crushed Surgifoam sponges)
[00491] 400 mL of 0.005% BAC w / w in MQ water
[00492] 40 g D-Mannitol (Sigma)
[00493] X g of NaHCO3 (Sigma) Default folder (control):
[00494] 50 g of gelatin powder (crushed Surgifoam sponges)
[00495] 200 mL of 0.005% BAC w / w in MQ water
[00496] 20 g D-Mannitol (Sigma)
[00497] A 2.5% citric acid solution was used to reconstitute the dry paste compositions. The pH of the solution was about 2. Equipment
[00498] Freeze dryer: Genesis 35
[00499] Mixer: Kenwood, major KM616
[00500] Texture analyzer: TA.XT.plus, Stable micro systems Method Preparation of the folders
[00501] 40 g of mannitol was completely dissolved in 400 ml of 0.005% solution of BAC w / w in MQ water with stirring. 100 g of powdered gelatin was added and mixed with the dissolved mannitol solution until a substantially homogeneous paste was obtained (approximately 10 minutes of mixing in the Kenwood mixer). The resulting paste was divided into two equally sized portions (265.6 g) exg of NaHCO3 were added to each portion according to the table below and mixed for a further 2 minutes.

[00502] The standard paste was prepared in a similar manner, except for the addition of NaHCO3 and the final mixing step. Lyophilization
[00503] The resulting pastes were filled in lyophilization syringes in portions of 5 g and the syringes were placed in the lyophilizer. Before freezing, a vacuum of approximately 450,000 Mtorr (about 600 kPa, that is, about 400 kPa less than the ambient pressure) was applied to the samples. Subsequently, the samples were frozen below -40 ° C. The samples were then dried in the lyophilizer until dry. Reconstitution
[00504] The dry pastes were reconstituted by adding 7.0 ml of a 2.5% citric acid solution. Specifically, the reconstitution liquid was added by connecting the syringe containing the dry paste with another syringe containing the citric acid solution and opening a valve, allowing communication between the two syringes. Due to the reduced pressure inside the syringe containing the dry paste, the reconstitution liquid is automatically removed from the syringe containing the dry paste. The paste layer spontaneously reconstituted in less than 10 seconds with no mechanical mixing required. Texture analysis
[00505] The consistency of the different formulations was tested using a texture analyzer (TA.XT.plus, Stable micro systems). TA adjustments were as indicated for Example 6. Results of
[00506] The contents of the compositions in the wet and dry state were as follows:

[00507] The consistencies of the reconstituted pastes were calculated as the area under the resulting curve and the results are shown in the following table.

[00508] The results are also shown in figure 23.
[00509] The study showed that the presence of 0.5% of sodium bicarbonate in the paste before drying (corresponding to about 1.9% in the dry composition) reduces the area under the curve by about 45%, while 1 % of sodium bicarbonate in the paste before drying (corresponding to about 3.7% in the dry composition) reduces the area under the curve by about 71%, compared to the control (0% NaHCO3). The area under the curve is a measure of the consistency or softness of the pastes.
[00510] The reconstituted pastes comprising sodium carbonate were noticeably whiter than the pastes reconstituted without sodium bicarbonate. The more gas a paste contains, the lighter the color of the paste will be. Conclusion
[00511] The consistency of the reconstituted paste softens as the concentration of NaHCO3 increases. This is probably due to the CO2 formed when the NaHCO3 base reacts with citric acid in the reconstitution of the dry paste compositions. The formed CO2 expands inside the paste, thus changing the consistency of the paste. A softer, lighter consistency is desirable in some applications of hemostatic pastes. Example 8. Effect of the incorporation of an acid in the dry composition and reconstitution with a base Materials Folder:
[00512] 50 g of gelatin powder (crushed Surgifoam sponges)
[00513] 200 mL of 0.005% BAC w / w in MQ water
[00514] 20 g of D-Mannitol (Sigma)
[00515] 1% Tartaric Acid (Sigma)
[00516] A 2.5% NaHCO3 solution was used to reconstitute the dry paste compositions. The pH of the solution was about 8.2. Equipment
[00517] Freeze dryer: Genesis 35
[00518] Mixer: Kenwood, major KM616
[00519] Texture analyzer: TA.XT.plus, Stable micro systems Method Preparation of the paste
[00520] To prepare the paste, 50 g of gelatin powder was placed in a mixing vessel and 200 ml of 0.005% BAC w / w in MQ water having 20 g of dissolved D-mannitol were added and stirred until it was a homogeneous paste is obtained (approximately 10 minutes of mixing in the Kenwood mixer). The resulting slurry was weighed and tartaric acid added in an amount that results in 1% weight / weight of slurry containing tartaric acid. The tartaric acid was mixed in the paste for a further 2 minutes.
[00521] Lyophilization
[00522] The resulting paste was filled in lyophilization syringes in portions of 5.5 g and the syringes were placed in the lyophilizer. Before freezing, a vacuum of approximately 450,000 Mtorr (about 600 mbar (60 kPa)) was applied to the samples. Subsequently, the samples were frozen to below -40 ° C and dried in the lyophilizer until dry. Reconstitution
[00523] The resulting pastes were reconstituted by adding 7.0 mL of a 2.5% NaHCO3 solution to each syringe. Specifically, the reconstitution liquid was added by connecting the syringe containing the dry paste with another syringe containing the reconstitution solution and opening a valve allowing communication between the two syringes. Due to the reduced pressure inside the syringe containing the dry paste, the reconstitution liquid is automatically removed from the syringe containing the dry paste. Texture analysis
[00524] The consistency of the reconstituted paste was tested using a texture analyzer (TA.XT.plus, Stable micro systems).

Results of
[00525] The contents of the compositions in the wet and dry state were as follows:

[00526] Consistency was calculated as the area under the resulting curve and the average consistency, and the reconstitution time is shown in the following table.

[00527] The samples reconstituted spontaneously without any necessary mechanical mixing.
[00528] The consistency of the reconstituted paste obtained having an acid incorporated in the paste before drying and reconstitution with a base was similar to the consistency obtained having a base incorporated in the paste before drying and reconstitution with an acid (see Examples 6 and 7). Conclusion
[00529] A smooth soft consistency was obtained on reconstitution. Upon reconstitution, tartaric acid in the dry compositions reacts with the liquid in the reconstitution of NaHCO3 and forms CO2. CO2 expands inside the paste, thus changing the consistency of the paste.

权利要求:
Claims (26)
[0001]
1. Method for preparing a dry composition to form a hemostatic paste, characterized by the fact that it comprises the steps of: a) providing an aqueous medium, a biocompatible polymer consisting of powder particles that are substantially insoluble in an aqueous medium and a alkaline compound, b) mixing the biocompatible polymer, the aqueous medium and the alkaline compound to obtain a paste, and c) drying the paste, where the alkaline compound is capable of reacting with an acidic compound in an aqueous medium to release a gas, where the biocompatible polymer is selected from the group consisting of gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, polyglycolic acid and polyacetic acid, where the alkaline compound is a carbonate salt, where the acidic compound is selected from the group consisting of acetic acid, citric acid, oxalic acid and tartaric acid, and in which the dry composition comprises from 0.1% to 10% of the alkaline compound, for example, from 0.5% to 8% of the compo alkaline, such as from 1% to 6% of the alkaline compound or from 1% to 5% of the alkaline compound.
[0002]
2. Method for preparing a dry composition to form a hemostatic paste, characterized by the fact that it comprises the steps of: a) providing an aqueous medium, a biocompatible polymer consisting of powder particles that are substantially insoluble in an aqueous medium and a acidic compound, b) mixing the biocompatible polymer, the aqueous medium and the acidic compound to obtain a paste, and c) drying the paste, in which the acidic compound is capable of reacting with an alkaline compound in an aqueous medium to release a gas, where the biocompatible polymer is selected from the group consisting of gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, polyglycolic acid and polyacetic acid, where the alkaline compound is a carbonate salt, where the acidic compound is selected from the group consisting of acetic acid, citric acid, oxalic acid and tartaric acid, and in which the dry composition comprises from 0.1% to 10% of the acidic compound, for example, from 0.5% to 8% of the compound acidic, such as from 1% to 6% of the acidic compound or from 1% to 5% of the acidic compound.
[0003]
Method according to any one of the preceding claims, characterized by the fact that the paste obtained in step b) is subjected to i) reduced pressure, thereby expanding the paste, and ii) the expanded paste is frozen before step c) .
[0004]
Method according to any one of the preceding claims, characterized in that the paste from step b) is additionally mixed with one or more hydrophilic compounds.
[0005]
Method according to any one of the preceding claims, characterized by the fact that the biocompatible polymer is cross-linked.
[0006]
Method according to any one of the preceding claims, characterized in that the biocompatible polymer comprises or consists of gelatin.
[0007]
7. Method according to any of the preceding claims, characterized by the fact that the gas is CO2.
[0008]
8. Method according to any one of the preceding claims, characterized in that the carbonate salt is selected from the group consisting of sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), potassium bicarbonate (KHCO3), carbonate potassium (K2CO3), calcium bicarbonate (Ca (HCO3) 2), calcium carbonate (CaCO3), magnesium carbonate (MgCO3), magnesium bicarbonate (Mg (HCO3) 2), ammonium bicarbonate (NH4HCO3), carbonate ammonium ((NH4) 2CO3), gadolinium bicarbonate (Gd (HCO3) 3, gadolinium carbonate (Gd (CO3) 3), lithium bicarbonate (LiHCO3), lithium carbonate (LiCO3), rubidium bicarbonate (RbHCO3), rubidium carbonate (Rb2CO3), zinc carbonate (ZnCO3), zinc bicarbonate (Zn (HCO3) 2, iron (II) carbonate (FeCO3), iron (Fe (II) (HCO3) 2) bicarbonate, silver (Ag2CO3), silver bicarbonate (AgHCO3), gold (III) carbonate Au2 (CO3) 3, gold (I) carbonate (Au2CO3) and mixtures thereof.
[0009]
Method according to claim 4, characterized in that one or more hydrophilic compounds is one or more polyols, such as one or more polyols selected from sugar alcohols and sugars optionally, in which the sugar alcohol is selected from the group consisting of glycol, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, polyglycol and mixtures thereof.
[0010]
Method according to any one of the preceding claims, characterized in that the drying is freeze-drying.
[0011]
Method according to any one of the preceding claims, characterized in that the dry composition additionally comprises one or more bioactive agents capable of stimulating homeostasis, wound healing, bone regeneration, tissue healing and / or tendon healing.
[0012]
12. Method according to claim 11, characterized by the fact that the bioactive agent is thrombin.
[0013]
Method according to any one of the preceding claims, characterized in that the dry composition additionally comprises an extrusion intensifier, such as albumin, preferably human serum albumin.
[0014]
Method according to any one of the preceding claims, characterized in that the paste obtained in step b) is transferred to a suitable container for drying the paste, optionally, in which the container is a medical release device suitable for reconstituting a dry composition and dispense a paste, such as a syringe.
[0015]
15. Method according to any one of the preceding claims, characterized in that the dry composition is in the form of a leaf.
[0016]
16. Method according to any one of the preceding claims, characterized in that it additionally comprises a step of adding i) an acidic compound in the dry form after step c) if the dry composition comprises an alkaline compound, or ii) a compound alkaline in dry form after step c) if the dry composition comprises an acidic compound, thereby obtaining a dry composition comprising an alkaline compound and an acidic compound.
[0017]
17. Method for reconstituting the dry composition obtained by the method as defined in any one of the preceding claims, characterized in that it additionally comprises a step of adding an aqueous medium to the dry composition, wherein the aqueous medium comprises: i) a compound acidic if the dry composition comprises an alkaline compound, ii) an alkaline compound if the dry composition comprises an acidic compound, or iii) neither an acid nor an alkaline compound if the dry composition comprises both an alkaline and an acid compound as the method as defined in the claim 16, wherein the acidic compound and the alkaline compound react to release a gas in the presence of said aqueous medium.
[0018]
18. Method according to claim 17, characterized in that the dry composition reconstitutes to a paste by adding the aqueous medium without mechanical mixing.
[0019]
19. Pasta, characterized by the fact that it can be obtained by the method as defined in any of claims 17 to 18.
[0020]
20. Dry composition, characterized by the fact that it comprises a biocompatible polymer ei) an alkaline compound, and / or ii) an acidic compound, in which the alkaline compound of i) is capable of reacting with an acidic compound in the presence of a medium aqueous to release a gas and / or in which the acidic compound ii) is capable of reacting with an alkaline compound in the presence of an aqueous medium to release a gas, in which the biocompatible polymer is selected from the group consisting of gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, polyglycolic acid and polyacetic acid, in which the alkaline compound is a carbonate salt, in which the acidic compound is selected from the group consisting of acetic acid, citric acid, oxalic acid and acid tartaric, and wherein the dry composition comprises from 0.1% to 10% of the alkaline compound and / or the acidic compound, for example, from 0.5% to 8% of the alkaline compound and / or the acidic compound, such as from 1% to 6% of the alkaline compound and / or the ac compound acidic or from 1% to 5% of the alkaline compound and / or the acidic compound.
[0021]
21. Dry composition, characterized by the fact that it can be obtained by the method as defined in any one of claims 1 to 16.
[0022]
22. Container, characterized by the fact that it comprises: a) a product chamber comprising i) the dry composition as defined in any of claims 20 to 21 or ii) the dry composition obtained by the method as defined in any of claims 1 to 16, and b) a valve.
[0023]
23. Container according to claim 22, characterized in that it is a medical dispensing device, preferably a syringe, such as a single-use plastic syringe.
[0024]
24. Method for reconstituting a dry composition, characterized in that it comprises the steps of: a) providing the container as defined in any of claims 22 to 23, said container being the first container, b) providing a second container comprising a aqueous medium, wherein the aqueous medium comprises i) an acidic compound if the dry composition comprises an alkaline compound, ii) an alkaline compound if the dry composition comprises an acidic compound, or iii) neither an acidic nor an alkaline compound if the composition it comprises both an alkaline and an acidic compound, c) connecting the first container and the second container using suitable connection means, and d) opening the valve.
[0025]
25. Homeostatic kit, characterized in that it comprises: a) a first container comprising the dry composition obtained by the method as defined in any one of claims 1 to 16 or the container as defined in any one of claims 22 to 23, b) a second container comprising an aqueous medium, wherein the aqueous medium comprises i) an acidic compound if the dry composition comprises an alkaline compound, ii) an alkaline compound if the dry composition comprises an acidic compound, or iii) neither an acidic compound nor an alkaline if the dry composition comprises both an alkaline compound and an acidic compound, and c) optionally an outer package.
[0026]
26. Use of a dry composition obtained by the method as defined in any of claims 1 to 16 or the dry composition as defined in any of claims 20 to 21, characterized by the fact that it is for the manufacture of a medicament for promoting hemostasis and / or wound healing in an individual in need of it.

类似技术:

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公开号 | 公开日 | 专利标题

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BR112017007466B1|2021-03-02|method for preparing a dry composition, method for reconstituting the dry composition, paste, dry composition, container, homeostatic kit, and, using a dry composition

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BR112015030612B1|2020-07-21|method for preparing a dry composition

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JP6394916B2|2018-09-26|Dry hemostatic composition

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JP6489485B2|2019-03-27|Dry composition containing an extrusion enhancing factor

同族专利:

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公开号 | 公开日

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US11046818B2|2021-06-29|

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CN106999621A|2017-08-01|

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BR112017007466A2|2018-01-23|

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JP2017531462A|2017-10-26|

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US20200140625A1|2020-05-07|

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RU2017116229A|2018-11-15|

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CA2960309A1|2016-04-21|

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EP3206726B1|2020-05-27|

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WO2016058612A1|2016-04-21|

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JP6726852B2|2020-07-22|

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RU2715235C2|2020-02-26|

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AU2015333206A1|2017-04-20|

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EP3206726A1|2017-08-23|

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RU2017116229A3|2019-04-17|

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CN106999621B|2020-07-03|

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AU2015333206B2|2019-07-11|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2899362A|1959-08-11|Hemostatic sponges and method of |

---

US41913A|1864-03-15|Joseph s |

---

US2465357A|1944-08-14|1949-03-29|Upjohn Co|Therapeutic sponge and method of making|

---

US2465860A|1945-10-13|1949-03-29|Standard Manifold Company Inc|Carbon holder|

---

GB648619A|1947-03-19|1951-01-10|Ferrosan As|Process of producing sponges of gelatine and the like proteins|

---

US2507244A|1947-04-14|1950-05-09|Upjohn Co|Surgical gelatin dusting powder and process for preparing same|

---

CH264752A|1947-06-03|1949-10-31|Hoffmann La Roche|Process for the manufacture of carriers for pharmaceuticals.|

---

GB697603A|1948-10-06|1953-09-23|Sydney Arthur Gladstone|Improvements in or relating to method of and devices for obtaining tissue from a tumour carried by a patient|

---

US3089815A|1951-10-11|1963-05-14|Lieb Hans|Injectable pharmaceutical preparation, and a method of making same|

---

US3224434A|1962-11-06|1965-12-21|Waldemar Medical Res Foundatio|Cell collector|

---

GB1037937A|1963-06-26|1966-08-03|Colgate Palmolive Co|Pressurized dispensing containers|

---

US3405712A|1966-02-07|1968-10-15|Richard L. Pierick|Desiccative syringe|

---

US3869539A|1966-12-01|1975-03-04|Ferrosan As|Preparations containing fat-soluble vitamins in dry, particulate, free-flowing form dispersible in cold water and method of producing such preparations|

---

US3514518A|1967-12-19|1970-05-26|Pierre Charier Vadrot|Process for preparation of gelatinous material from animal collagen|

---

US3470109A|1968-01-31|1969-09-30|Aloe Creme Lab Inc|Method of making reconstitutable aloe gel in crystalline form|

---

US3608593A|1970-02-27|1971-09-28|Lilly Co Eli|Method of filling powders into containers|

---

US3678933A|1970-07-17|1972-07-25|Moore Perk Corp|Surgical sponge or bandage|

---

US3892876A|1971-11-30|1975-07-01|Leiner & Sons Wales Limited P|Process of preparing freeze-dried gelatin|

---

FR2167197B1|1972-01-10|1974-06-21|Pont Brule Sa|IMPROVED COMPOSITIONS CONTAINING GELATIN|

---

US3815580A|1972-08-31|1974-06-11|C Oster|Apparatus for and method of collecting and preserving cytologic samples|

---

US3946732A|1973-08-08|1976-03-30|Ampoules, Inc.|Two-chamber mixing syringe|

---

SE420565B|1974-06-06|1981-10-19|Pharmacia Ab|AID FOR INTRAVASCULAR ADMINISTRATION FOR USE IN CONNECTION WITH INTRAVASCULAR ADMINISTRATION OF A SOLUTION OR SUSPENSION OF A DIAGNOSTIC AGENT|

---

US4002173A|1974-07-23|1977-01-11|International Paper Company|Diester crosslinked polyglucan hydrogels and reticulated sponges thereof|

---

US4107288A|1974-09-18|1978-08-15|Pharmaceutical Society Of Victoria|Injectable compositions, nanoparticles useful therein, and process of manufacturing same|

---

JPS5823410B2|1974-11-12|1983-05-14|Kuraray Co|

---

US4013078A|1974-11-25|1977-03-22|Feild James Rodney|Intervertebral protector means|

---

US4006220A|1975-06-04|1977-02-01|Gottlieb Sheldon K|Compositions and methods useful for repairing depressed cutaneous scars|

---

US4280954A|1975-07-15|1981-07-28|Massachusetts Institute Of Technology|Crosslinked collagen-mucopolysaccharide composite materials|

---

US4160022A|1975-09-15|1979-07-03|Colgate Palmolive Company|Toothpaste|

---

US4098728A|1976-01-02|1978-07-04|Solomon Rosenblatt|Medical surgical sponge and method of making same|

---

US4150744A|1976-02-27|1979-04-24|Smith & Nephew Pharmaceuticals Ltd.|Packaging|

---

US4089957A|1976-06-11|1978-05-16|Ab Kabi|Therapeutic compositions against recurrent thrombosis|

---

JPS5636174B2|1976-08-31|1981-08-22|

---

SE430609B|1976-12-21|1983-11-28|Sca Development Ab|SET TO CELLULOUS DERIVATIVES MAKE ABSORBING MATERIAL|

---

DE2816130A1|1977-06-10|1978-12-21|Ato Chimie|METHOD AND DEVICE FOR MEASURING THE ADHESIVE CAPACITY OF AN ADHESIVE ADHESIVE|

---

US4164559A|1977-09-21|1979-08-14|Cornell Research Foundation, Inc.|Collagen drug delivery device|

---

GB1584080A|1977-12-05|1981-02-04|Ethicon Inc|Absorbable hemostatic composition|

---

US4265233A|1978-04-12|1981-05-05|Unitika Ltd.|Material for wound healing|

---

US4179400A|1978-05-09|1979-12-18|W. R. Grace & Co.|Process for preparing catalytic solutions of sulfonium salts|

---

DE2843963C2|1978-10-09|1988-02-18|Merck Patent Gmbh, 6100 Darmstadt, De|

---

AT359653B|1979-02-15|1980-11-25|Immuno Ag|METHOD FOR PRODUCING A TISSUE ADHESIVE|

---

AT359652B|1979-02-15|1980-11-25|Immuno Ag|METHOD FOR PRODUCING A TISSUE ADHESIVE|

---

US4300494A|1979-09-26|1981-11-17|Shell Oil Company|Thermal insulated intake ports|

---

DE2943520C2|1979-10-27|1982-05-19|Fa. Carl Freudenberg, 6940 Weinheim|Process for the production of collagen sponge for medical or cosmetic purposes|

---

JPS6222589B2|1980-01-18|1987-05-19|Nitta Gelatin Kk|

---

US4292972A|1980-07-09|1981-10-06|E. R. Squibb & Sons, Inc.|Lyophilized hydrocolloio foam|

---

DE3036033A1|1980-09-24|1982-05-06|Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen|POWDERED WOUND TREATMENT AND METHOD FOR THE PRODUCTION THEREOF|

---

DE3105624A1|1981-02-16|1982-09-02|Hormon-Chemie München GmbH, 8000 München|MATERIAL FOR SEALING AND HEALING Wounds|

---

DE3267499D1|1981-03-18|1986-01-02|Fujirebio Kk|Support material for use in serological testing and process for the production thereof|

---

WO1983001244A1|1981-10-06|1983-04-14|Frutin, Bernard, Derek|Pressurized dispensing apparatus|

---

DE3146841A1|1981-11-26|1983-06-01|Beiersdorf Ag, 2000 Hamburg|Wound-treatment compositions|

---

US4424208A|1982-01-11|1984-01-03|Collagen Corporation|Collagen implant material and method for augmenting soft tissue|

---

EP0086627B1|1982-02-12|1985-08-28|Unitika Ltd.|Anti-cancer device|

---

US4482386A|1982-03-26|1984-11-13|Warner-Lambert Company|Method of conditioning a water swellable hydrocolloid|

---

US4543332A|1982-03-29|1985-09-24|Miles Laboratories, Inc.|Method for the preparation of spherical microorganism cell aggregates|

---

JPS6318469B2|1982-08-09|1988-04-19|Koken Kk|

---

EP0106648B1|1982-10-16|1988-05-18|Johnsen & Jorgensen Jaypak Limited|Bag apparatus|

---

US4540410A|1982-11-16|1985-09-10|Serono Pharmaceutical Partners|Lyophilized compositions, preparation and use thereof|

---

JPS59113889A|1982-12-17|1984-06-30|Sumitomo Chem Co Ltd|Preparation of immobilized enzyme or immobilized microbial cell|

---

US4492305A|1983-07-08|1985-01-08|Marion Laboratories, Inc.|Package for collecting cultures|

---

EP0132983B2|1983-07-14|1991-06-12|Hitachi Chemical Co., Ltd.|Production of gelatin spherical gels and their use|

---

JPH0157087B2|1983-11-04|1989-12-04|Takeda Chemical Industries Ltd|

---

JPS60110669A|1983-11-12|1985-06-17|Hayashibara Biochem Lab|Pressure discharging vessel and manufacture thereof|

---

US4515637A|1983-11-16|1985-05-07|Seton Company|Collagen-thrombin compositions|

---

US4522302A|1984-03-05|1985-06-11|Sterling Drug Inc.|Pre-sterilized medical procedure kit packages|

---

AT389815B|1984-03-09|1990-02-12|Immuno Ag|METHOD FOR INACTIVATING VARIABLE FILTERABLE DISEASERS IN BLOOD PRODUCTS|

---

US4600574A|1984-03-21|1986-07-15|Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte|Method of producing a tissue adhesive|

---

US4837285A|1984-03-27|1989-06-06|Medimatrix|Collagen matrix beads for soft tissue repair|

---

ZA851661B|1984-03-29|1986-10-29|Minnesota Mining & Mfg|Sorbent sheet material|

---

JPS60214728A|1984-04-06|1985-10-28|Unitika Ltd|Sustained release material of physiologically active substance|

---

SE456346B|1984-07-23|1988-09-26|Pharmacia Ab|GEL TO PREVENT ADHESION BETWEEN BODY TISSUE AND SET FOR ITS PREPARATION|

---

JPS6144825A|1984-08-09|1986-03-04|Unitika Ltd|Hemostatic agent|

---

GB8422950D0|1984-09-11|1984-10-17|Warne K J|Hydrogel|

---

JPH0430927B2|1984-11-19|1992-05-25|

---

US5178883A|1984-11-29|1993-01-12|Regents Of The University Of Minnesota|Method for promoting hair growth|

---

US5165938A|1984-11-29|1992-11-24|Regents Of The University Of Minnesota|Wound healing agents derived from platelets|

---

US4600533A|1984-12-24|1986-07-15|Collagen Corporation|Collagen membranes for medical use|

---

JPS61209590A|1985-03-13|1986-09-17|Asama Kasei Kk|Novel immobilized cell and method for fermentative production utilizing same|

---

US4997753A|1985-04-04|1991-03-05|Verax Corporation|Weighted collagen microsponge for immobilizing bioactive material|

---

US4863856A|1985-04-04|1989-09-05|Verax Corporation|Weighted collagen microsponge for immobilizing bioactive materials|

---

US4861714A|1985-04-04|1989-08-29|Verax Corporation|Weighted collagen microsponge for immobilizing bioactive material|

---

AT382783B|1985-06-20|1987-04-10|Immuno Ag|DEVICE FOR APPLICATING A TISSUE ADHESIVE|

---

US5112750A|1985-06-25|1992-05-12|Asama Chemical Co., Ltd.|Immobilized cells and culture method utilizing the same|

---

US4851521A|1985-07-08|1989-07-25|Fidia, S.P.A.|Esters of hyaluronic acid|

---

US5007916A|1985-08-22|1991-04-16|Johnson & Johnson Medical, Inc.|Method and material for prevention of surgical adhesions|

---

JPS6270318A|1985-09-25|1987-03-31|Nippon Kayaku Co Ltd|Hemostatic and wound-protecting agent|

---

US4696812A|1985-10-28|1987-09-29|Warner-Lambert Company|Thrombin preparations|

---

US5180583A|1985-11-26|1993-01-19|Hedner Ulla K E|Method for the treatment of bleeding disorders|

---

US20020192271A1|1985-11-26|2002-12-19|Hedner Ulla Karin Elisabeth|Method for causing local hemostasis and hemostatic composition for local hemostasis|

---

IE59361B1|1986-01-24|1994-02-09|Akzo Nv|Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension|

---

JPS62221357A|1986-03-20|1987-09-29|Jekusu Kk|Coating agent to surface of living body|

---

IL78826A|1986-05-19|1991-05-12|Yissum Res Dev Co|Precursor composition for the preparation of a biodegradable implant for the sustained release of an active material and such implants prepared therefrom|

---

US5300494A|1986-06-06|1994-04-05|Union Carbide Chemicals & Plastics Technology Corporation|Delivery systems for quaternary and related compounds|

---

US4946870A|1986-06-06|1990-08-07|Union Carbide Chemicals And Plastics Company Inc.|Delivery systems for pharmaceutical or therapeutic actives|

---

US4832686A|1986-06-24|1989-05-23|Anderson Mark E|Method for administering interleukin-2|

---

US4803075A|1986-06-25|1989-02-07|Collagen Corporation|Injectable implant composition having improved intrudability|

---

US4702737A|1986-07-14|1987-10-27|Pizzino Joanne L|Dual dose syringe|

---

US4743229A|1986-09-29|1988-05-10|Collagen Corporation|Collagen/mineral mixing device and method|

---

US4965203A|1987-01-28|1990-10-23|Warner-Lambert Company|Purified thrombin preparations|

---

CA1305069C|1987-03-11|1992-07-14|John Cornell|Wound dressings in sheet or gelled paste form|

---

US4885161A|1987-03-11|1989-12-05|Medi-Tech International Corporation|Wound dressings in gelled paste form|

---

US5350573A|1988-05-31|1994-09-27|University Of Florida Research Foundation, Inc.|Method and composition for preventing surgical adhesions|

---

US5080893A|1988-05-31|1992-01-14|University Of Florida|Method for preventing surgical adhesions using a dilute solution of polymer|

---

US5140016A|1988-05-31|1992-08-18|University Of Florida|Method and composition for preventing surgical adhesions using a dilute solution of polymer|

---

US5690954A|1987-05-22|1997-11-25|Danbiosyst Uk Limited|Enhanced uptake drug delivery system having microspheres containing an active drug and a bioavailability improving material|

---

US4887743A|1987-06-10|1989-12-19|Blake William S|Aerosol valve|

---

US5447966A|1988-07-19|1995-09-05|United States Surgical Corporation|Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin|

---

US4752466A|1987-08-31|1988-06-21|Johnson & Johnson Products, Inc.|Thrombin aerosol|

---

DK158336C|1987-09-22|1990-10-01|Coloplast As|CONNECTOR MATERIALS FOR THE TREATMENT OF WOUNDS AND TEMPLES FOR USE IN MANUFACTURING THEREOF|

---

JPH0236261B2|1987-09-28|1990-08-16|Terumo Corp|

---

JPH01130519A|1987-11-16|1989-05-23|Mitsubishi Electric Corp|Mocvd crystal growing apparatus|

---

AT111360T|1988-05-02|1994-09-15|Project Hear|SURGICAL ADHESIVE MATERIAL.|

---

IT1219587B|1988-05-13|1990-05-18|Fidia Farmaceutici|SELF-CROSS-LINKED CARBOXYLY POLYSACCHARIDES|

---

US4936835A|1988-05-26|1990-06-26|Haaga John R|Medical needle with bioabsorbable tip|

---

US5024841A|1988-06-30|1991-06-18|Collagen Corporation|Collagen wound healing matrices and process for their production|

---

BG51589A1|1988-08-26|1993-07-15|Bg Min Na Narodnata Otbrana|Method for the production of haemostatic layer material|

---

US4925677A|1988-08-31|1990-05-15|Theratech, Inc.|Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents|

---

US5041292A|1988-08-31|1991-08-20|Theratech, Inc.|Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents|

---

EP0365705A1|1988-10-26|1990-05-02|Zentralna Problemna Laboratoria Po Kryobiologia I Lyophilisazia|Biopreparation for the treatment of wounds|

---

US5135751A|1988-11-16|1992-08-04|Mediventures Incorporated|Composition for reducing postsurgical adhesions|

---

US5126141A|1988-11-16|1992-06-30|Mediventures Incorporated|Composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides|

---

US5162430A|1988-11-21|1992-11-10|Collagen Corporation|Collagen-polymer conjugates|

---

US5614587A|1988-11-21|1997-03-25|Collagen Corporation|Collagen-based bioadhesive compositions|

---

US5510418A|1988-11-21|1996-04-23|Collagen Corporation|Glycosaminoglycan-synthetic polymer conjugates|

---

US4891359A|1988-12-08|1990-01-02|Johnson & Johnson Patient Care, Inc.|Hemostatic collagen paste composition|

---

US4948575A|1989-01-24|1990-08-14|Minnesota Mining And Manufacturing Company|Alginate hydrogel foam wound dressing|

---

DE3903672C1|1989-02-08|1990-02-01|Lohmann Gmbh & Co Kg|

---

US5062834A|1989-02-24|1991-11-05|Product Development Ltd|Device for dispensing a liquid particularly useful for delivering medicaments at a predetermined rate|

---

DK223389D0|1989-05-05|1989-05-05|Ferrosan As|SAUCE FUNGI|

---

US5356883A|1989-08-01|1994-10-18|Research Foundation Of State University Of N.Y.|Water-insoluble derivatives of hyaluronic acid and their methods of preparation and use|

---

WO1991001711A1|1989-08-10|1991-02-21|W.L. Gore & Associates, Inc.|A medical dispensing system for tissue adhesive components|

---

US5196185A|1989-09-11|1993-03-23|Micro-Collagen Pharmaceutics, Ltd.|Collagen-based wound dressing and method for applying same|

---

FR2652573B1|1989-10-03|1991-12-13|Atochem|PROCESS FOR THE MANUFACTURE OF 1,1,1-CHLORODIFLUOROETHANE.|

---

US4920158A|1989-10-11|1990-04-24|Medipro Sciences Limited|Hydrogel-forming wound dressing or skin coating material|

---

US5061274A|1989-12-04|1991-10-29|Kensey Nash Corporation|Plug device for sealing openings and method of use|

---

US5350581A|1989-12-14|1994-09-27|Pharmetrix Corporation|Method for manufacturing transdermal devices|

---

US5281528A|1989-12-18|1994-01-25|Warner-Lambert Company|Process for purified thromboplastin for ultra-pure thrombin preparation|

---

US5219328A|1990-01-03|1993-06-15|Cryolife, Inc.|Fibrin sealant delivery method|

---

US5134229A|1990-01-12|1992-07-28|Johnson & Johnson Medical, Inc.|Process for preparing a neutralized oxidized cellulose product and its method of use|

---

US4982769A|1990-02-21|1991-01-08|Survival Technology, Inc.|Package|

---

JPH0813750B2|1990-03-01|1996-02-14|持田製薬株式会社|Oral thrombin formulation|

---

US5306501A|1990-05-01|1994-04-26|Mediventures, Inc.|Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers|

---

US5595735A|1990-05-23|1997-01-21|Johnson & Johnson Medical, Inc.|Hemostatic thrombin paste composition|

---

US5017229A|1990-06-25|1991-05-21|Genzyme Corporation|Water insoluble derivatives of hyaluronic acid|

---

US5634943A|1990-07-12|1997-06-03|University Of Miami|Injectable polyethylene oxide gel implant and method for production|

---

US5209776A|1990-07-27|1993-05-11|The Trustees Of Columbia University In The City Of New York|Tissue bonding and sealing composition and method of using the same|

---

US5292362A|1990-07-27|1994-03-08|The Trustees Of Columbia University In The City Of New York|Tissue bonding and sealing composition and method of using the same|

---

US5108421A|1990-10-01|1992-04-28|Quinton Instrument Company|Insertion assembly and method of inserting a vessel plug into the body of a patient|

---

US5192300A|1990-10-01|1993-03-09|Quinton Instrument Company|Insertion assembly and method of inserting a vessel plug into the body of a patient|

---

DE59005286D1|1990-10-04|1994-05-11|Kallies Import Export Vertrieb|Stabilized thrombin, its preparation and its use as a thrombin time reagent.|

---

US5468505A|1992-02-28|1995-11-21|Board Of Regents, The University Of Texas System|Local delivery of fibrinolysis enhancing agents|

---

NO302481B1|1990-10-16|1998-03-09|Takeda Chemical Industries Ltd|Polymer for an extended release preparation, as well as an extended release preparation|

---

US5129882A|1990-12-27|1992-07-14|Novoste Corporation|Wound clotting device and method of using same|

---

US6391343B1|1991-01-15|2002-05-21|Hemosphere, Inc.|Fibrinogen-coated particles for therapeutic use|

---

US5669934A|1991-02-13|1997-09-23|Fusion Medical Technologies, Inc.|Methods for joining tissue by applying radiofrequency energy to performed collagen films and sheets|

---

US5749895A|1991-02-13|1998-05-12|Fusion Medical Technologies, Inc.|Method for bonding or fusion of biological tissue and material|

---

US5690675A|1991-02-13|1997-11-25|Fusion Medical Technologies, Inc.|Methods for sealing of staples and other fasteners in tissue|

---

WO1992014513A1|1991-02-13|1992-09-03|Interface Biomedical Laboratories Corp.|Filler material for use in tissue welding|

---

US5931165A|1994-09-06|1999-08-03|Fusion Medical Technologies, Inc.|Films having improved characteristics and methods for their preparation and use|

---

DE69116144T2|1991-02-14|1996-05-09|Baxter Int|BONDING SUBSTRATE-SPECIFIC AFFINITY SUBSTANCES TO LIPOSOMES|

---

US5605938A|1991-05-31|1997-02-25|Gliatech, Inc.|Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate|

---

DE4119140C2|1991-06-11|1994-05-11|Merz & Co Gmbh & Co|Porous spongeoid moldings soluble in body fluids and secretions, their preparation and use|

---

CA2089487A1|1991-06-14|1992-12-15|Suk-Zu Song|Collagen film drug delivery for proteins|

---

NL9101051A|1991-06-18|1993-01-18|Ashridge Ag|CLOSING DEVICE FOR A VESSEL OR THE LIKE.|

---

FR2679772B1|1991-08-02|1995-05-19|Peters Sa|EMBOLS IN NON-RESORBABLE PARTICLES COATED WITH HEMOSTATIC MATERIAL.|

---

IT1251151B|1991-08-05|1995-05-04|Fidia Spa|SPONGY MATERIAL ESSENTIALLY CONSTITUTED BY HYALURONIC ACID, OR ITS DERIVATIVES|

---

JPH07500035A|1991-10-09|1995-01-05|

---

US6620436B1|1991-10-09|2003-09-16|Lectec Corporation|Mixing and dispensing package for a wound dressing|

---

HUT67693A|1991-10-11|1995-04-28|Novo Nordisk As|Hemostatic composition for arresting local bleedings|

---

AT398079B|1991-11-04|1994-09-26|Immuno Ag|PREPARATION WITH THROMBINE ACTIVITY AND METHOD FOR THEIR PRODUCTION|

---

ES2087565T3|1991-12-05|1996-07-16|Alfatec Pharma Gmbh|PHARMACEUTICALLY APPLICABLE NANOSOL AND PROCEDURE FOR ITS PREPARATION.|

---

US5204382A|1992-02-28|1993-04-20|Collagen Corporation|Injectable ceramic compositions and methods for their preparation and use|

---

AT193037T|1992-02-28|2000-06-15|Collagen Corp|HIGHLY CONCENTRATED, HOMOGENIZED COLLAGEN COMPOSITIONS|

---

AT208217T|1992-02-28|2001-11-15|Cohesion Tech Inc|INJECTABLE, CERAMIC COMPOUNDS AND METHOD FOR THE PRODUCTION AND USE THEREOF|

---

US5384333A|1992-03-17|1995-01-24|University Of Miami|Biodegradable injectable drug delivery polymer|

---

GB9206509D0|1992-03-25|1992-05-06|Jevco Ltd|Heteromorphic sponges containing active agents|

---

GB2266239B|1992-03-25|1996-03-06|Jevco Ltd|Wound healing compositions containing chondroitin sulphate oligosaccharides|

---

WO1993021844A1|1992-04-23|1993-11-11|Scimed Life Systems, Inc.|Apparatus and method for sealing vascular punctures|

---

IL105529D0|1992-05-01|1993-08-18|Amgen Inc|Collagen-containing sponges as drug delivery for proteins|

---

JPH05308969A|1992-05-13|1993-11-22|Japan Vilene Co Ltd|Enzyme holder and its production|

---

AU4406793A|1992-06-04|1993-12-30|Clover Consolidated, Limited|Water-soluble polymeric carriers for drug delivery|

---

US5547376A|1992-06-18|1996-08-20|Harrel; Stephen K.|Methods and apparatus for containing and recovering abrasive powders from an abrasive polisher|

---

US5385606A|1992-07-06|1995-01-31|Kowanko; Nicholas|Adhesive composition and method|

---

US5413571A|1992-07-16|1995-05-09|Sherwood Medical Company|Device for sealing hemostatic incisions|

---

US5443481A|1992-07-27|1995-08-22|Lee; Benjamin I.|Methods and device for percutaneous sealing of arterial puncture sites|

---

US5428022A|1992-07-29|1995-06-27|Collagen Corporation|Composition of low type III content human placental collagen|

---

US5514379A|1992-08-07|1996-05-07|The General Hospital Corporation|Hydrogel compositions and methods of use|

---

DE4227681C2|1992-08-21|1995-05-18|Becker & Co Naturinwerk|Wound covering material based on collagen fibers and process for its production|

---

AU4926193A|1992-09-21|1994-04-12|Vitaphore Corporation|Embolization plugs for blood vessels|

---

RO113214B1|1992-10-19|1998-05-29|Dura Pharma Inc|Dry powder inhalator|

---

EP0668747B1|1992-11-12|2001-10-10|ALLEYNE, Neville|Cardiac protection device|

---

US5334216A|1992-12-10|1994-08-02|Howmedica Inc.|Hemostatic plug|

---

US5667839A|1993-01-28|1997-09-16|Collagen Corporation|Human recombinant collagen in the milk of transgenic animals|

---

IT1263144B|1993-02-04|1996-08-01|Lanfranco Callegaro|PHARMACEUTICAL COMPOSITIONS INCLUDING SPONGY MATERIAL CONSTITUTED FROM FOREIGN DERIVATIVES OF HYALURONIC ACID IN ASSOCIATION WITH OTHER PHARMACOLOGICALLY ACTIVE SUBSTANCES|

---

JPH08131B2|1993-03-05|1996-01-10|新田ゼラチン株式会社|Hemostasis pad|

---

WO1994022468A1|1993-04-02|1994-10-13|Anticancer, Inc.|Method for delivering beneficial compositions to hair follicles|

---

WO1994023788A1|1993-04-20|1994-10-27|Medchem Products, Inc.|Apparatus and method for applying a particulate hemostatic agent to living tissue|

---

US5723308A|1993-05-14|1998-03-03|Minnesota Mining And Manufacturing Company|Culture medium for rapid count of coliform bacteria|

---

US5951583A|1993-05-25|1999-09-14|Vascular Solutions, Inc.|Thrombin and collagen procoagulant and process for making the same|

---

EP0702959B1|1993-05-31|2001-08-08|Kaken Pharmaceutical Co., Ltd.|Cross-linked gelatin gel preparation containing basic fibroblast growth factor|

---

US5387208A|1993-07-26|1995-02-07|The Procter & Gamble Co.|Absorbent core having improved dry/wet integrity|

---

US5798091A|1993-07-30|1998-08-25|Alliance Pharmaceutical Corp.|Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement|

---

US6861046B1|1993-08-18|2005-03-01|Dow Corning France|Device for dispensing a therapeutic or cosmetic substance onto the skin and a method of skin treatment|

---

US5394886A|1993-09-20|1995-03-07|Nabai; Hossein|Skin biopsy plug and method|

---

JPH0790241A|1993-09-22|1995-04-04|Menicon Co Ltd|Temporary adhesive for eye lens material|

---

ES2227542T3|1993-11-03|2005-04-01|Clarion Pharmaceuticals, Inc.|HEMOSTATIC PATCH.|

---

DE69430054T2|1993-12-30|2002-10-24|Nitta Gelatin Kk|METHOD FOR EMBEDDING ANIMAL CULTURE CELLS|

---

FR2715309B1|1994-01-24|1996-08-02|Imedex|Adhesive composition, for surgical use, based on collagen modified by oxidative cutting and not crosslinked.|

---

US5441491A|1994-02-04|1995-08-15|Verschoor; Jacob|Method and composition for treating biopsy wounds|

---

DE4407875C2|1994-03-04|1996-04-04|Ankerpharm Gmbh Ankerwerk Rudo|Medical sponge made from bioabsorbable materials, process and device for its production|

---

AU695266B2|1994-03-18|1998-08-13|Baxter International Inc.|Topical fibrinogen complex|

---

ITPD940054A1|1994-03-23|1995-09-23|Fidia Advanced Biopolymers Srl|SULPHATED POLYSACCHARIDES|

---

US5674275A|1994-04-06|1997-10-07|Graphic Controls Corporation|Polyacrylate and polymethacrylate ester based hydrogel adhesives|

---

US5531759A|1994-04-29|1996-07-02|Kensey Nash Corporation|System for closing a percutaneous puncture formed by a trocar to prevent tissue at the puncture from herniating|

---

CA2146090C|1994-05-10|1998-11-24|Mark E. Mitchell|Apparatus and method of mixing materials in a sterile environment|

---

EP0712635B1|1994-05-13|2003-05-02|Kuraray Co., Ltd.|Medical polymer gel|

---

JP3107726B2|1994-05-13|2000-11-13|株式会社クラレ|Water-swellable polymer gel|

---

AT168554T|1994-05-23|1998-08-15|Liposome Co Inc|DEVICE FOR PRODUCING A FORMULATION|

---

US5462860A|1994-06-06|1995-10-31|Minnesota Mining And Manufacturing Company|Conditioned culture medium for rapid growth and detection of microbes|

---

GB9415739D0|1994-07-30|1994-09-21|Scimat Ltd|Gel wound dressing|

---

US5599735A|1994-08-01|1997-02-04|Texas Instruments Incorporated|Method for doped shallow junction formation using direct gas-phase doping|

---

US5516532A|1994-08-05|1996-05-14|Children's Medical Center Corporation|Injectable non-immunogenic cartilage and bone preparation|

---

US5588745A|1994-09-02|1996-12-31|Howmedica|Methods and apparatus for mixing bone cement components using an evacuated mixing chamber|

---

JP2858087B2|1994-09-19|1999-02-17|グンゼ株式会社|Tissue culture substrate and tissue culture method|

---

AU1287895A|1994-10-03|1996-04-26|Otogen Corporation|Differentially biodegradable biomedical implants|

---

FR2726571B1|1994-11-03|1997-08-08|Izoret Georges|BIOLOGICAL GLUE, PREPARATION METHOD AND APPLICATION DEVICE FOR BIOLOGICAL GLUE, AND HARDENERS FOR BIOLOGICAL GLUE|

---

US5660854A|1994-11-28|1997-08-26|Haynes; Duncan H|Drug releasing surgical implant or dressing material|

---

US5804203A|1994-12-21|1998-09-08|Cosmederm Technologies|Topical product formulations containing strontium for reducing skin irritation|

---

EP0917444A1|1996-07-12|1999-05-26|Baxter Travenol Laboratories, Inc.|A fibrin delivery device and method for forming fibrin on a surface|

---

EP0804257B1|1995-01-16|2003-07-09|Baxter International Inc.|Self-supporting sheet-like material of cross-linked fibrin for preventing post operative adhesions|

---

US5698213A|1995-03-06|1997-12-16|Ethicon, Inc.|Hydrogels of absorbable polyoxaesters|

---

US5580923A|1995-03-14|1996-12-03|Collagen Corporation|Anti-adhesion films and compositions for medical use|

---

US5876372A|1995-03-22|1999-03-02|Abbott Laboratories|Syringe system accomodating seperate prefilled barrels for two constituents|

---

DE19513666C1|1995-04-11|1996-11-28|Behringwerke Ag|Device for bringing together a first liquid and a second solid or liquid component by means of negative pressure under sterile conditions|

---

JP3799626B2|1995-04-25|2006-07-19|有限会社ナイセム|Cardiovascular repair material and method for producing the same|

---

US5677284A|1995-06-06|1997-10-14|Regen Biologics, Inc.|Charged collagen particle-based delivery matrix|

---

WO1996040033A1|1995-06-07|1996-12-19|Clarion Pharmaceuticals Inc.|Non-biological patch for hemostasis|

---

US6129761A|1995-06-07|2000-10-10|Reprogenesis, Inc.|Injectable hydrogel compositions|

---

DE19521324C1|1995-06-12|1996-10-31|Immuno Ag|Tissue adhesive and use thereof as a hemostatic|

---

BG99900A|1995-09-04|1997-03-31|Bildireva|Absorbent sponge of haemostatic application and method for its preparation|

---

US6458889B1|1995-12-18|2002-10-01|Cohesion Technologies, Inc.|Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|

---

WO1997013461A1|1995-10-11|1997-04-17|Fusion Medical Technologies, Inc.|Device and method for sealing tissue|

---

AU7671196A|1995-11-07|1997-05-29|Fusion Medical Technologies, Inc.|Methods and articles for fusing matrix layers containing non-collagenous proteins to tissue|

---

WO1997017024A1|1995-11-07|1997-05-15|Fusion Medical Technologies, Inc.|Methods and articles for fusing matrix layers containing non-biologic polymers to tissue|

---

EP0865255A1|1995-11-07|1998-09-23|Fusion Medical Technologies, Inc.|Methods and articles for fusing polysaccharide-containing matrix layers to tissue|

---

US6464111B2|1995-11-13|2002-10-15|L'oreal|Dispenser containing a product and dispensing method|

---

EP0876165B1|1995-12-18|2006-06-21|Angiotech BioMaterials Corp.|Crosslinked polymer compositions and methods for their use|

---

US5752974A|1995-12-18|1998-05-19|Collagen Corporation|Injectable or implantable biomaterials for filling or blocking lumens and voids of the body|

---

US5748318A|1996-01-23|1998-05-05|Brown University Research Foundation|Optical stress generator and detector|

---

EP0885020A1|1996-02-20|1998-12-23|Cohesion Corporation|Tissue sealant compositions and methods of use thereof|

---

US5782917A|1996-02-26|1998-07-21|Sunmed, Inc.|Intramedullary bone plug|

---

DK0796623T3|1996-03-20|2005-08-01|Baxter Ag|Pharmaceutical composition for the treatment of blood clotting disorders|

---

CA2251475C|1996-04-04|2006-09-05|Immuno Aktiengesellschaft|Hemostatic sponge based on collagen|

---

US5948427A|1996-04-25|1999-09-07|Point Medical Corporation|Microparticulate surgical adhesive|

---

AU725654B2|1996-05-03|2000-10-19|Innogenetics N.V.|New medicaments containing gelatin cross-linked with oxidized polysaccharides|

---

WO1997044015A1|1996-05-17|1997-11-27|Andaris Limited|Microparticles and their use in wound therapy|

---

FR2749759B1|1996-06-17|1999-11-26|Adir|USE OF STRONTIUM SALTS FOR THE PRODUCTION OF PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ARTHROSIS|

---

US5791352A|1996-06-19|1998-08-11|Fusion Medical Technologies, Inc.|Methods and compositions for inhibiting tissue adhesion|

---

US5902832A|1996-08-20|1999-05-11|Menlo Care, Inc.|Method of synthesizing swollen hydrogel for sphincter augmentation|

---

US7871637B2|1996-08-27|2011-01-18|Baxter International Inc.|Dry hemostatic compositions and methods for their preparation|

---

US8603511B2|1996-08-27|2013-12-10|Baxter International, Inc.|Fragmented polymeric compositions and methods for their use|

---

US8303981B2|1996-08-27|2012-11-06|Baxter International Inc.|Fragmented polymeric compositions and methods for their use|

---

US6066325A|1996-08-27|2000-05-23|Fusion Medical Technologies, Inc.|Fragmented polymeric compositions and methods for their use|

---

US6063061A|1996-08-27|2000-05-16|Fusion Medical Technologies, Inc.|Fragmented polymeric compositions and methods for their use|

---

US7320962B2|1996-08-27|2008-01-22|Baxter International Inc.|Hemoactive compositions and methods for their manufacture and use|

---

CA2211629A1|1996-09-17|1998-03-17|Bernard Sams|Vial connector assembly for a medicament container|

---

WO1998012274A1|1996-09-23|1998-03-26|Chandrashekar Pathak|Methods and devices for preparing protein concentrates|

---

US5795330A|1996-10-10|1998-08-18|Etex Corporation|Mixing device|

---

US7341598B2|1999-01-13|2008-03-11|Boston Scientific Scimed, Inc.|Stent with protruding branch portion for bifurcated vessels|

---

US5863496A|1996-11-25|1999-01-26|Prepared Media Laboratory, Inc.|Sterile packaging|

---

WO1998031403A1|1997-01-16|1998-07-23|Cohesion Corporation|Lyophilized collagen-based biomaterials, process of preparation and uses thereof|

---

US5782860A|1997-02-11|1998-07-21|Biointerventional Corporation|Closure device for percutaneous occlusion of puncture sites and tracts in the human body and method|

---

US6045570A|1997-02-11|2000-04-04|Biointerventional Corporation|Biological sealant mixture and system for use in percutaneous occlusion of puncture sites and tracts in the human body and method|

---

US5905029A|1997-02-19|1999-05-18|Fritz Berthold|Method for rapid hygiene testing|

---

ES2251073T3|1997-02-20|2006-04-16|Cook Incorporated|IMPLANTABLE MEDICAL DEVICE WITH A COVER.|

---

FR2759980A1|1997-02-25|1998-08-28|Bras Michel|Container for mixable food ingredients|

---

US5965377A|1997-03-24|1999-10-12|Baystate Medical Center|Method for determining the presence of mutated BRCA protein|

---

US5939259A|1997-04-09|1999-08-17|Schleicher & Schuell, Inc.|Methods and devices for collecting and storing clinical samples for genetic analysis|

---

US6117444A|1997-04-10|2000-09-12|Brigham & Women's Hospital|Polyethylene glycol/microfibrillar collagen composite serves as a resorbable hemostatic agent|

---

ES2293719T3|1998-03-06|2008-03-16|Baxter International Inc.|MIXING HEAD WITH TURBULENCE FOR A SURGICAL ADHESIVE APPLICATOR AND CORRESPONDING SPRAY HEAD.|

---

US6716435B1|1997-04-18|2004-04-06|Ganeden Biotech, Inc.|Absorbent product containing absorbent structure and Bacillus coagulans|

---

EP1173233A1|1999-04-14|2002-01-23|Ganeden Biotech, Inc.|Methods for inhibiting microbial infections associated with sanitary products|

---

US20020039594A1|1997-05-13|2002-04-04|Evan C. Unger|Solid porous matrices and methods of making and using the same|

---

JP3602145B2|1997-06-03|2004-12-15|イノジェネティックス・ナムローゼ・フェンノートシャップ|New pharmaceuticals based on polymers composed of methacrylamide-modified gelatin|

---

US5908054A|1997-06-16|1999-06-01|Fusion Medical Technologies, Inc.|Fluid dispersion and delivery assembly and method|

---

US5957166A|1997-06-16|1999-09-28|Fusion Medical Technologies, Inc.|Method and apparatus for dispersing fluid into a material|

---

WO1998057678A2|1997-06-18|1998-12-23|Cohesion Technologies, Inc.|Compositions containing thrombin and microfibrillar collagen|

---

IT1294797B1|1997-07-28|1999-04-15|Fidia Advanced Biopolymers Srl|USE OF HYALURONIC ACID DERIVATIVES IN THE PREPARATION OF BIOMATERIALS WITH PHYSICAL AND BUFFERING HEMOSTATIC ACTIVITIES|

---

US6042262A|1997-07-29|2000-03-28|Stryker Technologies Corportion|Apparatus for storing, mixing, and dispensing two-component bone cement|

---

ZA987019B|1997-08-06|1999-06-04|Focal Inc|Hemostatic tissue sealants|

---

US6171276B1|1997-08-06|2001-01-09|Pharmacia & Upjohn Ab|Automated delivery device and method for its operation|

---

KR100374666B1|1997-08-22|2003-03-04|덴끼 가가꾸 고교 가부시키가이샤|Hyaluronic acid gel, process for producing the same and medical material containing the same|

---

WO1999012032A1|1997-09-04|1999-03-11|Pharmacia & Upjohn Company|A method for the evaluation of antiviral drugs|

---

DE69831964T2|1997-09-16|2006-07-27|Integra Lifesciences Corp.|COMPOSITION FOR PROMOTING THE GROWTH OF DURAL OR MENINGEAL TISSUE CONTAINING COLLAGEN|

---

US5997895A|1997-09-16|1999-12-07|Integra Lifesciences Corporation|Dural/meningeal repair product using collagen matrix|

---

US6168788B1|1997-09-26|2001-01-02|Leon Wortham|Fibrin glue without fibrinogen and biosealant compositions and methods|

---

GB2329840C|1997-10-03|2007-10-05|Johnson & Johnson Medical|Biopolymer sponge tubes|

---

US6303323B1|1997-10-21|2001-10-16|Cancer Research Campaign Technology Limited|Detection of dysplastic or neoplastic cells using anti-MCM5 antibodies|

---

JPH11155951A|1997-12-01|1999-06-15|Kaken Pharmaceut Co Ltd|Decompression syringe and manufacture thereof|

---

GB9727102D0|1997-12-22|1998-02-25|Andaris Ltd|Microparticles and their therapeutic use|

---

JP3483753B2|1997-12-29|2004-01-06|タキロン株式会社|Biodegradable absorbent plastic adhesive|

---

US6099952A|1998-02-18|2000-08-08|Xomed Surgical Products, Inc.|Medical sponge having mucopolysaccharide coating|

---

AUPP223498A0|1998-03-06|1998-04-02|Southcorp Australia Pty Ltd|A container|

---

AU2900599A|1998-03-10|1999-09-27|Baxter International Inc.|Thrombin preparation and products and fibrin sealant methods employing same|

---

US6179872B1|1998-03-17|2001-01-30|Tissue Engineering|Biopolymer matt for use in tissue repair and reconstruction|

---

US6092543A|1998-03-18|2000-07-25|Roh; Warren E.|Protective cover for a baby carrier which provides sun, insect, and impact protection|

---

US20020025921A1|1999-07-26|2002-02-28|Petito George D.|Composition and method for growing, protecting, and healing tissues and cells|

---

EP1067910B1|1998-04-03|2004-05-26|Egalet A/S|Controlled release composition|

---

US20020061842A1|1998-04-10|2002-05-23|Octapharma Ag|Method for sterilizing a native collagen in liquid medium, sterile native collagen obtained, compositions containing it and uses|

---

US6200328B1|1998-05-01|2001-03-13|Sub Q, Incorporated|Device and method for facilitating hemostasis of a biopsy tract|

---

US6056970A|1998-05-07|2000-05-02|Genzyme Corporation|Compositions comprising hemostatic compounds and bioabsorbable polymers|

---

ITPD980169A1|1998-07-06|2000-01-06|Fidia Advanced Biopolymers Srl|AMIDES OF HYALURONIC ACID AND ITS DERIVATIVES AND PROCESS FOR THEIR PREPARATION.|

---

AU5247799A|1998-08-04|2000-02-28|Fusion Medical Technologies, Inc.|Percutaneous tissue track closure assembly and method|

---

US6613070B2|1998-08-04|2003-09-02|Baxter International Inc.|System and method for sealing vascular penetrations with hemostatic gels|

---

US6334865B1|1998-08-04|2002-01-01|Fusion Medical Technologies, Inc.|Percutaneous tissue track closure assembly and method|

---

US6274090B1|1998-08-05|2001-08-14|Thermogenesis Corp.|Apparatus and method of preparation of stable, long term thrombin from plasma and thrombin formed thereby|

---

US20020015724A1|1998-08-10|2002-02-07|Chunlin Yang|Collagen type i and type iii hemostatic compositions for use as a vascular sealant and wound dressing|

---

WO2000009018A1|1998-08-10|2000-02-24|Fibrogen, Inc.|Collagen type i and type iii hemostatic compositions for use as a vascular sealant and wound dressing|

---

AT444084T|1998-11-12|2009-10-15|Internat Mfg Group Inc|HEMOSTATIC NETWORKED DEXTRANPERLEN USEFUL FOR FAST BLOODING AND HEMOSTASIS|

---

US20020019062A1|1999-06-18|2002-02-14|Peter Lea|Assay devices|

---

US6110484A|1998-11-24|2000-08-29|Cohesion Technologies, Inc.|Collagen-polymer matrices with differential biodegradability|

---

US6454787B1|1998-12-11|2002-09-24|C. R. Bard, Inc.|Collagen hemostatic foam|

---

US6361551B1|1998-12-11|2002-03-26|C. R. Bard, Inc.|Collagen hemostatic fibers|

---

US6328229B1|1998-12-18|2001-12-11|Cohesion Technologies, Inc.|Low volume mixing spray head for mixing and dispensing of two reactive fluid components|

---

US6283933B1|1998-12-23|2001-09-04|Closure Medical Corporation|Applicator for dispensable liquids|

---

ES2183606T5|1998-12-23|2008-05-16|Csl Behring Gmbh|GRANULATE FIBRINE ADHESIVE AND PROCEDURE FOR PREPARATION.|

---

US6977231B1|1999-01-21|2005-12-20|Nipro Corporation|Suturable adhesion-preventing membrane|

---

US6862470B2|1999-02-02|2005-03-01|Senorx, Inc.|Cavity-filling biopsy site markers|

---

NZ513517A|1999-02-19|2003-08-29|Denki Kagaku Kogyo Kk|Hyaluronic acid gel composition containing a polymer for use as a wound dressing|

---

US6312725B1|1999-04-16|2001-11-06|Cohesion Technologies, Inc.|Rapid gelling biocompatible polymer composition|

---

EP1053758A1|1999-05-19|2000-11-22|Resorba Chirurgisches Nahtmaterial Franz Hiltner GmbH & Co.|Bioabsorbable implant|

---

US6544541B1|1999-06-02|2003-04-08|Cardiovascular Solutions, Inc.|Devices and compounds for treating arterial restenosis|

---

US6472162B1|1999-06-04|2002-10-29|Thermogenesis Corp.|Method for preparing thrombin for use in a biological glue|

---

US6706690B2|1999-06-10|2004-03-16|Baxter Healthcare Corporation|Hemoactive compositions and methods for their manufacture and use|

---

AT434010T|1999-08-27|2009-07-15|Angiodevice Internat Gmbh|INTERPENDENT POLYMER NETWORKS FOR USE AS HIGH-STRENGTH MEDICAL SEALING COMPOUNDS|

---

US6312474B1|1999-09-15|2001-11-06|Bio-Vascular, Inc.|Resorbable implant materials|

---

US6221109B1|1999-09-15|2001-04-24|Ed. Geistlich Söhne AG fur Chemische Industrie|Method of protecting spinal area|

---

JP2003512097A|1999-10-15|2003-04-02|ジェネティックス・インスチチュート・リミテッド・ライアビリティ・カンパニー|Formulations for the delivery of bone morphogenetic proteins|

---

JP2001199903A|1999-11-09|2001-07-24|Eizo Mori|Nucleic acid-containing complex|

---

AU2351601A|1999-12-28|2001-07-09|Asger Lau Dalmose|Dual chamber syringe with a dual function piston|

---

WO2001054735A2|2000-01-28|2001-08-02|Orthogene, Inc.|Gel-infused sponges for tissue repair and augmentation|

---

US20030095993A1|2000-01-28|2003-05-22|Hanne Bentz|Gel-infused sponges for tissue repair and augmentation|

---

IT1317832B1|2000-02-15|2003-07-15|Eurores S R L|PROCEDURE FOR THE PREPARATION OF MICRONIZED COLLAGEN AND THERAPEUTIC APPLICATIONS.|

---

CA2399224A1|2000-02-18|2001-08-23|Regeneration Technologies, Inc.|Implantable tissues infused with growth factors and other additives|

---

US7220276B1|2000-03-06|2007-05-22|Surmodics, Inc.|Endovascular graft coatings|

---

EP1193487A4|2000-04-04|2011-10-26|Lintec Corp|Device and method for measuring adhesive strength|

---

CN1114728C|2000-04-21|2003-07-16|中国石油化工集团公司|Staltic fibre and its manufacture method|

---

EP1149906A1|2000-04-25|2001-10-31|Pliva, Farmaceutska, Industrija, Dionicko Drustvo|Thrombopoietin receptor modulating peptide|

---

AU2001255716B2|2000-04-28|2006-02-02|Fziomed, Inc.|Hemostatic compositions of polyacids and polyalkylene oxides and methods for their use|

---

AU6692601A|2000-06-16|2002-01-02|Univ New Jersey Med|Hemostatic compositions, devices and methods|

---

AT412445B|2000-06-20|2005-03-25|Biering Wolfgang|LIQUID COLLAGE HEMOSTATIC|

---

AT411326B|2000-06-20|2003-12-29|Biering Wolfgang|HEMOSTATIC COLLAGEN PELLETS|

---

US20020012982A1|2000-07-13|2002-01-31|Invitrogen Corporation|Methods and compositions for rapid protein and peptide extraction and isolation using a lysis matrix|

---

US6554903B1|2000-07-19|2003-04-29|Nylok Corporation|Unitary spray nozzle|

---

US20030032143A1|2000-07-24|2003-02-13|Neff Thomas B.|Collagen type I and type III compositions for use as an adhesive and sealant|

---

EP1305064B1|2000-07-28|2008-04-23|Anika Therapeutics Inc.|Bioabsorbable composites of derivatized hyaluronic acid|

---

US6890342B2|2000-08-02|2005-05-10|Loma Linda University|Method and apparatus for closing vascular puncture using hemostatic material|

---

IT1317358B1|2000-08-31|2003-06-16|Fidia Advanced Biopolymers Srl|CROSS-LINKATED DERIVATIVES OF HYALURONIC ACID.|

---

JP2004508137A|2000-09-12|2004-03-18|ヴァージニア　コモンウェルス　ユニバーシティ|Treatment for high pressure bleeding|

---

WO2002022184A2|2000-09-18|2002-03-21|Organogenesis Inc.|Bioengineered flat sheet graft prosthesis and its use|

---

US6364519B1|2000-09-26|2002-04-02|Smith & Nephew, Inc.|Bone cement system|

---

US6635272B2|2000-11-09|2003-10-21|Richard N. Leaderman|Wound dressing and drug delivery system|

---

US6458380B1|2000-11-09|2002-10-01|Richard Leaderman|Dressing and preparation delivery system|

---

US20030009194A1|2000-12-07|2003-01-09|Saker Mark B.|Tissue tract sealing device|

---

US20020082620A1|2000-12-27|2002-06-27|Elaine Lee|Bioactive materials for aneurysm repair|

---

US7041868B2|2000-12-29|2006-05-09|Kimberly-Clark Worldwide, Inc.|Bioabsorbable wound dressing|

---

US20020164322A1|2001-01-25|2002-11-07|Alfred Schaufler|Suspension comprising fibrinogen, thrombin and alcohol, a method for preparing such a suspension, a method for coating a carrier with such a suspension, a method of drying a coating of a carrier, and a coated collagen sponge|

---

WO2002070594A2|2001-01-25|2002-09-12|Nycomed Pharma As|A method of preparing a collagen sponge, a device for extracting a part of a collagen foam, and an elongated collagen sponge|

---

US6733774B2|2001-01-25|2004-05-11|Nycomed Pharma As|Carrier with solid fibrinogen and solid thrombin|

---

US7052713B2|2001-02-13|2006-05-30|Nycomed Pharma As|Carrier with solid fibrinogen and solid thrombin|

---

AU2002247154A1|2001-02-14|2002-08-28|Focal, Inc.|Biocompatible fleece for hemostasis and tissue engineering|

---

US8187625B2|2001-03-12|2012-05-29|Boston Scientific Scimed, Inc.|Cross-linked gelatin composition comprising a wetting agent|

---

TW526069B|2001-04-10|2003-04-01|Sod Conseils Rech Applic|Injection device|

---

US6685745B2|2001-05-15|2004-02-03|Scimed Life Systems, Inc.|Delivering an agent to a patient's body|

---

BR0102637A|2001-05-17|2003-02-25|Johnson & Johnson Ind Com|Adhesive bandage|

---

US20050271737A1|2001-06-07|2005-12-08|Chinea Vanessa I|Application of a bioactive agent to a substrate|

---

US7371403B2|2002-06-14|2008-05-13|Providence Health System-Oregon|Wound dressing and method for controlling severe, life-threatening bleeding|

---

US6676987B2|2001-07-02|2004-01-13|Scimed Life Systems, Inc.|Coating a medical appliance with a bubble jet printing head|

---

US7435425B2|2001-07-17|2008-10-14|Baxter International, Inc.|Dry hemostatic compositions and methods for their preparation|

---

US20030039695A1|2001-08-10|2003-02-27|Ed. Geistlich Soehne Ag Fuer Chemische Industrie|Collagen carrier of therapeutic genetic material, and method|

---

US20060189516A1|2002-02-19|2006-08-24|Industrial Technology Research Institute|Method for producing cross-linked hyaluronic acid-protein bio-composites|

---

EP2957281A1|2001-09-21|2015-12-23|Egalet Ltd.|Polymer release system|

---

US20050019399A1|2001-09-21|2005-01-27|Gina Fischer|Controlled release solid dispersions|

---

JP4668510B2|2001-09-29|2011-04-13|持田製薬株式会社|Pharmaceutical composition for local hemostasis in a flexible container|

---

US6962715B2|2001-10-24|2005-11-08|Hewlett-Packard Development Company, L.P.|Method and dosage form for dispensing a bioactive substance|

---

JP4112851B2|2001-11-27|2008-07-02|テルモ株式会社|Two-chamber prefilled syringe|

---

US7923431B2|2001-12-21|2011-04-12|Ferrosan Medical Devices A/S|Haemostatic kit, a method of preparing a haemostatic agent and a method of promoting haemostatis|

---

DE60234469D1|2001-12-21|2009-12-31|Ferrosan As|HEMOSTATIC GARNISH, METHOD FOR THE PREPARATION OF A HEMOSTATIC AGENT AND METHOD FOR BLOOD-TREATMENT|

---

AU2003211376A1|2002-02-20|2003-09-09|New X-National Technology K.K.|Drug administration method|

---

AU2003215330B2|2002-02-21|2008-03-13|Encelle, Inc.|Immobilized bioactive hydrogel matrices as surface coatings|

---

AU2003224710A1|2002-03-18|2003-10-08|Carnegie Mellon University|Method and apparatus for preparing biomimetic scaffold|

---

WO2003094983A1|2002-05-08|2003-11-20|Rheinisch-Westfälische Technische Hochschule Aachen |Resorbable pharmaceutical formulation for the continuous release of thrombin|

---

US7670623B2|2002-05-31|2010-03-02|Materials Modification, Inc.|Hemostatic composition|

---

US20070264130A1|2006-01-27|2007-11-15|Phluid, Inc.|Infusion Pumps and Methods for Use|

---

WO2005000265A2|2002-09-11|2005-01-06|Elan Pharma International Ltd.|Gel-stabilized nanoparticulate active agent compositions|

---

GB2393120A|2002-09-18|2004-03-24|Johnson & Johnson Medical Ltd|Compositions for wound treatment|

---

US20040146546A1|2002-09-26|2004-07-29|Angiotech Pharmaceuticals, Inc.|Perivascular wraps|

---

GB2393655B|2002-09-27|2005-08-24|Johnson & Johnson Medical Ltd|Wound treatment device|

---

IL152030D0|2002-09-30|2003-05-29|Nvr Labs Ltd Neural & Vascular|Cohesive biopolymers comprising sulfated polysaccharides and fibrillar proteins and use thereof for tissue repair|

---

AU2003279730A1|2002-09-30|2004-04-19|Fibrogen, Inc.|Dry tissue sealant compositions|

---

GB2393656B|2002-10-01|2005-11-16|Johnson & Johnson Medical Ltd|Enzyme-sensitive therapeutic wound dressings|

---

US7135027B2|2002-10-04|2006-11-14|Baxter International, Inc.|Devices and methods for mixing and extruding medically useful compositions|

---

ITPD20020271A1|2002-10-18|2004-04-19|Fidia Farmaceutici|CHEMICAL-PHARMACEUTICAL COMPOUNDS CONSISTING OF TAXAN DERIVATIVES COVALENTLY LINKED TO HYALURONIC ACID OR ITS DERIVATIVES.|

---

US20040079763A1|2002-10-29|2004-04-29|Powell Cindy Hagood|Duplex storage pouch|

---

JP2004147959A|2002-10-31|2004-05-27|Nipro Corp|Two-component mixing type prefilled syringe|

---

IL152574A|2002-10-31|2009-09-22|Transpharma Medical Ltd|Transdermal delivery system for dried particulate or lyophilized medications|

---

CA2520312C|2003-03-26|2013-06-18|Egalet A/S|Matrix compositions for controlled delivery of drug substances|

---

US20060121080A1|2002-11-13|2006-06-08|Lye Whye K|Medical devices having nanoporous layers and methods for making the same|

---

US20040101546A1|2002-11-26|2004-05-27|Gorman Anne Jessica|Hemostatic wound dressing containing aldehyde-modified polysaccharide and hemostatic agents|

---

PL377477A1|2002-12-11|2006-02-06|Ferrosan A/S|Gelatine-based materials as swabs|

---

US20040120993A1|2002-12-20|2004-06-24|Guanghui Zhang|Hemostatic wound dressing and fabric and methods of making and using same|

---

US7699804B2|2003-01-31|2010-04-20|Creare Inc.|Fluid ejection system|

---

US20080091277A1|2004-08-13|2008-04-17|Kai Deusch|Surgical prosthesis having biodegradable and nonbiodegradable regions|

---

GB0304716D0|2003-02-28|2003-04-02|Uws Ventures Ltd|Method for producing partially frozen ice-water-air mixtures|

---

US7112713B2|2003-03-12|2006-09-26|Gelsus Research And Consulting, Inc.|Dressing based on the Teorell-Meyer gradient|

---

US20040181183A1|2003-03-12|2004-09-16|Sceusa Nicholas A.|Bandage based on the teorell-meyer gradient|

---

US7051654B2|2003-05-30|2006-05-30|Clemson University|Ink-jet printing of viable cells|

---

DK1484070T3|2003-06-05|2006-03-06|Baxter Int|Methods for healing and regeneration of human dura mater|

---

US8834864B2|2003-06-05|2014-09-16|Baxter International Inc.|Methods for repairing and regenerating human dura mater|

---

CA2530032C|2003-06-16|2015-11-24|Loma Linda University Medical Center|Deployable multifunctional hemostatic agent|

---

CA2529717C|2003-06-16|2013-04-02|Loma Linda University Medical Center|Deployable hemostatic agent|

---

US7129210B2|2003-07-23|2006-10-31|Covalent Medical, Inc.|Tissue adhesive sealant|

---

US7927626B2|2003-08-07|2011-04-19|Ethicon, Inc.|Process of making flowable hemostatic compositions and devices containing such compositions|

---

KR100588614B1|2003-11-10|2006-06-13|주식회사 바이오레인|Anti-adhesion agent with gas bubble|

---

EP1682196A2|2003-11-10|2006-07-26|Angiotech International Ag|Medical implants and anti-scarring agents|

---

JP2005169008A|2003-12-15|2005-06-30|Nipro Corp|Method of sterilizing biocompatible material|

---

US20050136112A1|2003-12-19|2005-06-23|Pediamed Pharmaceuticals, Inc.|Oral medicament delivery system|

---

US20050137512A1|2003-12-23|2005-06-23|Campbell Todd D.|Wound dressing and method for controlling severe, life-threatening bleeding|

---

US20060019868A1|2004-01-30|2006-01-26|Pendharkar Sanyog M|Hemostatic compositions and devices|

---

JP2007519450A|2004-01-30|2007-07-19|フェロサンアー／エス|Hemostasis sprays and compositions|

---

US7109163B2|2004-01-30|2006-09-19|Ethicon, Inc.|Hemostatic compositions and devices|

---

EP1602365A1|2004-03-03|2005-12-07|Switch Biotech Aktiengesellschaft|Pharmaceutical composition for topical use in form of xerogels or films and methods for production|

---

US20050218541A1|2004-04-02|2005-10-06|Peng Henry T|Method of producing interpenetrating polymer network|

---

US20050245905A1|2004-04-30|2005-11-03|Schmidt Steven P|Local drug-delivery system|

---

GB2414021A|2004-05-10|2005-11-16|Johnson & Johnson Medical Ltd|Absorbable haemostatic materials|

---

DK2258349T3|2004-05-11|2014-10-13|Egalet Ltd|Swellable dosage form comprising gellan gum|

---

US7393674B2|2004-06-22|2008-07-01|Zymogenetics, Inc.|Thrombin compositions|

---

SE527528C2|2004-06-22|2006-04-04|Bone Support Ab|Apparatus for the preparation of curable pulp and use of the apparatus|

---

US8119160B2|2004-06-29|2012-02-21|Ethicon, Inc.|Hemostatic compositions and devices|

---

US7968085B2|2004-07-05|2011-06-28|Ascendis Pharma A/S|Hydrogel formulations|

---

AU2005262070B2|2004-07-09|2011-01-27|Ferrosan Medical Devices A/S|Haemostatic composition comprising hyaluronic acid|

---

WO2006031358A2|2004-08-13|2006-03-23|Hyperbranch Medical Technology, Inc.|Dendritic polymers, crosslinked gels, and their uses as ophthalmic sealants and lenses|

---

WO2006036984A2|2004-09-28|2006-04-06|Atrium Medical Corporation|Stand-alone film and methods for making the same|

---

CA2580357C|2004-09-30|2014-01-28|Covalon Technologies Inc.|Non-adhesive elastic gelatin matrices|

---

ES2226587B1|2004-10-22|2005-12-16|Probitas Pharma, S.A.|STABLE THROMBINE COMPOSITION.|

---

AU2005315876A1|2004-12-14|2006-06-22|Fidia Advanced Biopolymers S.R.L.|Process for the preparation of two and three dimensional polymer scaffolds|

---

JP2006296896A|2005-04-22|2006-11-02|Tohoku Univ|Collagen thin film sheet, its manufacturing method, reconstruction method using it, and autologous tissue regeneration inducible artificial skin or mucosa|

---

US20060255053A1|2005-05-16|2006-11-16|Empire Industrial Corp.|Sealable container|

---

AU2006254554B2|2005-06-03|2011-11-24|Egalet Ltd|A solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids|

---

US20060282138A1|2005-06-10|2006-12-14|Ohshin Mlp Co., Ltd.|Exothermic structure that is directly applied to skin|

---

WO2007001926A2|2005-06-24|2007-01-04|Hyperbranch Medical Technology, Inc.|Low-swelling hydrogel sealants for wound repair|

---

US20070086958A1|2005-10-14|2007-04-19|Medafor, Incorporated|Formation of medically useful gels comprising microporous particles and methods of use|

---

US8166909B2|2005-11-15|2012-05-01|Surmodics, Inc.|Apparatus and methods for applying coatings|

---

AT512682T|2006-02-09|2011-07-15|Deka Products Lp|PERIPHERAL SYSTEMS|

---

US9456860B2|2006-03-14|2016-10-04|Kci Licensing, Inc.|Bioresorbable foaming tissue dressing|

---

US20070250007A1|2006-04-23|2007-10-25|Nilimedix Ltd.|Drug Delivery Device With Air Pressure Spring And Safety Valve|

---

US8496953B2|2006-05-12|2013-07-30|W. L. Gore & Associates, Inc.|Immobilized biologically active entities having a high degree of biological activity following sterilization|

---

US9114194B2|2006-05-12|2015-08-25|W. L. Gore & Associates, Inc.|Immobilized biologically active entities having high biological activity following mechanical manipulation|

---

CN101472624B|2006-05-12|2013-10-23|戈尔企业控股股份有限公司|Immobilized biologically active entities having high biological activity following mechanical manipulation|

---

CA2652559A1|2006-05-18|2007-11-29|Biobalance Llc|Biotherapeutic compositions and uses thereof|

---

JP5231401B2|2006-05-31|2013-07-10|バクスター・インターナショナル・インコーポレイテッド|Method of guided cell ingrowth and controlled tissue regeneration in spinal surgery|

---

KR100751046B1|2006-07-21|2007-08-21|이가식품|Manufacturing method of noodles having chitosan of solubility in water|

---

TWI436793B|2006-08-02|2014-05-11|Baxter Int|Rapidly acting dry sealant and methods for use and manufacture|

---

NZ574653A|2006-08-04|2012-11-30|Stb Lifesaving Technologies Inc|Solid dressing for treating wounded tissue|

---

US20080095830A1|2006-10-20|2008-04-24|Van Holten Robert W|Method for making a dressing|

---

US20080114277A1|2006-11-09|2008-05-15|Archel Ambrosio|Porous bioresorbable dressing conformable to a wound and methods of making same|

---

RU2436556C2|2006-11-09|2011-12-20|КейСиАй Лайсензинг Инк.|Porous biodegradable bandage, corresponding to wound sizes, and methods of its obtaining|

---

RU2464015C2|2006-12-15|2012-10-20|Лайфбонд Лтд.|Gelatin-transglutaminase hemostatic bandages and isolating agents|

---

RU2009127718A|2006-12-19|2011-01-27|Ферросан А/С |WOUND OR TISSUE BANDING MATERIAL CONTAINING LACTIC ACID BACTERIA|

---

WO2008090555A2|2007-01-22|2008-07-31|Elutex Ltd.|Medical devices having a matrix adhered thereof|

---

WO2008127497A2|2007-02-21|2008-10-23|The Regents Of The University Of California|Hemostatic compositions and methods of use|

---

WO2009131752A2|2008-04-25|2009-10-29|Schapira Jay N|Programmed-release, nanostructured biological construct for stimulating cellular engraftment for tissue regeneration|

---

US20080311172A1|2007-04-25|2008-12-18|Schapira Jay N|Programmed-release, nanostructured biological construct|

---

CA2687968C|2007-06-15|2016-09-27|Zymogenetics, Inc.|Stabilized thrombin compositions|

---

WO2009020612A1|2007-08-06|2009-02-12|Stb Lifesaving Technologies, Inc.|Methods and dressing for sealing internal injuries|

---

US9048945B2|2007-08-31|2015-06-02|Intel Corporation|Antenna training and tracking protocol|

---

US20090087569A1|2007-09-27|2009-04-02|Fenchem Enterprises Ltd.|Methods for Preparing Highly Stable Hyaluronic Acid|

---

TWI461227B|2007-10-30|2014-11-21|Baxter Int|Use of a regenerative biofunctional collagen biomatrix for treating visceral or parietal defects|

---

RU2545810C2|2008-02-29|2015-04-10|Ферросан Медикал Дивайсиз А/С|Device for fastening haemostasis and/or wound healing|

---

US8475812B2|2008-03-03|2013-07-02|Omrix Biopharmaceuticals Ltd.|Gelatin sponge comprising an active ingredient, its preparation and use|

---

EP2265728A4|2008-04-03|2012-08-01|Zymogenetics Inc|Hemostatic microspheres|

---

WO2009140502A1|2008-05-14|2009-11-19|Biolyph, Llc|Reagent preparation and dispensing device and methods for the same|

---

US20100048758A1|2008-08-22|2010-02-25|Boston Scientific Scimed, Inc.|Lubricious coating composition for devices|

---

DE102009004828B4|2009-01-13|2010-12-09|Lts Lohmann Therapie-Systeme Ag|Injector with displaceable plug part|

---

JP5088342B2|2009-03-25|2012-12-05|三菱マテリアル株式会社|Method for producing porous sintered body|

---

US20100256671A1|2009-04-07|2010-10-07|Biomedica Management Corporation|Tissue sealant for use in noncompressible hemorrhage|

---

US9039783B2|2009-05-18|2015-05-26|Baxter International, Inc.|Method for the improvement of mesh implant biocompatibility|

---

WO2010145817A2|2009-06-16|2010-12-23|Baxter International Inc.|Hemostatic sponge|

---

US8429831B2|2009-09-04|2013-04-30|Abbott Cardiovascular Systems Inc.|Drug-eluting coatings applied to medical devices by spraying and drying to remove solvent|

---

US20110092918A1|2009-10-19|2011-04-21|Ferrosan A/S|Malleable tip for applying an agent to a target site|

---

EP2521538B1|2010-01-08|2018-10-24|Mallinckrodt Pharma IP Trading D.A.C.|Dry powder fibrin sealant|

---

JP2011212182A|2010-03-31|2011-10-27|Terumo Corp|Prefilled syringe|

---

ES2682302T3|2010-06-01|2018-09-19|Baxter International Inc|Process for the production of dry and stable hemostatic compositions|

---

WO2011151384A1|2010-06-01|2011-12-08|Baxter International Inc.|Process for making dry and stable hemostatic compositions|

---

US8940335B2|2010-06-01|2015-01-27|Baxter International Inc.|Process for making dry and stable hemostatic compositions|

---

JP2012045358A|2010-08-25|2012-03-08|Terumo Corp|Therapeutic agent for pulmonary emphysema|

---

CN106390186B|2011-04-27|2020-07-03|比奥马普公司|Hemostatic compositions|

---

RU2013155713A|2011-07-06|2015-08-20|Профибрикс Бв|COMPOSITIONS FOR TREATMENT OF THE RAS|

---

RU2487701C2|2011-07-26|2013-07-20|Общество с ограниченной ответственностью "Инмед"|Solution for preparing chitosan material, method for preparing haemostatic material of this solution and medical device with using chitosan fibres|

---

CN103957948B|2011-10-11|2016-10-26|巴克斯特国际公司|Hemostatic composition|

---

US20130096063A1|2011-10-11|2013-04-18|Baxter Healthcare S.A.|Hemostatic compositions|

---

CA2851332C|2011-10-11|2020-08-25|Baxter International Inc.|Hemostatic compositions|

---

TWI548417B|2011-10-27|2016-09-11|巴克斯特國際公司|Hemostatic compositions|

---

RU2657955C2|2012-03-06|2018-06-18|Ферросан Медикал Дивайсиз А/С|Pressurised container containing haemostatic paste|

---

CN104349797B|2012-06-12|2017-10-27|弗罗桑医疗设备公司|Dry hemostatic composition|

---

JP6110102B2|2012-10-23|2017-04-05|アース製薬株式会社|Foaming bath product and foaming method of foaming bath|

---

ES2804534T3|2012-12-07|2021-02-08|Baxter Int|Hemostatic foam|

---

JP2014171416A|2013-03-07|2014-09-22|Riken Vitamin Co Ltd|Expandable food|

---

US9724078B2|2013-06-21|2017-08-08|Ferrosan Medical Devices A/S|Vacuum expanded dry composition and syringe for retaining same|

---

CN203601542U|2013-08-06|2014-05-21|杭州林黄丁新能源研究院有限公司|Tidal current power generation device and installation frame thereof|

---

EP3470094B1|2013-12-11|2020-07-22|Ferrosan Medical Devices A/S|Dry composition comprising an extrusion enhancer|

---

EP3237041B1|2014-12-24|2020-01-29|Ferrosan Medical Devices A/S|Syringe for retaining and mixing first and second substances|

---

JP6747651B2|2015-07-03|2020-08-26|フェロサン メディカル デバイシーズ エイ／エス|Syringe for holding vacuum in storage and for mixing two components|

---

IL242984D0|2015-12-08|2016-02-29|Omrix Biopharmaceuticals Ltd|Thrombin microcapsules, preparation and uses thereof|RU2657955C2|2012-03-06|2018-06-18|Ферросан Медикал Дивайсиз А/С|Pressurised container containing haemostatic paste|

---

CN104349797B|2012-06-12|2017-10-27|弗罗桑医疗设备公司|Dry hemostatic composition|

---

EP3470094B1|2013-12-11|2020-07-22|Ferrosan Medical Devices A/S|Dry composition comprising an extrusion enhancer|

---

EP3237041B1|2014-12-24|2020-01-29|Ferrosan Medical Devices A/S|Syringe for retaining and mixing first and second substances|

---

JP6747651B2|2015-07-03|2020-08-26|フェロサン メディカル デバイシーズ エイ／エス|Syringe for holding vacuum in storage and for mixing two components|

---

KR20210008479A|2018-05-09|2021-01-22|훼로산 메디칼 디바이스 에이/에스|How to prepare a hemostatic composition|

---

WO2020081247A1|2018-10-18|2020-04-23|The Board Of Regents Of The University Of Oklahoma|Potentiated antibiotic compositions and methods of use for treating bacterial infections and biofilms|

---

EP3943126A1|2019-03-20|2022-01-26|Astellas Pharma Inc.|Thrombin-loaded hemostatic sheet|

---

CN109821059A|2019-04-16|2019-05-31|大连医科大学附属第一医院|A kind of preparation method of absorbable fluid gelatin hemostatic material|

---

KR102283464B1|2019-06-28|2021-08-02|경북대학교 산학협력단|Wound Dressing Based on Hydrogel Comprising VEGF Peptide and Method for Producing the Same|

---

CN111388748B|2020-03-03|2021-08-06|东华大学|Antibacterial and hemostatic multifunctional composite hydrogel dressing and preparation method thereof|

---

CN111514369A|2020-04-29|2020-08-11|中国科学院大学温州研究院|Hemostatic powder and preparation method thereof|

法律状态:
2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-09-29| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-01-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-03-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 13/10/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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DKPA201470634|2014-10-13|

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DKPA201470634|2014-10-13|

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DKPA201570450|2015-07-07|

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DKPA201570450|2015-07-07|

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PCT/DK2015/050311|WO2016058612A1|2014-10-13|2015-10-13|Dry composition for use in haemostasis and wound healing|

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