method for preparing a dry composition

专利摘要:
The present description relates to a method for vacuum expanding a slurry before lyophilizing said slurry to obtain a dry slurry composition that efficiently reconstitutes to form a slurry with the addition of an aqueous medium. The present description further relates to a syringe for maintaining a dry paste composition in a vacuum.
公开号:BR112015030612B1
申请号:R112015030612-8
申请日:2014-06-20
公开日:2020-07-21
发明作者:Kristian Larsen；Michael Wrang Mortensen
申请人:Ferrosan Medical Devices A/S；
IPC主号:

专利说明:

[0001] [001] The present description refers to a method for vacuum expansion of a slurry before lyophilizing said slurry to obtain a dry slurry composition, which efficiently reconstitutes to form a slurry with the addition of an aqueous medium . The present description further relates to a syringe for maintaining a dry paste composition in a vacuum. Fundamentals of the invention
[0002] [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 slurry or slurry that is useful as a hemostatic composition for use in cases of diffuse bleeding, particularly from uneven surfaces or difficult areas to achieve, depending on the mixing conditions and relative proportions of the materials.
[0003] [003] Conventional hemostatic pastes are prepared at the time of use by mechanical stirring and mixing of liquid and loose powder to provide uniformity of the composition. The mixing of the powder and the fluid can be conducted in a container, such as a beaker. This mixture requires transferring the powder from its original container to the beaker, adding fluid to the beaker containing the powder, and then kneading the mixture to form the paste. Only after the paste is so formed can it be placed in a delivery medium or applicator, for example, a syringe, and applied to the wound.
[0004] [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.
[0005] [005] Alternatively, attempts have been made to preload a syringe (syringe I) with loose powdered gelatin, and a second syringe (syringe II) with the liquid. When it is time to make a paste, syringes I and II will be connected via a device and the solution in syringe II is pushed into syringe I. In an attempt to pass the solution and powder repeatedly back and forth between the syringes. syringes I and II, a homogeneous paste is eventually formed. Often, in a surgical situation, a hemostatic paste with an ideal powder: liquid ratio needs to be prepared by mixing in order to generate a homogeneous paste. Mixing a powder with a liquid requires the powder to be hydrated, which may require a longer preparation time in order to achieve a homogeneous paste. Even if such mixing methods are successful in forming a paste, the time and mechanical efforts required to form the paste are undesirable or even unacceptable. In addition, mixing may affect the final density of the paste (too intense mixing may result in a lower density paste) and, consequently, the consistency of the paste will become unstable over time.
[0006] [006] Floseal ® Haemostatic Matrix (Baxter) is a kit for the production of a hemostatic gelatin paste. The gelatin paste is produced by first making a thrombin solution and then transferring the gelatin-thrombin matrix solution mixture between two syringes connected for a total of at least twenty times. The paste can then be applied in a hemorrhage to promote hemostasis directly from the syringe.
[0007] [007] Likewise, the Surgiflo® Haemostatic Matrix (Ethicon) is a kit for the production of a hemostatic gelatin paste comprising thrombin, which is prepared by transferring the gelatin-thrombin matrix solution mixture between two syringes connected by a total at least six times.
[0008] [008] US 2005/0284809 relates to a method for the preparation of a hemostatic paste that more readily absorbs aqueous liquids, such that less mechanical force and time is required to form a hemostatic fluid 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.
[0009] [009] 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.
[0010] [0010] WO 2013/185776 describes a dry paste composition that comprises one or more polyols suitable for hemostatic use that reconstitutes spontaneously to form a slurry, that is, without any necessary mixing, with the addition of an aqueous medium. The reconstituted paste is suitable for direct application to a patient, for example, by syringe distribution.
[0011] [0011] Mixing procedures and manipulations that are time-consuming in a bleeding room (OR) environment are not acceptable, as the surgeon will have to interrupt your procedure while waiting for hemostasis. Mixing can also potentially compromise the sterility of the hemostatic paste and can negatively affect the consistency of the hemostatic paste. Correct paste consistency is important for a satisfactory hemostatic effect. It may be desirable if a hemostatic composition that can be supplied eliminates the need for such undesirable mixing requirements. It may also be desirable to provide a pulp product in the form of drying, which reliably and consistently reconstitutes to form a slurry in seconds. Summary of the invention
[0012] a. fornecer um agente na forma de pó e um meio aquoso, b. misturar o agente na forma de pó e o meio aquoso para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, d. congelar a pasta expandida, e e. secar a pasta. [0012] The present description addresses the preceding problems and, thus, refers to a dry composition, which with the addition of an adequate amount of an aqueous medium forms a substantially homogeneous paste. The invention thus relates to a method for preparing a dry composition that comprises the steps of: The. provide a powdered agent and an aqueous medium, B. mix the agent in powder form and the aqueous medium to obtain a folder, ç. subject the paste to reduced pressure, while expanding the paste, d. freeze the expanded paste, and and. dry the paste.
[0013] [0013] The expanded dry paste reconstitutes efficiently with the addition of a liquid. Preferably, the paste forms independently of external stimuli, such as mixing or stirring of any kind. Thus, in one embodiment, the dry composition spontaneously reconstitutes with the addition of a liquid, that is, no mechanical mixing is required for a paste to form.
[0014] a. fornecer um polímero biocompatível na forma de pó, um meio aquoso e opcionalmente um ou mais compostos hidrofílicos, tais como um ou mais polióis, b. misturar o polímero biocompatível, o meio aquoso e opcionalmente o um ou mais compostos hidrofílicos para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, d. congelar a pasta expandida, e e. secar a pasta. [0014] The agent is preferably a biocompatible polymer suitable for use in hemostasis and / or wound healing. Thus, in a preferred aspect, the invention relates to a method for preparing a dry composition that comprises the steps of: The. providing a biocompatible polymer in powder form, an aqueous medium and optionally one or more hydrophilic compounds, such as one or more polyols, B. mixing the biocompatible polymer, the aqueous medium and optionally the one or more hydrophilic compounds to obtain a paste, ç. subject the paste to reduced pressure, while expanding the paste, d. freeze the expanded paste, and and. dry the paste.
[0015] [0015] The present description further 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 open 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 fluid opening in a first position, and form a fluid passage between the first and second fluid opening in a second position, a piston configured to be axially displaced in the vacuum chamber through the open proximal end, and one or more vacuum bypass channels.
[0016] [0016] With the addition of an adequate amount of an aqueous medium to the syringe, keeping the paste dry, a ready-to-use fluid paste suitable for use in hemostasis and / or wound healing spontaneously forms in seconds. Vacuum lyophilization and vacuum storage of the dry paste composition can be provided via the syringe described herein. In addition, mixing with an aqueous medium, subsequent reconstitution and controlled release of the ready-to-use paste can also be provided via the syringe described here. Description of the drawings
[0017] [0017] Figure 1. Average reconstitution time +/- standard deviation of the standard lyophilized gelatin pastes comprising different polyols of example 1, which do not have an expanded vacuum. Inclusion of different polyols in the lyophilized paste composition resulted in spontaneous reconstitution of the pastes in about 30 seconds.
[0018] [0018] Figure 2. Average reconstitution time +/- standard deviation of the standard freeze-dried and freeze-dried gelatin pastes of example 3. Vacuum expansion greatly reduces the spontaneous reconstitution time of pastes comprising mannitol.
[0019] [0019] Figures 3 to 14 represent different modalities and stages of the method of the present description.
[0020] [0020] 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 bypass in the syringe body. The pressure valve is closed.
[0021] [0021] Figure 4 shows the concept 1 and 2 syringes with a quantity of paste.
[0022] [0022] Figure 5 shows a syringe fitted with a lyophilization plunger comprising a deviation (lyophilization plunger; concept 1) or a syringe comprising a deviation in the syringe body being fitted with a standard plunger (concept 2). Deviations from both concept 1 and 2 allow gaseous communication between the product chamber and the log part 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 application of vacuum.
[0023] [0023] Figure 6 shows the syringes of concepts 1 and 2 after the paste is frozen. Freezing results in a closed expanded paste structure.
[0024] [0024] Figure 7 shows the syringes of concepts 1 and 2 that undergo vacuum lyophilization. Lyophilization does not change the volume of the frozen paste.
[0025] [0025] Figure 8 shows the syringes of concepts 1 and 2, in which the deviations were closed with a removable shelf. The syringes contain the dry paste in a vacuum product chamber.
[0026] [0026] 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.
[0027] [0027] Figure 10 shows the syringes of concepts 1 and 2 after assembling a piston rod and flanges.
[0028] [0028] Figure 11 shows the concept 1 syringe being sterilized by irradiation.
[0029] [0029] 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.
[0030] [0030] 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.
[0031] [0031] Figure 14 represents a paste ready for use in a syringe fitted with an applicator tip.
[0032] [0032] 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.
[0033] [0033] Figures 16a-d show perspective views of the barrel of a currently described syringe modality.
[0034] [0034] Figures 17a-b show proximal views in perspective of two different modalities of the syringe barrel currently described.
[0035] [0035] Figures 18a-b are cross-sectional side view illustrations of the barrel of a currently described syringe embodiment, with the pressure valve in two different positions.
[0036] [0036] Figure 19a shows another modality of a pressure valve.
[0037] [0037] 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.
[0038] [0038] 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.
[0039] [0039] Figures 20a-b are illustrations of side cross-sectional views of the pressure valve of figure 19a inside the pressure chamber of figure 19.
[0040] [0040] Figures 20c-d are illustrations of perspective view of the barrel with the pressure valve and pressure chamber of figure 19.
[0041] [0041] Figure 21 shows the average reconstitution time +/- standard deviation of dry gelatin paste compositions comprising different amounts of mannitol (wt% wet paste) with and without vacuum expansion. Vacuum expansion has greatly reduced the spontaneous reconstitution time of dry pastes, which is further shortened by increasing concentrations of mannitol in dry pastes.
[0042] [0042] 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 reconstitution time compared to vacuum expanded compositions without PEG.
[0043] [0043] The drawings are only exemplary and should not be construed as limiting the scope of the invention Definitions
[0044] [0044] "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.
[0045] [0045] "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.
[0046] [0046] A "bioactive agent" means any agent, medication, 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 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 comprising or consisting 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.
[0047] [0047] "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.
[0048] [0048] "Biologically absorbable" or "resorbable" are terms that in the present context are used to describe that the materials from which said powder is made can be broken down 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.
[0049] [0049] "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.
[0050] [0050] 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 where the solid is the continuous phase and the liquid is the discontinuous phase. A gel is not a slurry. For example, uncrosslinked gelatin particles are soluble and can form a gel upon contact with an aqueous medium such as water. A gel has no pores that comprise expandable gas or air.
[0051] [0051] "Hemostasis" is a process that causes bleeding to decrease or cease. Haemostasis 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.
[0052] [0052] "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 UI, UI, or as IE. It is used to quantify vitamins, hormones, some drugs, vaccines, blood products, and similar biologically active substances.
[0053] [0053] 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. Flowable 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 their most unusual properties; this makes the folders demonstrate fragile properties. The paste is not a gel / jelly. A “slurry” is a fluid mixture of a powdered / powdered solid with a liquid (usually water). Slurry behaves somewhat like thick fluids, which flow by gravity and are capable of being pumped, if not very thick. A slurry can functionally be thought of as a thin, watery slurry, but a slurry generally contains more water than a slurry. 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 cross-linked gelatin particles, will form a paste upon mixing with an aqueous medium.
[0054] [0054] "Percentage". If nothing else is indicated, the percentage is percentage by weight:% w / w or% by weight.
[0055] [0055] The reasons are indicated as weight by weight (p: p).
[0056] [0056] 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.
[0057] [0057] "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.
[0058] [0058] "Vacuum" is defined as a region with a gas pressure lower than the ambient pressure, that is, the surrounding atmospheric pressure. At sea level on Earth, the atmospheric pressure is approximately 1 bar, that is, 100 kPa (1000 mbar) at 25 ° C. The following table shows the approximate pressures at “low”, “medium” and “high” vacuum at sea level on Earth in millibar (mbar).
[0059] [0059] The present description refers to a dry composition, which with the addition of an adequate amount of an aqueous medium forms a substantially homogeneous paste.
[0060] a. fornecer um agente na forma de pó e um meio aquoso, b. misturar o agente na forma de pó e o meio aquoso para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, d. congelar a pasta expandida, e e. secar a pasta. [0060] The invention thus relates to a method for preparing a dry composition that comprises the sequential steps of: The. provide a powdered agent and an aqueous medium, B. mix the agent in powder form and the aqueous medium to obtain a folder, ç. subject the paste to reduced pressure, while expanding the paste, d. freeze the expanded paste, and and. dry the paste.
[0061] [0061] The expanded dry paste reconstitutes efficiently with the addition of a liquid to form a fluid paste. Preferably, the paste forms independently of external stimuli, such as mixing or stirring of any kind, so, in one embodiment, the dry composition spontaneously reconstitutes with the addition of a liquid to the container that keeps the composition dry, that is, none mechanical mixing is required for a paste to form.
[0062] [0062] The powdered agent can be any powdered agent capable of forming a paste when mixed with an aqueous medium. The agent can be cross-linked. Preferably, the agent is a biocompatible polymer suitable for use in hemostasis and / or wound healing, such as a crosslinked hemostatic agent in powder form, for example, gelatin crosslinked powder.
[0063] [0063] Drying is preferably lyophilization. Steps c) to d) can be conveniently performed directly on the freeze dryer as a continuous process. Thus, suitable containers that hold the pulp from step b) can be placed in a lyophilizer, in which the pulp is expanded in a low vacuum, frozen to prepare the expanded pulp structure and lyophilized until dry. Figures 3 to 14 show different modalities of the process steps.
[0064] a. fornecer um polímero biocompatível na forma de pó, um meio aquoso, e opcionalmente um ou mais compostos hidrofílicos, b. misturar o polímero biocompatível, o meio aquoso e opcionalmente o um ou mais compostos hidrofílicos para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, d. congelar a pasta expandida, e e. secar a pasta. [0064] In a preferred aspect, the invention relates to a method for preparing a dry composition suitable for use in hemostasis and / or wound healing, comprising the sequential steps of: The. provide a biocompatible polymer in the form of powder, an aqueous medium, and optionally one or more hydrophilic compounds, B. mixing the biocompatible polymer, the aqueous medium and optionally the one or more hydrophilic compounds to obtain a paste, ç. subject the paste to reduced pressure, while expanding the paste, d. freeze the expanded paste, and and. dry the paste.
[0065] [0065] The dry paste is preferably contained in a medical delivery device, such as a syringe. With the addition of an adequate amount of an aqueous medium to the container containing the dry paste, a ready-to-use slurry forms spontaneously in seconds, that is, no mechanical mixing is required for said paste to form. The slurry is substantially homogeneous and can be applied directly to a site that requires hemostasis and / or wound healing.
[0066] • Menos tempo gasto na preparação da pasta, por exemplo, o sangramento pode ser interrompido mais rápido. • Diminuição do risco de comprometer a esterilidade da pasta durante a preparação devido a menos etapas de manuseio. • Diminuição do risco de cometer erros durante a preparação devido à preparação simplificada da pasta. • Consistência ideal da pasta obtida todas as vezes. • Reconstituição confiável e consistente em um curto período de tempo. • Os agentes bioativos, que são instáveis em solução podem ser adicionados à pasta antes da secagem e, assim, vão estar presente na composição seca da presente invenção. Por exemplo, a trombina pode ser adicionada à pasta antes da secagem, evitando-se assim etapas de diluição da trombina que são demorados e propensos a erros. • Minimiza os custos do bloco cirúrgico, uma vez que a preparação do produto atualmente descrito é muito simples e rápida, e não existe nenhuma razão para pré-preparar substâncias escoáveis hemostáticas antes da cirurgia, as quais podem não ser usadas. [0066] The advantages of dry composition and reconstituted paste obtained by the methods of the present description are numerous and include: • Less time spent preparing the paste, for example, bleeding can be stopped faster. • Decreased risk of compromising the paste's sterility during preparation due to fewer handling steps. • Reduced risk of making mistakes during preparation due to simplified preparation of the paste. • Optimal consistency of the paste obtained every time. • Reliable and consistent replenishment over a short period of time. • Bioactive agents, which are unstable in solution, can be added to the paste before drying and thus will be present in the dry composition of the present invention. For example, thrombin can be added to the paste before drying, thus avoiding thrombin dilution steps that are time-consuming and prone to errors. • Minimizes the costs of the surgical block, since the preparation of the product currently described is very simple and fast, and there is no reason to pre-prepare flowable hemostatic substances before surgery, which may not be used.
[0067] [0067] All of the above factors lead to increased patient safety. Agent in powder form
[0068] [0068] The powdered agent can be any agent capable of forming a paste when mixed with an aqueous medium. A paste is formed when the powdered particles are insoluble in water, that is, when the powdered particles are substantially insoluble in the aqueous medium they are mixed with it. Thus, the powdered agent 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.
[0069] [0069] In one embodiment, the paste of the present description comprises one or more agents in powder form, such as a simple biocompatible polymer or a combination of two or more biocompatible polymers.
[0070] [0070] In a preferred embodiment, the present description refers to a method for preparing a dry composition as a dry paste composition, which reconstitutes spontaneously in seconds with the addition of an appropriate amount of an aqueous medium to the container containing the dry composition to form a ready-to-use paste suitable for hemostatic and / or wound healing purposes, ie, which can be distributed directly to a patient without any additional mixing required.
[0071] [0071] 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) breakdown of the polymeric main chain or (2) degradation of the side chains that result in water solubility.
[0072] [0072] In one 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 of these, 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.
[0073] [0073] 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.
[0074] [0074] In a preferred embodiment the 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.
[0075] [0075] 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 120 to 150 ° C. The time period for crosslinking can be optimized by a person skilled in the art and is normally a period of 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.
[0076] [0076] 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 cross-linking agents include, but are not limited to, aldehydes, especially glutaraldehyde and formaldehyde, acyl azide, caboiimides, hexamethylene diisocyanate, polyether oxide, 1,4-butanedioldiglycidyl ether, tannic acid, aldose sugars, for example , D-fructose, genipin and photo-oxidation by dye mediation. Specific compounds include, but are not limited to 1- (3-dimethylaminopropyl) -3-ethylcarboiimide (EDC), dithiobis (propanoic dihydrazide) (DTP), 1-ethyl-3- (3-dimethylamino-propyl) - carbodiimide (EDAC).
[0077] [0077] In a preferred embodiment, the biocompatible polymer was 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 powder form, 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).
[0078] [0078] 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.
[0079] [0079] In one embodiment, the powdered agent 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.
[0080] [0080] 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 crosslinking the dry foam upon exposure to dry heat. 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.
[0081] [0081] In another embodiment, the powdered agent 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-crosslinked 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 cross-linking, 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, cross-linked gelatin particles are prepared essentially in the manner described in U.S. 6,066,325.
[0082] [0082] 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.
[0083] [0083] In general, at least 90% of the powder particles have a diameter between 1 µm and 1200 µm.
[0084] [0084] 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 pm and 400 pm, such as about 300 μm.
[0085] [0085] 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.
[0086] [0086] 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 dust 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.
[0087] [0087] In one embodiment, the paste obtained by mixing the agent 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 polymer biocompatible, 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 , 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.
[0088] [0088] In one embodiment, the paste of the present description 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.
[0089] [0089] In one embodiment, the paste of the present description 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.
[0090] [0090] 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.
[0091] [0091] 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.
[0092] [0092] In one embodiment, the composition after drying 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 biocompatible polymer.
[0093] [0093] 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.
[0094] [0094] 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. Aqueous medium
[0095] [0095] An aqueous medium is used in the methods of the present description to initially prepare the paste, which is subsequently vacuum-expanded and dried, and to reconstitute the dry paste.
[0096] [0096] 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, saline or a buffered aqueous medium. The water can be WFI (Water for Injection). It is important that the aqueous medium is selected in such a way that the reconstituted paste product is isotonic when intended for use on a human or animal subject, such as for hemostatic and / or wound healing purposes. The aqueous medium is preferably sterile.
[0097] [0097] The aqueous medium of the present description is, in one embodiment, a saline solution.
[0098] [0098] In one embodiment, the aqueous medium is a solution of calcium chloride.
[0099] [0099] In other modalities, the aqueous medium is water.
[0100] [00100] The aqueous medium can also be a buffered aqueous medium suitable for use in a hemostatic paste. Any suitable buffering agent known to a person skilled in the art can be used, such as one or more buffering agents selected from the group consisting of: sodium citrate; citric acid, sodium citrate; acetic acid, sodium acetate; K2HPO4, KH2PO4; Na2HPO4, NaH2PO4; CHES; Borax, sodium hydroxide; TAPS; Bicin; Tris; Tricin; TAPSO; HEPES; TES; MOPS; PIPES; Cacodilate; SSC; MON, or others. The pH of the buffered aqueous medium must be suitable for the creation of a hemostatic paste intended for human use and can be determined by a person skilled in the art.
[0101] [00101] The aqueous medium is 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 a paste intended, for example, for surgical use, in such a way that less water is removed. in the drying process.
[0102] [00102] During the reconstitution of the dry paste, the amount of aqueous medium is adjusted to the amount of biocompatible polymer for a paste, of a suitable consistency to form.
[0103] [00103] In one embodiment, the paste of the present description comprises, before drying, less than 99% water, preferably less than 95% water.
[0104] [00104] 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.
[0105] [00105] 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.
[0106] [00106] 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.
[0107] [00107] 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
[0108] [00108] In one embodiment, the paste 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 the expansion and drying of said paste has a beneficial effect on the humidification of the paste, thus improving the efficiency of reconstitution of the dry paste.
[0109] [00109] 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. The inclusion of a hydrophilic compound in the dry composition improves the rate of spontaneous reconstitution.
[0110] [00110] 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), Poly (allylamine) hydrochloride and poly (vinyl) acid. In one embodiment, the hydrophilic compound is PEG.
[0111] [00111] 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.
[0112] [00112] In a preferred embodiment, the hydrophilic compound is a polyol. Thus, according to an embodiment of the invention, one or more polyols can be included in the paste prior to expansion and drying of the paste. Polyols greatly improve the rate of reconstitution of the dry paste composition and play a role in ensuring an optimal consistency of the reconstituted paste.
[0113] [00113] 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.
[0114] [00114] Monosaccharides include, but are not limited to, glucose, fructose, galactose, xylose and ribose.
[0115] [00115] Disaccharides include, but are not limited to sucrose (sucrose), lactulose, lactose, maltose, trehalose and cellobiose.
[0116] [00116] Polysaccharides include, but are not limited to, starch, glycogen, cellulose and chitin.
[0117] [00117] 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.
[0118] [00118] In one embodiment, the dry composition comprises a simple hydrophilic compound, such as a simple polyol.
[0119] [00119] In one embodiment of the invention, the dry composition comprises more than one hydrophilic compound, such as two, three, four, five, six or even more different hydrophilic compounds.
[0120] [00120] In a preferred embodiment, the hydrophilic compound is a polyol.
[0121] [00121] In one embodiment of the invention, the dry composition comprises two polyols, for example, mannitol and glycerol or trehalose and a glycol.
[0122] [00122] In one embodiment of the invention, 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.
[0123] [00123] 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.
[0124] [00124] 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.
[0125] [00125] In one embodiment, the dry composition does not comprise a sugar just like the polyol.
[0126] [00126] In one embodiment of the invention, the dry composition comprises mannitol.
[0127] [00127] In one embodiment of the invention, the dry composition comprises sorbitol.
[0128] [00128] In one embodiment of the invention, the dry composition comprises glycerol.
[0129] [00129] In one embodiment of the invention, the dry composition comprises trehalose.
[0130] [00130] In an embodiment of the invention, the dry composition comprises glycol, such as propylene glycol.
[0131] [00131] In one embodiment of the invention, the dry composition comprises xylitol.
[0132] [00132] In one embodiment of the invention, the dry composition comprises maltitol.
[0133] [00133] In one embodiment of the invention, the dry composition comprises sorbitol.
[0134] [00134] 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.
[0135] [00135] 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 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% to about 11% of one or more hydrophilic compounds, such as about 2% to about 10% of one or more hydrophilic compounds.
[0136] [00136] In one embodiment, the paste according to the invention comprises, before drying, about 3% to about 40% of one or more polyols, for example, from about 3% to about 30% of one or more polyols, such as from about 3% to about 25% of one or more polyols, for example, from about 3% to about 20% of one or more polyols, such as from about 3% to about 18 % of one or more polyols, for example, from about 3% to about 17% of one or more polyols, such as from about 3% to about 16% of one or more polyols, for example, from about 3% to about 15% of one or more polyols, such as from about 3% to about 14% of one or more polyols, for example, from about 3% to about 13% of one or more polyols, such as from about 3% to about 12% of one or more polyols, for example, from about 3% to about 11% of one or more polyols, such as about 3% to about 10% of a or more polyols.
[0137] [00137] In one embodiment, the paste according to the invention comprises, before drying, about 4% to about 40% of one or more polyols, for example, from about 4% to about 30% of one or more polyols, such as from about 4% to about 25% of one or more polyols, for example, from about 4% to about 20% of one or more polyols, such as from about 4% to about 18 % of one or more polyols, for example, from about 4% to about 17% of one or more polyols, such as from about 4% to about 16% of one or more polyols, for example, from about 4% to about 15% of one or more polyols, such as from about 4% to about 14% of one or more polyols, for example, from about 4% to about 13% of one or more polyols, such as from about 4% to about 12% of one or more polyols, for example, from about 4% to about 11% of one or more polyols, such as about 4% to about 10% of one or more polyols.
[0138] [00138] In one embodiment, the pulp according to the invention comprises before drying more than about 5% of one or more hydrophilic compounds, therefore in one embodiment, the pulp 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 13% of one or more with 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.
[0139] [00139] 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% to about 11% of one or more hydrophilic compounds, such as about 6% to about 10% of one or more hydrophilic compounds.
[0140] [00140] In one embodiment, the paste according to the invention comprises, before drying, about 10% to about 40% of one or more hydrophilic compounds, for example, from about 10% to about 30% of one or more more hydrophilic compounds, such as from about 10% to about 25% of one or more hydrophilic compounds, for example, from about 10% to about 20% of one or more hydrophilic compounds, such as from about 10% to about 18% of one or more hydrophilic compounds, for example, from about 10% to about 17% of one or more hydrophilic compounds, such as from about 10% to about 16% of one or more hydrophilic compounds , for example, from about 10% to about 15% of one or more hydrophilic compounds.
[0141] [00141] In one embodiment, the slurry according to the invention comprises before 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.
[0142] [00142] In one embodiment, the slurry according to the invention comprises less than about 20% of one or more hydrophilic compounds before drying, such as less than about 18% of one or more hydrophilic compounds, for example, less than about 17% of one or more hydrophilic compounds, such as less than about 16% of one or more hydrophilic compounds, for example, less than about 15% of one or more hydrophilic compounds, such as less than about 14 % of one or more hydrophilic compounds, for example, less than about 13% of one or more hydrophilic compounds, such as less than about 12% of one or more hydrophilic compounds, for example, less than about 11% of one or more hydrophilic compounds, such as less than about 10% of one or more hydrophilic compounds.
[0143] [00143] 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, 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.
[0144] [00144] 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.
[0145] [00145] 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 from about 20 % to about 30% of one or more hydrophilic compounds.
[0146] [00146] 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% one or more hydrophilic compounds, such as from about 25% to about 30% of one or more hydrophilic compounds.
[0147] [00147] In one embodiment, the dry composition comprises from about 27% to about 60% of one or more hydrophilic compounds, such as from about 27% to about 50% of one or more hydrophilic compounds, for example, from about 27% to about 45% of one or more hydrophilic compounds, such as from about 27% to about 40% of one or more hydrophilic compounds, for example, from about 27% to about 35% of one or more hydrophilic compounds, such as from about 27% to about 30% of one or more hydrophilic compounds.
[0148] [00148] In one embodiment, the dry composition comprises from about 30% to about 60% of one or more hydrophilic compounds, such as from about 30% to about 50% of one or more hydrophilic compounds, for example, from about 30% to about 45% of one or more hydrophilic compounds, such as from about 30% to about 40% of one or more hydrophilic compounds, for example, from about 30% to about 35% one or more hydrophilic compounds.
[0149] [00149] 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.
[0150] [00150] 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.
[0151] [00151] 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
[0152] [00152] In one embodiment, the hydrophilic compound of the present description is not polyethylene glycol (PEG). Additional compounds
[0153] [00153] The dry composition of the invention may further 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.
[0154] [00154] In one embodiment, the dry composition of the present description comprises one or more antimicrobial agents, such as one or more antibacterial agents.
[0155] [00155] In one embodiment, the dry composition of the present description comprises benzalkonium chloride.
[0156] [00156] In one embodiment, the dry composition of the present description does not comprise an antimicrobial agent.
[0157] [00157] In one embodiment, the dry composition additionally comprises an extrusion intensifier, that is, a compound capable of facilitating extrusion of a paste from a syringe.
[0158] [00158] It has been previously 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 intensifiers in appropriate quantities. The amounts are preferably high enough to achieve 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.
[0159] [00159] The extrusion intensifier is preferably albumin, especially human serum albumin.
[0160] [00160] In the paste composition of the present invention, prior to vacuum expansion and drying, the extrusion intensifier, 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% about 4%.
[0161] [00161] In the dry paste composition of the present invention, the extrusion intensifier, 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%.
[0162] [00162] In one embodiment, the extrusion intensifier is not present in the dry composition, but is instead introduced into the paste composition during reconstitution. For example, the extrusion intensifier may be present in the aqueous medium used for the reconstitution of the paste, thereby obtaining a wet paste composition comprising the extrusion intensifier.
[0163] [00163] 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.
[0164] [00164] Another class of extrusion intensifiers according to the present invention are phospholipids, such as phosphatidylcholine and -serine, or complex mixtures such as lecithins or soybean oils. Bioactive agent
[0165] [00165] In an embodiment of the invention, the dry composition comprises one or more bioactive agents, that is, one or more bioactive agents are included in the paste before expansion and drying. It is essential that the bioactive agent maintains its bioactivity throughout the process, that is, that the agent has 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 lose their secondary structure when water is present.
[0166] [00166] In one embodiment, the bioactive agent stimulates wound healing and / or hemostasis, such as thrombin.
[0167] [00167] 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 should 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 dilution of thrombin.
[0168] [00168] 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, such as water, will comprise a desired amount of thrombin, without the need delay and propensity to errors in the dilution and thrombin addition 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.
[0169] [00169] The present inventors have shown that thrombin can be included in a paste and freeze-dried in accordance with the present description, with essentially no loss of thrombin activity measured in the reconstituted paste.
[0170] [00170] 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 in 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 paste, for example, about 200 IU / ml of paste to about 400 IU / ml of paste, such as about 250 IU / ml of paste to about 350 IU / ml of paste.
[0171] [00171] In one embodiment, thrombin is added to the paste before drying, in a concentration in the range of about 50 IU / g of paste to about 5000 IU / g of paste, preferably between about 100 IU / g of paste paste to about 1000 IU / g of paste, such as between about 200 IU / g of paste to about 800 IU / g of paste. In such embodiments, the dry composition will comprise thrombin. In another embodiment, 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.
[0172] [00172] The 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 .
[0173] [00173] Thrombin is a "trypsin-like" serine protease protein that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is cleaved proteolytically 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 into Xla, VIII into Villa, V into Va, and fibrinogen into fibrin.
[0174] [00174] A preferable bioactive agent according to the invention is thrombin. In one embodiment, thrombin is added as a prothrombin.
[0175] [00175] 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).
[0176] [00176] 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.
[0177] [00177] 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.
[0178] [00178] All of 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 initial 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-β 1, 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.
[0179] [00179] 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.
[0180] [00180] 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; painkillers and combinations of painkillers; 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 antiarrhythmics; antihypertensives; 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 / Xla, Factor XlI / 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. Make the folder
[0181] [00181] According to the method of the invention, the agent in powder form, for example, a biocompatible polymer, and optionally one or more hydrophilic compounds are mixed with a suitable amount of an aqueous medium to obtain a paste. The mixing 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.
[0182] [00182] The powder particles are generally substantially insoluble in the aqueous medium, allowing a paste to form. In general, cross-linking makes biocompatible polymers, such as gelatin, insoluble in water.
[0183] [00183] Mixing the paste in the mixing vessel introduces a batch gas phase substantially dispersed homogeneously through the paste, that is, the mixed paste will have pores or compartments comprising an expandable gas, such as air.
[0184] [00184] In one embodiment, the slurry is prepared by mixing an aqueous medium, a gaseous and a quantity of powder particles in a mixing vessel, under conditions that result in the formation of a slurry with a substantially homogeneously dispersed discontinuous gas phase through folder. The gas, for example, can be air, nitrogen, carbon dioxide, xenon, argon or mixtures thereof.
[0185] - introduzir um volume de um líquido em um vaso de mistura equipado com um meio para misturar o dito líquido, - introduzir um volume de um gás no dito volume de líquido, embora os ditos meios para misturar sejam funcionar em condições eficiente para misturar o dito líquido e o dito gás juntos para formar uma espuma compreendendo uma fase gasosa descontínua que compreende o dito gás disperso em uma fase líquida contínua compreendendo o dito líquido, - introduzir na dita espuma uma quantidade de partículas em pó de um polímero biocompatível adequado para uso em hemostase, e que é substancialmente insolúvel no dito líquido; e - misturar a dita espuma e as ditas partículas em pó juntas, em condições eficientes para formar uma composição de pasta substancialmente homogênea compreendendo a dita fase gasosa descontínua e as ditas partículas substancialmente dispersas de maneira homogênea em toda a dita fase líquida, formando por meio disso a dita composição de pasta fluida. [00185] In a particular mode, 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 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, thereby forming said slip composition.
[0186] [00186] In one embodiment, the substantially homogeneous paste composition comprises a continuous liquid phase, that is, a liquid phase that is released when the force applied to the paste when the paste is contained in an enclosed space.
[0187] [00187] 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.
[0188] [00188] 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.
[0189] [00189] The mixing of the paste can, in general, be carried out at room temperature (20 to 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 avoid 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.
[0190] [00190] Another way or an additional way of preserving 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, 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.
[0191] [00191] The inventor of the present application found that it is not essential to mix the pulp at low temperatures to avoid the loss of thrombin activity, since no detectable decrease in thrombin activity was discovered when mixing the pulp at room temperatures . Containers
[0192] [00192] Any suitable container known to a person 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.
[0193] [00193] In one embodiment, the paste is prepared in a volume container and transferred / aliquoted in another container for expansion, freezing and drying, in which said other container is selected from an applicator, such as a syringe, a bottle, a jar, a tube, a tray and a cartridge. Preferably, the other container is a medical delivery device suitable for dispersing hemostatic compositions flowable to a patient who needs them. In one embodiment, the container containing the paste composition during expansion, freezing and drying is a syringe.
[0194] [00194] A "bottle" according to the invention is a rigid, approximately cylindrical container with a wide mouth opening. Vials may comprise a cap / closure unit that can be closed again applied to the mouth of the vial.
[0195] [00195] The containers can consist of any soluble material, such as plastic, glass, ceramic or metal, such as stainless steel.
[0196] [00196] Examples of suitable plastic materials include, but are not limited to, polyethylene, polypropylene, polystyrene, polyvinyl chloride, and polytetrafluoroethylene (PTFE).
[0197] [00197] In one embodiment, the paste is filled and dried in a suitable applicator to disperse flowable hemostatic compositions.
[0198] a. uma câmara de produto compreendendo uma composição seca capaz de formar uma pasta com a adição de um meio aquoso, em que a pressão na câmara de produto é menor que a pressão dentro da câmara de produto, e b. uma válvula. [00198] In one embodiment, the present description refers to a container comprising: The. a product chamber comprising a dry composition capable of forming a paste with the addition of an aqueous medium, wherein the pressure in the product chamber is less than the pressure within the product chamber, and B. a valve.
[0199] [00199] Preferably, the dry composition reconstitutes spontaneously with the addition of an aqueous medium in the dry composition that is present in the container.
[0200] [00200] In modalities where the container does not include a diversion, gaseous communication during vacuum expansion and drying occurs through the valve.
[0201] [00201] 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 tokens, discs, rods, tubes, conical cylinders, spheres, half spheres, tablets, globules, granules or sheets. Medical delivery device
[0202] [00202] In one embodiment, the paste is placed and dried in a medical delivery device suitable for dispersing flowable hemostatic compositions, such as a syringe. The transfer occurs before the vacuum expansion of the paste.
[0203] [00203] In one embodiment, the medical delivery device is a disposable syringe comprising a valve. In one embodiment, the syringe comprises a lyophilization bypass channel, which is a gaseous communication between the syringe product chamber and the outside of the container, that is, the external environment. The bypass can be in an open state, allowing gaseous communication between the product chamber and the outside, and a closed state. The deviation 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 deviation in the body of the syringe (figure 5, concept 2), the syringe can be adjusted with a standard plunger.
[0204] [00204] 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 for containing the paste with a proximal end and a distal end 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 fluid opening in a first position, and form a fluid passage between the first and second fluid opening in a second position, a configured plunger to be moved axially in the vacuum chamber through the open proximal end, and one or more vacuum bypass channels. The syringe is preferably a disposable syringe.
[0205] [00205] During lyophilization of the paste, the vacuum that can be created in the vacuum chamber is important to expand the paste. And keeping the paste dry in a vacuum in the vacuum chamber of the syringe, that is, at a pressure level lower than the pressure of the surrounding environment, the addition of liquid through preparation and use of the paste are facilitated, due to the liquid being sucked into the vacuum chamber due to reduced pressure in the vacuum chamber.
[0206] [00206] The barrel can be supplied with a flange 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.
[0207] [00207] 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 18 a, 18b, 20a and 20b.
[0208] [00208] In a currently presented syringe embodiment, 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. As 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 geometric 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 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 portion connector, regardless of the rotational position of the pressure valve.
[0209] [00209] 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.
[0210] [00210] 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.
[0211] [00211] 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 can 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.
[0212] [00212] Thus, in relation to the syringe currently described, the liquid for reconstitution of a paste in the vacuum chamber can be supplied from the distal end of the syringe, through the second opening of fluid in the connector portion and through the chamber of pressure and 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 for reconstitution of the paste. The syringe currently described is therefore safe, easy and quick to use when reconstituting a dry paste, such as a hemostatic paste.
[0213] [00213] 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 geometric axis of the syringe. In addition, the pressure valve can project from the pressure chamber in the first position of the pressure valve. In addition, the pressure valve can be flush 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 flange at one end of the pressure valve protruding from the pressure chamber.
[0214] [00214] This valve flange can protrude from the pressure chamber in said first position, and the valve flange can be flush with the pressure chamber in said second position. The valve flange can then function as a stop flange for the pressure valve, that is, the pressure valve can be configured in such a way that the valve flange protrudes from the pressure chamber in the second position of the pressure valve. pressure.
[0215] [00215] 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. As also exemplified in these figures, the pressure valve can comprise a passage channel that forms the fluid passage 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.
[0216] [00216] 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.
[0217] [00217] 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, such that the opening extends in the longitudinal direction of the barrel when inserted into the pressure chamber.
[0218] [00218] 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 geometric 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 projections, 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 project to the narrowing in the first position of the pressure valve. A narrowing can be provided by means of one or more "lugs" of an internal side wall of the pressure chamber, as exemplified in figures 19c and 19d.
[0219] [00219] In an additional embodiment, the pressure valve projects 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.
[0220] [00220] 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, through an opening in the pressure chamber, for example, an opening in the lower part of the pressure chamber where an upper opening in the pressure chamber can be, where through the pressure valve it extends in the first position.
[0221] [00221] 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 bypass channel (s) The vacuum can (m) function as the lyophilization bypass channel, as described herein. 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.
[0222] [00222] Consequently, the one or more vacuum bypass channels can be configured to prevent the seal between the vacuum chamber and the plunger at a predefined 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.
[0223] [00223] 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 manufacturing 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.
[0224] [00224] However, alternatively, the vacuum chamber, the pressure chamber and the connecting portion can be formed as separate elements and configured to be assembled during the manufacture of the syringe.
[0225] [00225] 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.
[0226] [00226] 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 a flange 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 flange 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 flange 6 protrudes into the pressure chamber 3.
[0227] [00227] The cut-through illustrations in figure 18a and 18b show more clearly the configuration of the pressure valve 5. In the first position in figure 18a, the pressure valve blocks the fluid communication between the outlet 11 of the internal volume 2 ' vacuum chamber 2 and 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 volume inner 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 which can subsequently be released in a controlled manner via outlet 7, operating a plunger (not shown) arranged in barrel 1, 1 '. Barrel 1 'in figure 17a does not have a flange.
[0228] [00228] As seen from 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 has symmetrical rotation.
[0229] [00229] 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 in the vacuum chamber when the (wet) paste must be formed.
[0230] [00230] Vacuum bypass channels 9 are provided in figures 16-18 as longitudinally extending grooves 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 flush with the vacuum bypass channels 9, this seal is not tight 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 securely attaching the vacuum chamber 2, and subsequently keeping the lyophilized paste in a vacuum.
[0231] [00231] Another exemplary 1 ”barrel of the syringe currently described is exemplified in figure 20 with another embodiment of the pressure valve 5 'and the pressure chamber 3', in the manner illustrated in more detail in figure 19, with figure 19a showing a pressure valve closure alone. This 5 'pressure valve is thin and supplied 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 projects radially from the pressure chamber 3 'with respect to the longitudinal geometric axis of 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' inside 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 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 at 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 leveled with each other .
[0232] [00232] 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 project 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 '.
[0233] [00233] 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 single cycle injection molding. After manufacture, the pressure valve 5 'can be inserted through opening 16. The pressure valve 5' 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
[0234] [00234] In one embodiment, the dry composition is in the form of a leaf, that is, a substantially flat composition.
[0235] [00235] A dry composition in the form of a sheet can be obtained by spreading the paste of the invention finely and evenly on a surface, expanding the paste in a vacuum, freezing and drying the paste to obtain a substantially flat dry leaf composition. A dry composition in the form of a leaf will, upon contact with a liquid, spontaneously reconstitute itself, forming a paste. Thus, a dry composition in the form of a sheet has the advantages of both surgical sponges used traditionally in that it can cover relatively large areas, and the advantage of a paste in which it easily molds to uneven surfaces once moistened.
[0236] [00236] The dry composition in the form of a leaf is soft and flexible.
[0237] [00237] In one embodiment of the invention it refers to a dry composition in the form of a leaf for use in hemostasis and / or wound healing.
[0238] [00238] 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.
[0239] [00239] 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.
[0240] [00240] 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. Dry sheet 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.
[0241] [00241] In one embodiment, the dry leaf-shaped composition is cut into the desired shape, before use. Vacuum
[0242] [00242] According to the method of the present description, the paste is expanded by subjecting the paste to a reduced pressure, that is, at pressures below ambient pressure, that is, in general less than 100 kPa (1000 mbar) (a low vacuum). Vacuum expansion results in an increase in the total volume of the paste by expanding captured air or another gas in the interstitial pores or wet paste compartments.
[0243] [00243] The vacuum pressure is selected so that the paste expands to 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.
[0244] [00244] 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 the ideal, or universal, constant gas constant.
[0245] [00245] Submitting a wet paste to subatmospheric pressure results in an expansion of air or other gas in the paste's interstitial spaces (pores), which in turn leads to an increase in the total volume of the paste and a decrease in the density of the paste. 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 reduced pressure.
[0246] [00246] 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.
[0247] [00247] In one embodiment, the density of the paste is decreased by about a factor 0.75 as a result of the vacuum expansion.
[0248] [00248] 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.
[0249] [00249] 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.
[0250] [00250] After vacuum expansion, the density of the wet paste 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.
[0251] [00251] 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.
[0252] [00252] 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.
[0253] [00253] 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.
[0254] [00254] 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.
[0255] [00255] 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.
[0256] [00256] 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.
[0257] [00257] In one embodiment, the pulp is subjected to a reduced pressure of at least 1 kPa (10 mbar) less than the ambient pressure, for example, at least 5 kPa (50 mbar) less than the ambient pressure, such as at at least 10 kPa (100 mbar) less than the ambient pressure, for example, at least 15 kPa (150 mbar) less than the ambient pressure, such as at least 20 kPa (200 mbar) less than the ambient pressure, for example, at minus 25 kPa (250 mbar) less than ambient pressure, such as at least 30 kPa (300 mbar) less than ambient pressure, for example, at least 35 kPa (350 mbar) less than ambient pressure, such as at least 40 kPa (400 mbar) less than ambient pressure, for example, at least 45 kPa (450 mbar) less than pressure, such as at least 50 kPa (500 mbar) less than ambient pressure, for example, at least 55 kPa (550 mbar) less than ambient pressure, such as at least 60 kPa (600 mbar) less than ambient pressure, for example, at least 65 kPa (650 mbar) less than the pressure, such as at least 70 kPa (700 mbar) less than the ambient pressure, for example, at least 75 kPa (750 mbar) less than the ambient pressure, such as at least 80 kPa (800 mbar) less than the ambient pressure, for example, at least 85 kPa (850 mbar) less than the ambient pressure, such as at least 90 kPa (900 mbar) less than the pressure.
[0258] [00258] The vacuum pressure is preferably selected so that the pressure is at least 5 kPa (50 mbar) less than the ambient pressure, but no more than 90 kPa (900 mbar) less than the ambient pressure, such as at least 10 kPa (100 mbar) less than ambient pressure, but not more than 80 kPa (800 mbar) less than ambient pressure.
[0259] [00259] The vacuum pressure is preferably selected, such that the pressure is no more than 100 kPa (1000 mbar) less than the ambient pressure, such as no more than 90 kPa (900 mbar) less than the ambient pressure, example, no more than 80 kPa (800 mbar) less than ambient pressure, just as no more than 70 kPa (700 mbar) less than ambient pressure, for example, no more than 60 kPa (600 mbar) less than ambient pressure, such as no more than 50 kPa (500 mbar) less than the ambient pressure.
[0260] [00260] In one embodiment, the vacuum pressure is between less than 100 kPa (1000 mbar) and 10 kPa (100 mbar), such as between 95 Kpa (950 mbar) and 10 kPa (100 mbar), for example, between 90 kPa (900 mbar) and 10 kPa (100 mbar), such as between 85 kPa (850 mbar) and 10 kPa (100 mbar), for example, between 80 kPa (800 mbar) and 10 kPa (100 mbar), as between 75 kPa (750 mbar) and 10 kPa (100 mbar), for example, between 70 kPa (700 mbar) and 10 kPa (100 mbar), such as between 65 kPa (650 mbar) and 10 kPa (100 mbar) , for example, between 60 kPa (600 mbar) and 10 kPa (100 mbar), such as between 55 kPa (550 mbar) and 10 kPa (100 mbar), for example, between 50 kPa (500 mbar) and 10 kPa ( 100 mbar), such as between 45 kPa (450 mbar) and 10 kPa (100 mbar), for example, between 40 kPa (400 mbar) and 10 kPa (100 mbar), such as between 35 kPa (350 mbar) and 10 kPa (100 mbar), for example, between 30 kPa (300 mbar) and 10 kPa (100 mbar), such as between 25 kPa (250 mbar) and 10 kPa (100 mbar), for example, between 20 kPa (200 mbar) ) and 10 kPa (100 mbar).
[0261] [00261] In one embodiment, the vacuum pressure is between less than 100 kPa (1000 mbar) and 20 kPa (200 mbar), such as between 100 kPa (1000 mbar) and 25 kPa (250 mbar), for example, between 1000 mbar and 30 kPa (300 mbar), such as between 100 kPa (1000 mbar) and 35 kPa (350 mbar), for example, between 100 kPa (1000 mbar) and 40 kPa (400 mbar), such as between 100 kPa (1000 mbar) and 45 kPa (450 mbar), for example, between 100 kPa (1000 mbar) and 50 kPa (500 mbar), such as between 100 kPa (1000 mbar) and 55 kPa (550 mbar), for example, between 100 kPa (1000 mbar) and 60 kPa (600 mbar), such as between 100 kPa (1000 mbar) and 65 kPa (650 mbar), for example, between 100 kPa (1000 mbar) and 70 kPa (700 mbar), such as between 100 kPa (1000 mbar) and 75 kPa (750 mbar), for example, between 100 kPa (1000 mbar) and 80 kPa (800 mbar), such as between 100 kPa (1000 mbar) and 85 kPa (850 mbar) ), for example, between 100 kPa (1000 mbar) and 90 kPa (900 mbar), such as between 100 kPa (1000 mbar) and 95 Kpa (950 mbar).
[0262] [00262] In a preferred embodiment, the vacuum pressure is between about 90 kPa (900 mbar) and 50 kPa (500 mbar).
[0263] [00263] 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. Low vacuum levels, according to the present description, are reached almost instantaneously, thus, the expansion of the slurry essentially occurs instantly after the start of the vacuum pump.
[0264] [00264] 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 at 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. Folder freeze
[0265] [00265] When the paste of the invention is expanded to a desired degree, the paste is generally frozen by subjecting the paste to a temperature below 0 ° C for a period of time sufficient for the paste 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 will not affect the volume of the frozen paste. Freezing is preferably carried out in a freeze dryer.
[0266] [00266] The temperature selected to freeze the paste depends on 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 lower 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. Dry the paste
[0267] [00267] According to the invention, the hemostatic paste is dried to obtain the dry hemostatic composition. The paste can be dried by any of the suitable methods known to those skilled in the art.
[0268] [00268] In a preferred embodiment, the paste is lyophilized. Any appropriate lyophilization technique and equipment known to a person skilled in the art may be used. When lyophilization is used to prepare the dry paste composition of the present invention, expansion, freezing and drying can be advantageously carried out as a continuous process in a simple apparatus.
[0269] [00269] Lyophilization (also known as freeze-drying) is a dehydration process, typically used to preserve a perishable material or to take the most suitable material 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.
[0270] [00270] There are basically three categories of freeze driers: the collector-type freeze dryer, the rotary freeze dryer and the tray-type freeze dryer. Two components are common to all types of lyophilisers: 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 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, generally circular tube is used to connect multiple containers with the dry product to a condenser. The rotary and tray freeze-dryers have a single large reservoir for the dry substance.
[0271] [00271] 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.
[0272] [00272] 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 bound water and produce a lower moisture content.
[0273] [00273] 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 dryers 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.
[0274] [00274] 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.
[0275] [00275] 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 lyophilization 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 upstream devices.
[0276] [00276] There are four stages of the complete lyophilization process: pre-treatment, freezing, primary drying and secondary drying.
[0277] [00277] Pre-treatment includes any method of treating the product before freezing. This can include product concentration, revision of the formulation (i.e., 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.
[0278] [00278] In a laboratory, freezing is often performed by placing the material in a lyophilization 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 it can be cycled up and down in temperature. 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.
[0279] [00279] 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.
[0280] [00280] 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, about 95% of the material's water 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.
[0281] [00281] In this phase, the pressure is controlled by applying 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 the water vapor to re-solidify. 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.
[0282] [00282] 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.
[0283] [00283] 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:
[0284] [00284] 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 increased 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 benefit from increased pressure as well.
[0285] [00285] After the lyophilization process is complete, the vacuum can be broken with an inert gas, such as nitrogen, before the material is sealed
[0286] [00286] In one embodiment, the vacuum is maintained in the product chamber to allow easy addition of liquid for reconstitution.
[0287] [00287] 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.
[0288] [00288] 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.
[0289] a. fornecer um agente na forma de pó e um meio aquoso, b. misturar o agente na forma de pó e o meio aquoso para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, e d. secar a pasta por calor seco. [00289] In an alternative embodiment of the present description, the expanded paste is not frozen prior to the drying of the paste. Neither 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 to 200 ° C, such as about 50 ° C to about 150 ° C. Thus, in an alternative embodiment, the method of the present description is a method for preparing a dry composition that comprises the steps of: The. provide a powdered agent and an aqueous medium, B. mix the agent in powder form and the aqueous medium to obtain a folder, ç. subject the paste to reduced pressure, while expanding the paste, and d. dry the paste by dry heat.
[0290] [00290] The present inventors have observed that expanding a wet pulp composition by vacuum, preferably low vacuum, before lyophilization greatly improves the rate of reconstitution of said pulp. Thus, a slurry that has been expanded under low vacuum reconstitutes faster than a comparable dry slurry composition, which has not been expanded by low vacuum. A paste that has been expanded by vacuum and dried will spontaneously reconstitute to form a substantially homogeneous fluid paste without any mechanical mixing. For example, a vacuum-expanded dry gelatin paste composition that is present in a medical delivery device will reconstitute into a ready-to-use paste, suitable for direct distribution to a patient with no mechanical mixing required, with the addition of an amount of an aqueous medium in the medical delivery device with the dry gelatin paste composition discarded there.
[0291] [00291] The vacuum expansion expands the pockets of air captured in the paste and such expanded air pockets are kept in the dry paste composition. The presence of larger air pockets in the dry composition makes it possible to humidify the dry composition due to a greater contact surface area between the dry composition and the liquid. It also facilitates the free distribution of the liquid in the dry composition, due to the channels formed.
[0292] [00292] The inventors also found that the volume of a paste aliquot is generally greater in samples that are aliquoted first, as opposed to the last of a single batch of paste. This is known to be due to a partial collapse of the pulp that occurs over time, causing variations in the density of the pulp. Such variations in density can lead to undesirable variations in the reconstitution period. The vacuum expansion of the pulp before drying allows the reduction or elimination of such "intrabatelada" variation in the pulp density and, thus, leads to the consistently rapid reconstitution of the dry pulps. Thus, vacuum expansion provides a greater degree of reproducibility with respect to reconstitution time.
[0293] [00293] The dry composition can be reconstituted by adding a suitable aqueous medium. The aqueous medium can be added by any suitable mechanism. Preferably, the aqueous medium is sterile. The aqueous medium is added in an amount sufficient to obtain a moist paste of a desired consistency. 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 case a thinner paste composition is desired, more liquid can be added to the dry paste than was initially removed by the drying procedure.
[0294] [00294] Preferably, the paste is reconstituted by adding an amount of liquid to a container, such as a medical delivery device, with the dry paste composition dispersed in it, even more preferably in the same container that kept the paste during the expansion steps vacuum, freezing and drying.
[0295] [00295] In one embodiment, the dry composition is reconstituted by attaching a second container containing an amount of an aqueous medium to the first container containing the dry composition. The first container containing the dry composition is preferably a syringe, such as the vacuum chamber of the syringe described herein.
[0296] [00296] 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.
[0297] [00297] 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.
[0298] [00298] 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 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.
[0299] a. fornecer um primeiro recipiente compreendendo uma câmara de produto que contém uma composição de pasta seca e uma válvula, preferivelmente em que a pressão na câmara de produto é menor que a pressão atmosférica ao redor, b. fornecer um segundo recipiente compreendendo um meio aquoso, preferivelmente em que a pressão no segundo recipiente é maior que a pressão na câmara de produto do primeiro recipiente, c. colocar o primeiro recipiente e o segundo recipiente em contato, usando meios de conexão adequados, e d. abrir a válvula. [00299] Thus, in one embodiment, the present description refers to a method for reconstituting a dry paste composition that comprises the steps of: The. providing a first container comprising a product chamber containing a dry paste composition and a valve, preferably where the pressure in the product chamber is less than the surrounding atmospheric pressure, B. providing a second container comprising an aqueous medium, preferably where the pressure in the second container is greater than the pressure in the product chamber of the first container, ç. bring the first container and the second container into contact, using suitable connection means, and d. open the valve.
[0300] [00300] In one embodiment, the second container is a removable container, 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.
[0301] [00301] In one 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.
[0302] [00302] Preferably, 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 paste composition is present in a medical delivery 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 delivery device doctor on an open wound.
[0303] [00303] In a preferred embodiment, a ready-to-use paste forms in less than about 5 seconds, such as less than about 3 seconds, for example, less than about 2 seconds.
[0304] [00304] After reconstitution, the container, for example, a syringe, such as the syringe described here, can be adjusted with a suitable applicator tip to more precisely deliver the paste, as illustrated in figure 14.
[0305] [00305] 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. Outdoor packaging
[0306] [00306] In one embodiment, the dry composition contained, for example, in a syringe, such as the syringe described here, or another containment unit, is still contained within an outer packaging, so that the product is kept sterile until to its use. This will allow the user to remove the outer packaging and transfer the hemostatic composition to a sterile environment. Here, a suitable amount of aqueous medium can be added, after which, a hemostatic paste will spontaneously form ready to be used within seconds without any need to move, mechanically shake, or stir.
[0307] [00307] The outer packaging is generally made of a semi-rigid, flexible 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.
[0308] [00308] In one embodiment, the outer packaging is an outer packaging of aluminum foil.
[0309] [00309] The outer packaging preferably forms a complete moisture barrier.
[0310] [00310] The outer packaging is preferably capable of withstanding a sterilization treatment, such as by radiation. Sterilization
[0311] [00311] The dry composition of the present description is preferably sterile. Any suitable sterilization technique known in the art can be used. Sterilization preferably takes place after the packaging step, that is, when the dry composition is contained within an outer packaging. Thus, in a preferred embodiment, sterilization is terminal sterilization
[0312] [00312] 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. Heat sterilization 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.
[0313] [00313] In one embodiment, the dry composition is sterilized by radiation, for example, ionizing radiation, in order to provide the composition with sterility. Such radiation may include e-beam (beta radiation) or gamma radiation. The radiation level and sterilization conditions, 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, a person skilled in the art will be able to easily determine the level of radiation required to provide sterile compositions.
[0314] [00314] 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 radiation.
[0315] [00315] In one embodiment, sterilization is performed with ethylene oxide.
[0316] [00316] Sterilization with dry heat can typically occur by heating the dry composition to a temperature 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 120 to 150 ° C. Heat sterilization is generally not used when the dry composition contains thrombin, since heat treatment can inactivate thrombin.
[0317] [00317] In one embodiment, the dry hemostatic composition is not sterilized after packaging. When the dry hemostatic composition is manufactured by aseptic production techniques, the product is already sterile, when placed in the outer packaging, and no further sterilization is necessary. Thus, in one embodiment of the present description it refers to a composition produced by aseptic techniques. Medical use
[0318] [00318] The present description also refers to the use of the paste obtained from the dry composition to promote hemostasis and / or wound healing.
[0319] [00319] The paste of the present description can, for example, be used in a variety of surgical procedures in which bleeding control is desired. The hemostatic paste molds to uneven surfaces to stop bleeding quickly and is therefore useful for providing rapid hemostasis on rough or uneven surfaces where hemostatic sponges are not effective.
[0320] [00320] Hemostatic pastes are prepared directly at the surgical site, in the time necessary by the medical professional, that is, doctors or nurses, by adding liquid to a container, such as a syringe, containing a quantity 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 it is therefore 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 use as a hemostatic paste and that the consistency of the product is independent of the preparation for preparation and over time.
[0321] [00321] The currently available slurry products (Floseal® and Surgiflo®) require mechanical mixing by passing the biocompatible polymer and the liquid between two syringes connected numerous times to obtain a substantially homogeneous paste. Such products are often pre-prepared in the OR prior to surgery, in case they are needed in surgery and the unused product is often discarded causing unnecessary high OR costs.
[0322] [00322] The paste of this description is superior to the flowable products currently available as it reduces or prevents the need for mechanical mixing steps. The paste of the present description can be prepared simply by adding an amount of an aqueous medium to a container comprising the dry composition, after which a ready-to-use hemostatic paste forms spontaneously, that is, in less than about 30 seconds. and, preferably in less than about 20 seconds and, more preferably in less than about 10 seconds, even more preferably in less than about 5 seconds, such as less than about 3 seconds or even less about 2 seconds. When the dry composition of the present invention is contained in a medical vacuum delivery device in the manner described herein, the aqueous medium is automatically drawn into the product chamber due to the pressure difference, and the dry composition spontaneously reconstitutes itself in a composition. fluid ready to use. The slurry can be extruded from the medical delivery device and applied to a patient, for example, on an open wound, within seconds of coming into contact with the aqueous medium.
[0323] [00323] The amount of liquid to be added to the dry composition can be adjusted by a person skilled in the art. The paste thus formed generally has an optimal consistency 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. Likewise, the dry composition of the present description can decrease the costs of the surgical block, since it is not necessary to pre-prepare the current product before surgery since the preparation is very simple and quick.
[0324] [00324] 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 drainable products.
[0325] [00325] 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 as described herein, comprised in a medical delivery device, and a container comprising an aqueous medium for reconstitution. Upon connection of the two, a ready-to-use slurry containing all the agents necessary for efficient hemostasis, including thrombin, is formed spontaneously when the aqueous medium is automatically drawn into the vacuum-expanded dry composition. Thus, no extra syringes, 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.
[0326] [00326] 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 reconstituted paste of the present description to the bleeding site.
[0327] [00327] 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, endocrine surgery, breast surgery, skin surgery, otolaryngology, gynecology, oral and maxillofacial surgery, dental surgery, orthopedic surgery, neurosurgery, ophthalmology, pediatric surgery, urology.
[0328] [00328] 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 the wound.
[0329] [00329] 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.
[0330] [00330] 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.
[0331] [00331] 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.
[0332] [00332] 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). It is more preferably that the 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.
[0333] [00333] In one embodiment the present description refers to a lyophilized paste expanded in a vacuum, such as the dry composition currently presented, for use in the treatment of a wound, for example, to contain bleeding or to promote wound healing. A hemostatic kit
[0334] [00334] 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 spontaneously, that is, within seconds.
[0335] a. um primeiro recipiente compreendendo a composição seca obtida pelo método da presente descrição, b. um segundo recipiente compreendendo um meio aquoso, e c. opcionalmente um acondicionamento exterior. [00335] Consequently, in one embodiment the present description refers to a hemostatic kit comprising: The. a first container comprising the dry composition obtained by the method of the present description, B. a second container comprising an aqueous medium, and ç. optionally an outer packaging.
[0336] a. a seringa atualmente descrita compreendendo uma composição seca b. um recipiente compreendendo um meio aquoso, e c. opcionalmente um acondicionamento exterior. [00336] In an additional embodiment, the present description refers to a hemostatic kit comprising: The. the currently described syringe comprising a dry composition B. a container comprising an aqueous medium, and ç. optionally an outer packaging.
[0337] [00337] 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.
[0338] [00338] The aqueous medium used to reconstitute the paste can, for example, be selected from water, saline, a solution of calcium chloride or a buffered aqueous solution.
[0339] [00339] In one embodiment, the aqueous medium used to reconstitute the dry composition is water. Preferably, the isotonicity of the aqueous medium is selected so that an isotonic paste will form after the addition of the aqueous medium in the dry composition.
[0340] [00340] In one embodiment, the aqueous medium used to reconstitute the dry composition is saline or a calcium chloride solution.
[0341] [00341] In one embodiment, the dry composition comprises thrombin.
[0342] [00342] In one embodiment, the kit additionally comprises one or more applicator tips.
[0343] [00343] The kit can optionally contain instructions for using the kit. Example 1 Materials 50 g gelatin powder (ground crosslinked gelatin sponges) 200 mL of buffer xg of Polyol 50% benzalkonium chloride (BAC) 0.9% saline Equipment Freeze dryer: Christ Alpha 1-4 LSC Mixer: Kenwood, Major KM616 Method
[0344] [00344] Buffer solution: Add 2.0 g ± 0.1 g BAC (50%) to a 250 ml blue cap bottle Add 98.0 g ± 0.5 g of water to the BAC Mix for 2 minutes using magnetic stirring, that is, it is the BAC stock solution Add 10 g ± 0.5 g of BAC stock solution Add water to the 2000 mL mark Put a stopper on the bottle and turn it upside down a few times Mix by magnetic stirring for 5 ± 1 minutes Folder:
[0345] [00345] 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. Lyophilization:
[0346] [00346] The resulting paste was filled in 10 ml single-use plastic syringes (5.5 ml per syringe) comprising a lyophilization bypass 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 dryer shelves were dismantled, thereby moving the plunger and the lyophilization bypass channel. The pressure in the lyophilizer chamber was then brought to room pressure, leaving a vacuum in the product chamber. Reconstitution:
[0347] [00347] The dry hemostatic composition was reconstituted by placing the syringe comprising the dry composition in contact with a collapsible 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 water to be automatically drawn into the syringe from the container that contains the water. Results
[0348] [00348] 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.
[0349] [00349] 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.
[0350] [00350] The polyol: gelatin ratio in the dry compositions was approximately 0.4: 1.
[0351] [00351] 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.
[0352] [00352] 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
[0353] [00353] 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.
[0354] [00354] 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 (dry) composition respectively.
[0355] [00355] The total concentration of polyol, ie mannitol and glycerol, in the paste was 13.56% and after drying 42.27%.
[0356] [00356] The polyol: gelatin ratio in the dry composition was approximately 0.75: 1.
[0357] [00357] The paste was dried by lyophilization and reconstituted in the manner described in Example 1.
[0358] [00358] Thrombin activity was measured in the reconstituted paste. The results are shown in the table below.
[0359] [00359] No loss of thrombin activity was measured in the reconstituted paste.
[0360] [00360] 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
[0361] [00361] 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.
[0362] [00362] The prepared pastes were either lyophilized directly in the manner described in example 1 (standard lyophilization) or subjected to a low vacuum of about 85 kPa (850 mbar), followed by a freezing step at -40 ° C without releasing the vacuum, and finally lyophilized essentially in the manner described in example 1 (expanded vacuum lyophilization). Vacuum expansion was performed at room temperature, that is, about 20 ° C. Upon exposure of the pastes to decreased pressure, ie vacuum, the pastes expanded in volume almost instantly.
[0363] [00363] Before the vacuum expansion, the gelatin paste density 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.
[0364] [00364] 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.
[0365] [00365] 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).
[0366] [00366] 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 expanded by vacuum. Reconstitution did not require any mechanical stirring, mixing or stirring of any kind, and a paste ready for hemostatic use of a consistency suitable for direct use in hemostatic procedures was formed in seconds. Example 4. Density of dry expanded vacuum paste
[0367] [00367] Gelatin pastes comprising mannitol were prepared in the manner described in examples 1 and 3. The pastes were vacuum expanded using different vacuum levels (100 kPa (1000 mbar) (in vacuum), 85 kPa (850 mbar) and 60 kPa (600 mbar)) and then frozen and lyophilized, as described in example 3.
[0368] [00368] The density of dry paste compositions is shown in the following table and in figure 15.
[0369] [00369] The dry compositions reconstitute spontaneously to form soft and moist pastes suitable for hemostatic and / or wound healing.
[0370] [00370] The results show that different pressures can be used to expand the paste before drying.
[0371] [00371] 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
[0372] [00372] 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 vacuum deviation, 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.
[0373] [00373] 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 85 kPa (850 mbar), 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 performed at room temperature, that is, about 20 ° C.
[0374] [00374] 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.
[0375] [00375] The average reconstitution time for dry paste compositions is shown in the table below and in figure 21. Each experiment was repeated 5 times (n = 5).
[0376] [00376] 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.
[0377] [00377] 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.
[0378] [00378] 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.
[0379] [00379] 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 last ones, 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 paste before drying is able to reduce or even eliminate such differences in the density of the paste, which may occur between the first and last portion of the pastes that are aliquoted from a single batch paste.
[0380] [00380] 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 paste compositions. In addition, the inclusion of hydrophilic compounds, such as polyols, in the dry pulp compositions also improved the consistency of the reconstituted pulps. Additional details of this description
[0381] a. fornecer um agente na forma de pó e um meio aquoso, b. misturar o agente na forma de pó e o meio aquoso para obter uma pasta, c. submeter a pasta a uma pressão reduzida, expandindo ao mesmo tempo a pasta, d. congelar a pasta expandida, e e. secar a pasta. 2. O método de acordo com item 1, em que a pressão reduzida é uma pressão de pelo menos 5 kPa (50 mbar) menor que a pressão ambiente, tal como pelo menos 10 kPa (100 mbar) menor que a pressão ambiente, por exemplo, pelo menos 15 kPa (150 mbar) menor que a pressão ambiente, tal como pelo menos 20 kPa (200 mbar) menor que a pressão ambiente, por exemplo, pelo menos 25 kPa (250 mbar) menor que a pressão ambiente, tal como pelo menos 30 kPa (300 mbar) menor que a pressão ambiente, por exemplo, pelo menos 35 kPa (350 mbar) menor que a pressão ambiente, tal como pelo menos 40 kPa (400 mbar) menor que a pressão ambiente, por exemplo, pelo menos 45 kPa (450 mbar) menor que a pressão, tal como pelo menos 50 kPa (500 mbar) menor que a pressão ambiente, por exemplo, pelo menos 55 kPa (550 mbar) menor que a pressão, tal como pelo menos 60 kPa (600 mbar) menor que a pressão ambiente, por exemplo, pelo menos 65 kPa (650 mbar) menor que a pressão, tal como pelo menos 70 kPa (700 mbar) menor que a pressão ambiente, por exemplo, pelo menos 75 kPa (750 mbar) menor que a pressão ambiente, tal como pelo menos 80 kPa (800 mbar) menor que a pressão ambiente, por exemplo, pelo menos 85 kPa (850 mbar) menor que a pressão ambiente, tal como pelo menos 90 kPa (900 mbar) menor que a pressão.3. O método de acordo com qualquer um dos itens precedentes, em que o volume da pasta é aumentado em cerca de um fator 1,05 a cerca de um fator 2,0, tal como cerca de um fator 1,1 a cerca de um fator 1,8, por exemplo, cerca de um fator 1,2 a cerca de um fator 1,6 como um resultado da pressão reduzida.4. O método de acordo com qualquer um dos itens precedentes, em que a densidade da pasta é diminuída em pelo menos um fator 0,95 como um resultado da expansão a vácuo, tal como pelo menos um fator 0,90, por exemplo, pelo menos um fator 0,85, tal como pelo menos um fator 0,80, por exemplo, pelo menos um fator 0,75, tal como pelo menos um fator 0,70, por exemplo, pelo menos um fator 0,65, tal como pelo menos um fator 0,60, por exemplo, pelo menos um fator 0,55, tal como pelo menos um fator 0,50 como um resultado da expansão a vácuo.5. O método de acordo com qualquer um dos itens precedentes, em que o agente na forma de pó é um polímero biocompatível.6. O método de acordo com qualquer um dos itens precedentes, em que o agente na forma de pó é reticulado.7. O método de acordo com qualquer um dos itens precedentes, em que o agente na forma de pó é biologicamente absorvível.8. O método de acordo com qualquer um dos itens precedentes, em que o agente na forma de pó é gelatina.9. O método de acordo com qualquer um dos itens precedentes, em que a secagem é liofilização.10. O método de acordo com qualquer um dos itens precedentes, em que a secagem resulta em uma composição seca que compreende menos de cerca de 5% de água, preferivelmente menor que cerca de 2% de água.11. O método de acordo com qualquer um dos itens precedentes, em que o agente na forma de pó e o meio aquoso é misturado com um ou mais compostos hidrofílicos.12. O método de acordo com item 11, em que a pasta compreende antes da secagem cerca de 2% a cerca de 40% de um ou mais compostos hidrofílicos, por exemplo, de cerca de 2% a cerca de 30% de um ou mais compostos hidrofílicos, tal como de cerca de 2% a cerca de 25% de um ou mais compostos hidrofílicos, por exemplo, de cerca de 2% a cerca de 20% de um ou mais compostos hidrofílicos, tal como de cerca de 2% a cerca de 18% de um ou mais compostos hidrofílicos, por exemplo, de cerca de 2% a cerca de 17% de um ou mais compostos hidrofílicos, tal como de cerca de 2% a cerca de 16% de um ou mais compostos hidrofílicos, por exemplo, de cerca de 2% a cerca de 15% de um ou mais compostos hidrofílicos.13. O método de acordo com qualquer um dos itens 11 a 12, em que a pasta antes da secagem compreende: a. de cerca de 2% a cerca de 40% de um ou mais compostos hidrofílicos, b. de cerca de 10% a cerca de 60% do agente na forma de pó, e c. de cerca de 50% a cerca de 90% de água. 14. O método de acordo com qualquer um dos itens 11 a 12, em que a pasta antes da secagem compreende: a. de cerca de 5% a cerca de 20% de um ou mais composto hidrofílicos, b. de cerca de 15% a cerca de 25% do agente na forma de pó, e c. de cerca de 60% a cerca de 80% de água. 15. O método de acordo com qualquer um dos itens 11 a 14, em que o um ou mais compostos hidrofílicos são um ou mais polióis.16. O método de acordo com item 15, em que o um ou mais polióis é selecionado de álcoois de açúcar, açúcares e/ou derivados do mesmo.17. O método de acordo com item 16, em que o um ou mais álcoois de açúcar é selecionado do grupo que consiste em glicol, glicerol, eritritol, treitol, arabitol, xilitol, ribitol, manitol, sorbitol, dulcitol, fucitol, iditol, inositol, volemitol, isomalte, maltitol, lactitol e poliglicitol.18. O método de acordo com qualquer dos itens 15 a 17, em que o um ou mais polióis é manitol e opcionalmente um ou mais compostos adicionais hidrofílicos.19. O método de acordo com qualquer um dos itens precedentes, em que a composição seca compreende adicionalmente um ou mais agentes bioativos capaz de estimular hemostase, cicatrização de feridas, cicatrização óssea, cicatrização de tecido e/ou cicatrização de tendão.20. O método de acordo com item 19, em que o agente bioativo é trombina.21. O método de acordo com qualquer um dos itens precedentes, em que o meio aquoso é selecionado do grupo que consiste em água, salina, uma solução de cloreto de cálcio e um meio aquoso tamponado.22. O método de acordo com qualquer um dos itens precedentes, em que o método compreende uma etapa adicional de colocar a composição seca em um acondicionamento exterior, tal como um acondicionamento de folha de alumínio.23. O método de acordo com qualquer um dos itens precedentes, em que o método compreende uma etapa adicional de esterilizar a composição seca.24. O método de acordo com qualquer um dos itens precedentes, em que a composição seca reconstitui sem mistura mecânica para formar uma pasta pronta para uso em menos de cerca de 30 segundos, preferivelmente em menos de cerca de 20 segundos, mais preferivelmente em menos de cerca de 10 segundos, ainda mais preferivelmente em menos de cerca de 5 segundos, tal como menor que cerca de 3 segundos, por exemplo, menor que cerca de 2 segundos.25. Uma composição de pasta úmida, que é uma pasta úmida expandida a vácuo, com uma densidade de entre cerca de 0,2 g/mL a cerca de 0,6 g/mL, mais preferivelmente entre cerca de 0,3 g/mL a cerca de 0,6 g/mL, tal como entre cerca de 0,4 g/mL a cerca de 0,5 g/mL.26. Uma composição seca obtida pelo método de qualquer dos itens 1 a 24.27. Uma composição seca que é uma pasta liofilizada expandida a vácuo com uma densidade entre cerca de 1 mg/mL a cerca de 40 mg/mL, tal como entre cerca de 5 mg/mL a cerca de 35 mg/mL, por exemplo, entre cerca de 10 mg/mL a cerca de 35 mg/mL.28. Uma seringa para manter uma pasta liofilizada em um vácuo compreendendoum barril compreendendouma câmara a vácuo para conter a pasta com uma extremidade proximal e uma extremidade distal abertas com uma primeira abertura de fluido, - uma porção conectora com uma segunda abertura de fluido e adaptada para se conectar a um receptor de líquido, e - uma câmara de pressão que conecta a porção conectora e a extremidade distal da câmara a vácuo, - uma válvula de pressão localizada na câmara de pressão e adaptada para vedar a primeira e segunda abertura de fluidos em uma primeira posição e formar/criar uma passagem de fluido entre a primeira e segunda abertura de fluidos em uma segunda posição, - um êmbolo configurado para ser deslocado axialmente na câmara a vácuo por meio da extremidade proximal aberta, e - um ou mais canais de desvio a vácuo. 29. A seringa de acordo com qualquer dos itens precedentes 28, em que o barril compreende um flange na extremidade proximal da câmara a vácuo.30. A seringa de acordo com qualquer dos itens precedentes 28 a 29, em que a seringa é adaptada para manter a composição seca de acordo com item 26.31. A seringa de acordo com qualquer dos itens precedentes 28 a 30, em que a pasta seca congelada é obtida pelo método de acordo com qualquer um dos itens 1 a 24.32. A seringa de acordo com qualquer dos itens precedentes 28 a 31, em que a porção conectora é um conector Luer lock ou Luer slip, preferivelmente um conector Luer lock ou Luer slip macho.33. A seringa de acordo com qualquer dos itens precedentes 28 a 32, em que a porção conectora compreende uma porção em rosca.34. A seringa de acordo com qualquer dos itens precedentes 28 a 33, em que a válvula de pressão é localizada na câmara de pressão e adaptada para vedar a primeira e segunda abertura de fluidos em uma primeira posição na câmara de pressão, e formar/criar uma passagem de fluido entre a primeira e segunda abertura de fluidos em uma segunda posição na câmara de pressão.35. A seringa de acordo com qualquer dos itens precedentes 28 a 34, em que a câmara de pressão é localizada entre a câmara a vácuo e a segunda abertura de fluido.36. A seringa de acordo com qualquer dos itens precedentes 28 a 35, em que a câmara de pressão compreende uma extremidade proximal ao lado da extremidade distal da câmara a vácuo e uma extremidade distal ao lado de uma extremidade proximal da porção conectora.37. A seringa de acordo com qualquer dos itens precedentes 28 a 36, em que a porção conectora compreende uma extremidade proximal ao lado de uma extremidade distal da câmara de pressão e uma extremidade distal adaptada para se conectar a um receptor de líquido.38. A seringa de acordo com qualquer dos itens precedentes 28 a 37, em que a segunda abertura de fluido forma um canal alongado através da porção conectora.39. A seringa de acordo com qualquer dos itens precedentes 28 a 38, em que a segunda abertura de fluido compreende uma extremidade proximal ao lado de uma extremidade distal da câmara de pressão e uma extremidade distal para entrada e saída de fluido.40. A seringa de acordo com qualquer dos itens precedentes 28 a 39, em que a válvula de pressão é adaptada para vedar uma extremidade distal da primeira abertura de fluido e uma extremidade proximal da segunda abertura de fluido na dita primeira posição.41. A seringa de acordo com qualquer dos itens precedentes 28 a 33, em que o interior da câmara de pressão é cilíndrico.42. A seringa de acordo com qualquer dos itens precedentes 28 a 41, em que a válvula de pressão compreende uma ranhura, e em que a ranhura forma a passagem de fluido na segunda posição da válvula de pressão.43. A seringa de acordo com qualquer dos itens precedentes 28 a 42, em que a válvula de pressão compreende duas seções cilíndricas axialmente divididas por uma ranhura, e em que a ranhura forma a passagem de fluido na segunda posição da válvula de pressão.44. A seringa de acordo com qualquer dos itens precedentes 28 a 43, em que a primeira e segunda posições da válvula de pressão são deslocadas radialmente com relação ao eixo geométrico longitudinal da seringa.45. A seringa de acordo com qualquer dos itens precedentes 28 a 44, em que a válvula de pressão se projeta da câmara de pressão na dita primeira posição.46. A seringa de acordo com qualquer dos itens precedentes 28 a 45, em que a válvula de pressão é nivelada com e/ou limita a câmara de pressão na dita segunda posição.47. A seringa de acordo com qualquer dos itens precedentes 28 a 46, em que a válvula de pressão compreende um flange de válvula em uma extremidade da válvula de pressão que se projeta a partir da câmara de pressão e em que dito flange de válvula se projeta a partir da câmara de pressão na dita primeira posição, e em que dito flange de válvula é nivelado com e/ou faz contato com a câmara de pressão em dita segunda posição.48. A seringa de acordo com qualquer dos itens precedentes 28 a 47, em que o primeira e segunda posições da válvula de pressão são deslocadas de maneira rotativa.49. A seringa de acordo com qualquer dos itens precedentes 28 a 48, em que a válvula de pressão compreende um canal de passagem que forma a passagem de fluido na segunda posição da válvula de pressão.50. A seringa de acordo com qualquer dos itens precedentes 28 a 49, em que a válvula de pressão compreende uma seção cilíndrica com um canal radial de passagem formando a passagem de fluido na segunda posição da válvula de pressão.51. A seringa de acordo com qualquer dos itens precedentes 28 a 50, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a segunda posição da válvula de pressão seja uma posição fechada.52. A seringa de acordo com qualquer dos itens precedentes 28 a 51, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a válvula de pressão seja axialmente fechada na segunda posição da válvula de pressão.53. A seringa de acordo com qualquer dos itens precedentes 28 a 52, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a válvula de pressão seja fechada de maneira rotativa na segunda posição da válvula de pressão.54. A seringa de acordo com qualquer dos itens precedentes 28 a 53, em que o dito um ou mais canais de desvio a vácuo são configurados para fornecer um fluido, tal como uma comunicação gasosa, entre a câmara a vácuo e a atmosfera ambiente.55. A seringa de acordo com qualquer dos itens precedentes 28 a 54, em que a seringa é configurada de maneira tal que o êmbolo se liga de maneira vedada à câmara a vácuo em pelo menos uma primeira posição axial do êmbolo dentro da câmara a vácuo, e de maneira tal que a comunicação do fluido seja estabelecida através do êmbolo em pelo menos uma segunda posição axial do êmbolo dentro da câmara a vácuo, por meio de um ou mais canais de desvio a vácuo.56. A seringa de acordo com qualquer dos itens precedentes 28 a 55, em que o dito um ou mais canais de desvio a vácuo são configurados para interromper a vedação entre a câmara a vácuo e o êmbolo em uma posição axial predefinida do êmbolo dentro da câmara a vácuo.57. A seringa de acordo com qualquer dos itens precedentes 28 a 56, em que o dito um ou mais canais de desvio a vácuo são formados na câmara a vácuo.58. A seringa de acordo com qualquer dos itens precedentes 28 a 57, em que o dito um ou mais canais de desvio a vácuo são um ou mais ranhuras longitudinais formados na superfície interna da extremidade proximal da câmara a vácuo.59. A seringa de acordo com qualquer dos itens precedentes 28 a 58, em que o dito um ou mais canais de desvio a vácuo são formados no êmbolo.60. A seringa de acordo com qualquer dos itens precedentes 28 a 59, em que o barril é formado em um único fragmento de material.61. A seringa de acordo com qualquer dos itens precedentes 28 a 60, em que o barril é adequado para fabricação por meio de moldagem por injeção de ciclo único.62. A seringa de acordo com qualquer dos itens precedentes 28 a 61, em que a câmara a vácuo, a câmara de pressão e a porção conectora são formadas como elementos separados e configurados para serem montados durante a fabricação da seringa.63. A seringa de acordo com qualquer dos itens precedentes 28 a 62, em que a câmara de pressão e a porção conectora são formadas como um elemento e configuradas para serem montadas com a câmara a vácuo durante a fabricação da seringa.64. A seringa de acordo com qualquer dos itens precedentes 28 a 63, em que a câmara a vácuo e a câmara de pressão são formadas como um elemento e configuradas para serem montadas com a porção conectora durante a fabricação da seringa.65. A seringa de acordo com qualquer dos itens precedentes 28 a 64, em que a válvula de pressão compreende uma abertura, e em que a abertura forma pelo menos uma parte da passagem de fluido na segunda posição da válvula de pressão, a dita abertura preferivelmente se estendendo na direção longitudinal do barril.66. A seringa de acordo com qualquer dos itens precedentes 28 a 65, em que a válvula de pressão compreende uma ou mais saliências, preferivelmente estendendo lateralmente, tal como transversal à passagem de fluido.67. A seringa de acordo com qualquer dos itens precedentes 28 a 66, em que a válvula de pressão se projeta radialmente e/ou transversalmente da câmara de pressão na dita primeira posição, e em que a válvula de pressão é nivelada ou totalmente submersa na câmara de pressão na dita segunda posição.68. A seringa de acordo com qualquer dos itens precedentes 28 a 67, em que a válvula de pressão compreende uma superfície superior, em que a dita superfície superior é nivelada com uma superfície superior da câmara de pressão na dita segunda posição.69. A seringa de acordo com qualquer dos itens precedentes 28 a 68, em que a válvula de pressão compreende a superfície superior arredondada, configurada para corresponder com uma superfície superior arredondada da câmara de pressão na dita segunda posição da válvula de pressão.70. A seringa de acordo com qualquer dos itens precedentes 28 a 69, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a válvula de pressão é transversalmente e/ou radialmente limitada na dita primeira posição.71. A seringa de acordo com qualquer dos itens precedentes 28 a 70, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a válvula de pressão seja transversalmente e/ou radialmente limitada na dita primeira posição por meio de uma ou mais saliências na válvula de pressão.72. A seringa de acordo com qualquer dos itens precedentes 28 a 71, em que uma parede lateral interna da câmara de pressão compreende um estreitamento adaptado para limitar o deslocamento transverso e/ou radial da válvula de pressão na primeira posição.73. A seringa de acordo com qualquer dos itens precedentes 28 a 72, em que a válvula de pressão e a câmara de pressão é configurada de maneira tal que a válvula de pressão possa ser inserida de um lado da câmara de pressão, preferivelmente apenas um lado da câmara de pressão.74. Um recipiente compreendendo: a. uma câmara de produto compreendendo uma composição seca capaz de formar uma pasta com a adição de um meio aquoso, em que a pressão na câmara de produto seja menor que a pressão fora da câmara de produto, e b. uma válvula. 75. O recipiente de acordo com item 74 sendo uma seringa, tal como uma seringa plástica de único uso, tal como a seringa de acordo com qualquer um dos itens 29 a 73.76. Um método para reconstituir uma composição seca que compreende as etapas de: a. fornecer o recipiente de qualquer dos itens 74-75, o dito recipiente sendo o primeiro recipiente, b. fornecer um segundo recipiente compreendendo um meio aquoso, em que a pressão no segundo recipiente seja maior que a pressão na câmara de produto do primeiro recipiente, c. colocar o primeiro recipiente e o segundo recipiente em contato, usando meios de conexão adequados, e d. abrir a válvula. 77. Um método para reconstituir uma composição seca que compreende as etapas de: a. fornecer a seringa de qualquer dos itens 29 a 73, compreendendo uma composição seca capaz de formar uma pasta com a adição de um meio aquoso, em que a composição seca é localizada na câmara a vácuo e em que a pressão na câmara a vácuo seja menor que a pressão fora da câmara a vácuo, e em que a válvula de pressão da seringa seja arranjada na primeira posição, b. fornecer um segundo recipiente compreendendo um meio aquoso, c. colocar a seringa e o segundo recipiente em contato por meio da porção conectora da seringa, usando meio de conexão adequados, e d. mover a válvula de pressão da seringa para a segunda posição, fornecendo por meio disso uma conexão de fluido entre a câmara a vácuo da seringa e o segundo recipiente. 78. O método de acordo com qualquer um dos itens 76 a 77, em que a composição seca reconstitui em menos de cerca de 30 segundos, preferivelmente em menos de cerca de 20 segundos, mais preferivelmente em menos de cerca de 10 segundos, ainda mais preferivelmente em menos de cerca de 5 segundos, tal como menos de 3 segundos, por exemplo, menos de 2 segundos.79. O método de acordo com qualquer um dos itens 76 a 78, em que o segundo recipiente compreendendo o meio aquoso é selecionado de i) um recipiente desmontável, tal como uma bolsa plástica, e ii) um recipiente não desmontável compreendendo um êmbolo.80. Um kit hemostático compreendendo: a) uma seringa de acordo com qualquer um dos itens 29 a 73 compreendendo uma composição seca, b) um recipiente compreendendo um meio aquoso, e c) opcionalmente um acondicionamento exterior. 81. O kit hemostático de acordo com item 80, em que a composição seca é uma composição seca que é configurada para formar uma pasta hemostática de uma consistência adequada para uso como uma pasta hemostática com a adição do meio aquoso, tal como se formar espontaneamente em segundos.82. O kit hemostático de acordo com qualquer um dos itens 80 a 81, em que a composição seca é obtida pelo método de qualquer dos itens 1 a 24.83. Um kit hemostático compreendendo: a) um recipiente compreendendo a composição seca obtida pelo método de qualquer dos itens 1 a 24 ou o recipiente de acordo com qualquer um dos itens 74-75, b) um recipiente compreendendo um meio aquoso, e c) opcionalmente um acondicionamento exterior. [00381] Additional details of this description are provided in the following items: 1. A method for preparing a dry composition that comprises the sequential steps of: The. provide a powdered agent and an aqueous medium, B. mix the agent in powder form and the aqueous medium to obtain a folder, ç. subject the paste to reduced pressure, while expanding the paste, d. freeze the expanded paste, and and. dry the paste. 2. The method according to item 1, in which the reduced pressure is a pressure of at least 5 kPa (50 mbar) less than the ambient pressure, such as at least 10 kPa (100 mbar) less than the ambient pressure, for example, at least 15 kPa (150 mbar) less than ambient pressure, such as at least 20 kPa (200 mbar) less than ambient pressure, for example, at least 25 kPa (250 mbar) less than ambient pressure, such as at least 30 kPa (300 mbar) less than ambient pressure, for example, at least 35 kPa (350 mbar) less than ambient pressure, such as at least 40 kPa (400 mbar) less than ambient pressure, for example , at least 45 kPa (450 mbar) less than the pressure, such as at least 50 kPa (500 mbar) less than the ambient pressure, for example, at least 55 kPa (550 mbar) less than the pressure, such as at least 60 kPa (600 mbar) less than the ambient pressure, for example, at least 65 kPa (650 mbar) less than the pressure, such as at least 70 kPa (700 mbar) less than the pressure s environment, for example, at least 75 kPa (750 mbar) less than ambient pressure, such as at least 80 kPa (800 mbar) less than ambient pressure, for example, at least 85 kPa (850 mbar) less than ambient pressure, such as at least 90 kPa (900 mbar) less than the pressure. 3. The method according to any of the preceding items, in which the volume of the paste is increased by about a factor 1.05 to about a factor 2.0, such as about a factor 1.1 to about a factor of 1.8, for example, about a factor of 1.2 to about a factor of 1.6 as a result of reduced pressure. 4. The method according to any of the preceding items, in which 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 one factor 0.55, such as at least one factor 0.50 as a result of vacuum expansion. 5. The method according to any of the preceding items, wherein the agent in powder form is a biocompatible polymer. 6. The method according to any of the preceding items, in which the agent in powder form is cross-linked. 7. The method according to any of the preceding items, wherein the agent in powder form is biologically absorbable. 8. The method according to any of the preceding items, wherein the agent in powder form is gelatin. 9. The method according to any of the preceding items, in which drying is freeze-drying. 10. The method according to any of the preceding items, wherein drying results in a dry composition comprising less than about 5% water, preferably less than about 2% water. 11. The method according to any of the preceding items, wherein the agent in powder form and the aqueous medium is mixed with one or more hydrophilic compounds. 12. The method according to item 11, wherein the paste 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 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. 13. The method according to any of items 11 to 12, wherein the paste before drying comprises: The. from about 2% to about 40% of one or more hydrophilic compounds, B. from about 10% to about 60% of the agent in powder form, and ç. from about 50% to about 90% water. 14. The method according to any of items 11 to 12, wherein the paste before drying comprises: The. from about 5% to about 20% of one or more hydrophilic compounds, B. from about 15% to about 25% of the agent in powder form, and ç. from about 60% to about 80% water.15. The method according to any of items 11 to 14, wherein the one or more hydrophilic compounds are one or more polyols. 16. The method according to item 15, in which the one or more polyols is selected from sugar alcohols, sugars and / or derivatives thereof. 17. The method according to item 16, in which the one or more sugar alcohols is selected from the group consisting of glycol, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol and polyglycitol. 18. The method according to any of items 15 to 17, wherein the one or more polyols is mannitol and optionally one or more additional hydrophilic compounds. 19. The method according to any of the preceding items, wherein the dry composition additionally comprises one or more bioactive agents capable of stimulating hemostasis, wound healing, bone healing, tissue healing and / or tendon healing. 20. The method according to item 19, in which the bioactive agent is thrombin. 21. The method according to any of the preceding items, in which the aqueous medium is selected from the group consisting of water, saline, a solution of calcium chloride and a buffered aqueous medium. 22. The method according to any of the preceding items, wherein the method comprises an additional step of placing the dry composition in an outer packaging, such as an aluminum foil packaging. 23. The method according to any of the preceding items, wherein the method comprises an additional step of sterilizing the dry composition. 24. The method according to any of the preceding items, wherein the dry composition reconstitutes without mechanical mixing to form a ready-to-use paste in less than about 30 seconds, preferably in less than about 20 seconds, more preferably in less of 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. 25. A wet paste composition, which is a vacuum expanded wet paste, with a density of between 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. 26. A dry composition obtained by the method of any of items 1 to 24. 27. A dry composition which is a vacuum-expanded lyophilized paste with a density 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. 28. A syringe for keeping a lyophilized paste in a vacuum comprising a barrel comprising a vacuum chamber for containing the paste with an open proximal and distal end 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 second fluid opening in a first position and to form / create a fluid passage between the first and second fluid opening in a second position, - a plunger configured to be axially displaced in the vacuum chamber through the open proximal end, and - one or more vacuum bypass channels.29. The syringe according to any of the preceding items 28, wherein the barrel comprises a flange at the proximal end of the vacuum chamber. 30. The syringe according to any of the preceding items 28 to 29, in which the syringe is adapted to keep the composition dry according to item 26. 31. The syringe according to any of the preceding items 28 to 30, in which the frozen dry paste is obtained by the method according to any of items 1 to 24. 32. The syringe according to any of the preceding items 28 to 31, wherein the connector portion is a Luer lock or Luer slip connector, preferably a Luer lock or Luer slip connector. 33. The syringe according to any of the preceding items 28 to 32, wherein the connector portion comprises a threaded portion. 34. The syringe according to any of the preceding items 28 to 33, in which the pressure valve is located in the pressure chamber and adapted to seal the first and second fluid opening in a first position in the pressure chamber, and to form / create a fluid passage between the first and second fluid openings in a second position in the pressure chamber. 35. The syringe according to any of the preceding items 28 to 34, wherein the pressure chamber is located between the vacuum chamber and the second fluid opening. 36. The syringe according to any of the preceding items 28 to 35, wherein 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. 37. The syringe according to any of the preceding items 28 to 36, wherein the connector portion comprises a proximal end next to a distal end of the pressure chamber and a distal end adapted to connect to a liquid receiver. 38. The syringe according to any of the preceding items 28 to 37, wherein the second fluid opening forms an elongated channel through the connector portion. 39. The syringe according to any of the preceding items 28 to 38, wherein the second fluid opening comprises a proximal end next to a distal end of the pressure chamber and a distal end for fluid inlet and outlet. 40. The syringe according to any of the preceding items 28 to 39, wherein the pressure valve is adapted to seal a distal end of the first fluid opening and a proximal end of the second fluid opening in said first position. 41. The syringe according to any of the preceding items 28 to 33, in which the inside of the pressure chamber is cylindrical. 42. The syringe according to any of the preceding items 28 to 41, in which the pressure valve comprises a groove, and in which the groove forms the passage of fluid in the second position of the pressure valve. 43. The syringe according to any of the preceding items 28 to 42, in which the pressure valve comprises two cylindrical sections axially divided by a groove, and in which the groove forms the passage of fluid in the second position of the pressure valve. 44. The syringe according to any of the preceding items 28 to 43, in which the first and second positions of the pressure valve are displaced radially with respect to the longitudinal geometric axis of the syringe. 45. The syringe according to any of the preceding items 28 to 44, in which the pressure valve protrudes from the pressure chamber in said first position. 46. The syringe according to any of the preceding items 28 to 45, wherein the pressure valve is leveled with and / or limits the pressure chamber in said second position. 47. The syringe according to any of the preceding items 28 to 46, in which the pressure valve comprises a valve flange at one end of the pressure valve projecting from the pressure chamber and in which said valve flange is it projects from the pressure chamber in said first position, and in which said valve flange is flush with and / or makes contact with the pressure chamber in said second position. 48. The syringe according to any of the preceding items 28 to 47, in which the first and second positions of the pressure valve are rotated. 49. The syringe according to any of the preceding items 28 to 48, wherein the pressure valve comprises a passage channel that forms the passage of fluid in the second position of the pressure valve. 50. The syringe according to any of the preceding items 28 to 49, wherein the pressure valve comprises a cylindrical section with a radial passage channel forming the passage of fluid in the second position of the pressure valve. 51. The syringe according to any of the preceding items 28 to 50, in which 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. 52. The syringe according to any of the preceding items 28 to 51, in which the pressure valve and the pressure chamber are configured in such a way that the pressure valve is axially closed in the second position of the pressure valve. 53. The syringe according to any of the preceding items 28 to 52, in which the pressure valve and the pressure chamber are configured in such a way that the pressure valve is rotationally closed in the second position of the pressure valve. 54. The syringe according to any of the preceding items 28 to 53, wherein said one or more vacuum bypass channels are configured to provide a fluid, such as a gaseous communication, between the vacuum chamber and the ambient atmosphere. 55. The syringe according to any of the preceding items 28 to 54, wherein the syringe is configured in such a way that the plunger is sealed to the vacuum chamber in at least one first axial position of the plunger within the vacuum chamber , and in such a way that the communication of the fluid is established through the piston in at least a second axial position of the piston within the vacuum chamber, by means of one or more vacuum bypass channels. 56. The syringe according to any of the preceding items 28 to 55, wherein said one or more vacuum bypass channels are configured to interrupt the seal between the vacuum chamber and the plunger at a predefined axial position of the plunger within the vacuum chamber. 57. The syringe according to any of the preceding items 28 to 56, wherein said one or more vacuum bypass channels are formed in the vacuum chamber. 58. The syringe according to any of the preceding items 28 to 57, wherein said one or more vacuum bypass channels are one or more longitudinal grooves formed on the inner surface of the proximal end of the vacuum chamber. 59. The syringe according to any of the preceding items 28 to 58, wherein said one or more vacuum bypass channels are formed on the plunger. 60. The syringe according to any of the preceding items 28 to 59, in which the barrel is formed from a single fragment of material. 61. The syringe according to any of the preceding items 28 to 60, in which the barrel is suitable for manufacture through single-cycle injection molding. 62. The syringe according to any of the preceding items 28 to 61, in which the vacuum chamber, the pressure chamber and the connector portion are formed as separate elements and configured to be assembled during the manufacture of the syringe. 63. The syringe according to any of the preceding items 28 to 62, in which the pressure chamber and the connecting portion are formed as an element and configured to be assembled with the vacuum chamber during the manufacture of the syringe. 64. The syringe according to any of the preceding items 28 to 63, in which the vacuum chamber and the pressure chamber are formed as an element and configured to be assembled with the connector portion during the manufacture of the syringe. 65. The syringe according to any of the preceding items 28 to 64, in which the pressure valve comprises an opening, and in which the opening forms at least part of the fluid passage in the second position of the pressure valve, said opening preferably extending in the longitudinal direction of the barrel. 66. The syringe according to any of the preceding items 28 to 65, wherein the pressure valve comprises one or more projections, preferably extending laterally, such as transverse to the fluid passage. 67. The syringe according to any of the preceding items 28 to 66, in which the pressure valve protrudes radially and / or transversely from the pressure chamber in said first position, and in which the pressure valve is leveled or fully submerged in the pressure chamber in said second position. 68. The syringe according to any of the preceding items 28 to 67, wherein the pressure valve comprises an upper surface, wherein said upper surface is flush with an upper surface of the pressure chamber in said second position. 69. The syringe according to any of the preceding items 28 to 68, wherein the pressure valve comprises the rounded upper surface, configured to correspond with a rounded upper surface of the pressure chamber in said second pressure valve position. 70. The syringe according to any of the preceding items 28 to 69, wherein the pressure valve and the pressure chamber are configured in such a way that the pressure valve is transversely and / or radially limited in said first position. 71. The syringe according to any of the preceding items 28 to 70, wherein the pressure valve and the pressure chamber are configured in such a way that the pressure valve is transversely and / or radially limited in said first position by means of one or more projections on the pressure valve. 72. The syringe according to any of the preceding items 28 to 71, wherein an internal side wall of the pressure chamber comprises a narrowing adapted to limit the transverse and / or radial displacement of the pressure valve in the first position. 73. The syringe according to any of the preceding items 28 to 72, in which the pressure valve and the pressure chamber are configured in such a way that the pressure valve can be inserted on one side of the pressure chamber, preferably only one side of the pressure chamber. 74. A container comprising: The. a product chamber comprising a dry composition capable of forming a paste with the addition of an aqueous medium, wherein the pressure in the product chamber is less than the pressure outside the product chamber, and B. a valve.75. The container according to item 74 being a syringe, such as a single-use plastic syringe, such as the syringe according to any of items 29 to 73. 76. A method for reconstituting a dry composition that comprises the steps of: The. providing the container of any of items 74-75, said container being the first container, B. providing a second container comprising an aqueous medium, wherein the pressure in the second container is greater than the pressure in the product chamber of the first container, ç. bring the first container and the second container into contact, using suitable connection means, and d. open the valve.77. A method for reconstituting a dry composition that comprises the steps of: The. supply the syringe of any of items 29 to 73, comprising a dry composition capable of forming a paste with the addition of an aqueous medium, where the dry composition is located in the vacuum chamber and where the pressure in the vacuum chamber is less that the pressure outside the vacuum chamber, and that the syringe pressure valve is arranged in the first position, B. providing a second container comprising an aqueous medium, ç. put the syringe and the second container in contact through the connector portion of the syringe, using suitable connection means, and d. move the syringe pressure valve to the second position, thereby providing a fluid connection between the syringe vacuum chamber and the second container.78. The method according to any of items 76 to 77, wherein the dry composition reconstitutes 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 3 seconds, for example, less than 2 seconds. 79. The method according to any of items 76 to 78, wherein the second container comprising the aqueous medium is selected from i) a collapsible container, such as a plastic bag, and ii) a non-collapsible container comprising a plunger. 80. A hemostatic kit comprising: a) a syringe according to any of items 29 to 73 comprising a dry composition, b) a container comprising an aqueous medium, and c) optionally an external packaging.81. The hemostatic kit according to item 80, in which the dry composition is a dry composition that is configured to form a hemostatic paste of a consistency suitable for use as a hemostatic paste with the addition of the aqueous medium, such as to form spontaneously in seconds. 82. The hemostatic kit according to any of items 80 to 81, in which the dry composition is obtained by the method of any of items 1 to 24. 83. A hemostatic kit comprising: a) a container comprising the dry composition obtained by the method of any of items 1 to 24 or the container according to any of items 74-75, b) a container comprising an aqueous medium, and c) optionally an external packaging.

权利要求:
Claims (22)
[0001]
Method for preparing a dry composition, characterized by the fact that it comprises the sequential steps of: The. provide a powdered agent and an aqueous medium, B. mix the agent in powder form and the aqueous medium to obtain a folder, ç. subjecting the paste to reduced pressure, thereby expanding the paste, d. freeze the expanded paste, and and. dry the paste.
[0002]
Method according to claim 1, characterized in that the reduced pressure is a pressure of at least 1 kPa (10 mbar) less than the ambient pressure, for example, at least 5 kPa (50 mbar) less than the ambient pressure , such as at least 10 kPa (100 mbar) less than ambient pressure, for example, at least 15 kPa (150 mbar) less than ambient pressure, such as at least 20 kPa (200 mbar) less than ambient pressure, for example, at least 25 kPa (250 mbar) less than ambient pressure, such as at least 30 kPa (300 mbar) less than ambient pressure, for example, at least 35 kPa (350 mbar) less than ambient pressure, such as at least 40 kPa (400 mbar) less than ambient pressure, for example, at least 45 kPa (450 mbar) less than pressure, such as at least 50 kPa (500 mbar) less than ambient pressure, for example , at least 55 kPa (550 mbar) less than the pressure, such as at least 60 kPa (600 mbar) less than the ambient pressure, eg by at least 65 kPa (650 mbar) less than the pressure, such as at least 70 kPa (700 mbar) less than the ambient pressure, for example, at least 75 kPa (750 mbar) less than the ambient pressure, such as at least 80 kPa (800 mbar) less than ambient pressure, for example, at least 85 kPa (850 mbar) less than ambient pressure, such as at least 90 kPa (900 mbar) less than pressure.
[0003]
Method according to any of the preceding claims, characterized in that the agent in powder form is a biocompatible polymer.
[0004]
Method according to any one of the preceding claims, characterized in that the agent in powder form is cross-linked.
[0005]
Method according to any one of the preceding claims, characterized in that the agent in powder form comprises or consists of gelatin.
[0006]
Method according to any of the preceding claims, characterized by the fact that drying is freeze-drying.
[0007]
Method according to any of the preceding claims, characterized in that the agent in powder form and the aqueous medium is further mixed with one or more hydrophilic compounds.
[0008]
Method according to claim 7, characterized in that the paste comprises, before drying, about 2% to about 40% of one or more hydrophilic compounds, for example, from about 2% to about 30% of a or 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 compounds hydrophilic, for example, from about 2% to about 15% of one or more hydrophilic compounds.
[0009]
Method according to any one of claims 7 to 8, characterized in that the one or more hydrophilic compounds are one or more polyols.
[0010]
Method according to claim 9, characterized in that the one or more polyols is selected from sugar alcohols, sugars and / or derivatives thereof.
[0011]
Method according to claim 10, characterized in that the one or more sugar alcohols is selected from the group consisting of glycol, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, fucitol, iditol , inositol, volemitol, isomalt, maltitol, lactitol and polyglycitol.
[0012]
Method according to claim 11, characterized in that the sugar alcohol is mannitol.
[0013]
Method according to any one of claims 7 to 8, characterized in that the one or more hydrophilic compounds is polyethylene glycol (PEG).
[0014]
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 hemostasis, wound healing, bone healing, tissue healing and / or tendon healing.
[0015]
Method according to claim 14, characterized by the fact that the bioactive agent is thrombin.
[0016]
Method according to any of the preceding claims, characterized in that the dry composition additionally comprises an extrusion intensifier, such as albumin, preferably human serum albumin.
[0017]
Method according to any one of the preceding claims, characterized in that the paste obtained in step b) is transferred in a suitable container for expansion, freezing and drying of the paste.
[0018]
Method according to claim 17, characterized in that the container is a syringe.
[0019]
Method according to any of the preceding claims, characterized by the fact that the method comprises an additional step of placing the dry composition in an outer packaging, such as an aluminum foil packaging.
[0020]
Method according to any of the preceding claims, characterized in that the method comprises an additional step of sterilizing the dry composition.
[0021]
Method according to any of the preceding claims, characterized in that it further comprises a step of adding a suitable amount of an aqueous medium to the dry composition, thereby reconstituting the dry composition.
[0022]
Method according to any of the preceding claims, characterized in that the dry composition reconstitutes without mechanical mixing to form a ready-to-use paste in less than about 30 seconds, preferably in less than about 20 seconds, more preferably in less 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.

类似技术:

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公开号 | 公开日 | 专利标题

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

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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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US10799611B2|2020-10-13|Dry haemostatic 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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EP3010419A2|2016-04-27|

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US10595837B2|2020-03-24|

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BR112015030612A8|2020-01-07|

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RU2016101631A|2017-07-26|

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JP2016536042A|2016-11-24|

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CA2912357C|2019-12-31|

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HK1221388A1|2017-06-02|

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CN105358071A|2016-02-24|

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CN105358071B|2018-07-31|

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RU2700162C2|2019-09-13|

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US20160120527A1|2016-05-05|

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AU2014283170B2|2017-11-02|

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WO2014202760A2|2014-12-24|

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CA2912357A1|2014-12-24|

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US20170311939A1|2017-11-02|

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AU2014283170A1|2015-11-12|

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BR112015030612A2|2017-07-25|

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EP3010419B1|2020-05-20|

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WO2014202760A3|2015-02-26|

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JP6390873B2|2018-09-19|

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US9724078B2|2017-08-08|

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法律状态:
2018-11-06| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2020-01-21| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61B 17/00 , A61M 5/178 Ipc: A61L 26/00 (2006.01), A61M 5/178 (2006.01), A61B 1 |

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2020-01-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-05-05| B09A| Decision: intention to grant|

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2020-07-21| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/06/2014, 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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DKPA201370342|2013-06-21|

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DKPA201370342|2013-06-21|

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EP13193427.5|2013-11-19|

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EP13193427|2013-11-19|

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EP14154117|2014-02-06|

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EP14154117.7|2014-02-06|

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PCT/EP2014/063041|WO2014202760A2|2013-06-21|2014-06-20|Vacuum expanded dry composition and syringe for retaining same|

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