JP5896359B2 - Pharmaceutical preparation and method for producing the same - Google Patents

Description

  The present invention relates to a pharmaceutical preparation which is prepared by mixing with other preparation ingredients including a preparation additive or the like immediately before administration with respect to a preparation ingredient comprising a drug substance which does not contain a preparation additive or the like, and a method for producing the same.

  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 secured. 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, preparations such as isotonic agents, pH adjusters, and surfactants are required for the preparations 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.

JP 2007-271527 A JP 2009-45140 A

  An object of the present invention is to provide a pharmaceutical preparation that can shorten the development period of a pharmaceutical preparation, can omit preparation additives and adjuvants, and is excellent in stability and sterility, and a method for producing the same. It is in.

  The inventors of the present application have studied a pharmaceutical preparation and a production method 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, the pharmaceutical preparation according to the present invention is a pharmaceutical preparation comprising a first preparation component and a second preparation component in order to solve the above-mentioned problems, and the first preparation component is composed only of an active ingredient and an arbitrary solvent. When the active ingredient is any one of a protein preparation ingredient, a nucleic acid preparation ingredient or a vaccine preparation ingredient, and the second preparation ingredient is a protein preparation ingredient or a nucleic acid preparation ingredient. Comprises at least one formulation additive, and when the active ingredient is the vaccine formulation component, contains at least one adjuvant and / or the formulation additive, It is characterized by being used by mixing with one preparation component.

  In the configuration of the pharmaceutical preparation, the first preparation component and the second preparation component are preferably sterilized.

  Moreover, in the structure of the said pharmaceutical formulation, it is preferable that the said 2nd formulation component does not contain the formulation additive which contributes to the stability as a formulation.

  In the composition of the pharmaceutical preparation, the second preparation component may not contain a surfactant.

  In order to solve the above problems, a method for producing a pharmaceutical preparation according to the present invention is the method for producing a pharmaceutical preparation described above, wherein stability, efficacy and safety have been shown in advance in a non-clinical test. Preparing the first formulation component and the second formulation component, mixing the first formulation component and the second formulation component at an arbitrary ratio to prepare a formulation, and evaluating the stability in a clinical trial And the step of making it possible to administer without any problem.

  The configuration of the method for producing the pharmaceutical preparation preferably includes a step of sterilizing the first preparation component immediately before mixing the first preparation component and the second preparation component.

  The therapeutic kit according to the present invention is a therapeutic kit in which the first formulation component and the second formulation component contained in the kit form are used in order to solve the above-mentioned problems, and the first formulation The ingredient is an active ingredient consisting of only an active ingredient and an arbitrary solvent, and the active ingredient is any one of a protein preparation ingredient, a nucleic acid preparation ingredient or a vaccine preparation ingredient, and the second preparation ingredient is the active ingredient is the protein. When it is a pharmaceutical ingredient or a nucleic acid pharmaceutical ingredient, it contains at least one kind of formulation additive. When the active ingredient is the vaccine pharmaceutical ingredient, it contains at least one adjuvant and / or the pharmaceutical additive. It is characterized by being used by mixing with the first preparation component immediately before administration.

  In the configuration of the treatment kit, the kit form includes a filter sterilization filter for sterilizing the first preparation component immediately before mixing with the second preparation component. preferable.

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

  In the composition of the therapeutic kit, the second preparation component may not contain a surfactant.

The present invention has the following effects by the means described above.
That is, the pharmaceutical formulation of the present invention comprises a first formulation component consisting of a drug substance and a second formulation component containing formulation additives and / or adjuvants, and the first formulation component and the second formulation component are mixed immediately before administration. And formulated for use. Therefore, it is not necessary to guarantee the long-term stability as a preparation required in clinical trials.

  Conventionally, when a stabilizer, preservative, or the like is used as a formulation additive, its effect has been 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 greatly shortened as compared with conventional pharmaceutical preparations. In addition, although formulation additives and the like may be harmful to the human body even if they are substances derived from natural products, as described above, the present invention contributes to guaranteeing stability as a formulation such as a stabilizer and a preservative. Since the formulation additive can be omitted, the safety to the human body can be improved.

One embodiment of the present invention will be described below.
The pharmaceutical preparation according to the present embodiment comprises a first preparation component and a second preparation component. In addition, the pharmaceutical preparation of the present embodiment is formulated by mixing the first preparation component and the second preparation component at an arbitrary ratio immediately before administration.

  The pharmaceutical preparation of the present embodiment has been confirmed to be effective and safe as a preparation in clinical trials. However, the stability as a preparation is not necessarily confirmed in clinical trials. As described above, the pharmaceutical preparation of the present embodiment is prepared by mixing the first preparation component and the second preparation component immediately before administration, and is a long-term preparation as a preparation required in clinical trials. This is because stability is not required.

  The first formulation component of the present embodiment refers to a drug whose stability, effectiveness and safety as a drug substance have been confirmed in a non-clinical test for animals. Here, the drug substance means a raw material for producing the pharmaceutical preparation of the present embodiment. The first pharmaceutical ingredient is preferably a drug substance that has been sterilized in advance. Moreover, it is preferable that the 1st formulation component is aseptically or sterilized after the sterilization treatment until it is just before formulation by mixing with the second formulation component. Even if sterility is not assured in a non-clinical test in a conventional drug substance, it is sufficient if sterility is guaranteed in a clinical test after it has been formulated. However, since the pharmaceutical preparation of the present embodiment is based on a special mode of use that is formulated just before its use, sterility is ensured even for the first preparation component consisting of the drug substance. Is preferred.

  A 1st formulation component consists only of an active ingredient and arbitrary solvents. 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.

  When the first preparation component is composed of a drug substance containing a protein preparation component or a nucleic acid preparation component as an active ingredient, the first preparation component contains no preparation additives other than the solvent. 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 formulation component may be any of liquid, solid, semi-solid, and powder, but is preferably liquid. 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.

  Moreover, the said nucleic acid formulation component means containing a DNA component, an RNA component, etc. 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 the present 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. Moreover, antigens such as pneumococcal capsular polysaccharide and anti-TNF antibody used for 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. A subunit vaccine refers to a vaccine that does not have all of the antigens of interest immunodeficiency virus and contains one or more selected protein antigens. The subunit vaccine is at least partially separated from other components of the virus and components 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. There are no particular limitations on the virus or microorganism used as the base for the live recombinant vaccine, and examples include poxvirus, adenovirus, salmonella, poliovirus, mycobacteria, influenza virus, and Semliki Forest virus.

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

  The said formulation additive means things other than an active ingredient among the components contained in the pharmaceutical formulation which concerns on this 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 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 solubilizer 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. 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 Salts of organic carboxylic acids and inorganic bases such as sodium citrate, sodium lactate, sodium acetate and sodium benzoate; salts of sulfonic acids and inorganic bases such as sodium methanesulfonate and sodium p-toluenesulfonate; aminosulfones such as taurine Acids; 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 and used depending on the type of protein preparation component or nucleic acid preparation component.

  The isotonizing agent is not particularly limited, and examples thereof include sodium chloride, glucose, fructose, lactose, D-mannitol, D-sorbitol, xylitol, and glycerin. 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 hydrogen sulfite, 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, benzyl alcohol and the like. 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-based 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, when the pharmaceutical formulation after mixing the first formulation component and the second formulation component is not adsorbed on the wall surface inside the container without adding a surfactant. Can omit the addition of the surfactant.

  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.

  The second preparation component contains at least one kind of the adjuvant and / or the preparation additive when the first preparation component is composed of a drug substance containing a vaccine preparation component as an active ingredient. 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 administered in admixture 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, 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 addition amount of the adjuvant 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 deterioration of the pharmaceutical formulation. However, the pharmaceutical formulation of the present embodiment is prepared by mixing the first formulation component and the second formulation component immediately before administration to the patient, and the first formulation component has stability as a drug substance. Since it is guaranteed on GCP (Good Clinical Practice), there is no need to consider 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, 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 first preparation component is assured of sterility. Therefore, it is not necessary to consider the inhibition of the growth of microorganisms. 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 mitigating irritation. However, since the pharmaceutical preparation of the present embodiment is prepared by mixing the first preparation component and the second preparation component immediately before administration to a patient, it is necessary to maintain the pH by adjusting the preparation. There is no. As a result, in the present embodiment, addition of a buffering agent to the second preparation component can be omitted.

  The pH adjuster is generally used to keep the formulation pH constant between about 2 and 8. 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 pharmaceutical preparation of this embodiment is prepared by mixing the first preparation component and the second preparation component immediately before administration to the patient, and the pH is stabilized within a predetermined range over a long period of time. There is no need to let them. 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 components in a pharmaceutical preparation. That is, an antioxidant action is exhibited by oxidizing a certain component in the pharmaceutical preparation instead of being oxidized. However, since 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, the purpose is to suppress the oxidation of the component in the pharmaceutical preparation. The addition of antioxidants at can be omitted.

  The pharmaceutical preparation of the present embodiment can be suitably applied to aseptic liquid preparations such as injections, instillations, eye drops, dialysis agents that can be administered intravenously or subcutaneously.

If the pharmaceutical formulation of this Embodiment is used, it can manufacture with the following method and can aim at the significant shortening of the development period of a pharmaceutical formulation.
First, the first formulation component and the second formulation component, which have been previously shown to be stable, effective, and safe in a nonclinical test, are prepared.

  The nonclinical test for the first formulation component means a test for the drug substance for animals. 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.

  It is preferable that sterility is also guaranteed in the first preparation component. The sterility can be ensured by, for example, handling the first preparation component in a liquid state and performing a sterilization treatment. The sterilization process is preferably performed by a method 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 guarantee sterility when the first preparation component is in a solid or powder state.

  Moreover, the 1st formulation component may be refrigerated storage or frozen storage until it mixes with the 2nd formulation component from the viewpoint of the effective period, stability, safety | security, 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.

  About the 2nd formulation component, what is chemically stable and the safety | security with respect to a human is confirmed. The stability and safety can be confirmed by a conventionally known test method. Moreover, also in the 2nd formulation component, the sterility is guaranteed like the 1st formulation component. 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.

  Next, immediately before administration, the first preparation component and the second preparation component are mixed at an arbitrary ratio to prepare a pharmaceutical preparation of the present embodiment. 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.

  In addition, the pharmaceutical formulation of this Embodiment can be used suitably also as a kit formulation. 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 the form as a kit preparation, in addition to the first preparation component and the second preparation component, a filter for filter sterilization for sterilizing the first preparation component by filtration may be combined. This ensures the sterility of the pharmaceutical preparation. The filter for sterilization by filtration is not particularly limited, and for example, a sterilization filter having a pore size of 0.22 μm or less is preferably used. More specifically, Durapore (registered trademark, manufactured by Nihon Millipore Corporation), Zaltopore 2 (registered trademark, manufactured by Sartorius Corporation) and the like can be mentioned.

  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)
A drug substance as a first pharmaceutical ingredient containing 5000 mg of infliximab (anti-TNF-α chimeric IgG 1K monoclonal antibody, trade name: Remicade (registered trademark) (Centocor, Inc., Malvern, Pennsylvania), Janssen. Biotec Inc.), The mixture was sterilized by filtration using a 0.22 μm membrane filter, and then 100 ml of the vial was filled, and foreign matter inspection and sterility inspection were performed. Furthermore, this drug substance was stored frozen in a freezer under a temperature condition 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.

  On the other hand, 20 mg of trometamol (tris (hydroxymethyl) aminomethane, buffer), 6 g of trehalose, 4 mg of polysorbate 80, an appropriate amount of sodium hydroxide, an appropriate amount of hydrochloric acid, and distilled water for injection are mixed as the second preparation component. The total amount was adjusted to 100 ml. 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 the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Further, the foreign substance inspection and sterility inspection of the second preparation component were performed and stored at room temperature. The storage period was 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

  The drug substance containing 50 mg / ml of infliximab was thawed at room temperature and then sterilized by filtration with a final filter (pore size 0.22 μm). 1 ml of drug substance was added and dissolved in a vial filled with 99 ml of the second formulation component to make the total volume 100 ml. Further, 1 ml was taken out from the solution obtained by diluting the drug substance with the second preparation component, and this was added to the vial containing the second preparation ingredient and dissolved to dilute to a total volume of 100 ml. Thereby, the stability test as a preparation was not required, and a 10 μg preparation capable of intravenous administration of 20 ml was obtained.

(Example 1-2)
In this example, 0.1 ml of the drug substance as the first pharmaceutical ingredient containing 50 mg / ml of infliximab was added to the vial containing the second pharmaceutical ingredient to dissolve it, and the total amount was 100 ml. A 1 mg formulation was obtained that allowed administration. Other than that was carried out similarly to the said Example 1-1.

(Reference Example 1-1)
7500 mg of powdered phosphenytoin (trade name: Host-in (trademark), manufactured by Eisai Co., Ltd.) was dissolved in distilled water for injection, and a total amount of 10 ml of the drug substance as the first pharmaceutical ingredient was prepared. Subsequently, this drug substance was sterilized by filtration using a membrane filter (pore size 0.22 μm), and then 100 ml was filled in a vial and sterilized by autoclaving at 121 ° C. for 20 minutes. Subsequently, the drug substance was checked for foreign substances and sterility, and stored in a cool and dark place. The storage period was 3 years. In addition, since it is difficult to guarantee that the powdered phosphenytoin is aseptic, it was used that dissolved in distilled water for injection. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

  On the other hand, as the second preparation component, 1.211 mg of trometamol (tris (hydroxymethyl) aminomethane, buffer) and an appropriate amount of hydrochloric acid were mixed with distilled water for injection to prepare a total amount of 100 ml. The second preparation component was filtered using a membrane filter (pore size 0.22 μm), filled into a 100 ml vial, stoppered with a rubber stopper, and the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Furthermore, foreign substance inspection and sterility inspection were performed, and this was stored at room temperature as the second preparation component. The storage period was 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

  Subsequently, 10 ml of the drug substance containing 750 mg of phosphenytoin was sterilized by filtration with a final filter (pore size 0.22 μm). Further, the filtrate was mixed with 10 ml of the second preparation component to make a total volume of 20 ml.

(Reference Example 1-2)
In this reference example, the drug substance as the first pharmaceutical ingredient containing 75 mg of phosphenytoin is added to the vial containing the second pharmaceutical ingredient and dissolved to make a total volume of 100 ml, enabling intravenous administration of 10 ml. A 7.5 mg formulation was obtained. Other than that was carried out similarly to the said reference example 1-1.

(Example 2-1)
30 ml of the drug substance as the first formulation ingredient containing 6000 mg of Eglizumab (trade name: Soliris (registered trademark), manufactured by Alexion Pharma GK) is sterilized by filtration using a membrane filter (pore size 0.22 μm), Thereafter, 30 ml of the vial was filled, and foreign matter inspection and sterility inspection were performed. This drug substance was stored in the dark, avoiding freezing under temperature conditions 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.

  On the other hand, 2.631 g of sodium chloride, 138 mg of sodium dihydrogen phosphate, 534 mg of sodium hydrogen hydrogen phosphate, 66 mg of polysorbate 80 as a second preparation component were mixed with distilled water for injection to prepare a total amount of 300 ml. . This second preparation component was sterilized by filtration using a 0.22 μm membrane filter, then filled into a 300 ml vial, stoppered with a rubber stopper, and the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Thereafter, foreign matter inspection and sterility inspection were performed and stored at room temperature. The storage period was 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

  Subsequently, 30 ml of the drug substance as a first preparation component containing 6000 mg of eglizumab was sterilized by filtration with a final filter (pore size 0.22 μm). Further, 1.5 ml of the drug substance was added and dissolved in a vial filled with the second preparation component to make the total volume 30 ml. As a result, a 300 mg formulation that enables 30 ml of intravenous infusion was obtained without the need for a stability test as a formulation.

(Example 2-2)
In this example, 0.15 ml of the drug substance as the first formulation component containing 6000 mg / 30 ml of eglizumab was added to the vial containing the second formulation component and dissolved to make a total volume of 300 ml. Thereby, the stability test as a formulation was not required, and a 3 mg formulation enabling 30 ml of intravenous infusion was obtained. Other than that was carried out similarly to the said Example 2-1.

(Example 3-1)
Drug substance (pore size 0) as a first drug substance containing 2.5 mg / ml of epoetin beta pegol (sustained erythropoiesis stimulating factor preparation, trade name: Mircera (registered trademark), manufactured by Chugai Pharmaceutical Co., Ltd.) .22 μm) and then sterilized by filtration and then filled with 3 ml of vials for foreign body inspection and sterility inspection. This drug substance was stored in the dark, avoiding freezing under temperature conditions 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.

  On the other hand, as the second preparation component, 200 mg of L-histidine, 4 g of D-mannitol, 4 mg of polysorbate 80, an appropriate amount of sodium hydroxide, an appropriate amount of hydrochloric acid, and distilled water for injection are mixed so that the total amount becomes 100 ml. Prepared. 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 the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Thereafter, foreign matter inspection and sterility inspection were performed and stored at room temperature. The storage period was 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

  Subsequently, the drug substance as the first preparation component containing 2.5 mg / ml of epoetin beta pegol was thawed at room temperature, and then sterilized by filtration with a final filter (pore size 0.22 μm). Thereafter, the second formulation component was added to 1 ml of the drug substance and mixed to a total volume of 100 ml to obtain a 25 μg formulation that allowed 1 ml subcutaneous administration.

(Example 3-2)
In this example, the drug substance as the first preparation component containing 2.5 mg / ml of epoetin beta pecol is sterilized by filtration with a final filter (pore size 0.22 μm), and then the total amount becomes 10 ml with the second preparation component. To obtain a 250 μg formulation allowing subcutaneous administration of 1 ml. Other than that was carried out similarly to the said Example 3-1.

(Reference Example 2-1)
25 mg of ganirelix acetate (trade name: Ganirest (registered trademark), manufactured by MSD Co., Ltd.) was dissolved in distilled water for injection, and a total amount of 1 ml of the drug substance as the first pharmaceutical ingredient was prepared. Subsequently, this drug substance was sterilized by filtration using a membrane filter (pore size 0.22 μm), and then 1 ml was filled in a vial for foreign substance inspection and sterility inspection. Thereafter, the drug substance was stored at room temperature. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

  On the other hand, 4.7 g of D-mannitol, 20 mg of glacial acetic acid, an appropriate amount of a pH adjuster, and distilled water for injection were mixed as the second preparation component to prepare a total amount of 100 ml. 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 the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Thereafter, foreign matter inspection and sterility inspection were performed and stored at room temperature. The storage period was 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 drug substance as the first preparation component containing 25 mg of ganirelix acetate was sterilized by filtration with a final filter (pore size 0.22 μm). Furthermore, the drug substance was added and dissolved in a vial filled with the second preparation component to make the total volume 100 ml. This gave a 0.25 mg formulation that allows 1 ml subcutaneous administration.

(Reference Example 2-2)
In this reference example, 1 ml of the drug substance as the first preparation component containing 25 mg of ganirelix acetate is sterilized by filtration with a final filter (pore size 0.22 μm), and then diluted to a total volume of 2 ml with the second preparation component. A 25 mg formulation was obtained that allowed 2 ml subcutaneous administration. Other than that was carried out similarly to the said reference example 2-1.

(Example 4-1)
The drug substance as the first preparation component containing 25 mg of Romiprostim (trademark, manufactured by Nplate, Amgen Inc.) is sterilized by filtration using a membrane filter (pore size 0.22 μm), filled into a vial with 5 ml, and examined for foreign substances and aseptic. Inspected. Thereafter, the drug substance was stored frozen in a freezer under a temperature condition 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.

  On the other hand, 3 g of D-mannitol, 1.5 g of purified sucrose, 120 mg of L-histidine, 3 mg of polysorbate 20, an appropriate amount of dilute hydrochloric acid and distilled water for injection are added as the second preparation component so that the total amount becomes 72 ml. Prepared. 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 the cap was tightened. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Thereafter, foreign matter inspection and sterility inspection were performed and stored at room temperature. The storage period was 3 years at room temperature. In addition, the 2nd formulation component used what has been subjected to the stability test.

  Subsequently, the drug substance as the first preparation component containing 25 mg / 5 ml of romiplostim was thawed at room temperature, and then filtered through a final filter (pore size 0.22 μm). Furthermore, 0.05 ml of the drug substance was added and dissolved in a vial filled with the second preparation component to make the total amount 0.72 ml. As a result, a 250 μg preparation capable of 0.72 ml subcutaneous administration was obtained without requiring a stability test as the preparation.

(Example 4-2)
In this example, the drug substance as the first preparation component containing 25 mg / 5 ml of romiplostim was thawed at room temperature and then sterilized by filtration with a final filter (pore size 0.22 μm). Thereafter, the second preparation component was added to make up a total volume of 144 ml. This gave a 25 μg formulation that allowed 0.72 ml of subcutaneous administration. Other than that was carried out similarly to the said Example 4-1.

(Example 5-1)
The drug substance as the first preparation component containing 4 mg of pneumococcal capsular polysaccharide (trade name: Prevener aqueous suspension subcutaneous injection, manufactured by Pfizer Inc.) is sterilized by filtration using a membrane filter (pore size 0.22 μm), The vial was filled with 10 ml and subjected to foreign substance inspection and sterility inspection. Thereafter, the drug substance was stored in the dark under temperature conditions of 2 ° C to 8 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

  On the other hand, the second preparation component was prepared as follows. That is, 25 mg of aluminum phosphate and 900 mg of sodium hydroxide were added to 50 ml of distilled water for injection, and the mixture was uniformly suspended for 5 minutes using a homogenizer having high shearing ability. Thereafter, the solution was sterilized by filtration through a membrane filter (pore size 0.22 μm), and sterilized by autoclaving at 121 ° C. for 20 minutes. Subsequently, foreign matter inspection and sterility inspection were performed and stored at room temperature. The storage period was 2 years. In addition, as the second preparation component, one having undergone the stability test was used.

  Subsequently, the drug substance as the first preparation component containing 4 mg / 10 ml of pneumococcal capsular polysaccharide was sterilized by filtration with a final filter (pore size 0.22 μm), and 1 ml was added to the vial containing the second preparation ingredient. The whole amount was adjusted to 10 ml. The vial was then left for 30 minutes at room temperature and stirred again. This gave a 200 μg / ml formulation that allowed 0.5 ml subcutaneous administration.

(Example 5-2)
In this example, the drug substance as the first preparation component containing 4 mg / 10 ml of pneumococcal capsular polysaccharide was sterilized by filtration with a final filter (pore size 0.22 μm). 0.1 ml of the second formulation component was added to make up a total volume of 100 ml. Otherwise in the same manner as in Example 5-1, a 2 μg / ml preparation capable of subcutaneous administration of 0.5 ml was obtained.

(Example 6-1)
The drug substance as a first formulation ingredient including thrombomodulin alpha 64000U / ml (trade name, for intravenous infusion, manufactured by Asahi Kasei Co., Ltd.) is sterilized by filtration using a membrane filter (pore size 0.22 μm) and filled into a vial. Foreign body inspection and sterility inspection were performed. Thereafter, the drug substance was stored frozen in a freezer at −40 ° C. The storage period was 6 months. The drug substance used was confirmed to be stable, effective and safe in non-clinical studies.

  On the other hand, as a second preparation component, 90 mg of sodium chloride was mixed with distilled water for injection to prepare a total amount of 100 ml. The second preparation component was sterilized by filtration with a membrane filter (pore size 0.22 μm), then filled into a 100 ml vial, stoppered with a rubber stopper, and the cap was wound. Subsequently, sterilization was performed in an autoclave under conditions of 121 ° C. and 20 minutes. Thereafter, foreign matter inspection and sterility inspection were performed and stored at room temperature.

  Next, the drug substance as the first preparation component containing thrombomodulin alpha 64000 U / ml was thawed at room temperature, and then sterilized by filtration with a final filter (pore size 0.22 μm). Furthermore, 1 ml of the drug substance was added to the vial containing the second preparation component and dissolved to make a total volume of 100 ml. Subsequently, 0.2 ml of the diluted drug substance was added to a vial containing 99.8 ml of the second preparation component and dissolved to make the total volume 100 ml. This gave a 128U formulation that allows 100 ml of intravenous infusion.

(Example 6-2)
In this example, the second preparation component was added to 0.2 ml of the drug substance as the first preparation ingredient containing thrombomodulin alpha 64000 U / ml to make a total volume of 100 ml. Other than that was carried out similarly to the said Example 6-1, and obtained the 12800U formulation which enables the intravenous administration of 100 ml.

Claims (10)

A pharmaceutical preparation comprising a first preparation ingredient and a second preparation ingredient,
The first preparation component is an active ingredient and optionally a solvent alone, and is a drug substance whose stability, effectiveness and safety have been shown in advance in a non-clinical test, and the active ingredient is a protein preparation component or a nucleic acid preparation Any of the ingredients,
The protein preparation component is a monoclonal antibody, albumin, globulin, human erythropoietin or romiplostim,
The nucleic acid preparation component is an antisense, siRNA, aptamer, ribozyme or decoy,
The second formulation component includes at least one formulation additive selected from a solvent, a stabilizer, a preservative, a buffer, a pH adjuster, an antioxidant, and a surfactant, and the first formulation is immediately before administration. A pharmaceutical formulation that is used in admixture with ingredients.   The pharmaceutical preparation according to claim 1, wherein the first preparation component and the second preparation component are sterilized.   The pharmaceutical preparation according to claim 1 or 2, wherein the second preparation component does not contain a preparation additive that contributes to stability as a preparation.   The pharmaceutical preparation according to any one of claims 1 to 3, wherein the second preparation component does not contain a surfactant. A method for producing the pharmaceutical preparation according to any one of claims 1 to 4,
Preparing the first formulation component and the second formulation component, which have been previously shown to be stable, effective and safe in non-clinical studies;
A method for producing a pharmaceutical preparation, comprising 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.   The method for producing a pharmaceutical preparation according to claim 5, comprising a step of sterilizing the first preparation component immediately before mixing the first preparation component and the second preparation component. A therapeutic kit using a mixture of a first formulation component and a second formulation component contained in the kit form,
The first formulation component is an active ingredient and optionally a drug substance consisting only of a solvent, and the active component is either a protein formulation component or a nucleic acid formulation component,
The protein preparation component is a monoclonal antibody, albumin, globulin, human erythropoietin or romiplostim,
The nucleic acid preparation component is an antisense, siRNA, aptamer, ribozyme or decoy,
The second formulation component includes at least one formulation additive selected from a solvent, a stabilizer, a preservative, a buffer, a pH adjuster, an antioxidant, and a surfactant, and the first formulation is immediately before administration. A therapeutic kit that is used in admixture with ingredients.   The therapeutic kit according to claim 7, wherein the kit form includes a filter sterilization filter for filter sterilizing the first formulation component immediately before mixing with the second formulation component.   The therapeutic kit according to claim 7 or 8, wherein the second preparation component does not contain a preparation additive that contributes to stability as a preparation.   The therapeutic kit according to any one of claims 7 to 9, wherein the second preparation component does not contain a surfactant.