Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions (Ma

专利摘要:
Sterile procedure for filling solids in pharmaceutical containers and sealing them under sterile conditions, including syringes, vials, capsules, ampoules, single-dose devices or cartridges that have been filled with solid substances selected from the group consisting of powder, granules, pellets, nanoparticles or microparticles, obtaining the tightness of these containers. More particularly, the procedure manages to avoid the adherence of the mentioned substances to the sides of the pharmaceutical containers, thus guaranteeing the tightness of the container sealing, as well as the accuracy of the weight of solid dosed to the container. (Machine-translation by Google Translate, not legally binding)
公开号:ES2758362A1
申请号:ES201831060
申请日:2018-11-02
公开日:2020-05-05
发明作者:Aduriz Ibón Gutierro；Amo María Garcia；Miranda Elena Cebadera
申请人:Laboratorios Farmaceuticos Rovi SA；
IPC主号:

专利说明:

[0001]
[0002] Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions
[0003]
[0004] Field of the Invention
[0005]
[0006] The present invention falls within the field of filling and sealing in sterile conditions of pharmaceutical containers, including syringes, vials, capsules, ampoules, single-dose devices or cartridges that have been filled with solid substances selected from the group consisting of powder, granules , pellets, nanoparticles or microparticles, obtaining the tightness of these solid substances. More particularly, the field of the invention relates to a process for filling and sealing pharmaceutical containers that have been filled with one or more sterile solid pharmaceutical substances or sterile excipients dosed and prepared in an aseptic environment that manages to avoid the adhesion of substances mentioned on the sides of the pharmaceutical containers, thus guaranteeing the sealing of the container.
[0007]
[0008] State of the art.
[0009]
[0010] In the pharmaceutical industry, the process of filling pharmaceutical containers is usually carried out with liquid pharmaceutical substances and / or lyophilized solids, since they are much easier to handle and pose fewer problems when it comes to dosing than the use of solids such as They can be powder, granules, pellets, nanoparticles or microparticles among others. The use of solids such as those mentioned above in the process of filling the containers has the great drawback that said solids tend to adhere to the walls or body of the containers, preventing or at least hindering the creation of the necessary sealing in container sealing. This adherence to the walls or the body, in addition to avoiding the desired sealing, leads to the contamination of said containers and the loss of doses, since the containers in which such adherence to the walls is observed must be discarded, because As part of the solid remains in the sealing area of the container walls, it is not possible to know exactly the amount of solid to be supplied to the patient. On the other hand, with regard to contamination, as the dosed solid adheres to the walls of said sealing area, the cap used to proceed with the sealing of the container does not close hermetically, so it will not be able to avoid entry of substances from the environment into the container and will not ensure product integrity, and its physical-chemical and microbiological properties may vary, affecting the quality of the medicine. This is the greatest inconvenience that the pharmaceutical industry can encounter in this field due to the strict conditions imposed by the regulations of said industry, which must also comply with the standards known as Correct Manufacturing Standards (NCF) or in English Good Manufacturing Practices (GMPs).
[0011]
[0012] Another concern for the pharmaceutical industry is to ensure the integrity of the closure, which also affects the level of security, since small losses of the drug can affect the safety of the medical personnel who handle it. Integrity is understood to be the ability of a container closure system to maintain sterility and product quality of pharmaceutical, biological and final sterile vaccine products throughout its life. Likewise, a sterile product is understood to be one that is free of microorganisms whose composition is one or more of the elements exposed to aseptic conditions and that, finally, make up the sterile finished pharmaceutical product. These items include the containers, closures and components of the finished pharmaceutical product.
[0013]
[0014] When dosing the powder in pharmaceutical containers, several factors must be taken into account that affect the cleaning of the interior walls of the containers, since the lack of this cleaning results in contamination. These factors are mentioned below:
[0015]
[0016] - The static load of the walls of the pharmaceutical containers used for filling, as well as the static load of the solid that is dosed in them: If it is the case that the loads of the walls and the solid are opposite, the dosed solid will adhere to the walls of the containers.
[0017]
[0018] - The kinetic energy that both the dosed solid and the elements that are in contact with it acquire when the solid falls into the containers: The higher the height at which the solid to be dosed falls in free fall to the bottom of the containers, the higher the kinetic energy it acquires, the solid and the elements due to friction with it
[0019]
[0020] - The length of the dispenser needles (also called "nozzle”) used for dosing, since the longer the dispenser is and the closer it is to the upper level of the solid dosed in the container, the less kinetic energy will have. Furthermore, the dispenser conducts the dosed solid to an area remote from the surface of the walls of the used container. The ideal distance between the dosed solid and the tip of the dispenser will depend on the dose of the dosing speed and the density of the solid used in the dosing.
[0021]
[0022] - The redirection of the displaced air inside the containers. This phenomenon is related to the kinetic energy of the dosed solid when it is released inside the container. During dosing, the bursting of the solid inside the container displaces the air inside the container upwards. This displaced solid is a solid filled with suspended particles. For this reason, the dispenser can be considered as a "chimney" that removes said air stream from the interior walls, preserving them from this contamination.
[0023]
[0024] - The use of large air flow currents (unidirectional or turbulent regime) in the booths or filling places required by the international Pharmacopoeias to ensure the removal of any particles outside the aseptic filling and sealing process that may contaminate the final product . The use of these air flow currents makes filling with solid substances quite difficult, since a disturbance is generated that causes the solid to adhere to the walls of the container used for filling.
[0025]
[0026] In order to eliminate the adhesion of the solid to the container walls, one of the measures to be taken is to carry out an ionization process for both the container and the solid to be filled in it. In the present invention, the terms "process", "stage" and "phase" are used interchangeably, as well as the terms "ionization" and "deionization" or "ionizer" and "deionizer".
[0027]
[0028] Ionization is a chemical or physical phenomenon through which ions are produced. Ions are electrically charged atoms or molecules due to excess or lack of electrons relative to a neutral atom or molecule. The chemical species with more electrons than the neutral atom or molecule is called an anion, and it has a negative net charge, and the one with fewer cation electrons, having a positive net charge.
[0029]
[0030] The ionization process used in the present invention is used both to neutralize the electrostatic charge of the pharmaceutical container to be filled with the pharmaceutical solid, and to neutralize the electrostatic charge of the solid to be dosed; that is to say, both the continent and the content. Likewise, this ionization is also used to neutralize the elements of the dosing and capping equipment that come into contact with the container and / or the powder. For this, the ionizer generates ions of both polarities that are projected to the surface of the object to be neutralized, where the ions of opposite signs are recombined and those of the same sign are rejected. Throughout this document, "ionizer" means any element or device that is capable of ionizing the surrounding air molecules, so that they are subsequently projected onto a surface that has static electrical charges in order to neutralize said charges, and consequently ionize said surface.
[0031]
[0032] However, only with this ionization process it is not possible to avoid the serious problem of adherence to the sides of the container that occurs during the process of filling the containers with solids, since when the filling of the solid through the Nozzle, the kinetic energy carried by the solid generates turbulence inside the container, which finally causes part of the solid to adhere to the walls or body of the container.
[0033]
[0034] Regarding the state of the art, the documents cited below describe the ionization technique that causes a neutralization of electric charges applied to various situations:
[0035]
[0036] Thus we find, the US patent publication US 2016/0200461 A1 requested by VANRX Pharmasystems INC., Which describes a method for volumetric filling and aseptic sealing of containers such as vials, bottles, syringes and ampoules with a liquid pharmaceutical product (which can lyophilize afterwards) in a controlled environment room. In this publication they refer to the concern of the materials with which the containers are made, whether it is glass or polymeric materials, since the glass containers suffer breaks, scratches, and particle emissions due to collisions between them. On the other hand, containers made of polymeric materials are more resistant than glass containers, although they suffer cosmetic defects such as scratches, being potential defects that can harm the quality of the pharmaceutical product due to collisions.
[0037]
[0038] A substantial difference that the present invention presents with respect to the indicated document is that the compounds that are handled are solid substances that are much more difficult to dose since they are highly charged and have a larger specific surface area. Furthermore, in the document cited above, the sealing process consists of two stages, a partial and a second full due to the need to lyophilize after the first partial seal, while in the present invention the sealing process is carried out in a single stage with a complete seal, without the need to resort to subsequent sealing stages .
[0039]
[0040] Additionally, it should be noted that the filling process for solid substances is much more complex due to the fact that solid substances remain adhered to the walls of pharmaceutical containers, impairing the precision of dosing, being more relevant in small-caliber containers where Small amounts of medication need to be dosed very precisely. This aspect is solved with the procedure proposed in the present invention, since it must be taken into account that, for the pharmaceutical industry, an error in the filling of the active ingredient can cause patients to perceive an inadequate dose of product.
[0041]
[0042] This represents a serious drawback in filling containers with solids due to the problem of adhesion of said solid to the body of the containers. For this reason, in most of the procedures used today in the pharmaceutical industry, the qualification of the equipment is mandatory, which ensures that the quantity dosed is adequate. In addition, various in-process controls are incorporated during packaging to verify the effective filling amount of all pharmaceutical containers. A common control is by weighing the containers that allow rectifying or discarding those in which the quantity of pharmaceutical substance, either medicine or active ingredient, does not meet the required weighing precision. The controls in process can be 100% or statistical; The latter are carried out from time to time to check the dosage. These controls represent a high production and economic cost necessary to control the precision of product dosing.
[0043]
[0044] Regarding the elimination of the electrostatic charge, there are several types of ionizers to end this problem. These ionizers have various shapes, such as ring, bar, gun, curtain, blades, barrels, needle or an ionizer filter, among which you can also find insulators with an ionizer on the roof of said insulator, among others. For the purpose of this invention, these ionizers can be installed in the machinery used for the filling process, producing ions of both polarities to neutralize the surface of the containers or products, or they can also be placed in the packaging, room or insulator areas. , specifically on the roof of These so that an ionization is produced that neutralizes both the environment and the air flow in the area, eliminating the problem of static charges.
[0045]
[0046] Regarding the elimination of the static charge of solids by means of ionizers, we find several documents cited below:
[0047]
[0048] European Patent Document EP 2711096 A2 requested by TRINC Corporation deals with a device for the removal of electrostatic charge and dirt from objects such as film, sheet, glass, clothing, paper or the like. Said device comprises a large container with an opening in the upper part and another one in the lower part for sucking and discharging the powder and a small container of cylindrical or conical shape inside the large container. This small container is built to generate a cyclone current and tornado current within it, and consists of at least one corona discharge ion generator. This ion generator consists of electric discharge needles that are arranged either above or inside the small container. The small container consists of air injection openings through which compressed air is injected, as well as ultrasonic generators inside or outside the small container so that the dust vibrates and can separate it from the desired object once it has been neutralized by the ion generator. This powder can be collected by vacuum suction inside the large container.
[0049]
[0050] The present invention, on the other hand, deals with the deionization of both the container and the powder prior to packaging to avoid the adherence of the powder to the walls of the container during the filling process and thus perform a complete seal. In addition, as a safety factor, a deionization is carried out on and / or inside the container to remove any possible residual dust adhering to the walls of the sealing area.
[0051]
[0052] The present invention, in addition, also uses an ionizer, either ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer in the ceiling of Said insulator, to eliminate static electricity but does so from both the solid powder and the container to be used, which is not done by the European patent EP 2711096 A2, since it only focuses on the ionization of the powder and does not ionize the container. Another substantial difference of the present invention with this publication is based on the fact that this European patent EP 2711096 uses compressed air to facilitate suction while the present invention does not need air flow and, if required, it should be a sterile carrier gas. Inside the carrier gases sterile, the ionized nitrogen stream has advantages that will be discussed later.
[0053]
[0054] A characterizing handicap of the present invention is the need to perform deionization in sterile environments, making the use of sterile carrier gases mandatory. It should be noted that this sterility condition of the carrier gas does not affect the deionization process.
[0055]
[0056] On the other hand, the European patent EP 2711096 A2 differs from the present invention in that, although for both it is important to eliminate the electrostatic charge of the solid, this publication does not mention in detail the method by which it is carried out, mentioning only the use of an ion generator such as discharge needles to deionize, not to mention the problem that electrical discharge needles cause when they approach any solid, such as a combustion phenomenon that burns the product generating impurities and altering the physicochemical composition of the product.
[0057]
[0058] Japanese patent document JP 2005001818 A applied for by YMS KK refers to a powder supply device and an air transport device capable of feeding the fluid charged powder and charged powder. This device comprises a hopper equipped with aeration means equipped in turn with a microporous diaphragm to aerate the powder in the hopper. The air for aeration is pre-ionized by an ionization device such as a corona discharge device. Compressed air supplied through an air compressor is used for aeration. This compressed air is ionized by an air ionization device comprising a corona discharge device or the like. When aeration is carried out by ionized air, ionized air neutralizes or removes the surface charge of the powder, so that the surface charge of the charged powder disappears. Furthermore, when aeration causes the powder in the hopper to inflate air and an air layer forms between the powder and the inner wall of the hopper, the powder is prevented from recharging again. On the other hand, this document refers to a nozzle or suction needle made of conductive material that is part of the air transport device. The nozzle is never dosing.
[0059]
[0060] In the present invention, on the other hand, ionization is carried out on the one hand of the solid substance and on the other hand of the pharmaceutical container, for which a stream of sterile carrier gas is used, such as ionized gas; generally a stream of sterile nitrogen. Another difference of the present invention with this Japanese patent is found on the nozzle or needle: in the case of this Japanese patent, it refers to a suction nozzle made with conductive material, while, in the present invention, the nozzle is a dispensing needle and is not made of conductive material. Contrary to this Japanese patent, the present invention also uses an ionizer, whether it be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with a ionizer on the roof of said insulator or of any other type, to neutralize the electrostatic charge of both the container to be filled and the solid to be dosed, while the Japanese patent only mentions the use of a corona discharge ionizing device or similar.
[0061]
[0062] The Chinese utility model CN 203265193U in the name of Meech Static Eliminators Shanghai Co LTD refers to the technical field of static electricity and the removal of dust from the inner wall of some bottles, prior to filling as cleaning the container, for this it uses a ion needle with compressed air to remove static electricity and remove dust adhering to the walls of the bottle. The device described in this utility model consists of a needle, a first tube that connects the needle and a second tube to connect the electric cable, whose two ends have an internal thread or an external thread respectively. The tip of the needle and the second tube are screwed and fixed together, the tip of the needle, the first tube and the second tube having an interconnected interior passage for the passage of air, and the second tube also has at least two threads , so that the lead wire is also connected to the internal bore of the first tube. The tube uniformly has wire holes between the inside and outside wall, each of these holes forming an ion generating end at one end of the second tube that fits into the first tube member. Ions can be introduced to the surface of the proposed object through the ion needle and with the help of compressed air.
[0063]
[0064] In the present invention, on the contrary, the ionizer can be of any type, ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or even an ionizer filter, among which you can also find insulators with a ionizer on the ceiling of said insulator, not being necessary to be in needle as specifically commented by the Chinese utility model. Furthermore, this utility model has the aid of compressed air to carry out the displacement of the ions, while the present invention may or may not use a stream of sterile carrier gas, which may be sterile nitrogen or compressed air, not only to facilitate the ionization process. by helping the solid dosage but also to maintain the necessary sterile conditions that are required in These procedures of the pharmaceutical industry by generating an inert atmosphere inside the containers. On the other hand, the utility model talks about cleaning bottles with dust prior to filling, on the contrary, in the present invention we talk about deionization and cleaning of walls after filling and applies to containers smaller than bottles such as syringes, vials, capsules, ampoules, single-dose devices or cartridges, these being more difficult to fill with a solid such as powder.
[0065]
[0066] International patent publication WO 2016/185230 A2 requested by 3P Innovation Limited describes an apparatus and method for filling pharmaceutical containers such as syringes, vials, capsules, cartridges and blisters with pharmaceutical powder material by vibration. This device has a support for the pharmaceutical container, a container for containing powdered pharmaceutical substance, this container is in contact with a filling nozzle or needle in charge of filling the pharmaceutical container with the powdered pharmaceutical substance, and a vibration device piezoelectric. This publication refers to the advantage of using a cylinder comprising an electrically conductive material, which can be grounded through the weighing cell, which can help to dissipate the static charge of plastic pharmaceutical containers. to achieve a better powder filling process without compromising cleaning. However, the invention described in that document would not require the material to be electrically conductive, since it is a filling procedure through the mouth of the container, so the sealing problem that does occur would not occur. when filling is carried out at the rear of said container.
[0067]
[0068] Instead, the present invention relates to a method for sealing pharmaceutical containers that are filled with solid pharmaceutical substances, and said filling is carried out under aseptic conditions without the need for terminal sterilization, while the international publication WO 2016/185230 A2 a filling through the mouth of the container is described as can be seen in figure number 2. On the other hand, this international publication only mentions the filling of plastic pharmaceutical containers as containers, while the present invention covers all kinds of materials , such as polymeric materials or glass, that make up the container. Furthermore, the international publication mentions a cylinder or puck with an electrically conductive material to dissipate the static charge of the pharmaceutical containers to be used, while, in the present invention, the existence of a cylinder that acts as Container support is an optional element, not related to the problem to be solved, and which is also aimed at various other functions, such as:
[0069]
[0070] - The use of this element for handling the container without contact with it.
[0071]
[0072] - The cylinder protects the process from air currents by being part of the "exclusion hood".
[0073]
[0074] - It is a vertical support element of the container on the weighing cell to carry out a precise weighing.
[0075]
[0076] Furthermore, in the present invention it is possible to use any ionizer, in any way, that is: ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator that can be installed in the packaging equipment prior to filling, during filling and after filling using or not using a sterile carrier gas, while the invention described in the cited international publication only It is a cylinder (puck) with electrically conductive material that can dissipate the static charge of the plastic container used during its filling.
[0077]
[0078] Summary of the Invention
[0079]
[0080] Consequently, the problem to be solved in the present invention is to provide a method for filling pharmaceutical containers that can take the form of vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, envelopes, bags, test tubes, Eppendorf® type tubes and syringes. The syringes of the present invention may be with a needle or with a catheter-type cone, or a Luer lock Luer-lock cone, that is, with a threadless mouthpiece or with a female or male thread-type mouthpiece, respectively. For the purpose of the present invention, "Luer cone" is understood to mean the cone-type nozzle invented by Wülfing Luer with a typical taper of 6%, which can be male or female depending on the coupling. Also, "Luer cone" is understood lock ”to the cone-type nozzle invented by the German Wülfing Luer with hermetic-fit screw closure.
[0081]
[0082] The compounds of the containers of the present invention are materials such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinylchloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in its main chain: poly (ethylene terephthalate), polycarbonate), acrylic polymers (pole (methyl methacrylate), polyacrylonitrile), thermopastic resins (polyacetals and polyhalostylenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenoplasts, aminoplasts, thioplasts, duroplastic resins, polyvinyldulose silicones, polycarbonate derivatives, lauryl derivatives of all of them, etc. Alternatively, the container can also be metallic, for example, steel or titanium suitable for drug administration, glass, crystal, etc., with solids under sterile conditions that overcome the problems existing in the state of the art, and in In particular, they avoid the adhesion of the solid to the walls of the container, at the same time ensuring its hermetic sealing.
[0083]
[0084] In turn, both the cylinder or puck, as well as the hopper and the nozzle or needle, will preferably be composed of diverse non-conductive materials such as different plastics, such as polyether ether ketone (PEEK), glass, stone, resin, crystal, although also they can be made of conductive, grounded materials such as steel or titanium, etc.
[0085] Both the materials used for the container and the cylinder materials must be watertight, inert, poorly permeable or impervious, that do not absorb and / or adsorb the contained product, not rough and free of particles.
[0086]
[0087] The solution to the problem set forth in the present invention is based on the fact that the inventors have found that such problem can be satisfactorily solved by the following techniques, which can be applied independently or in any combination:
[0088]
[0089] On the one hand, ionizing both the solid and the pharmaceutical container where it will be deposited, in addition to ionizing the elements of the dosing and capping equipment that comes into contact with the container and / or the powder. in one or more stages of the filling procedure, in order to avoid that the solid tends to adhere to the walls of the container, as well as that the walls of the container tend to attract solid particles, so that the only tendency of the solid be that of falling towards the bottom of the container and not depositing on its walls. This deionization technique can be applied both to the container and to the solid separately, and to the container with product inside. This last form of deionization can be applied as many times as the packaging and capping steps the process has .;
[0090] On the other hand, controlling the potential applied to the ionizers, which should be such that the resulting electrostatic charge on the container walls and / or the dispensed solid should preferably be less than 2,000 V, more preferably less than 500 V, and most preferably less than 200 V.
[0091]
[0092] On the other hand, preferably the filling of the pharmaceutical container with the solid is carried out using a dispensing needle whose tip or dosing end is, throughout the filling stage, at a height of between 1 to 3 mm per above the surface of the solid deposited at the bottom of the container, so as to avoid turbulences that could lift the deposited solid towards the walls. And even if this phenomenon of turbulence were to occur to some extent, ionization of both the solid and the interior walls of the container will cause such high particles to deposit again at the bottom of the container, without substantial loss of product on the walls of the container. .
[0093]
[0094] Consequently, in a first aspect, the invention is directed to a process for filling sterile conditions of pharmaceutical containers with solids, comprising the steps of:
[0095]
[0096] a) providing a pharmaceutical container (1) having walls and a bottom, b) dispensing the solid in the pharmaceutical container (1) by means of a dispensing needle (4), gravimetrically controlling the weight of solid dispensed in the container (1) ; and
[0097] c) sealing the pharmaceutical container by means of a stopper (6),
[0098]
[0099] characterized in that, in at least one of the steps a), b) and c), or a plurality thereof in any combination, the static electric charges existing on the interior walls of the container (1) and / or in the dispensed solid are neutralized by an ionizer (2) to prevent the solid from tending to adhere to the interior walls of the container (1), and also characterized in that the ionization potential applied by the ionizer (2) is such that the electrostatic charge of the interior walls The container (1) and / or the solid dispensed after each ionization is less than 2,000 volts.
[0100]
[0101] In a second aspect, the invention is directed to a container (1) containing a solid product, in which the solid product has been dispensed into the container using the described method.
[0102]
[0103] In the case of ionization in the case of rod / ring, preferably it will be ionized again with a needle with or without gas flow.
[0104] In general, throughout the present description, filling is preferably carried out by means of a dispensing needle whose tip or dosing end is located, throughout the filling stage, at a height of 1 to 3 mm above the surface of the solid deposited at the bottom of the container, in order to avoid the generation of turbulence that could lift the solid towards the walls of the container.
[0105] This procedure has two advantages. On the one hand, the advantage of achieving precision in the filling of substances in a single container even in the case that two or more filling stations are used, by avoiding the adherence of said solid substances to the sides of the container. On the other hand, the advantage of ensuring the sealing integrity of the pharmaceutical container, made especially important in the case of medicines, since it prevents both the entry of foreign agents into the container that would contaminate the product and the exit of the product to the outside, affecting the effective dose of product.
[0106]
[0107] Additionally, the present invention also solves the problem of static loads produced by collisions generated by containers used for filling, be they glass or polymeric material, in a sterile environment that is generally subjected to laminar or turbulent flows, which increases the movement and dispersion of electrostatic charges.
[0108]
[0109] While the invention is generally applicable to pulverulent solid compounds of any nature, however. This procedure is particularly applicable to solids that have the following particle size distribution:
[0110]
[0111] D ^{10 s} 20 microns
[0112] 70 micron ^< D ^{50 <} 110 micron
[0113] 150 micron ^< D ^{90 <} 215 micron
[0114]
[0115] where D ¹⁰ indicates the average value of the particle size that divides the population into exactly two equal halves, being 50% of the distribution above this value, and 50% below. In general, throughout this specification, a value called "d0, X" or "Dx" represents the mass fraction of the drug with particle sizes below the specified value, having a range of 0.0 to 1 , 0. According to this definition, a value of d0.1 or D ¹⁰ means that 10% of the total mass of the drug particles have a particle size equal to or less than 10 microns.
[0116] And optimally it is applicable to solids that have the following particle size distribution:
[0117]
[0118] D ¹⁰ > 25 microns
[0119] 100 micron <D ⁵⁰ <155 micron
[0120] 245 micron <D ⁹⁰ <325 micron
[0121]
[0122] Examples of this type of compound are risperidone, paliperidone, fentanyl, olanz compound, activone, letrozole, aripiprazole, anastrozole, asen compound, activone, brexiprazole, caripracin, cloz compound, activone, iloperidone, lurasidone, any other, ziprasidone, kinetidone compound, metabolite salt (such as pamoate or palmitate) alone or in combination.
[0123]
[0124] Other examples of this type of compounds are also biocompatible polymers of the lactic polyacid type, (PLA), polyacid glycolic acid (PGA) and their polyacid-coglycolic polyacid copolymers (PLGA) including any derivatives or copolymer, alone or in combination.
[0125]
[0126] Brief description of the figures
[0127]
[0128] The figures accompanying the present invention serve to illustrate the nature thereof. These figures are included for illustrative purposes only and are not to be construed as limitations on the invention claimed herein. Regarding the ionization phenomenon, the present invention proposes different methods to carry out, showing some of them in Figures 1 to 7 that are described below. In order to properly interpret the figures, the ionization phenomenon is represented by the alternating positive (+) and negative (-) signs taking into account that this ion current of different sign may or may not be accompanied by a gas current sterile carrier, even though this last point is not represented as such in the figures.
[0129]
[0130] Figure 1: Figure 1 illustrates a particular embodiment of the aseptic filling and sealing procedure according to the present invention, in which the represented pharmaceutical container is, in this case, a male syringe (1) that remains capped with a the nozzle (8) throughout the process. The syringe (1) undergoes a first stage of ionization (a) with the help of an ionizer (2), which can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter , among which you can also find insulators with an ionizer on the ceiling of said insulator, although in this case one is represented in needle. Next, the male syringe (1) passes to the filling station (b), and in the method of the invention there may be multiple filling stations, particularly if there are multiple solids to be filled in the syringe. In said station, the syringe, which can be optionally inserted in a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle (4). After filling, the male syringe (1) is subjected to another ionization stage (c) by means of an ionizer (2) provided in said stage, be it a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or a ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, although in this case one is represented in a ring. Finally, the male syringe (1) is transferred to a sealing station (d) where it will be hermetically closed at the top with a cap (6).
[0131]
[0132] Figure 2: Another particular embodiment of the process of the present invention, in which the male syringe of Figure 1 has been replaced as a pharmaceutical container (1) by a female syringe.
[0133]
[0134] Figure 3: Particular embodiment of the procedure of the present invention, which, the syringe has been replaced as a pharmaceutical container (1) by a tube of the Eppendorf® type, is subjected to an ionization step (a) thanks to the presence in said step of an ionizer (2) either ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, in this case it is a needle ionizer. Subsequently it is transferred to the filling station (b), and there may be multiple filling stations, in which the presence of an ionizer (2) in ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, this time being an ionizing filter. In addition to the ionizer, in this stage there are a weighing cell (5), a hopper (3) and a nozzle or dispensing needle (4). Finally, after filling the Eppendorf® type tube is subjected to an ionization process using a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the roof of said insulator, in this case being a bar ionizer (2).
[0135]
[0136] Figure 4: Particular embodiment of the procedure of the present invention in which the represented container is, in this case, a syringe with a needle (1) pre-capped with the mouthpiece cover (8) during the entire sealing process, which is subjected to a first ionization process (a) with the help of an ionizer (2) that can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with a ionizer on the ceiling of said insulator, although in this case a needle is shown. Next, the needle syringe (1) passes to the filling station (b), in the procedure described in the present invention, there may be multiple filling stations, particularly if there are multiple solids to be filled in the syringe. In this station, the syringe with needle, which can be optionally inserted in a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle (4). After filling, the needle syringe (1) is subjected to another ionization stage (c) by means of an ionizer (2), which can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or a ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, although in this case one is represented in a ring. Finally, the syringe with needle (1) is transferred to a sealing station (d) where it will be hermetically closed at the top with a cap (6), while it is subjected to an additional ionization phase by means of an ionizer (2 ) provided in said stage, which can be a ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, being this time a bar ionizer.
[0137]
[0138] Figure 5: Another particular embodiment of the process of the present invention in which the represented container is, in this case, a female syringe (1) capped throughout the process with a nozzle cap (8), is subjected to a first ionization process (a) with the help of an ionizer (2) that can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with a ionizer on the ceiling of said insulator, although in this case one is represented in a ring. Next, the female syringe (1) passes to the filling station (b), in the procedure described in the present invention, there may be multiple filling stations, particularly if there are multiple solids to be filled in the syringe. In this station, the syringe, which can be optionally inserted in a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle ( 4). After filling, the syringe goes through an ionization process (c) thanks to an ionizer (2), whether it be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which You can also find insulators with an ionizer on the ceiling of said insulator, although in this case one is represented in a needle. Finally, the female syringe (1) is transferred to a sealing station (d) where it will be hermetically closed at the top with a cap (6) while it is subjected to an additional deionization phase by means of an ionizer (2), provided in said stage, which can be ring, bar, gun, curtain, blades, barrels , needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, in this case, it is a bar ionizer.
[0139]
[0140] Figure 6: Another particular embodiment of the method of the present invention in which the container represented is, on this occasion, a cartridge (1), is subjected to a first ionization process (a) with the help of an ionizer (2) It can be a ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, although in the present case it is represents one needle. The cartridge (1) then passes to the filling station (b), in the procedure described in the present invention, there may be multiple filling stations, particularly if there are multiple solids to be filled in the cartridge. In said station, the cartridge is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle (4). Finally, the cartridge (1), which can be optionally inserted into a cylinder (7), is transferred to an ionization station where an ionizer (2) provided in said stage will act, which can be a ring, bar, gun, curtain , blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, although in this case one is shown in a bar.
[0141]
[0142] Figure 7: Particular embodiment of the method of the present invention in which the represented container is, in this case, a pre-capped female syringe (1) that is first subjected to an ionization process (a) with the help of an ionizer (2 ) ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, although in the present case one is represented ring. After this, the syringe that is filled by its threaded end is located in the filling station (b), and in the procedure described in the present invention, there may be multiple filling stations, particularly if there are multiple solids to be filled in the syringe. . In said station, the syringe, which can be optionally inserted in a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle (4). After filling, the female syringe (1) is subjected to another ionization phase (c) by means of an ionizer (2), be it a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, between those that can also be found insulators with an ionizer on the ceiling of said insulator, in this case it is a bar ionizer).
[0143]
[0144] Detailed description of the invention.
[0145]
[0146] The filling of solid substances either by volumetric or gravimetric filling such as powder, granules, pellets, nanoparticles or microparticles in small pharmaceutical containers such as vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, envelopes, bags, test tubes, Eppendorf® type tubes and syringes (with female or male threaded nozzle, or without thread) and of different materials, such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene , polyvinylchloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in its main chain: poly (ethylene terephthalate), polycarbonate), acrylic polymers (pole (methyl methacrylate), polyacrylonitrile), thermopastic resins (polyacetals and polyhaloestylenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenoplasts, aminoplasts, thioplasts, duroplastic resins (unsaturated polyester, polyurethanes), polyvinylenic silicones, cellulose derivatives, polycarbonates, and mixtures of all of them, etc., alternatively, the container can also be metal, for example, steel or titanium suitable for administration drug, glass, crystal, among others, is currently a serious problem for the pharmaceutical industry due to the great inconvenience of adhering these substances to the walls of the sealing area of the containers used. This adherence implies important drawbacks for said industry since it must comply with the regulations indicated in the different international Pharmacopoeias, in addition to complying with the correct manufacturing standards (known by the acronym NCF). The present invention focuses on solving the problems related to the adherence of said solid substances to the walls of the containers used for filling, since this adherence makes both the filling and aseptic sealing process difficult. For the aseptic filling and sealing process to which the present invention refers, only solid substances such as those mentioned above are used.
[0147]
[0148] International Pharmacopoeias require the presence of large air flow currents (unidirectional or turbulent regime) for aseptic fillers and seals to ensure the removal of any particles outside the process that may contaminate the final product. The use of these air flow streams makes filling with solid substances It is quite difficult, since a disturbance is generated that makes the solid adhere to the walls of the container used for filling.
[0149]
[0150] As the dosed solid substances adhere to the walls of the container sealing area, they are not capable of joining in the container mouth area, thus avoiding the necessary sealing phenomenon. The lack of sealing entails two serious problems such as loss of dose of the dosed solid substance and contamination of the container used in the filling.
[0151]
[0152] The loss of dose causes an inaccuracy in the administration of the pharmaceutical product, since when solid substances remain adhered to the walls of the container sealing area, they will be measured by the weighing cell indicating the precise amount of product that must administered to the patient, but at the time of administration to said patient, he will receive a lower dose than indicated, since the solid substances adhered to the sides of the container will not be administered to the patient, remaining attached to said sides.
[0153]
[0154] With regard to the contamination of the container that has been used for filling, this is, perhaps, the most serious of the drawbacks that can be obtained from the lack of tightness produced by adhesion to the walls of the sealing area since it affects the integrity of the medicine and the impact on the health of the patient receiving the pharmaceutical product. When sealing the container with the stopper, if the walls of the container have adhered solid substances in the sealing area, these will continue in that area once the container is sealed, which means that the stopper cannot ensure the integrity of the sealed product since Any type of substance from the foreign medium could enter the product after the capping step. Microbial contamination is a very serious issue for pharmaceutical companies since their products are ideal fields for the proliferation of microorganisms such as bacteria, fungi or yeasts. A theoretically sterile but contaminated product can lead to the deterioration of said product, in the loss of the potential of this product, pyrogenic reactions may occur after being administered to the patient, particularly in parenterals, infection and colonization of microorganisms in the patient, having the risk of suffering a secondary infection. Any microorganism, whether pathogenic or non-pathogenic, found in an allegedly sterile pharmaceutical product is a hazard.
[0155] Observing the important problems caused by the lack of tightness, the present invention offers a solution to the adhesion of solid substances to the sides of the sealing area of the pharmaceutical container when obtaining the tightness of said substance. To promote the tightness of solid substances, two methods are used, such as controlling the height of the dispensing needle and ionizing both the pharmaceutical container used for filling and the solid substance to be dosed, thus such as the ionization of the elements of the dosing and capping equipment that comes into contact with the syringe and / or the powder.
[0156]
[0157] As mentioned in the state of the art, there are a number of factors that affect the adhesion of solids to the interior walls of the container, among these factors is the length of the nozzle. The longer the nozzle is and the closer it is to the upper level of the powder in the container, the less kinetic energy it will have. In addition, the nozzle conducts dust to an area remote from the surface of the sealing walls. The inventors of the present invention have found that the ideal distance between the powder and the nozzle tip depends on the dose, dosing speed and powder density, although it is typically between 1 and 3 mm, more preferably around 2 mm. The present invention proposes several options regarding the height of the nozzle:
[0158]
[0159] - The first one is based on having a nozzle with an exact height (h) of it with respect to the bottom of the container. In this case, the filling process is carried out at the rear of the container, that is, when the container is a syringe, at the mouth or end with the largest diameter. A minimum h height must always be respected between the solid being dosed and the nozzle, this height (h) being 2mm.
[0160]
[0161] - The second option is to always keep the nozzle at a minimum distance of h = 2 mm from the solid substance that is being dispensed into the container. This method would suppose that the nozzle was not a fixed element, but that it was mobile and could rise and fall as filling occurs, always keeping the distance of 2 mm with the solid substance.
[0162]
[0163] - An alternative to the above could be that the nozzle has a containment element to prevent the powder from dispersing over the area being filled during filling.
[0164] Regarding ionization, it is based on the solution to avoid electrostatic charges that contain both the pharmaceutical container to be filled and the solid substance with which it is to be filled. The walls of the container and the solid have static charge, in case these charges are of opposite signs, the solid will adhere to the internal walls of the container. It is for this reason that the ionization of both the container and the solid is carried out.
[0165]
[0166] There are two types of electrostatic charges, the negative ones that are electrons of the atoms of the chemical elements, and the positive ones that are equivalent to the action of the protons of the atomic nucleus deprived of the electrons of the last shell. The electrons that are on the surface of an insulating material cannot be easily dissipated as long as they do not have a conductive path to ground, which is why the cylinder is a conductive element as previously discussed. As they cannot circulate easily, they give rise to so-called static electricity. Electrons are free to move from one molecule to another in conductors, but protons are inseparable from the atom and cannot move unless the atom itself does. The magnitude of the electrostatic charge is related to the relative position or distance of the materials in the series and their sign is determined by the propensity of a material to give up or gain electrons, which is what this series actually indicates.
[0167]
[0168] The present invention uses any type of ionizer, such as ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. For example, a bar can be used to ionize and neutralize both the environment and air flow, thereby eliminating static charges. The ionizer can be implemented in practice by means of a sterile carrier gas stream such as compressed air or N2 nitrogen, preferably using a nitrogen stream, which has the following functions and / or advantages:
[0169]
[0170] - This nitrogen stream serves as a vehicle for the displacement of the ions generated in the electrodes of the ionization elements that ionize the surrounding air, producing ions that are carried by the N2 current. These positive and negative ions are generated by supplying alternating current, which, through a transformer, rises to values of up to 8,000 volts with an almost negligible current (4mA). Surfaces treated in this way end up having a neutral charge, due to the recombination of charges of different sign and repulsion of charges of the same sign.
[0171] - Generator of an inert atmosphere inside the containers by displacing the oxygen inside and thus preserving the product from its oxidative effect. The introduction of an inert gas into a container, known as inerting, is based on the reduction of the percentage of oxygen below the limit concentration of oxygen (C. L. O).
[0172]
[0173] - Means of drag in the sweeping effect inside the containers. The generation of ions alternately eliminates the static forces that adhere the dust to the walls of the container. This causes the solid to remain in the position it is in, but without any adhesion to the container or between the solid itself. It is then when a slight current of air (0.1-0.8 l / min) performs a sweeping effect with this now disaggregated solid.
[0174]
[0175] With respect to the ionization phenomenon, the present invention proposes different methods to be carried out, shown in the attached Figures 1-7, in which the pharmaceutical container is represented in a non-limiting way as a male or female type syringe, a syringe with needle, cartridge or carpule or tube of the Eppendorf® type. The use of ionizers can be done with any type of ionizer (accompanied or not by a stream of sterile carrier gas), such as ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, such as a bar, to ionize and neutralize both the environment and air flow, thus eliminating static charges. In the case of insulators, and in accordance with a preferred embodiment, prior to the dosing operation set forth in the present invention, sterilization with nebulized or vaporized hydrogen peroxide or mixture of hydrogen peroxide with peracetic acid is required.
[0176]
[0177] As soon as the pharmaceutical container is removed from the tray, it has a very high electrostatic charge (more than 30,000 Volts). This is due to the continuous friction between the container and the tray. That is why, as shown in the various figures, both before introducing the container into the cylinder, and once it has been introduced, the containers are preferably exposed to an ionizer regardless of what type a gas stream is already. sterile carrier. As it can be nitrogen that carries ionized air molecules or compressed air that falls both inside the container and in the sealing area to be able to eliminate the electrostatic charge that they have.
[0178] Figure 1 shows a general procedure for aseptic filling of a container that consists of various steps:
[0179]
[0180] The container (1), optionally inserted into a support cylinder (7) and capped with a nozzle cover (8), is subjected to an ionization step (a) by means of an ionizer (2), of whatever type, for example, ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, or any other type of ionizer. The ionizer (2) serves to eliminate the electrostatic charge from the container both on the interior walls and in the sealing area. This ionizer may or may not be applied in conjunction with a sterile carrier gas stream such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used . The nitrogen stream that carries the ionized air molecules used reaches both the interior of the container and the sealing zone; With these two ionization processes (ionization with ionizer and the optional application of sterile gas current) it is possible to eliminate the electrostatic charges from the container in order to proceed to its filling.
[0181]
[0182] After the ionization process (a), the syringe (1) goes to the aseptic filling station (b). At this stage the aseptic filling of the container (1) with the solid substance is carried out. For this process the use of a hopper (3) where the solid substance to be dosed is required and a dispensing needle or nozzle (4) by which said solid substance is dosed. A weighing cell (5) is also needed to measure the amount of solid substance that is accurately dosed. At this station you may or may not find a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen carrying ionized air molecules to serve as a vehicle for ions. There will be as many filling stations as products to be filled or combinations thereof.
[0183]
[0184] After the container (1) is filled with the solid, it is subjected to a deionization step (c) by means of a deionizer (2), which may be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the roof of said insulator. Along with the ionizer, a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules may or may not be applied; preferably nitrogen is used that carries ionized air molecules and thus avoid adhesion of the solid to the walls of the sealing area of the container (1).
[0185] Finally, there is the aseptic sealing station (d), in which the cap (6) is inserted to seal the container. In this last station a sterile carrier gas stream can be used or not as compressed air or a nitrogen stream that carries preferably ionized air molecules.
[0186]
[0187] Figure 2 shows another embodiment of the ionization process consisting of four stages:
[0188] The first stage deals with an ionization process (a) similar to that of figure 1, in which a stream of sterile carrier gas can be introduced or not, such as nitrogen carrying ionized air molecules or compressed air carrying molecules of ionized air in the container (1), the syringe has been previously capped with the nozzle cover (8) and optionally can be inserted into the carrier cylinder (7). This sterile carrier gas stream is used in conjunction with an ionizer (2), either ring, bar, gun, curtain, blades, barrel, needle or nozzle, or an ionizer filter, among which you can also find insulators with a ionizer on the ceiling of said insulator. The current and the ionizer (2) reach both the interior of the container (1) and the sealing area; In the present figure, the sterile carrier gas stream used is preferably a nitrogen stream carrying ionized air molecules. After using this current, the container is free of electrostatic charges to start filling it.
[0189]
[0190] For the second stage of the described process, the container (1) passes to the aseptic filling station (b) where the aseptic filling with the solid is carried out. In this station there are several elements such as: a hopper (3) where the solid substance to be dosed is located, a dispensing needle or nozzle or dispensing nozzle (4) in charge of dispensing the solid, a weighing cell (5) to control the exact amount of solid that is dispensed. There will be as many filling stations as products to be filled or combinations thereof. In order to ensure the cleaning of the sealing area, a third stage is used, which is an ionization stage (c) in which an ionizer (2) is used, which can be a ring, bar, gun, curtain, blades , cannons, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, being able to apply or not jointly a stream of sterile carrier gas such as nitrogen that carries molecules of ionized air or compressed air in order to end the adherence of the solid to the sides of the container in the sealing area. A nitrogen stream is preferably used that carries ionized air molecules to serve as a vehicle for displacing ions and as a means of entrainment in the sweeping effect, obtaining in this station the desired sealing phenomenon. There will be a different number of ionization stations depending on the needs of each product.
[0191]
[0192] And with this, we go to the last stage, it is a sealing stage (d) in which the container is sealed with a cap (6). In this stage, a sterile carrier gas stream such as nitrogen is used or not, which preferably carries ionized air molecules, since, although the sealing area is clean of solid substances, it is necessary to ensure complete cleanliness of the container and that no of the dosed solid substances adhere to the cap used for sealing and to the container walls due to the electrostatic charges created by rubbing when placing the container in the sealer.
[0193]
[0194] Figure 3 shows another particular embodiment of the ionization procedure, which consists of the following steps:
[0195]
[0196] The container (1) is subjected to an ionization process (a), using an ionizer (2) of the type that is a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, between you can also find insulators with an ionizer on the ceiling of said insulator. This ionizer may or may not work in conjunction with a sterile carrier gas stream as nitrogen carrying ionized air molecules or as compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used. The ionizer (2) serves to remove the electrostatic charge from the container both on the interior walls and in the sealing area. On the other hand, the nitrogen stream that carries the ionized air molecules used reaches both the interior of the container and the sealing area; With these two ionization processes it is possible to eliminate the electrostatic charges from the container in order to proceed to its filling.
[0197]
[0198] Subsequently, after this ionization phase (a), the container (1) passes to the aseptic filling station (b) where aseptic filling is carried out with the solid. In this station there are several elements such as a hopper (3) where the solid substance to be dosed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, a weighing cell (5) to control the exact quantity of solid that is dispensed and an ionizer (2), which can be a ring, bar, pistol, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer in the ceiling of said insulator. A sterile carrier gas stream such as compressed air or nitrogen carrying ionized air molecules may or may not be found at this station, preferably nitrogen carrying ionized air molecules so that Serve as a vehicle for ions. This ensures that the metered solid does not remain in the sealing zone. There will be as many filling stations as products to be filled or combinations thereof, in the same way there will be as many ionization phases as necessary.
[0199]
[0200] After the container (1) is filled with the solid in the filling station (b), in order to ensure the cleaning of the sealing area of the latter, the last stage is carried out, which is an ionization process ( c) in which an ionizer (2) is used, either ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator that may or may not act together with a stream of sterile carrier gas such as nitrogen that carries ionized air molecules or compressed air in order to end the adherence of the solid to the sides of the container in the sealing area . A nitrogen stream carrying ionized air molecules is preferably used to serve as a vehicle for displacing ions and as a means of entrainment in the sweeping effect, obtaining in this station the desired sealing phenomenon. There will be a different number of ionization stations depending on the needs of each product.
[0201]
[0202] Figure 4 shows another particular embodiment of the procedure described in the present invention:
[0203]
[0204] The container (1) optionally inserted into a support cylinder (7) and previously capped with the mouthpiece cover (8), is subjected to an ionization process (a), by means of an ionizer (2) of any type ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. This ionizer may or may not be found in conjunction with a sterile carrier gas stream as nitrogen carrying ionized air molecules or as compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used. The ionizer (2) serves to remove the electrostatic charge from the container both on the interior walls and in the sealing area. On the other hand, the nitrogen stream that carries the ionized air molecules used reaches both the interior of the container and the sealing area; With these two ionization processes it is possible to eliminate the electrostatic charges from the container in order to proceed to its filling.
[0205]
[0206] Following this ionization phase (a), the container (1) passes to the aseptic filling station (b) where aseptic filling is carried out with the solid. For this process the use of a hopper (3) is required where the solid substance to be dosed is found and a dispensing needle or nozzle (4) through which said solid substance is dosed. A weighing cell (5) is also needed to measure the amount of solid substance that is accurately dosed. At this station you may or may not find a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen carrying ionized air molecules to serve as a vehicle for ions. There will be as many filling stations as products to be filled or combinations thereof.
[0207]
[0208] After the container (1) is filled with the solid in the filling station (b), in order to ensure the cleaning of the sealing area of the solid, a third stage is carried out, which is an ionization process (c) in which an ionizer (2) is used, either in a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. Said ionizer may or may not act together with a stream of sterile carrier gas such as nitrogen that carries ionized air or compressed air molecules in order to end the adhesion of the solid to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferably used to serve as a vehicle for displacing ions and as a means of entrainment in the sweeping effect, obtaining in this station the desired sealing phenomenon. There will be a different number of ionization stations depending on the needs of each product.
[0209]
[0210] Finally, the container (1), passes to the sealing station (d) where its closure with a cap (6) takes place. In this stage, an ionizer (2) is used, which can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer in the ceiling of Said insulator, which may or may not act together with a stream of sterile carrier gas such as nitrogen, which preferably carries ionized air molecules, since, although the sealing area is clean of solid substances, it is necessary to ensure complete cleanliness of the container and of that none of the dosed solid substances adhere to the cap used for sealing and to the container walls due to the electrostatic charges created by rubbing when placing the container in the sealer.
[0211]
[0212] Figure 5 shows another particular embodiment of the procedure described in the present invention.
[0213]
[0214] The container (1) that has been capped with the mouthpiece cover (8) and optionally inserted into a support cylinder (7) is subjected to an ionization process (a), by an ionizer (2) is of the type that is a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the roof of said insulator, which may or may not be found in conjunction with a stream of sterile carrier gas as nitrogen carrying ionized air molecules or as compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used. The ionizer (2) serves to remove the electrostatic charge from the container both on the interior walls and in the sealing area. On the other hand, the nitrogen stream that carries the ionized air molecules used reaches both the interior of the container and the sealing area; With these two ionization processes it is possible to eliminate the electrostatic charges from the container in order to proceed to its filling.
[0215]
[0216] Following this ionization process (a), the container (1) passes to the aseptic filling station (b) where aseptic filling is carried out with the solid. In this station it is necessary to use various elements such as a hopper (3) where the solid substance to be dosed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, a weighing cell (5) to control the exact amount of solid that is dispensed. At this station you may or may not find a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen carrying ionized air molecules to serve as a vehicle for ions. This ensures that the metered solid does not remain in the sealing zone. There will be as many filling stations as products to be filled or combinations thereof.
[0217] After this filling stage (b), the container is subjected to an ionization stage (c) in which the ionizer (2) can be in the form of a ring, bar, gun, curtain, blades, barrels, needle or nozzle , or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, which may or may not be found together with a stream of sterile carrier gas such as nitrogen that carries molecules of ionized air or as compressed air It carries ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used.
[0218] Finally, the container (1 passes to the sealing station (d) where its closure takes place with a cap (6). In this stage an ionizer (2) is also used, which can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator that may or may not act together with a stream of sterile carrier gas such as compressed air or preferably nitrogen that it carries ionized air molecules, since, although the The seal is clean of solid substances, it is necessary to ensure the complete cleanliness of the container and that none of the dosed solid substances adhere to the cap used for sealing and to the container walls due to the electrostatic charges created by rubbing against the Place the container in the sealer.
[0219]
[0220] Figure 6 consists of three stages:
[0221]
[0222] In the first process, the ionization of the container (1) occurs, it is subjected to an ionization process (a), by means of an ionizer (2) of the type that is ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizing filter, among which you can also find insulators with an ionizer on the ceiling of said insulator, together or not with a stream of sterile carrier gas such as nitrogen carrying ionized air molecules or as compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used. The ionizer (2) serves to remove the electrostatic charge from the container both on the interior walls and in the sealing area. On the other hand, the nitrogen stream that carries the ionized air molecules used reaches both the interior of the container and the sealing area; With these two ionization processes it is possible to eliminate the electrostatic charges from the container in order to proceed to its filling.
[0223]
[0224] After this ionization process (a), the container (1) is transferred to the aseptic filling station (b) where aseptic filling with the solid proceeds. For this process the use of a hopper (3) where the solid substance to be dosed is required and a dispensing needle or nozzle (4) by which said solid substance is dosed. A weighing cell (5) is also needed to measure the amount of solid substance that is accurately dosed. At this station you may or may not find a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen carrying ionized air molecules to serve as a vehicle for ions. There will be as many filling stations as products to be filled or combinations thereof.
[0225]
[0226] Finally, the container (1) goes to the ionization station. In this stage, an ionizer (2) is used, which can be a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer in the ceiling of Said insulator, which may or may not act together with a stream of sterile carrier gas such as nitrogen, which preferably carries ionized air molecules, since, although the sealing area is clean of solid substances, it is necessary to ensure complete cleanliness of the container and of that none of the solid substances Dosages adhere to the container walls due to electrostatic charges created by rubbing when placing the container in the sealer.
[0227]
[0228] Figure 7 shows a particular embodiment of the procedure described in the present invention.
[0229]
[0230] The container (1) previously capped with a cap (6) and optionally inserted into a cylinder (7) is ionized in an ionization phase (a) by means of an ionizer (2), which can be ring, bar, gun, curtain, blades , cannons, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. At this station, a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules can be found or not, preferably nitrogen carrying ionized air molecules to serve as a vehicle for the ions.
[0231]
[0232] Next, the container is located in the aseptic filling station (b) where it is aseptically filled with the desired solid through the nozzle part. In this station it is necessary to use various elements such as a hopper (3) where the solid substance to be dosed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, a weighing cell (5) to control the exact amount of solid that is dispensed. A stream of sterile carrier gas may be found or not as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen carrying ionized air molecules to serve as a vehicle for ions. This ensures that the metered solid does not remain in the sealing zone. There will be as many filling stations as products to be filled or combinations thereof.
[0233] After the container (1) is filled with the solid in the filling station (b), in order to ensure the cleaning of the sealing area of the latter, a final stage is carried out, which is an ionization process (c) in which an ionizer (2) is used, either in a ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. It may or may not be next to a sterile carrier gas stream such as nitrogen that carries ionized air molecules or compressed air in order to end the adherence of the solid to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferably used to serve as a vehicle for displacing ions and as a means of entrainment in the sweeping effect, obtaining in this station the desired sealing phenomenon. There will be a different number of ionization stations depending on the needs of each product.
[0234] In the preferred embodiments shown in the Figures, a further ionization step of the container can be carried out after filling with the solid substance and just before sealing with the stopper. Preferably, ionization should also be performed when the container is empty, prior to filling with the solid, and more preferably at each station in the filling and sealing process there should be ionizers to ionize both the container and the solid and thus avoid its adherence to the interior walls and ensure the cleanliness of the container. These ionizers can be of any type, either ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionizer filter, among which you can also find insulators with an ionizer on the ceiling of said insulator. To facilitate dosing, a sterile carrier gas stream can be used as compressed air or nitrogen that carries ionized air molecules, preferably, the stream is nitrogen that carries ionized air molecules since it serves as a vehicle for the movement of ions , generates an inert atmosphere and serves as a means of entrainment in the sweep effect. This stream of nitrogen carrying ionized air molecules is used in ionization stations, along with an ionizer, more preferably, it is used in all stations of the aseptic filling and sealing process.
[0235]
[0236] Examples
[0237]
[0238] The following specific examples provided herein serve to illustrate the nature of the present invention. These examples are included for illustrative purposes only and are not to be construed as limitations on the invention claimed herein.
[0239]
[0240] In said examples, cartridges or cartridges, syringes with both a needle and a catheter-type cone, a Luer-cone or a Luer-lock cone have been used as containers; all of them with a male or female type mouthpiece and Eppendorf® type tubes, as biocompatible polymer excipients of the PLGA (lactic or glycolic acid) and PLA (polylactic acid) type, and as active compounds Risperidone and Letrozole respectively.
[0241]
[0242] Example 1: Filling a 50 mg dose of Letrozole in a syringe with a male nozzle or male syringe.
[0243]
[0244] In this example, we want to fill two products in a pharmaceutical container, specifically a syringe with a glass male nozzle that has been pre-capped with the nozzle cap (8). The products with which it is intended to fill are the excipient PLA and the active compound Letrozole, particularly a dose of 50 mg. It should be noted that the filling process takes place inside a rigid-walled aseptic insulator. Before beginning the filling process, all equipment must be clean and sterile. For this, firstly, the equipment is sterilized with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid.
[0245] The isolator consists of two main sections: (i) the first is the transfer chamber (TC), which is a chamber that facilitates the loading of sterile materials to and from the isolator's working chamber since all the materials and Tools that are loaded into the sterile isolator must be previously sterilized and (ii) the second is the working chamber (MC) that contains filling equipment for the excipient and for the active compound and a syringe capper or sealer unit.
[0246]
[0247] To start filling, start by taking the male-type syringes (1) and the caps (6), both sterile, delivering these caps to the operator who is at the capping or sealing station (d) so that they can be incorporated into the filling machine. syringe sealing. There will be as many filling stations as products to be filled or combinations thereof.
[0248]
[0249] Both the PLA used as an excipient and the Letrozole used as an active compound are delivered to the operators who are in the filling station (b) and they load them into their respective hoppers (3). The male-type syringes (1) to be used for filling undergo an ionization process at the back of the syringes or by the syringe collar part thanks to a needle ionizer (2). In this way, the male type syringes (1) are ionized (a) to achieve the elimination of the electrostatic charge inside them and in the sealing area of the syringe body itself. Next, the male syringe (1) is placed upside down inside a cylinder (7).
[0250]
[0251] The cylinder (7) containing the ionized male syringe (1) is directed towards the filling station (b) to fill with the PLA. The male syringe (1) is placed in the weighing cell (5), setting its weight to zero. After this, the filling of the male syringe (1) begins at the proximal end of the collar with an amount of 90 mg ± 30% PLA, this filling is carried out by means of a nozzle (4) or dispensing needle, both made of a non-conductive material. The male syringe (1) is continuously weighed during filling, so that the system can be controlled to stop filling when the desired weight is reached accurately, in this case between 90 mg ± 30%.
[0252] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 1075 volts.
[0253]
[0254] After the filling station (b) with the PLA excipient, the male syringe (1) is subjected to an ionization process (c) using a ring ionizer located on the outside of the syringe to facilitate sealing by preventing the PLA sticks to the walls of the male syringe (1). While this process is carried out, the presence of a stream of sterile nitrogen or carrier gas with ionized air molecules is necessary so that it displaces the ions and serves as a drag in the dust sweeping effect.
[0255]
[0256] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 775 volts.
[0257]
[0258] Once the excipient has been filled and its subsequent ionization, the cylinder (7) with the PLA-filled male syringe (1) is located in the filling station (b) in order to fill it with 50 mg ± 30 Letrozole%. The cylinder with the male syringe (1) is placed in the weighing cell (5) where it is tared before filling the active compound. The male syringe (1) is continuously weighed during filling, so that filling can be stopped once the desired weight is reached.
[0259]
[0260] After this filling process of the male syringe (1), it is subjected to another ionization process (c) with the help of a ring ionizer (2) to prevent both the excipient and the active ingredient with which the syringe male (1) has been filled to adhere to the walls of said syringe (1). In order to carry out this process, the presence of a stream of sterile nitrogen or carrier gas with ionized air molecules is necessary so that it displaces the ions and serves as a drag in the dust sweeping effect.
[0261]
[0262] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 645 volts.
[0263]
[0264] After filling with the active compound and subsequent ionization, the cylinder (7) with the male syringe (1) goes to the sealing station (d) in which the cap (6) is placed. To carry out this process, the presence of a stream of sterile nitrogen or carrier gas that carries ionized air molecules is required to displace the ions and serve as entrainment.
[0265]
[0266] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 375 volts.
[0267] By this means, the desired sealing phenomenon is achieved and the cleaning of the sealing area inside the body of the syringe at its end distal to the mouthpiece of the syringe is ensured, in addition, it is possible to prevent both the PLA and the Letrozole from adhere to the stopper (6) used for sealing and to the container walls due to the electrostatic charges created by rubbing when placing the container in the sealer.
[0268] Once the procedure for filling the male syringe is finished, and having proceeded to seal it, it can be placed on a tray with the rest of the syringes filled and sealed.
[0269]
[0270] Example 2: Filling a 400 mg dose of Letrozole in a syringe with a female type nozzle or a plastic female syringe.
[0271]
[0272] In this second example, PLA is also used as an excipient and as an active compound, for a dose of 400 mg, and the filling process also takes place within a rigid-walled aseptic insulator in the same way as Example 1.
[0273]
[0274] Both the PLA used as an excipient and the Letrozole used as an active compound are delivered to the operators who are in the filling station (b) and they load them into their respective hoppers (3), in this case without being material hoppers insulating. The female syringes (1) pre-capped with the nozzle cap (8), which are to be used for filling, are arranged under a stream of sterile nitrogen or carrier gas carrying ionized air molecules, to this process is added a needle ionizer (2), and in this way the female syringes (a) are ionized to achieve the elimination of the electrostatic charge inside and in the sealing area.
[0275]
[0276] The cylinder (7) containing the ionized female syringe (1) is directed towards the filling station (b) with PLA. The female syringe (1) is placed in the weighing cell (5), setting its weight to zero. After this, the filling of the syringe (1) begins at the back of the syringes or at the side of the syringe collar, with an amount of 500 mg ± 30% PLA, this filling is carried out using a nozzle (4) or dispensing needle, which is not made of insulating material. The syringe (1) is continuously weighed during filling, so that the system can be controlled to stop filling when the desired weight is reached, in this case between 500 mg ± 30%. While this process is carried out, the presence of a stream of sterile nitrogen or carrier gas with ionized air molecules is necessary so that it displaces the ions and serves as a drag in the sweeping effect.
[0277] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 1770 volts.
[0278]
[0279] Subsequently, the cylinder (7) with the female syringe (1) filled with PLA undergoes an ionization process (c) before being filled in a second filling station (b) with the active compound Letrozole. For ionization, a ring ionizer (2) is used, ionizing the PLA adhered to the walls of the sealing area of the syringe (1). A stream of sterile nitrogen or carrier gas that carries ionized air molecules is also used to serve as a vehicle for displacing ions and as a means of entrainment in the sweep effect, obtaining in this ionization process the desired sealing phenomenon.
[0280] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 975 volts.
[0281]
[0282] Once ionization has been carried out, the cylinder (7) with the PLA-filled female syringe (1) is located in the filling station (b) with 400 mg ± 30% of the active compound Letrozole. The cylinder (7) with the female syringe (1) is placed in the weighing cell (5) where it is tared before filling with said active compound, after which the filling with Letrozole begins. The syringe (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
[0283]
[0284] Next, it is transferred to an ionization station (c) in which a ring ionizer (2) is used to prevent adhesion of both the excipient and the active ingredient to its walls.
[0285]
[0286] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 895 volts, since both the dispensing needle and the hopper are not insulating materials.
[0287]
[0288] After filling with the active compound and subsequent ionization, the cylinder (7) with the female syringe (1) (d) where a plug (6) is inserted. To carry out this process, the presence of a stream of sterile nitrogen or carrier gas that carries ionized air molecules is necessary to displace the ions and serve as entrainment of the dust. By this means, the desired sealing phenomenon is achieved and the cleaning of the sealing area inside the body of the syringe is ensured to leave the area where the stopper is inserted clean, in addition to preventing both the PLA and Letrozole adhere to the stopper (6) used for sealing and to the container walls due to the electrostatic charges created by rubbing when placing the container in the sealer.
[0289] At this point, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 495 volts.
[0290]
[0291] Once the filling procedure of the syringe is finished, and having proceeded to seal it, it can be placed on a tray with the rest of the syringes filled and sealed.
[0292]
[0293] Example 3: Filling a 50 mg dose of Letrozole into Eppendorf® type tubes.
[0294]
[0295] In this example, PLA is used as an excipient and as an active compound Letrozole, for a dose of 50 mg. It should be noted that the filling process takes place inside a rigid-walled aseptic insulator, just as in the previous examples.
[0296]
[0297] Both the PLA used as an excipient and the Letrozole used as an active compound are delivered to the operators who are in the filling station (b) and they load them into their respective hoppers (3). The Eppendorf® type tubes (1) to be used for filling are arranged under a stream of sterile nitrogen or carrier gas carrying ionized air molecules, a needle ionizer (2) is added to this process and In this way, the Eppendorf® type tubes (1) are ionized to achieve the elimination of the electrostatic charge inside and in the sealing area.
[0298]
[0299] At this point, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 695 volts, since the tube is made of insulating material and its dimensions are significantly different from syringes, since they are wider and shorter than the syringes of examples 1 and 2.
[0300]
[0301] The ionized Eppendorf® (1) tube is directed to the filling station with 50 mg ± 30% Letrozole. The Eppendorf® type tube (1) is placed in the weighing cell (5), setting its weight to zero. After this, the filling of the Eppendorf® type tube (1) with the active compound begins with a nozzle (4) of insulating material. The Eppendorf® type tube (1) is continuously weighed during filling, so that the system can be controlled to stop filling when the desired weight is reached. While filling with Letrozole, the use of an ionization filter (2) is necessary to avoid its adherence to the walls of the sealing area.
[0302]
[0303] After the filling stage (b), the Eppendorf® type tube (1) is again subjected to an ionization process (c) with the help of a bar ionizer (2), in order to ensure that there are no remnants of active compound adhered to the walls of the container (1).
[0304] Again, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 700 volts.
[0305]
[0306] After filling with the active compound, the Eppendorf® type tube (1) filled with Letrozole is located in the second filling station (b), this time with 90 ± 30% of the PLA excipient. The Eppendorf® type tube (1) is placed in the weighing cell (5) where it is tared before proceeding with filling with said excipient, after which filling with PLA begins. The Eppendorf® type tube (1) is continuously weighed during filling, so that filling can be stopped once the desired weight is reached. During this process, the use of an ionization filter (2) is necessary to prevent both Letrozole and PLA from adhering to the sealing zone.
[0307]
[0308] After this filling process of the Eppendorf® type tube (1), it is subjected to another ionization process (c) with the help of a bar ionizer (2) to prevent both the excipient and the active ingredient with which the Eppendorf® type tube (1) has been filled to adhere to the walls of said container (1). The presence of a stream of sterile nitrogen or carrier gas that carries ionized air molecules is also necessary to displace the ions and serve as a drag. By means of these two means, it is achieved that the electrostatic charge inside the interior walls of the container (1) is about 595 volts, achieving the desired sealing phenomenon and ensuring the cleaning of the sealing area, in addition to preventing both the PLA like Letrozole adhere to the stopper (6) used for sealing and to the container walls due to the electrostatic charges created by rubbing when placing the container in the sealer.
[0309]
[0310] Example 4. Filling a 75 mg dose of Risperidone in a syringe needle or plastic syringe needle.
[0311]
[0312] In this example, PLGA is used as an excipient and as an active compound, Risperidone, for a dose of 75 mg. The filling process also takes place within a rigid-walled aseptic insulator employing the same material sterilization procedure as in the previous examples.
[0313]
[0314] The syringes with a needle (1) to be used for filling are capped by means of the mouthpiece cap (8) and undergo an ionization process thanks to a needle ionizer (2), and thus it proceeds to ionize (a) the syringes (1) to achieve the elimination of the electrostatic charge inside and in the sealing area. The cylinder (7) that contains the syringe with the ionized needle (1) in this case is made of an insulating material. The syringe (1) is placed in the weighing cell (5), tare its weight to zero. After this, the male syringe (1) is filled with a quantity of 75 mg ± 30% PLGA, this filling is carried out using a nozzle (4) of insulating material. The syringe (1) is continuously weighed during filling, so that the system can be controlled to stop filling when the desired weight is reached, in this case between 75 mg ± 30%.
[0315]
[0316] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 775 volts.
[0317]
[0318] After filling the syringe with a needle (1) with the excipient, it is subjected to an ionization process (c) thanks to a ring ionizer (2), thus avoiding the adherence of the PLGA to the walls of the sealing area of the container (1).
[0319]
[0320] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 550 volts.
[0321]
[0322] After filling with the excipient and subsequent ionization, the cylinder (7) with the PLGA-filled syringe (1) is located in the next filling station (b) with the active compound Risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before filling with said active compound, after which the filling with Risperidone begins. The syringe (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
[0323]
[0324] Once the filling with the active compound has been carried out, the cylinder (7) with the syringe with needle (1) is again subjected to an ionization process, where with the help of a ring ionizer (2), adhesion to the walls of the sealing area of the male syringe (1) of both the active compound and the excipient. After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 470 volts.
[0325]
[0326] After this ionization process, the male syringe (1) goes to the sealing station (d) where a cap (6) is placed and where it is subjected to an ionization process again. To carry out this process, a bar ionizer (2) is necessary, ionizing the PLGA and the Risperidone that are adhered to the walls of the sealing area.
[0327]
[0328] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 199 volts.
[0329] By means of the ionization process, the optimum sealing phenomenon is achieved and total cleaning of the sealing area is ensured. Furthermore, it is possible to prevent both PLGA and Risperidone from adhering to the plug (6) used for sealing and to the walls of the container due to electrostatic charges created by rubbing when placing the container in the sealer.
[0330]
[0331] Example 5: Filling a 100 mg dose of Risperidone in a syringe with a female type nozzle or a plastic female syringe.
[0332]
[0333] In this example, PLGA is used as an excipient and as an active compound, Risperidone, for a dose of 100 mg. The filling process also takes place within a rigid-walled aseptic insulator employing the same material sterilization procedure as in the previous examples.
[0334]
[0335] The female type syringes (1) pre-caps with the mouthpiece cap (8) to be used for filling undergo an ionization process thanks to a ring ionizer (2), and in this way the ionization (a) of the syringes (1) to achieve the elimination of the electrostatic charge inside them and in the sealing area. The cylinder (7) containing the ionized syringe (1) in this case is made of an insulating material. The syringe (1) is placed in the weighing cell (5), setting its weight to zero. After this, the filling of the syringe (1) with an amount of 100 mg ± 30% of PLGA begins, this filling is carried out by means of a nozzle (4) of insulating material. The syringe (1) is weighed continuously during filling, so that the system can be controlled to stop filling when the desired weight is reached, in this case between 100 mg ± 30%.
[0336]
[0337] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 785 volts.
[0338]
[0339] After filling the female syringe (1) with the excipient, it is subjected to an ionization process (c) thanks to a needle ionizer (2) thus avoiding the adherence of the PLGA to the walls of the container sealing area (one).
[0340]
[0341] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 580 volts.
[0342]
[0343] After filling with the excipient and subsequent ionization, the cylinder (7) with the PLGA-filled syringe (1) is located in the next filling station (b) with the active compound Risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before proceeding to fill with said active compound, beginning after this the filling with Risperidone. The syringe (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
[0344]
[0345] After filling with the active compound, the cylinder (7) with the syringe (1) is again subjected to an ionization process, where with the help of a needle ionizer (2), adhesion to the walls is avoided of the sealing area of the syringe (1) of both the active compound and the excipient. After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 440 volts.
[0346]
[0347] After this ionization process, the syringe (1) goes to the sealing station (d) so that the cap (6) is placed and where it is subjected to an ionization process again. To carry out this process, a bar ionizer (2) is necessary, ionizing the PLGA and the Risperidone that are adhered to the walls of the sealing area. After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 197 volts.
[0348]
[0349] By means of the ionization process, the optimum sealing phenomenon is achieved and total cleaning of the sealing area is ensured. Furthermore, it is possible to prevent both PLGA and Risperidone from adhering to the plug (6) used for sealing and to the walls of the container due to electrostatic charges created by rubbing when placing the container in the sealer.
[0350]
[0351] Example 6: Filling a 75 mg dose of Risperidone in cartridges or cartridges.
[0352]
[0353] In this other example, PLGA is used as an excipient and as an active compound, Risperidone, for a dose of 75 mg. The filling process also takes place within a rigid-walled aseptic insulator employing the same material sterilization procedure as in the previous examples.
[0354]
[0355] Both the PLGA used as an excipient and the Risperidone used as an active compound and the cartridges are delivered to the operators at the filling station (b) and they are loaded into their respective hoppers (3). The cartridges or cartridges (1) to be used for filling are arranged under a stream of sterile nitrogen or carrier gas that carries ionized air molecules, a process is added to this needle ionizer (2), and in this way the cartridges (1) are ionized to achieve the elimination of the electrostatic charge inside.
[0356]
[0357] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 1285 volts.
[0358]
[0359] The ionized cartridge or carpule (1) is directed to the filling station (b) with 75 mg ± 30% Risperidone. The cartridge (1) is placed in the weighing cell (5), face up, setting its weight to zero. After this, the filling of the cartridge (1) with Risperidone through the cartridge nozzle begins, this filling is carried out by means of a nozzle (4) or dispenser needle of insulating material. Cartridge (1) is continuously weighed during filling, so that the system can be controlled to stop filling when the desired weight is reached.
[0360]
[0361] Once the cartridge (1) has been filled with the active ingredient, it is placed in the second filling station (b), this time with 100 mg ± 30% of the PLGA excipient, the cartridge (1) is placed in the cell weighing (5) where it is tared before proceeding to fill with said active compound, after which filling with PLGA is also started from the mouthpiece. The cartridge (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
[0362]
[0363] Once the PLGA excipient has been filled, the cartridge (1) undergoes an ionization process again using a bar ionizer (2), in addition to the presence of a stream of nitrogen or sterile carrier gas that It carries ionized air molecules to move the ions and serves as a drag to insert the cartridge mouthpiece cover. Through both processes, both the excipient and the active compound are prevented from adhering to its walls, thus achieving the sealing phenomenon.
[0364]
[0365] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 1085 volts.
[0366]
[0367] Example 7. Filling a 400 mg dose of Risperidone in a pre-capped female syringe.
[0368] In this example, PLGA is used as an excipient and as an active compound, Risperidone, for a dose of 400 mg. The filling process also takes place within a rigid-walled aseptic insulator employing the same material sterilization procedure as in the previous examples.
[0369]
[0370] The female-type syringes (1) to be used for filling undergo an ionization process thanks to a ring ionizer (2), and in this way the ionization (a) of the syringes (1) to achieve the elimination of the electrostatic charge inside them and in the sealing area. The cylinder (7) containing the ionized syringe (1) in this case is made of an insulating material. The syringe (1) is placed in the weighing cell (5) face up since it is previously capped with a cap (6), setting its weight to zero. After this, the filling of the syringe (1) by the nozzle with an amount of 100 mg ± 30% of PLGA begins, this filling is carried out by means of a nozzle (4) of insulating material. The syringe (1) is weighed continuously during filling, so that the system can be controlled to stop filling when the desired weight is reached, in this case between 100 mg ± 30%.
[0371]
[0372] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 735 volts.
[0373]
[0374] After filling the female syringe (1) with the excipient, it is subjected to an ionization process (c) thanks to a stick ionizer (2) thus avoiding the adherence of the PLGA to the walls of the container (1) near the mouthpiece.
[0375]
[0376] After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 530 volts.
[0377]
[0378] After filling with the excipient and subsequent ionization, the cylinder (7) with the PLGA-filled syringe (1) is located in the next filling station (b) with the active compound Risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before filling with said active compound, after which the filling with Risperidone begins. The syringe (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
[0379]
[0380] After filling with the active compound, the cylinder with the syringe (1) is again subjected to an ionization process, where with the help of a bar ionizer (2), adhesion to the walls of the syringe is avoided (1) both the active compound and the excipient. After this process, the electrostatic charge inside the interior walls of the container (1) is measured and the measurement obtained is 215 volts.
[0381]
[0382] The ionization process achieves the optimum sealing phenomenon and the precise dose required.

权利要求:
Claims (43)
[1]
1. Procedure for filling pharmaceutical containers (1) with at least one solid and sealing them under sterile conditions, comprising the steps of:
a) providing a pharmaceutical container (1) having walls and a bottom,
b) dispensing the solid in the pharmaceutical container (1) by means of a dispensing needle (4), gravimetrically controlling the weight of the solid dispensed in the container (1); and
c) sealing the pharmaceutical container by means of a stopper (6),
characterized in that, in at least one of steps a), b) and c), or a plurality thereof in any combination, the static electric charges existing on the walls of the container (1), in the dispensed solid and / or in any part in contact with the container or with the solid dispensed, are neutralized by an ionizer (2) to which an ionization potential is applied such that the electrostatic charge inside the container (1) after each ionization is less than 2000 volts .
[2]
The method according to claim 1, wherein, between step b) and step c), an additional static electric charge ionization is carried out inside the pharmaceutical container (1).
[3]
3. Process according to claims 1 or 2, in which, in step a), the ionization is carried out with the empty pharmaceutical container (1).
[4]
4. Process according to any one of claims 1 to 3, wherein, in step b), the ionization is carried out before, during and / or after the solid is dispensed into the container (1).
[5]
5. Process according to any of claims 1 to 4, wherein, in step c), the ionization is carried out before and / or during sealing
[6]
6. Method according to any of the preceding claims, characterized in that the static electric charges are less than 1000 volts.
[7]
7. Method according to any of the preceding claims, characterized in that the static electric charges are less than 500 volts.
[8]
8. Method according to any of the preceding claims, characterized in that the static electric charges are less than 200 volts.
[9]
9. Process according to any of the preceding claims, in which step b) is carried out under vibration of the dispensing needle (4) to assist in the homogeneous dosing of the solid.
[10]
Process according to any one of the preceding claims, in which step b) is repeated as many times as necessary depending on the number, type and / or volume of solids to be dispensed.
[11]
Method according to any of the preceding claims, in which, in step b), the tip of the dosing end of the dispensing needle (4) is at a height h of 1 to 3 mm above the surface of the solid deposited in the bottom of the container (1).
[12]
12. Method according to any of the preceding claims, wherein, in step b), the container (1) is in a fixed position during the entire filling step while the dispensing needle (4) is a mobile element that is it moves upwards as the filling stage progresses, in order to maintain the distance h between the dosing end of the dispensing needle and the surface of the solid deposited at the bottom of the container (1).
[13]
13. Method according to any of claims 1 to 11, wherein, in step b), the dispensing needle (4) is in a fixed position during the entire filling step while the container (1) is a mobile element that moves downwards as the filling stage progresses, in order to maintain the distance h between the dosing end of the dispensing needle and the surface of the solid deposited at the bottom of the container (1).
[14]
The method according to any of claims 1 to 11, wherein, in step b), both the dispensing needle (4) and the container (1) are mobile elements that move synchronously with respect to each other during the filling stage, in order to maintain the distance h between the dosing end of the dispensing needle (4) and the surface of the solid deposited at the bottom of the container (1).
[15]
Method according to any of the preceding claims, in which, in step b), the container (1) is filled by the distal part of the collar of the container when the container is a syringe or cartridge.
[16]
16. The method according to any of the preceding claims 1 to 13, in which, in step b), the container (1) is filled by the part distal to the nozzle of the container when the container is a syringe or cartridge.
[17]
17. Process according to any one of the preceding claims, in which step c) is carried out under vacuum.
[18]
18. Process according to any one of the preceding claims, in which, in at least one of steps a), b) and c) or in a plurality thereof in any combination, it is applied inside the pharmaceutical container (1 ) a stream of sterile carrier gas such as N2 or sterile compressed air.
[19]
The method according to any one of the preceding claims, wherein the ionizer (2) is selected from the group consisting of ring, bar, gun, curtain, blades, barrel, needle or filter ionizers, and insulators with a ionizer on the roof of it.
[20]
20. Method according to any one of the preceding claims, in which the dispensing needle (d) dispenses the solid contained in a hopper (c), and both the hopper (c) and the dosing needle (d) are of a non-conductive material.
[21]
The method according to any one of the preceding claims, wherein the pharmaceutical container (1) is inserted into a cylinder of an electrically conductive material and is grounded, to help dissipate the static charge of the pharmaceutical container.
[22]
22. A method according to any one of the preceding claims 1 to 20, wherein the pharmaceutical container (1) is inserted into a cylinder of an electrically non-conductive material, to help dissipate the static charge of the pharmaceutical container.
[23]
23. Process according to any one of the preceding claims, in which the pharmaceutical container (1) is made of an electrically non-conductive material.
[24]
24. Method according to any one of the preceding claims, in which the pharmaceutical container (1) is selected from the group consisting of a male syringe, a female syringe, a syringe with a needle, a vial, a capsule, an ampoule, a single-dose device , a cartridge, an inhaler, a bottle, a blister, an envelope, a bag, a test tube, and an Eppendorf® type tube.
[25]
25. Process according to any one of the preceding claims, in which the pharmaceutical container (1) is composed of glass, crystal, metal such as steel or titanium suitable for drug administration, or plastic-type materials.
[26]
26. The process of claim 25, wherein the plastic materials are selected from polyolefins, cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polyetheretherketone, polystyrene, polyvinylchloride, polyacrylonitrile, polyamides, polyesters such as polyethylene terephthalate, polycarbonate, acrylic polymers such as poly (methyl methacrylate), polyacrylonitrile, thermoplastic resins such as polyacetals and polyhalostylenes, polyurethanes, formaldehyde resins such as phenol resin and urea resin, phenoplasts, aminoplasts, thioplasts, duroplastic resins such as , polyvinylenic silicones, cellulose derivatives, polycarbonates, and their combinations.
[27]
27. Process according to any one of the preceding claims, in which the pharmaceutical container (1) has a diameter between 9 and 80 mm.
[28]
28. The method according to any one of the preceding claims, in which the dispensing needle (4) is provided with a containment element to prevent the powder from dispersing above the level of the dispensing tip or end of the dispenser during filling. same.
[29]
29. Process according to any one of the preceding claims, in which the solid product to be dispensed in the container (1) has the following distribution of particle sizes:
- not more than 10% of the total volume of particles is less than or equal to 20 microns, - not more than 10% of the total volume of particles is greater than or equal to 230 microns nor less than or equal to 140 microns,
- a value d0.5 in the range of 60-160 microns,
where d0.5 indicates the average value of the particle size that divides the population into exactly two equal halves, 50% of the distribution being above this value, and 50% below.
[30]
30. Process according to any one of claims 1 to 28 above, in which the solid product to be dispensed in the container (1) has the following particle size distribution:
- not more than 10% of the total volume of particles is less than or equal to 20 microns, - not more than 10% of the total volume of particles is greater than or equal to 325 microns or less than or equal to 245 microns,
- a d0.5 value in the range of 100-155 microns,
[31]
31. The process according to any one of the preceding claims, in which the solid product to be dispensed in the container (1) is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole , caripracin, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.
[32]
32. Process according to any one of the preceding claims, in which the solid product to be dispensed in the container (1) is selected from the group consisting of biocompatible polymers of the lactic polyacid type, (PLA), polyacid glycolic acid (PGA) and its lactic-co-glycolic polyacid copolymers (PLGA) including any derivative or copolymer, alone or in combination.
[33]
33. Method according to any one of the preceding claims, characterized in that it is carried out in an aseptic environment in an area with unidirectional air flow or turbulent regime.
[34]
34. Method according to any one of the preceding claims, characterized in that it is carried out in an insulator.
[35]
35. Process according to claim 33, characterized in that before step b) a sterilization of the insulator is carried out with nebulized or vaporized hydrogen peroxide, or a mixture of hydrogen peroxide with peracetic acid.
[36]
36. Method according to any one of the preceding claims, which is implementable in software that can be executed on a computer.
[37]
37. Container (1) containing a solid product, wherein the solid product has been dispensed into the container (1) using the method described in any one of claims 1 to 35 above.
[38]
38. Container (1) containing a solid product according to claim 36, wherein the solid product has the following particle size distribution:
- not more than 10% of the total volume of particles is less than or equal to 20 microns, - not more than 10% of the total volume of particles is greater than or equal to 230 microns or less than or equal to 140 microns,
- a d0.5 value in the range of 60-160 microns,
where d0.5 indicates the average value of the particle size that divides the population into exactly two equal halves, 50% of the distribution being above this value, and 50% below.
[39]
39. Container (1) containing a solid product according to claim 36, wherein the solid product has the following particle size distribution:
- not more than 10% of the total volume of particles is less than or equal to 20 microns, - not more than 10% of the total volume of particles is greater than or equal to 325 microns or less than or equal to 245 microns,
- a d0.5 value in the range of 100-155 microns.
[40]
40. Container (1) containing a solid product according to any one of claims 36 to 38, wherein the solid product is a medicament.
[41]
41. Container (1) containing a solid product according to claim 39, wherein the medicament is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, caripracin, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite, or salt thereof, alone or in combination.
[42]
42. Container (1) containing a solid product according to any one of claims 36 to 38, wherein the solid product is a biocompatible polymer.
[43]
43. Container (1) containing a solid product according to claim 41, wherein the biocompatible polymer is selected from the group consisting of biocompatible polymers of the lactic polyacid type, (PLA), glycolic polyacid (PGA) and its copolymers lactic-co-glycolic polyacid (PLGA) including any derivative or copolymer, alone or in combination.

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同族专利:

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公开号 | 公开日

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IL282762D0|2021-06-30|

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EA202191172A1|2021-11-23|

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BR112021008161A2|2021-08-03|

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EP3875377A1|2021-09-08|

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PH12021550936A1|2021-11-22|

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JP2022506053A|2022-01-17|

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UY38430A|2020-05-29|

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SG11202104253WA|2021-05-28|

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US20210316890A1|2021-10-14|

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ES2758362B2|2021-03-29|

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AR116955A1|2021-06-30|

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CN112912314A|2021-06-04|

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WO2020089503A1|2020-05-07|

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CO2021006113A2|2021-05-31|

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CA3118038A1|2020-05-07|

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CL2021000993A1|2021-09-20|

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AU2019370779A1|2021-05-20|

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法律状态:
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优先权:

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申请号 | 申请日 | 专利标题

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ES201831060A|ES2758362B2|2018-11-02|2018-11-02|Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions|ES201831060A| ES2758362B2|2018-11-02|2018-11-02|Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions|

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UY0001038430A| UY38430A|2018-11-02|2019-10-29|PROCEDURE FOR FILLING SOLIDS IN PHARMACEUTICAL CONTAINERS AND SEALING THEM IN STERILE CONDITIONS|

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JP2021523206A| JP2022506053A|2018-11-02|2019-10-30|Procedure for filling a drug container with solid matter in a sterilized state and sealing it|

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CA3118038A| CA3118038A1|2018-11-02|2019-10-30|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

---

SG11202104253WA| SG11202104253WA|2018-11-02|2019-10-30|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

---

BR112021008161-5A| BR112021008161A2|2018-11-02|2019-10-30|procedure for filling solid substances into pharmaceutical containers and sealing them under sterile conditions|

---

EP19879123.8A| EP3875377A1|2018-11-02|2019-10-30|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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EA202191172A| EA202191172A1|2018-11-02|2019-10-30|METHOD FOR FILLING SOLID SUBSTANCES IN PHARMACEUTICAL CONTAINERS AND THEIR SEALING UNDER STERILE CONDITIONS|

---

AU2019370779A| AU2019370779A1|2018-11-02|2019-10-30|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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CN201980070813.9A| CN112912314A|2018-11-02|2019-10-30|Method for filling and sealing solid into medicine container under aseptic condition|

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PCT/ES2019/070740| WO2020089503A1|2018-11-02|2019-10-30|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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ARP190103194A| AR116955A1|2018-11-02|2019-11-01|PROCEDURE FOR FILLING SOLIDS IN PHARMACEUTICAL CONTAINERS AND SEALING THEM IN STERILE CONDITIONS|

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CL2021000993A| CL2021000993A1|2018-11-02|2021-04-20|Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions|

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US17/235,012| US20210316890A1|2018-11-02|2021-04-20|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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PH12021550936A| PH12021550936A1|2018-11-02|2021-04-26|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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IL282762A| IL282762D0|2018-11-02|2021-04-28|Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions|

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CONC2021/0006113A| CO2021006113A2|2018-11-02|2021-05-11|Procedure for filling solids in pharmaceutical containers and sealing them in sterile conditions|