WO2014207956A1

WO2014207956A1 - Production method for medicinal preparation, and medicinal preparation kit

Info

Publication number: WO2014207956A1
Application number: PCT/JP2013/081190
Authority: WO
Inventors: 清忠安井
Original assignee: Yasui Kiyotada
Priority date: 2013-06-24
Filing date: 2013-11-19
Publication date: 2014-12-31

Abstract

Provided is a production method for a medicinal preparation comprising a first preparation component and a second preparation component, wherein the method includes: a step of preparing a first preparation component that is an active pharmaceutical ingredient previously demonstrated in non-clinical studies to be stable, effective, and safe, and that comprises an effective component and a solvent only, the effective component being either a protein preparation component, a nucleic acid preparation component, or a vaccine preparation component; a step of preparing a second preparation component which, in the event that the effective component is a protein preparation component or a nucleic acid preparation component, contains at least one type of preparation additive, or in the event that the effective component is a vaccine preparation component, contains at least one type of adjuvant and/or preparation additive; a step in which an adsorption preventive agent is filtered through a filtration sterilization filter to effect adsorption preventive treatment of the filtration sterilization filter; a step of filtration sterilization of the first preparation component through the filtration -sterilization filter; and a step of formulation through mixing the filtration-sterilized first preparation component and the second preparation component in any proportion, making possible administration without the need to evaluate stability in clinical studies.

Description

Method for producing pharmaceutical preparation and pharmaceutical preparation kit

The present invention relates to a method for producing a pharmaceutical preparation that can be formulated and used by mixing with other pharmaceutical ingredients containing a pharmaceutical additive or the like immediately before administration with respect to a pharmaceutical ingredient comprising a drug substance that does not contain a pharmaceutical additive or the like And a pharmaceutical preparation kit.

When developing new drugs, non-clinical studies targeting animals and clinical studies targeting humans are conducted. In non-clinical studies, the drug substance is administered to animals and its stability, efficacy and safety are tested. In clinical trials, the drug substance that has passed non-clinical trials is formulated, and this formulation is tested for stability, efficacy and safety in human subjects.

Here, for example, in order to examine the stability of a preparation in a stability test in clinical trials, after obtaining the drug substance, the preparation is actually manufactured and preliminary stability is examined, and then a preparation for clinical trial is prepared. Need to be done. Long-term (about 3 years) guarantees are required for the stability of the drug product, but if a preliminary test of stability is made before the clinical drug product is manufactured and clinical trials are conducted, The development period at this stage will be long, resulting in an increase in new drug development costs and loss of sales opportunities.

However, if a clinical trial is conducted without confirming preliminary stability, the clinical trial must be conducted without denying the possibility that the stability required as a product cannot be ensured. As a result, even if the efficacy and safety are confirmed, if the stability in clinical trials is not shown, the development itself must be stopped. Therefore, in the development of new drugs, efficient development and shortening of the development period are required.

On the other hand, the formulation requires formulation additives such as an isotonic agent, a pH adjuster, and a surfactant for hemolysis, stability, irritation, and prevention of adsorption to the container wall surface. However, pharmaceutical additives may be harmful to the human body even if they are substances derived from natural products. Therefore, it is preferable that the formulation additive is not added to the formulation as much as possible.

Also, since protein preparations and nucleic acid preparations are denatured by heating, heat sterilization is difficult. Therefore, for these preparations, bactericides such as cresol and formalin are added as preparation additives, thereby ensuring sterility. However, since disinfectants are prohibited from being added to large-volume injections (infusion solutions), they can be applied only to small-volume injections.

JP 2007-271527 A JP 2009-45140 A

The object of the present invention is to enable the production of a pharmaceutical preparation which can shorten the development period of the pharmaceutical preparation, can omit the preparation additives and adjuvants and is excellent in stability and sterility. And a pharmaceutical preparation kit.

The inventors of the present application examined pharmaceutical preparations and production methods thereof in order to solve the conventional problems. As a result, the inventors have found that the above problems can be solved by adopting the following configuration, and have completed the present invention.

That is, in order to solve the above-mentioned problems, the method for producing a pharmaceutical preparation according to the present invention is a method for producing a pharmaceutical preparation comprising a first preparation component and a second preparation component. And a first active ingredient comprising only an active ingredient and an optional solvent, wherein the active ingredient is a protein preparation ingredient, a nucleic acid preparation ingredient or a vaccine preparation ingredient. A step of preparing and when the active ingredient is the protein preparation component or the nucleic acid preparation component, it contains at least one preparation additive, and when the active ingredient is the vaccine preparation ingredient, at least one adjuvant and And / or preparing the second formulation component containing the formulation additive, and filtering the adsorption inhibitor through a filter sterilization filter immediately before administration to prepare the first formulation component. A process for preventing adsorption of the active ingredient in the filter for filter sterilization, a process for filter sterilizing the first preparation component with the filter sterilization filter after the adsorption prevention process, A step of mixing the first preparation component and the second preparation component in an arbitrary ratio to prepare a preparation, which can be administered without evaluating the stability in a clinical test.

Moreover, in order to solve the above-mentioned problem, another method for producing a pharmaceutical formulation according to the present invention is a method for producing a pharmaceutical formulation comprising a first formulation component and a second formulation component, Effectiveness and safety are indicated, and the drug substance is composed only of an active ingredient and an arbitrary solvent, and the active ingredient is any one of a protein preparation ingredient, a nucleic acid preparation ingredient, and a vaccine preparation ingredient. A step of preparing an ingredient, and when the active ingredient is the protein preparation ingredient or the nucleic acid preparation ingredient, it contains at least one preparation additive, and when the active ingredient is the vaccine preparation ingredient, at least one kind Preparing the second formulation component containing an adjuvant and / or the formulation additive; and immediately before administration, filtering the adsorption inhibitor through a filter sterilization filter, A step of treating the active ingredient in the agent component to prevent adsorption to the filter for filter sterilization, a step of mixing the first formulation component and the second formulation component in an arbitrary ratio to prepare a mixture, And sterilizing the mixed solution with the filter for filtration sterilization after the adsorption preventing treatment so that the mixed solution can be administered without evaluating the stability in a clinical test.

In the above method, after the mixed solution is sterilized by filtration with the filter sterilization filter, the second preparation component is further added to the filtrate so that it can be administered without evaluating the stability in clinical trials. It is preferable to do.

In the above method, it is preferable that the second preparation component does not contain a preparation additive that contributes to stability as a preparation.

In the above method, the second preparation component preferably does not contain a surfactant.

In the above method, it is preferable that the adsorption inhibitor is the second formulation component containing an adsorption inhibitor component.

Furthermore, in the above method, the adsorption inhibitor is preferably a surfactant component.

In the above method, the step of sterilizing the first preparation component with the filter sterilization filter after the adsorption prevention treatment, or the mixed solution of the first preparation component and the second preparation component after the adsorption prevention treatment In the step of filter sterilization with the filter sterilization filter, it is preferable that air is permeated after the first formulation component or a mixed solution of the first formulation component and the second formulation component is filtered through the filter sterilization filter.

The pharmaceutical preparation kit according to the present invention is a pharmaceutical preparation kit that is used by mixing the first preparation component and the second preparation component contained in the kit form in order to solve the above-mentioned problems. A pharmaceutical ingredient is a drug substance that has been previously shown to be stable, effective and safe in non-clinical studies, and consists of only an active ingredient and an optional solvent, and the active ingredient is a protein pharmaceutical ingredient, a nucleic acid pharmaceutical ingredient or a vaccine pharmaceutical ingredient. And when the active ingredient is the protein preparation ingredient or the nucleic acid preparation ingredient, the second preparation ingredient contains at least one preparation additive, and the active ingredient is the vaccine preparation ingredient. Includes at least one adjuvant and / or the above-mentioned formulation additive, and the kit form contains the first formulation component, or the first formulation component and the second formulation component. Filtration sterilization filter for filtering sterilizing liquid mixture engaged, and wherein the adsorption inhibitor for performing adsorption preventing process to the filtration sterilization filter is further included.

In the composition of the pharmaceutical preparation kit, it is preferable that the second preparation component does not contain a preparation additive that contributes to stability as a preparation.

In the composition of the pharmaceutical preparation kit, the second preparation component preferably does not contain a surfactant.

Moreover, it is preferable that the adsorption inhibitor is the second preparation component containing an adsorption inhibitor component.

Furthermore, in the above configuration, it is preferable that the adsorption inhibitor is a surfactant component.

The present invention has the following effects by the means described above. That is, the present invention relates to a method for producing a pharmaceutical preparation comprising a first preparation component as a drug substance and a second preparation component containing a preparation additive and / or an adjuvant. The second formulation component is mixed and formulated for use. Therefore, it is not necessary to guarantee the long-term stability as a preparation required in clinical trials.

In addition, since the present invention performs filtration sterilization using a filter sterilization filter on the first formulation component or the mixture of the first formulation component and the second formulation component immediately before administration, addition of a bactericidal agent or heating Sterilization is unnecessary. As a result, safety can be improved and denaturation of the active ingredient contained in the first preparation component can be prevented.

Furthermore, in the present invention, before the filter sterilization using the filter sterilization filter, an adsorption inhibitor is used to prevent the adsorption of the active ingredient in the first preparation component to the filter sterilization filter. Perform the anti-adsorption treatment. Therefore, even in a pharmaceutical preparation in which the concentration of the first preparation component is extremely low, the loss due to adsorption of the active ingredient to the filter for filter sterilization can be reduced, and the pharmaceutical that can stably exhibit the pharmacological effect as designed. A formulation can be produced.

Conventionally, when a stabilizer or preservative is used as a formulation additive, its effect was confirmed to determine the amount and type of addition, but in the present invention, a long-term formulation is used. Since there is no need to ensure stability, there is no need to use formulation additives that contribute to the stability of such formulations. As a result, the manufacturing process for determining the type and amount of stabilizer and preservative can be omitted.

Therefore, according to the present invention, the development period can be significantly shortened as compared with conventional pharmaceutical preparations. In addition, it is possible to manufacture a pharmaceutical preparation method and a pharmaceutical preparation kit that are excellent in stability and sterility as a preparation while ensuring safety to the human body.

It is a flowchart for demonstrating the manufacturing method of the pharmaceutical formulation which concerns on one Embodiment of this invention. It is a flowchart for demonstrating the manufacturing method of the pharmaceutical formulation which concerns on other embodiment of this invention.

One embodiment of the present invention will be described below. FIG. 1 is a flowchart for explaining a method for producing a pharmaceutical preparation according to the present embodiment.
As shown in FIG. 1, the manufacturing method of the pharmaceutical formulation which concerns on this Embodiment is the process (S1) which each prepares a 1st formulation component and a 2nd formulation component, and the said filtration of the active ingredient in a 1st formulation component A step of performing an anti-adsorption treatment on the sterilization filter (S2), a step of sterilizing the first preparation component with the filter for filter sterilization (S3), and a first preparation component and a second preparation component after filter sterilization. And a step (S5) of mixing and formulating at an arbitrary ratio.

As the first formulation component, one that has been confirmed to be stable, effective and safe as a drug substance in a non-clinical test for animals is used. For example, the first formulation component that has shown stability is one that has been confirmed to be stable as a drug substance by a stability test in a non-clinical test, more specifically, a severe test, a long-term storage test and an accelerated test. Means. The drug substance means a raw material for producing the pharmaceutical preparation of the present embodiment.

The first formulation component is sterilized by filtration using a filter sterilization filter prior to formulation by mixing with the second formulation component, but is preferably a drug substance that has been sterilized in advance. Here, for sterilization of the first preparation component, for example, it is preferable to handle the first preparation component in a liquid state in order to ensure sterility. The sterilization process is performed in a manner most suitable for the first formulation component. For example, when the first preparation component is composed of a component that decomposes by heating, it is preferable to sterilize the first preparation component by filtration. In addition, when the first preparation component is a component to which the final sterilization method can be applied, the final sterilization method may be performed after filling the first preparation component in a container such as a vial. In the final sterilization method, a heating method, an irradiation method, or a gas method can be selected as appropriate based on the physicochemical properties of the material to be sterilized and the first preparation component. The heating method is not particularly limited, and examples thereof include a high pressure steam method and a drying method. The irradiation method is not particularly limited, and examples thereof include a radiation method and a high frequency method. The reason why the first preparation component is handled in a liquid state is that it is difficult to make them sterile when the first preparation component is in a solid or powder state.

In addition, the first preparation component may be refrigerated or frozen until it is mixed with the second preparation component from the viewpoint of the effective period, stability, safety and effectiveness. In this case, it is sufficient that the storage conditions satisfy the storage conditions in the drug substance. Therefore, in the pharmaceutical preparation of the present embodiment, it is not necessary to obtain information necessary for setting the storage conditions and the effective period after preparation. As a result, the development period of new drugs can be further shortened.

The first formulation component consists of the active ingredient and any solvent. The active ingredient means an ingredient having a useful effect such as a pharmacologically active ingredient or a physiologically active ingredient, and specifically, any of a protein preparation ingredient, a nucleic acid preparation ingredient or a vaccine preparation ingredient. When the active ingredient is a protein preparation ingredient, the pharmaceutical preparation of the present embodiment is a protein preparation, and when the active ingredient is a nucleic acid preparation ingredient, it is a nucleic acid preparation. Further, when the first preparation component is a vaccine preparation component, the pharmaceutical preparation of the present embodiment is a vaccine preparation.

In the case where the first formulation component is composed of a drug substance containing a protein formulation component or a nucleic acid formulation component as an active ingredient, formulation additives other than the solvent are not included in the first formulation component. Although a solvent may be contained, it is not preferable that the amount of the solvent is too large. This is because if the amount of the solvent is large, the first preparation component may need to be guaranteed as a preparation in clinical trials for stability and the like. Furthermore, when the first preparation component includes a protein preparation component, the protein may be hydrolyzed, and it becomes difficult to ensure stability. In the case where the first preparation component is composed of a drug substance containing a vaccine preparation component as an active ingredient, the first preparation component does not contain an adjuvant or a preparation additive. In this case, however, a solvent may be contained.

The first preparation component may be any of liquid, solid, semi-solid and powder, but liquid is preferred. When it is in a solid, semi-solid or powder form, it may be difficult to guarantee sterility. On the other hand, when the first preparation component is liquid, sterilization can be easily performed by filtration sterilization or the like described later, and the sterility of the first preparation component can be ensured. In addition, if the 1st formulation component has been sterilized and removed foreign substances when it is in a liquid state, it can be stored as a solid by freezing.

The protein preparation component means a protein (including glycoprotein and lipoprotein) component as an active ingredient. Specific examples include active ingredients in monoclonal antibody preparations, albumin preparations, globulin preparations, human erythropoietin preparations, romiplostim preparations, and the like, but the present embodiment is not limited thereto.

In addition, the nucleic acid preparation component means that a DNA component, an RNA component, or the like is included as an active ingredient. Specific examples include active ingredients in antisense preparations, siRNA (small interference) RNA preparations, aptamer preparations, ribozyme preparations, decoy preparations, and the like, but this embodiment is not limited thereto.

In the case where the first preparation component of the present embodiment is composed of a drug substance containing a vaccine preparation component as an active ingredient, the vaccine preparation component is not particularly limited. For example, BCG, seed vat, polio used in live vaccines , Chickenpox, measles, rubella, mumps, rinderpest, NDV, Marek's disease and other live and attenuated bacteria. In addition, antigens such as pneumococcal capsular polysaccharide, anti-TNF antibody, inactivated Japanese encephalitis virus and the like used in inactivated vaccines can be mentioned.

The vaccine refers to an antigenic suspension or solution containing an infectious agent or a part of the infectious agent that is administered into the human body and generates active immunity. The antigenic portion comprising the vaccine can be a microorganism (eg, a virus or a bacterium) or a natural product purified from a microorganism, a synthetic product or a genetically engineered protein, peptide, polysaccharide or similar product. In addition, the inactivated vaccine means a vaccine in which an antigen that has lost its infectivity but retains immunogenicity (inactivated antigen) is used as a vaccine, and includes a subunit vaccine. Subunit vaccines refer to vaccines that do not have all of the antigens from the immunodeficiency virus of interest and contain one or more selected protein antigens. The subunit vaccine is at least partially separated from other components of the virus and components derived from infected cells. Subunit vaccines can be prepared by at least partially purifying the immunodeficiency virus protein. It can also be produced by recombinant production or synthesis. The virus or microorganism used as the base of the live recombinant vaccine is not particularly limited, and examples thereof include poxvirus, adenovirus, salmonella, poliovirus, mycobacteria, influenza virus, and Semliki Forest virus.

The second formulation component may be any component that is chemically stable and has been confirmed to be safe for humans. The stability and safety can be confirmed by a conventionally known test method. In addition, the second preparation component needs to have sterility in consideration of the case where the first preparation component is sterilized by filtration and then mixed with the first preparation component to prepare the preparation. However, when the mixture is sterilized by filtration with the first formulation component, the sterility of the second formulation component may not be guaranteed. Furthermore, sterility can be ensured by performing sterilization treatment as in the case of the first preparation component. In this case, the sterilization treatment is preferably performed by a method most suitable for the second preparation component. For example, when the second preparation component is composed of a component that decomposes by heating, it is preferable to sterilize the second preparation component by filtration. In addition, when the second preparation component is a component to which the final sterilization method can be applied, the final sterilization method may be performed after filling the second preparation component in a container such as a vial. The method of final sterilization is as described above.

When the first formulation component is composed of a drug substance including a protein formulation component or a nucleic acid formulation component, the second formulation component includes at least one formulation additive. The second preparation component may contain the solvent, but does not contain an active ingredient.

The formulation additive means a component other than the active component among the components contained in the pharmaceutical formulation according to the present embodiment. Therefore, it is preferable that the formulation additive does not exhibit a pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Moreover, it is preferable that it is chemically stable and does not interfere with the Japanese Pharmacopoeia test.

Specific examples of the formulation additive include a solvent, a solubilizer, a stabilizer, a preservative (preservative), a buffer, an isotonic agent, a pH adjuster, an antioxidant, and a soothing agent. , Flavoring agents, surfactants, bactericides, excipients and the like. In the second preparation component, these preparation additives can be used alone or in combination of two or more as required.

The solvent is not particularly limited, and examples thereof include purified water, water for injection, physiological saline, ethanol, glycerin, and vegetable oil. These solvents are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The solubilizing agent is not particularly limited, and examples thereof include sodium benzoate, ethylenediamine, nicotinamide, cyclodextrin, ethanol, propylene glycol, and polyethylene glycol. These solubilizers are appropriately selected and used depending on the type of protein preparation component or nucleic acid preparation component.

The stabilizer is not particularly limited, and examples thereof include sodium bisulfite, ascorbic acid, tocopherol, sodium edetate, and sodium pyrosulfite. These stabilizers are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The preservative is not particularly limited. For example, benzoic acid, sodium benzoate, sodium sulfite, salicylic acid, sodium salicylate, dibutylhydroxytoluene, sorbic acid, potassium sorbate, sodium dehydroacetate, isobutyl paraoxybenzoate, paraoxybenzoic acid Examples include isopropyl, ethyl paraoxybenzoate, methyl paraoxybenzoate, and the like. These preservatives are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The buffer is not particularly limited, and examples thereof include acids, bases, acid-base salts, amino acids, and the like, and these may be used in combination. More specifically, mineral acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid and carbonic acid; organic carboxylic acids such as oxalic acid, citric acid, succinic acid, maleic acid, tartaric acid, lactic acid, acetic acid and benzoic acid; Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; monoethanolamine, diethanolamine, triethanolamine, diisopropanol Organic bases such as amine, meglumine, trometamol; sodium chloride, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, borax, carbonic acid Salts of mineral acids and inorganic bases such as sodium and sodium bicarbonate; sodium citrate Salts of organic carboxylic acids and inorganic bases such as sodium, sodium lactate, sodium acetate and sodium benzoate; salts of sulfonic acids and inorganic bases such as sodium methanesulfonate and sodium p-toluenesulfonate; aminosulfonic acids such as taurine; And acidic amino acids such as aspartic acid and glutamic acid; neutral amino acids such as glutamine and glycine; and basic amino acids such as arginine and lysine. These buffering agents are appropriately selected according to the type of protein preparation component, nucleic acid preparation component or vaccine preparation component. In addition, by selecting an appropriate buffer, it is possible to standardize the second formulation component according to each stage of the pH value.

The isotonic agent is not particularly limited, and examples thereof include sodium chloride, glucose, fructose, lactose, D-mannitol, D-sorbitol, xylitol, glycerin and the like. These tonicity agents are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The pH adjuster is not particularly limited. For example, ammonia water, hydrochloric acid, citric acid, succinic acid, acetic acid, potassium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, lactic acid, sodium lactate, sulfuric acid, phosphoric acid Examples thereof include sodium hydrogen, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. These pH adjusters are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The antioxidant is not particularly limited, and examples thereof include vitamin C, vitamin E, sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, sodium bisulfite, sodium ascorbate, and sodium thiosulfate. These antioxidants are appropriately selected and used depending on the type of protein preparation component or nucleic acid preparation component.

The soothing agent is not particularly limited, and examples thereof include procaine hydrochloride, lidocaine, and benzyl alcohol. These soothing agents are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The flavoring agent is not particularly limited, and examples thereof include sucrose, saccharin sodium, licorice extract, sorbitol, xylitol, and glycerin. These flavoring agents are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The surfactant is not particularly limited, and examples thereof include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and tetra-2-ethylhexyl. Sorbitan fatty acid esters such as diglycerol sorbitan acid; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50) ), Hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (poly Polyoxyethylenes such as rubate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate Sorbitan fatty acid esters polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; polyoxyethylene methyl Such as polysiloxane copolymers, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone Ricone surfactants; natural surfactants such as phospholipids, surfactins, and saponins; fatty acid amide amines such as diethylaminoethylamide stearate and diethylaminopropylamide stearate; trilaurylamine, dimethylstearylamine, and di-2 -Alkylamines such as ethylhexylamine; betaine amphoteric surfactants such as dimethylaminopropylamide stearate and laurylhydroxysulfobetaine. These surfactants are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component. The surfactant is used for stabilizing an unstable dispersion preparation having an interface, and is added for the purpose of solubilization, wetting, defoaming and the like. Furthermore, it may be added for the purpose of preventing adsorption of the pharmaceutical preparation to the wall surface of the container. However, surfactants are cytotoxic to humans. Therefore, it is preferable that the surfactant is not added to the pharmaceutical preparation. In the present embodiment, since the adsorption sterilization treatment of the filter sterilization filter is performed using the adsorption inhibitor before the first formulation component is sterilized by filtration, the addition of the surfactant can be omitted. .

The fungicide is not particularly limited, and examples thereof include cresol, formalin, benzalkonium chloride, cetylpyridium chloride, decalinium chloride, and chlorhexidine hydrochloride. However, since the addition of these bactericides is limited when the pharmaceutical preparation is an injection or the like having a relatively large dosage such as an infusion solution, the addition of the bactericides is not preferable. On the other hand, when the pharmaceutical preparation is an injection or the like with a small dose, addition is permitted within the allowable range. Therefore, the bactericidal agent can be added as long as safety to the human body is not hindered.

The excipient is not particularly limited, and examples thereof include sugars such as lactose hydrate, anhydrous lactose, lactose G, sucrose, and sucrose; sugars such as D-mannitol, erythritol, sorbitol, maltose, xylitol, sorbitol, and trehalose. Examples include alcohols. By adding an excipient, even when the first preparation component is small, a certain bulk and mass can be given, and a function as a bulking agent or a diluent can be imparted. These excipients are appropriately selected and used according to the type of protein preparation component or nucleic acid preparation component.

The amount of each formulation additive exemplified above in the second formulation component is not particularly limited, and can be appropriately selected according to the type of the first formulation component.

When the first preparation component is composed of a drug substance containing a vaccine preparation component as an active ingredient, the second preparation component includes at least one kind of the adjuvant and / or the preparation additive. However, the active ingredient is not included in the second preparation component.

The adjuvant means fine particles such as a compound or an emulsion that enhances a specific immune response to an antibody when mixed with an antibody having immunological activity. Examples of such an adjuvant include the following. Namely, adjuvants of mineral salts such as aluminum hydroxide, aluminum phosphate, aluminum chloride, aluminum sulfate, aluminum salts; toxins such as cholera toxin, Escherichia coli heat labile toxin, salmonella toxin; MF59 (trademark), AS03, Probax ( O / W type emulsion such as Provax; W / O type emulsion such as Montanide ISA51 / mineral oil and plant-derived surfactant; Biopolymers such as PLG, PMM, Inulin, Advax / biopolymer; QS21, Quil A (Quil A ), Plant-derived adjuvants such as Iscomatrix and Iscom (ISCOM); Romultide, Detox (DETOX), MPL, CWS, Mannose, CpG7909, ISS-1018, IC31, Midazoquinoline, Ampligen, Ribi529 (Ribi529), Imoxine (IMOXine), IRIV, VLP, Cholera toxin, E. coli heat-labile toxin, Salmonella toxin, Pam3Cys, Flagellin, GPI anchor, LNFPIII / Lewis X, antibacterial Peptides, UC-1V150, RSV fusion protein, microorganism-derived adjuvants such as cdiGMP; cytokines such as IL-12 and GM-CSF; cations such as DOTAP and DDA; polypeptides such as N′-CARD-PTD . These adjuvants are appropriately selected and used depending on the type of antigen.

The amount of the adjuvant added in the second formulation component is not particularly limited, and can be appropriately selected according to the type of the first formulation component.

In the second formulation component, formulation additives that contribute to the stability of the formulation can be omitted. The formulation additive contributing to the stability as a formulation means a component for maintaining the long-term stability as a formulation required in clinical trials. More specifically, for example, the stabilizer, preservative (preservative), buffer, pH adjuster, antioxidant and the like can be mentioned. By not including these components in the second preparation component, it is possible to eliminate as much as possible components that are cytotoxic to the human body, and further improve safety. The omission of the formulation additive that contributes to the stability as a formulation does not matter whether the pharmaceutical formulation of the present embodiment is a protein formulation or a nucleic acid formulation, or an adjuvant formulation.

The formulation additive that contributes to the stability as the formulation will be described in more detail. For example, the stabilizer is generally used for preventing the alteration of the pharmaceutical formulation. However, the method for producing a pharmaceutical preparation of the present embodiment is a preparation in which the first preparation component and the second preparation component are mixed immediately before administration to a patient, and the first preparation component is used as a drug substance. Since stability is guaranteed on GCP (Good Clinical Practice), it is possible to predict the prevention of alteration after formulation. As a result, in the present embodiment, the addition of a stabilizer to the second preparation component can be omitted.

The preservative (preservative) is generally used for the purpose of inhibiting the growth of microorganisms in pharmaceutical preparations. However, since the pharmaceutical preparation method of the present embodiment is prepared by mixing the first preparation component and the second preparation component immediately before administration to the patient, the inhibition of the growth of microorganisms is taken into consideration. There is no need. As a result, in this embodiment, the addition of a preservative to the second preparation component can be omitted.

Furthermore, the buffer is used for the purpose of appropriately adjusting and maintaining the pH of the liquid preparation or alleviating irritation. However, since the method for producing the pharmaceutical preparation of the present embodiment is formulated by mixing the first preparation component and the second preparation component immediately before administration to the patient, the pH is adjusted and maintained and stable. There is no need to ensure sex. As a result, in the present embodiment, addition of a buffering agent to the second preparation component can be omitted.

In addition, the pH adjusting agent is generally used to keep the pH of the preparation constant between about 2 and 8, thereby maintaining stability near the isoelectric point and reducing irritation. For example, when the preparation is acidic, a basic compound is used as the pH adjusting agent, and when the drug is basic, an acidic compound is used as the pH adjusting agent. However, the method for producing the pharmaceutical preparation of the present embodiment is prepared by mixing the first preparation component and the second preparation component immediately before administration to the patient, and the pH is maintained at a predetermined value over a long period of time. There is no need to stabilize within the range. Therefore, in the present embodiment, the addition of a pH adjuster to the second preparation component can be omitted.

The antioxidant is generally used to suppress oxidation of ingredients in pharmaceutical preparations. That is, instead of oxidizing a certain component in the pharmaceutical preparation, the antioxidant is oxidized to exert an antioxidant action. However, since the method for producing the pharmaceutical preparation of the present embodiment is formulated by mixing the first preparation component and the second preparation component immediately before administration to the patient, Addition of an antioxidant for the purpose of suppressing oxidation can be omitted.

The above-mentioned disinfectant is generally added for sterilization of pathogenic microorganisms and inhibition of growth. However, in the method for producing a pharmaceutical preparation of the present embodiment, sterility is ensured because the first preparation component is sterilized by filtration using a filter sterilization filter in advance. In addition, since the preparation is prepared by mixing the first preparation component and the second preparation component immediately before administration, the growth of microorganisms, fungi and the like in the pharmaceutical preparation can be suppressed. Therefore, addition of a bactericide can be omitted.

The step (S2) of applying the anti-adsorption treatment to the filter sterilization filter prevents the active ingredient in the first preparation component from adsorbing to the surface of the filter sterilization filter immediately before administration to the human body. To be done. Specifically, the adsorption inhibitor is preliminarily adsorbed on the filter surface by filtering the adsorption inhibitor with a filter sterilization filter. Thereby, when filter-sterilizing the 1st formulation component, it can prevent that the active ingredient adsorb | sucks to the surface of the filter for filter sterilization, and is lost. As a result, it is possible to prevent a decrease in reliability such as a pharmacological effect.

Examples of the adsorption inhibitor include surfactants, albumin, and aqueous gelatin solutions. Further, the surfactant is not particularly limited, and examples thereof include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and tetra-2 Sorbitan fatty acid esters such as diglycerol sorbitan ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO -50), hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene monolaurate (20) sorbita Polyoxys such as (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate Ethylene sorbitan fatty acid esters Polyoxyethylene mono coconut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; stearylamine and amines such as ole Polyoxyethylene methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone Natural surfactants such as phospholipids, surfactins, and saponins; fatty acid amidoamines such as diethylaminoethylamide stearate and diethylaminopropylamide stearate; trilaurylamine, dimethylstearylamine, and Examples thereof include alkylamines such as di-2-ethylhexylamine; betaine amphoteric surfactants such as dimethylaminopropylamide stearate and laurylhydroxysulfobetaine. These adsorption inhibitors are appropriately selected and used according to the type of protein preparation component, nucleic acid preparation component or vaccine preparation component.

Further, as the adsorption inhibitor, a second preparation component containing an adsorption inhibitor component may be used. In this case, the adsorption preventing component is not particularly limited, and examples thereof include the surfactant, albumin, and aqueous gelatin solution.

The filtration sterilization filter is not particularly limited, and examples thereof include a filter sterilization filter having a pore size of 0.22 μm or less. More specifically, Durapore (registered trademark, manufactured by Nihon Millipore Corporation), Zaltopore 2 (registered trademark, manufactured by Sartorius Corporation) and the like can be mentioned.

The step of sterilizing the first preparation component with a filter for filter sterilization (S3) is performed for the purpose of sterilizing the first preparation component. Since it is sterilization using the filter for filter sterilization, it can also sterilize also about the 1st formulation component which denatures by heat sterilization. In addition, in conventional pharmaceutical preparations, bactericides are sometimes added for the purpose of maintaining sterility, but these bactericides are prohibited from being added to large-volume injections, infusions, and the like. In the present invention, since the first preparation component is sterilized by filtration immediately before administration, it is not necessary to ensure long-term sterility unlike conventional pharmaceutical preparations. Therefore, the addition of a bactericidal agent can be omitted, so that sterility can be ensured even for a large-volume injection or the like in which the addition of a bactericidal agent is restricted. As a result, it is possible to produce a pharmaceutical preparation that ensures sterility and is excellent in safety to the human body.

The filter sterilization filter is preliminarily subjected to an adsorption prevention treatment for preventing the adsorption of the active ingredient of the first formulation component, so that the loss caused by the adsorption of the active ingredient to the filter sterilization filter is reduced. be able to.

Here, after filtration sterilization of the first formulation component, as shown in FIG. 1, it is preferable to further allow air to pass through the filter sterilization filter (S4). As a result, the first formulation component remaining in the filter for filter sterilization can also be filtered, the residue can be reduced, and the production efficiency can be further improved.

Next, the first preparation component after filter sterilization and the second preparation component are mixed at an arbitrary ratio to prepare a pharmaceutical preparation of the present embodiment (S5). Since the pharmaceutical preparation of the present embodiment is formulated immediately before administration, it is not necessary to consider the alteration after the preparation and the growth of microorganisms. Therefore, the pharmaceutical preparation of the present embodiment can omit a stability test (more specifically, a severe test, a long-term storage test, and an accelerated test) in a clinical test. As a result, the development period of new drugs can be significantly shortened. In addition, the pharmaceutical formulation of this Embodiment needs to be what was confirmed by the clinical test about the effectiveness and safety | security as a formulation.

The mixing of the first formulation component and the second formulation component is preferably performed within the effective period of the first formulation component as an active ingredient and a retest period that can be used for formulation. Moreover, it does not specifically limit about the mixing method of a 1st formulation component and a 2nd formulation component.

Here, in the present embodiment, the first formulation component is sterilized by filtration with a filter sterilization filter after the adsorption prevention treatment, and then the first formulation component and the second formulation component are mixed in an arbitrary ratio. Thus, the mode of formulation is described. However, the present invention is not limited to this embodiment. For example, as shown in FIG. 2, after preparing the liquid mixture by mixing the first preparation component and the second preparation component at an arbitrary ratio (S6), the mixture liquid is filtered with an anti-adsorption treatment filter sterilization filter. The pharmaceutical preparation may be manufactured by sterilizing by filtration (S7).

In this case, after filtration sterilization of the mixed solution of the first formulation component and the second formulation component, it is preferable to further allow air to pass through the filter for filtration sterilization (S4). Thereby, the residue of the liquid mixture remaining on the filter for filter sterilization can also be filtered, and the production efficiency can be further improved.

In addition, after the mixture of the first preparation component and the second preparation component is sterilized by filtration, the second preparation component may be further added to the filtrate. Thereby, it can be set as the formulation density | concentration suitable for administration.

The method for producing a pharmaceutical preparation of the present embodiment can be provided as a pharmaceutical preparation kit. Thereby, the burden at the time of mixing of a 1st formulation component and a 2nd formulation component, an error, and prevention of contamination can be aimed at. When adopting a form as a pharmaceutical preparation kit, in addition to the first preparation component and the second preparation component, a filter for filter sterilization for sterilizing the first preparation component and an anti-adsorption treatment for the filter for filter sterilization Combined with anti-adsorption agent for applying. In addition, when the second preparation component contains an anti-adsorption component, the second preparation component can be used for anti-adsorption treatment of a filter sterilization-like filter, so that the second preparation component is used as an anti-adsorption agent. Can do. Furthermore, by incorporating a filter sterilization filter into the kit form, sterility can be ensured without adding a bactericidal agent to the first formulation component or the second formulation component.

In addition, the pharmaceutical preparation obtained by the method for producing a pharmaceutical preparation of the present embodiment has been confirmed to be effective and safe as a preparation in a non-clinical test. However, the stability as a preparation is not necessarily confirmed in clinical trials. As described above, the method for producing the pharmaceutical preparation of the present embodiment is a preparation prepared by mixing the first preparation component and the second preparation component immediately before administration, and is required in clinical trials. This is because there is no need for guaranteeing the long-term stability. The pharmaceutical preparation obtained by the production method of the present embodiment is suitably applied to aseptic liquid preparations such as injections, instillations, eye drops, dialysis agents that can be administered intravenously or subcutaneously. can do.

Hereinafter, preferred embodiments of the present invention will be described in detail by way of example. However, the materials, blending amounts, and the like described in the examples do not limit the scope of the present invention only to those unless otherwise limited.

Example 1-1
10 ml of a stock solution as a first preparation component containing 1 g / ml of golimumab (trade name: symbony subcutaneous injection, human anti-human TNF antibody: Kyowa Hakko Kirin Co., Ltd.) is sterilized by filtration with a membrane filter (pore size 0.22 μm), Thereafter, it was filled into a cleaned vial. The vial was stoppered with a rubber stopper, and after tightening, the foreign matter was inspected. Furthermore, this drug substance was stored in a refrigerator while avoiding freezing under a temperature condition of 2-8 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

In addition, 410 mg of D-sorbitol and 1.5 mg of polysorbate 80 were dissolved in distilled water for injection and mixed to a total volume of 10 ml to prepare the second formulation component. This second preparation component was sterilized by filtration using a membrane filter (pore size 0.22 μm), then filled into a 10 ml vial, stoppered with a rubber stopper, and wound up. Subsequently, an autoclave sterilization treatment was performed at 121 ° C. for 20 minutes. Further, the foreign substance inspection and sterility inspection of the second preparation component were performed and stored at room temperature. Storage conditions were 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

Next, immediately before administration to humans, 3 ml of the second preparation component as an adsorption inhibitor is passed through a final filter (pore size 0.22 μm), thereby adsorbing the active ingredient in the first preparation component to the final filter. Prevention treatment was applied. In addition, the polysorbate 80 contained in a 2nd formulation component becomes an adsorption | suction prevention component. Furthermore, 1 ml of the first preparation component was filled in a syringe barrel filled with about 1 ml of air, and first, 1 ml of the first preparation component was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe was passed through the final filter, thereby reducing the residue of the first formulation component on the surface of the final filter as much as possible.

Subsequently, 1 ml of the first preparation component was injected into a vial filled with 1 ml of the second preparation component to obtain 2 ml of a preparation for subcutaneous administration containing 1 g / ml of golimumab. As a result, a 0.5 mg 500 mg preparation for subcutaneous injection was obtained, which did not contain a bactericidal agent, ensured sterility, and did not require a stability test as a preparation.

Example 1-2
Golimumab (trade name: Symbony subcutaneous injection, human anti-human TNF antibody: Kyowa Hakko Kirin Co., Ltd.) 1 ml of a stock solution as a first preparation component containing 1 g / ml is sterilized by filtration with a membrane filter (pore size 0.22 μm), Thereafter, it was filled into a cleaned vial. The vial was stoppered with a rubber stopper, and after tightening, the foreign matter was inspected. Furthermore, this drug substance was stored in a refrigerator while avoiding freezing under a temperature condition of 2-8 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

Next, immediately before administration to humans, 3 ml of the second preparation component as an adsorption inhibitor is passed through a final filter (pore size 0.22 μm), thereby adsorbing the active ingredient in the first preparation component to the final filter. Prevention treatment was applied. In addition, the polysorbate 80 contained in a 2nd formulation component becomes an adsorption | suction prevention component.

Further, 1 ml of the first preparation component and 9 ml of the second preparation component were mixed to obtain a 10 ml mixed solution. Subsequently, 10 ml of the mixed solution was filled in a syringe barrel that was previously filled with about 1 ml of air, and first, 10 ml of the mixed solution was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe barrel was passed through the final filter, so that the residue of the mixed liquid remained on the final filter surface as much as possible. 99 ml of the second preparation component was added to 1 ml of this filtrate to make a total volume of 100 ml. As described above, a 0.5 mg formulation for 0.5 ml subcutaneous injection that does not contain a bactericidal agent, ensures sterility, and does not require a stability test as a formulation was obtained.

Example 2-1
Liraglutide (trade name: Pictosa Subcutaneous Injection, Glucagon-like Peptide: Novo Nordisk Pharma Co., Ltd.) 600 ml / ml of the stock solution as the first formulation component was sterilized by filtration with a membrane filter (pore size 0.22 μm) and then washed. Filled a used vial. The vial was stoppered with a rubber stopper, and after tightening, the foreign matter was inspected. Furthermore, this drug substance was stored in a refrigerator while avoiding freezing under a temperature condition of 2-8 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

In addition, 90 mg of NaCl and 15 mg of polysorbate 80 were dissolved in 100 ml of distilled water for injection to prepare a second preparation component. This second preparation component was sterilized by filtration using a membrane filter (pore size 0.22 μm), then filled into a 100 ml vial, stoppered with a rubber stopper, and wound up. Subsequently, an autoclave sterilization treatment was performed at 121 ° C. for 20 minutes. Furthermore, the foreign substance inspection and sterility inspection of the 2nd formulation component were performed, and it preserve | saved at room temperature. Storage conditions were 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

Subsequently, 1 ml of the first preparation component and 2 ml of the second preparation component were mixed to obtain a 3 ml mixed solution. Subsequently, 3 ml of the mixed solution was filled in a syringe barrel which was previously filled with about 1 ml of air, and first, 3 ml of the mixed solution was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe barrel was passed through the final filter, so that the residue of the mixed liquid remained on the final filter surface as much as possible. As described above, a 180 mg preparation for 3 ml subcutaneous injection containing no bactericidal agent, ensuring sterility and not requiring a stability test as a preparation was obtained.

(Example 2-2)
Liraglutide (trade name: Pictosa Subcutaneous Injection, Glucagon-like Peptide: Novo Nordisk Pharma Co., Ltd.) 600 ml / ml of the stock solution as the first formulation component was sterilized by filtration with a membrane filter (pore size 0.22 μm) and then washed. Filled a used vial. The vial was stoppered with a rubber stopper, and after tightening, the foreign matter was inspected. Furthermore, this drug substance was stored in a refrigerator while avoiding freezing under a temperature condition of 2-8 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

In addition, 90 mg of NaCl and 15 mg of polysorbate 80 were dissolved in 100 ml of distilled water for injection to prepare a second preparation component. This second preparation component was sterilized by filtration using a membrane filter (pore size 0.22 μm), then filled into a 100 ml vial, stoppered with a rubber stopper, and wound up. Subsequently, an autoclave sterilization treatment was performed at 121 ° C. for 20 minutes. Further, the foreign substance inspection and sterility inspection of the second preparation component were performed and stored at room temperature. Storage conditions were 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

Next, immediately before administration to humans, 1 ml of the first formulation component and 2999 ml of the second formulation component were mixed.

In addition, 3 ml of the second preparation component as an adsorption inhibitor was passed through a final filter (pore size 0.22 μm), thereby performing an adsorption prevention treatment of the active ingredient in the first preparation component on the final filter. In addition, the polysorbate 80 contained in a 2nd formulation component becomes an adsorption | suction prevention component.

Subsequently, 1 ml of the first preparation component and 2999 ml of the second preparation component were mixed to obtain 3 l of a mixed solution. Subsequently, 3 ml of the mixed solution was filled in a syringe barrel which was previously filled with about 1 ml of air, and first, 3 ml of the mixed solution was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe barrel was passed through the final filter, so that the residue of the mixed liquid remained on the final filter surface as much as possible. As a result, a 180 μg preparation for 3 ml subcutaneous injection was obtained, which did not contain a bactericidal agent, ensured sterility, and did not require a stability test as a preparation.

Example 3-1
Liraglutide-inactivated Japanese encephalitis virus (trade name: Ensevac subcutaneous injection, vaccine: Chemical and Serum Therapy Laboratory) 4 mg titer (as protein content) 10 ml of the stock solution as a first formulation component was added to a membrane filter (pore size 0. 22 μm) and then sterilized by filtration and then filled into washed vials. The vial was stoppered with a rubber stopper, and after tightening, foreign matter inspection and sterility test were performed. Further, this drug substance was stored frozen at a temperature of −40 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

In addition, 273 mg of NaCl, 2.5 mg of polysorbate 80, 205 g of lactose hydrate were dissolved in 60 ml of distilled water for injection to prepare a second preparation component. This second preparation component was sterilized by filtration using a membrane filter (pore size 0.22 μm), then filled into a 100 ml vial, stoppered with a rubber stopper, and wound up. Subsequently, an autoclave sterilization treatment was performed at 121 ° C. for 20 minutes. Furthermore, the foreign substance inspection and sterility inspection of the 2nd formulation component were performed, and it preserve | saved at room temperature. Storage conditions were 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

Subsequently, 1 ml of the first preparation component and 6 ml of the second preparation component melted at room temperature were mixed to obtain a 7 ml mixture. Subsequently, 0.7 ml of the mixed solution was filled in a syringe barrel previously filled with about 1 ml of air. First, 0.7 ml of the mixed solution was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe barrel was passed through the final filter, so that the residue of the mixed liquid remained on the final filter surface as much as possible. As described above, a 40 μg titer preparation for subcutaneous injection of 0.7 ml was obtained, which did not contain a bactericidal agent, ensured sterility, and did not require a stability test as a preparation.

(Example 3-2)
Liraglutide-inactivated Japanese encephalitis virus (trade name: Ensebak subcutaneous injection, vaccine: Chemical and Serum Therapy Laboratories) 4 mg titer (as protein content) 1 ml of the stock solution as a first formulation component, membrane filter (pore size 0. 22 μm) and then sterilized by filtration and then filled into washed vials. The vial was stoppered with a rubber stopper, and after tightening, foreign matter inspection and sterility test were performed. Further, this drug substance was stored frozen at a temperature of −40 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

Next, immediately before administration to humans, 1 ml of the first formulation component and 699 ml of the second formulation component were mixed.

In addition, 3 ml of the second preparation component as an adsorption inhibitor was passed through a final filter (pore size 0.22 μm), thereby performing adsorption prevention treatment of the active ingredient in the first preparation component on the final filter. In addition, the polysorbate 80 contained in a 2nd formulation component becomes an adsorption | suction prevention component.

Subsequently, 1 ml of the first preparation component containing 4 mg titer of inactivated Japanese encephalitis virus and 699 ml of the second preparation ingredient were mixed to obtain a 700 ml mixed solution. Subsequently, 0.7 ml of the mixed solution was filled in a syringe barrel previously filled with about 1 ml of air. First, 0.7 ml of the mixed solution was passed through a final filter and sterilized by filtration. Subsequently, the air filled in the syringe barrel was passed through the final filter, so that the residue of the mixed liquid remained on the final filter surface as much as possible. As described above, a 0.04 μg titer preparation for 0.7 ml subcutaneous injection was obtained, which does not contain a bactericidal agent, ensures sterility, and does not require a stability test as a preparation.

Claims

In the manufacturing method of the pharmaceutical formulation which consists of a 1st formulation component and a 2nd formulation component,
Stability, efficacy and safety have been shown in advance in non-clinical studies, and it is a drug substance consisting only of an active ingredient and an arbitrary solvent, wherein the active ingredient is a protein formulation component, a nucleic acid formulation component or a vaccine formulation component. Preparing the first formulation component which is any one of the following:
When the active ingredient is the protein preparation ingredient or the nucleic acid preparation ingredient, it contains at least one kind of preparation additive, and when the active ingredient is the vaccine preparation ingredient, at least one adjuvant and / or the preparation addition Preparing the second formulation component containing an agent;
Immediately before administration, a process for preventing adsorption of the active ingredient in the first formulation component to the filter sterilization filter by passing a solution containing an adsorption inhibitor through the filter sterilization filter;
Sterilizing the first formulation component with the filter sterilization filter after adsorption prevention treatment;
A method for producing a pharmaceutical preparation, comprising the steps of mixing the first preparation component after filtration sterilization and the second preparation component in an arbitrary ratio to prepare a preparation, and enabling administration without evaluating the stability in a clinical test.
In the manufacturing method of the pharmaceutical formulation which consists of a 1st formulation component and a 2nd formulation component,
Stability, efficacy and safety have been shown in advance in non-clinical studies, and it is a drug substance consisting only of an active ingredient and an arbitrary solvent, wherein the active ingredient is a protein formulation component, a nucleic acid formulation component or a vaccine formulation component. Preparing the first formulation component which is any one of the following:
When the active ingredient is the protein preparation ingredient or the nucleic acid preparation ingredient, it contains at least one kind of preparation additive, and when the active ingredient is the vaccine preparation ingredient, at least one adjuvant and / or the preparation addition Preparing the second formulation component containing an agent;
Immediately before administration, a process for preventing adsorption of the active ingredient in the first formulation component to the filter sterilization filter by passing a solution containing an adsorption inhibitor through the filter sterilization filter;
Mixing the first formulation component and the second formulation component at an arbitrary ratio to produce a mixed solution;
A method of producing a pharmaceutical preparation comprising: sterilizing the mixed solution with the filter for filtration sterilization after adsorption prevention treatment, and enabling administration without evaluating stability in a clinical test.
3. The pharmaceutical according to claim 2, wherein the mixture is sterilized by filtration with the filter sterilization filter, and then the second preparation component is added to the filtrate to enable administration without evaluating the stability in clinical trials. Preparation method of the preparation.
The method for producing a pharmaceutical preparation according to any one of claims 1 to 3, wherein the second preparation component does not include any of the preparation additives that contributes to stability as a preparation.
The method for producing a pharmaceutical preparation according to any one of claims 1 to 3, wherein the second preparation component does not contain a surfactant.
The method for producing a pharmaceutical preparation according to any one of claims 1 to 3, wherein the adsorption inhibitor is a surfactant.
Filter sterilizing the first formulation component with the filter sterilization filter after adsorption prevention treatment, or filter sterilization with the filter sterilization filter after adsorption prevention treatment of the mixed solution of the first formulation component and the second formulation component 4. The method of any one of claims 1 to 3, wherein, in the step of performing, the air is permeated after the first formulation component or a mixed solution of the first formulation component and the second formulation component is filtered through a filter sterilization filter. A method for producing a pharmaceutical preparation.
A pharmaceutical preparation kit used by mixing the first preparation component and the second preparation component contained in the kit form,
The first formulation component is a drug substance consisting of only an active ingredient and an arbitrary solvent, which has been previously shown to be stable, effective and safe in non-clinical studies, and the active component is a protein formulation component, a nucleic acid formulation component or Any of the vaccine formulation components,
The second preparation component contains at least one preparation additive when the active ingredient is the protein preparation ingredient or the nucleic acid preparation ingredient,
When the active ingredient is the vaccine formulation component, it contains at least one adjuvant and / or the formulation additive,
In the kit form, a filter for sterilization for filtration sterilization of the first formulation component or a mixed solution obtained by mixing the first formulation component and the second formulation component, and an anti-adsorption treatment on the filter sterilization filter A pharmaceutical preparation kit further comprising an adsorption inhibitor for application.
The pharmaceutical preparation kit according to claim 9, wherein the second preparation component does not contain a preparation additive that contributes to stability as a preparation.
The pharmaceutical preparation kit according to claim 8 or 9, wherein the second preparation component does not contain a surfactant.
The pharmaceutical preparation kit according to claim 8 or 9, wherein the adsorption inhibitor is a surfactant.