Drug container, closing member, method for manufacturing a drug container, and method for inspecting microbial contaminants, as well as solid agent for preparing buffer solution

Abstract

To enable easy and reliable preparation of a mixed solution containing drugs and an auxiliary agent while minimizing reduction in storage stability of drugs without requiring preparation and storage management of auxiliary agent solutions.SOLUTION: A drug container is provided, comprising a container body having an opening at one end and a closing member for closing the opening of the container body, where the container body with the opening closed by the closing member contains therein a drug and an auxiliary agent separately. The agent and the auxiliary agent are solid.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to a drug container used for preparing a mixed solution containing a drug and an adjuvant. The present disclosure also relates to a closing member used for the drug container, a method for manufacturing the drug container, a method for inspecting microbial contaminants using the drug container, and a solid agent for preparing a buffer solution.

Background Art

[0002] In the preparation of a reagent solution used for inspecting microbial contaminants (hereinafter, referred to as a reagent solution for inspecting microbial contaminants, or simply a reagent solution), or a medicine (for example, a biological preparation such as an injection preparation), in one aspect, for example, a container in which a solid or liquid drug (solid drug or drug solution) is preliminarily enclosed in a desired amount, an operation is performed to introduce a predetermined amount of a liquid adjuvant (adjuvant solution) to dissolve or dilute the drug to prepare a mixed solution. Specifically, this operation is an operation of introducing a solution containing an adjuvant such as a buffer or a solubilizing agent in order to adjust the pH of the mixed solution to be suitable for the use, or to assist the dissolution of the solid drug. In one aspect of the inspection of microbial contaminants, an operation of introducing a test subject to be subjected to the inspection of microbial contaminants into the prepared mixed solution and using the mixed solution as a reagent solution is subsequently performed.

[0003] In the hygiene management of medicines and foods and the diagnosis of animals including humans, inspection of microbial contaminants may be performed to measure the degree of microbial contamination. As a means for performing the above inspection, the Limulus test is widespread. The Limulus test is a technique for measuring the degree of microbial contamination with endotoxin or (1→3)-β-D-glucan as a measurement target, and is a method for measuring microbial contaminants utilizing the property that protease precursors (factor C, factor B, factor G, proclotting enzyme) possessed by horseshoe crabs are sequentially activated by these microbial contaminants. The Limulus test is performed using a reagent (hereinafter referred to as a Limulus reagent) containing all or part of the above protease precursors such as a hemocyte extract of horseshoe crab (Limulus amebocyte lysate (LAL), hereinafter referred to as a lysate reagent).

[0004] Regarding the method for preparing the above mixed solution, it will be described below by taking the endotoxin test as an example. The reagent solution used in the endotoxin test is prepared, for example, through the operations of opening a container (vial) in which freeze-dried Limulus reagent is enclosed, weighing a required amount of an auxiliary agent solution containing a buffer, etc. and introducing it into the interior of the above container, covering the above container with a dry-heat sterilized aluminum foil, and stirring the above container with a test tube mixer to dissolve the Limulus reagent. In the endotoxin test, for example, thereafter, through the operations of introducing a test sample into the above reagent solution, covering the above container with a dry-heat sterilized aluminum cap, and stirring the above container with a test tube mixer to mix the Limulus reagent and the test sample in the above reagent solution, a sample for measuring endotoxin is prepared (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] In one aspect of the method for inspecting microbial contaminants, a plurality of operations are required for preparing a reagent solution containing a Limulus reagent and a sample to be used for measuring microbial contaminants (hereinafter sometimes simply referred to as a "measurement sample"), which is complicated and time-consuming. Therefore, some persons skilled in the art recognize that the inspection method of the above aspect is not suitable for immediately inspecting microbial contaminants when necessary, and reduction of the working steps is demanded. Further, for example, in the above aspect, when a misoperation is made such that distilled water included in a measurement kit is introduced by mistake instead of an auxiliary agent solution (buffer solution) in the preparation of a mixed solution, a protease precursor included in the Limulus reagent may not be sufficiently activated by microbial contaminants, and a problem of false negative misjudgment may occur. Also from the above viewpoints, there are problems to be solved in the above inspection aspect.

[0007] In the preparation of the mixed solution, the operation for preparing the above auxiliary agent solution is a complicated and time-consuming operation. Further, since it is necessary to prepare a plurality of auxiliary agent solutions according to the types of drugs, not only is it time-consuming for the storage management, but also problems such as misidentification of the auxiliary agent solution may occur during the preparation of the above mixed solution. Therefore, problems such as the above mixed solution prepared by misidentifying the auxiliary agent solution not being able to be prepared and used immediately when necessary, and the above mixed solution not showing a desired effect may occur. Although a prepared auxiliary agent solution whose concentration and the like are adjusted in advance and enclosed in an ampoule tube or the like has been commercialized, even when using it, problems such as the trouble of storage management and misidentification of the auxiliary agent solution still remain. In particular, an injection preparation used for treating animals including humans may not only not show a desired drug effect if the preparation operation is incorrect, but may also cause harm to the body. Also from these viewpoints, a simpler and more reliable method for preparing a mixed solution is demanded.

[0008] In order to omit the preparation work and storage management of the auxiliary agent solution, for example, a method of previously enclosing a lyophilized product of a mixed solution containing a drug and an auxiliary agent in a container body can also be considered. According to the above method, a desired mixed solution can be obtained only by the operation of introducing a predetermined amount of an aqueous solvent into the container body. However, the above method has problems such as the storage stability of the drug may decrease depending on the combination of the drug and the auxiliary agent, and it is difficult to obtain a lyophilized product with the drug when using an auxiliary agent containing a highly sublimable component, etc., and it is hard to say that it is an appropriate method. For example, when lyophilizing a mixed solution of a Limulus reagent and a buffer, due to extremely trace microbial contaminants that may be mixed in the manufacturing process, the activation of the protease precursor proceeds before the microbial contaminant inspection, resulting in a problem that a false positive misjudgment may occur during the measurement of the subject.

[0009] The present disclosure has been made in view of the above problems, and provides means for eliminating the preparation and storage management of the auxiliary agent solution, suppressing a decrease in the storage stability of the drug, and easily and surely preparing a mixed solution containing the drug and the auxiliary agent. Further, the present disclosure provides means for easily and surely performing the inspection of microbial contaminants. Furthermore, the present disclosure provides means for easily adjusting the pH of the above mixed solution and a sample using the same. That is, the main object of the present disclosure is to provide a drug-containing container capable of easily and surely preparing a mixed solution containing a drug and an auxiliary agent, a closing member used in the drug-containing container for detachably holding a solid agent containing a drug or an auxiliary agent, a method for manufacturing the drug-containing container, a method for inspecting microbial contaminants using the drug-containing container, and a solid agent for preparing a buffer solution.

Means for Solving the Problems

[0010] <1> Drug-containing container One embodiment of the present disclosure includes a container body having an opening at one end, and a closing member for closing the opening of the container body. In the container body with the opening closed by the closing member, a drug and an adjuvant are separated and present. A drug-containing container is provided (hereinafter sometimes referred to as the drug-containing container of the present invention).

[0011] According to the drug-containing container of the present invention, in the container body with the opening closed by the closing member (i.e., in the closed space), the drug and the adjuvant are separated and present. By mixing both substances in the coexistence of an aqueous solvent such as water or an aqueous solution, the drug and the adjuvant can be dissolved or diluted to prepare a mixed solution. Therefore, the labor involved in preparing and storing and managing the adjuvant solution when preparing a mixed solution containing the drug and the adjuvant can be omitted. In addition, since the operation of introducing the adjuvant solution into the container body can be omitted, accidents due to misplacement of the adjuvant solution can be prevented. Therefore, according to the drug-containing container of the present invention, a mixed solution containing a drug and an adjuvant can be simply and surely prepared at the time of use by a single mixing operation. Further, since the drug and the adjuvant are separated and present in the closed space before the preparation of the mixed solution, the storage stability of the drug can be prevented from being reduced due to the presence of the adjuvant in the drug-containing container of the present invention.

[0012] In the above invention, the drug is not particularly limited. The drug may be, for example, a pharmaceutical such as a drug substance of a pharmacologically active substance or a preparation containing the same. Among them, it is preferable that the drug is a protein or a protein preparation. In the above invention, the adjuvant is not particularly limited. The adjuvant may be, for example, a substance added to the drug substance to form a pharmaceutical composition suitable for administration to animals including humans. Among them, it is preferable that the adjuvant is an adjuvant containing at least one selected from solubilizing agents, isotonic agents, and soothing agents as adjuvant components. This is because by setting the drug and the adjuvant to the above composition, a pharmaceutical such as a biological preparation can be simply and surely prepared using the drug-containing container of the present invention. In the above invention, it is preferable that the auxiliary agent is an auxiliary agent containing a buffer as an auxiliary component. This is because by including a buffer as an auxiliary component, it becomes possible to adjust the pH of pharmaceuticals such as biological preparations.

[0013] In the above invention, for example, it is preferable that the drug is a Limulus reagent. Also, it is preferable that the auxiliary agent is an auxiliary agent containing a buffer as an auxiliary component. By setting the drug and the auxiliary agent to the above composition, a reagent solution for microbial contaminant inspection can be prepared using the drug-containing container of the present invention. Further, after the preparation of the above reagent solution or simultaneously with the preparation of a mixed solution containing the drug and the auxiliary agent, by the operation of directly introducing the test subject into the drug-containing container of the present invention only, the preparation of a measurement sample containing the drug, the auxiliary agent, and the test subject can be easily and surely performed within the same closed space.

[0014] In the above invention, it is preferable that the auxiliary agent contains a buffer as an auxiliary component. In the above case, it is preferable that the auxiliary agent contains the buffer in an amount such that the pH becomes neutral when mixed with a predetermined aqueous solvent. Since the pH of the resulting mixed solution can be made neutral by a single mixing operation of the drug and the auxiliary agent, a separate pH adjustment operation becomes unnecessary and the mixed solution can be used immediately after its preparation.

[0015] In the above invention, it is preferable that the drug or the auxiliary agent is detachably held by the closing member. At this time, the other substance of the drug or the auxiliary agent that is not held by the closing member may exist on the inner wall or the bottom surface of the container body without contacting the closing member. By separating and making the drug and the auxiliary agent exist in the closed space, it becomes easy to prepare a mixed solution simply by detaching the drug or the auxiliary agent held by the closing member.

[0016] In the above invention, it is preferable that the dosage form of the above drug or the above adjuvant is a solid dosage form. Among these, it is preferable that the dosage form of the above drug or the above adjuvant held by the above closing member is a solid dosage form. By making the dosage form a solid dosage form, it becomes easy to hold the above drug or the above adjuvant on the above closing member and to detach it from the above closing member.

[0017] In the above invention, it is preferable that the above closing member has a plug portion that fits into the above opening of the above container body, and the above drug or the above adjuvant is held by the above plug portion. This is because when the above plug portion fits into the above opening of the above container body, the above drug and the above adjuvant can be stored in a sealed state.

[0018] Also, in the case of the above invention, it is preferable that the above plug portion of the above closing member has a concave portion on a surface intersecting the insertion direction, and the above drug or the above adjuvant is held by the above concave portion. This is because the above drug or the above adjuvant can be reliably held when the above drug or the above adjuvant is held by the above concave portion of the above plug portion.

[0019] <2>Closing member One embodiment of the present disclosure is a closing member used for the above drug storage container, which is characterized by detachably holding the above solid dosage form containing the above drug or the above adjuvant (hereinafter, may be referred to as the closing member of the present invention).

[0020] According to the closing member of the present invention, when the closing member of the present invention is used for the above drug storage container, even when there are other substances in the container body for which premixing is contraindicated or not preferable, they can be separated and present individually at the stage before the preparation of the mixed solution. Further, since the above closing member detachably holds the above solid dosage form, by detaching the above solid dosage form and introducing an aqueous solvent as necessary, it becomes possible to prepare a mixed solution with another substance present in the above main body container at the time of use. For example, it is possible to easily prepare a mixed solution containing a drug or an adjuvant with poor storage stability in an aqueous solvent.

[0021] <3>Method for manufacturing a drug container One embodiment of the present disclosure is the method for manufacturing a drug container described above, which includes an introduction step of introducing the drug from the opening of the container body, and a closing step of closing the container body with the surface of the closing member that holds the auxiliary agent facing the opening side of the container body while the closing member holds the auxiliary agent. Alternatively, it includes an introduction step of introducing the auxiliary agent from the opening of the container body, and a closing step of closing the container body with the surface of the closing member that holds the drug facing the opening side of the container body while the closing member holds the drug. (Hereinafter, it may be referred to as the first aspect of the method for manufacturing a drug container of the present invention.)

[0022] According to the first aspect of the method for manufacturing a drug container of the present invention, it is possible to easily obtain a drug container in which the drug and the auxiliary agent are separated and present in the container body (closed space) with the opening of the container body closed by the closing member.

[0023] Also, one embodiment of the present disclosure is the method for manufacturing a drug container described above, which includes an introduction step of introducing the liquid drug from the opening of the container body, a closing step of closing the container body with the surface of the closing member that holds the auxiliary agent facing the opening side of the container body while the closing member holds the auxiliary agent, and a drying step of freeze-drying and solidifying the liquid drug in the container body. Alternatively, it includes an introduction step of introducing the liquid auxiliary agent from the opening of the container body, a closing step of closing the container body with the surface of the closing member that holds the drug facing the opening side of the container body while the closing member holds the drug, and a drying step of freeze-drying and solidifying the liquid auxiliary agent in the container body. (Hereinafter, it may be referred to as the second aspect of the method for manufacturing a drug container of the present invention.)

[0024] According to the second aspect of the method for manufacturing the drug-containing container of the present invention, in a state where the opening of the container body is closed by the closing member holding the drug or the auxiliary agent, the liquid auxiliary agent or drug in the container body is freeze-dried, thereby reliably preventing the mixing of the auxiliary agent and the drug. As a result, a drug-containing container in which the drug and the auxiliary agent are separated and present can be easily obtained. Further, by performing freeze-drying by the above method, it is possible to prevent a decrease in the storage stability of the drug before preparing the mixed solution.

[0025] Moreover, one embodiment of the present disclosure is the method for manufacturing the drug-containing container described above, which includes an introduction step of introducing the liquid drug from the opening of the container body, and a closing step of temporarily fitting the plug portion of the closing member to the opening of the container body with the auxiliary agent held on the plug portion of the closing member to close the container body, and a drying step of freeze-drying and solidifying the liquid drug in the container body in the temporarily fitted state, or an introduction step of introducing the liquid auxiliary agent from the opening of the container body, and a closing step of temporarily fitting the plug portion of the closing member to the opening of the container body with the drug held on the plug portion of the closing member to close the container body, and a drying step of freeze-drying and solidifying the liquid auxiliary agent in the container body in the temporarily fitted state (hereinafter, may be referred to as the third aspect of the method for manufacturing the drug-containing container of the present invention).

[0026] According to the third aspect of the method for manufacturing the drug container of the present invention, the drug or the auxiliary agent is held in the stopper portion of the closing member, and in a state where the stopper portion is temporarily fitted into the opening of the container body, the liquid auxiliary agent or drug in the container body is freeze-dried, so that mixing of the auxiliary agent and the drug can be surely prevented. Thereby, a drug container in which the drug and the auxiliary agent are separated and present can be easily obtained. Further, by performing freeze-drying by the above method, it is possible to prevent a decrease in the storage stability of the drug before preparing the mixed solution. Furthermore, since the opening of the container body is temporarily fitted by the stopper portion in the drying step, air in the container body can be easily degassed from the gap at the temporarily fitting position, and freeze-drying can be efficiently performed, and at the same time, contamination by external impurities can be prevented.

[0027] In the case of the above invention, the stopper portion of the closing member has the concave portion on a plane intersecting the insertion direction, and the concave portion of the stopper portion has a depth such that a part thereof can be exposed from the opening of the container body when temporarily fitted into the opening of the container body in the closing step, and it is preferable that the drug or the auxiliary agent is held in the concave portion of the stopper portion. This is because when a part of the concave portion of the stopper portion is exposed from the opening of the container body, the exposed portion of the concave portion functions as a degassing path for air in the container body in the drying step, and freeze-drying can be performed more efficiently.

[0028] <4> Method for inspecting microbial contaminants One embodiment of the present disclosure is a method for inspecting microbial contaminants using the above-described drug container, the method including a preparation step of introducing a test subject into the container body of the drug container and preparing a sample (measurement sample) for measuring microbial contaminants including the drug, the auxiliary agent, and the test subject, and a detection step of detecting the microbial contaminants in the sample. A method for inspecting microbial contaminants (hereinafter, may be referred to as the method for inspecting microbial contaminants of the present invention) is provided.

[0029] According to the method for inspecting microbial contaminants of the present invention, by introducing a test sample into the container body of the above-described chemical agent storage container, a measurement sample containing a chemical agent, an auxiliary agent, and the test sample can be prepared collectively within the container body. That is, according to the present invention, the measurement sample can be easily prepared in a single step without the need for steps such as preparing and weighing an auxiliary agent solution, and introducing the auxiliary agent solution into the container body containing the chemical agent to prepare a reagent solution. Then, detection of microbial contaminants can be performed using the chemical agent storage container in which the measurement sample has been prepared. Thus, according to the method for inspecting microbial contaminants of the present invention, the preparation of the measurement sample can be easily performed, and the presence or absence and the amount of microbial contaminants in the test sample contained in the measurement sample can be simply and reliably measured, and the degree of microbial contamination can be simply measured.

[0030] In the above invention, the microbial contaminant means a component derived from a microorganism (carbohydrates such as nucleic acids, proteins, lipids, and saccharides), which is a component other than the constituent components of the above chemical agent and the above auxiliary agent and the test sample itself (contaminant). In the above invention, it is preferable that the microbial contaminant is endotoxin or (1→3)-β-D-glucan.

[0031] <5> Solid agent for preparing buffer solution One embodiment of the present disclosure is a solid agent for preparing a buffer solution containing at least a buffer agent and a molding agent, which is characterized in that it contains an amount of the buffer agent that makes the pH neutral when mixed with a predetermined aqueous solvent (hereinafter, may be referred to as the solid agent for preparing a buffer solution of the present invention).

[0032] According to the solid agent for preparing a buffer solution of the present invention, since the pH becomes neutral by mixing with a predetermined aqueous solvent, a buffer solution having a predetermined pH can be easily adjusted. Further, when preparing a mixed solution containing a chemical agent and an auxiliary agent, and a sample using the mixed solution, by using the solid agent for preparing a buffer solution of the present invention, the pH of the mixed solution and the sample can be easily adjusted.

[0033] In the above invention, it is preferable that the solid agent substantially does not contain microbial contaminants. This is because the solid agent for preparing a buffer solution of the present invention can be directly used for preparing a mixed solution for the purpose of administration to animals including humans and for preparing a measurement sample for microbial contaminant inspection.

Advantages of the Invention

[0034] According to the present disclosure, it is possible to provide a means for eliminating the need to prepare an auxiliary agent solution, suppressing a decrease in the storage stability of a drug, and easily and surely preparing a mixed solution containing the drug and the auxiliary agent. Further, by using the above means, it is possible to provide a method for inspecting microbial contaminants that enables simple and reliable evaluation. Furthermore, it is possible to provide a solid agent for preparing a buffer solution that can easily adjust the pH of a mixed solution or a sample using the mixed solution.

Brief Description of the Drawings

[0035]

Figure 1

Figure 2

Figure 3

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Figure 11

Figure 12

Mode for Carrying Out the Invention

[0036] Hereinafter, a drug storage container, a closing member, a method of manufacturing a drug storage container, a method of inspecting microbial contaminants, and a solid agent for preparing a buffer solution according to an embodiment of the present disclosure will be described in detail.

[0037] I. Drug Storage Container The drug storage container of the present invention has a container body having an opening at one end and a closing member for closing the opening of the container body, and drugs and adjuvants are separated and present in the container body with the opening closed by the closing member.

[0038] The drug storage container of the present invention will be described with reference to the drawings. FIGS. 1(a) and 1(b) are schematic cross-sectional views showing an example of the drug storage container of the present invention. FIG. 1(a) shows before the opening is closed by the closing member 2, and FIG. 1(b) shows after the opening is closed by the closing member 2. Further, FIG. 2(a) is a schematic perspective view of the closing member in the drug storage container shown in FIGS. 1(a) and 1(b), and FIG. 2(b) is a schematic plan view seen from the stopper side of FIG. 2(a). The drug storage container 10 shown in FIGS. 1(a) and 1(b) has a container body 1 having an opening O at one end and a closing member 2 for closing the opening O. The arrow Y in FIG. 1(a) indicates the insertion direction Y when the closing member 2 is fitted into the opening O. As shown in FIG. 1(b), drugs 11 and adjuvants 12 are separated and present in the container body 1 (in the closed space) with the opening O closed by the closing member 2.

[0039] Also, in the examples shown in FIGS. 1 and 2, the auxiliary agent 12 is held by the closing member 2. Specifically, the closing member 2 has a top plate portion 2a and a plug portion 2b that fits into the opening O on the surface of the top plate portion 2a on the side of the container body 1, and a solid agent (tablet) containing the auxiliary agent 12 is held by the plug portion 2b. More specifically, as shown in FIGS. 2(a) and 2(b), a concave portion P is formed on the surface of the plug portion 2b that intersects the insertion direction Y, and the auxiliary agent 12 is held sandwiched in the concave portion P. The closing member 2 illustrated in FIGS. 1 and 2 is a sealing member in which the plug portion 2b fits into the opening O of the container body 1 and can be sealed.

[0040] FIG. 3 is a schematic perspective view showing another example of the drug-containing container of the present invention, and shows an example in which the container body 1 of the drug-containing container 10 of the present invention is a syringe having openings O at both ends. In the example shown in FIG. 3, the openings O at both ends of the container body 1 are each closed by a different closing member 2. The above-mentioned closing member 2 is entirely a plug portion 2b that fits into the opening O. Further, in the container body 1 in which the opening O is closed by the closing member 2, the drug 11 and the auxiliary agent 12 are separated and present. In the example shown in FIG. 3, the drug 11 and the auxiliary agent 12 are each held by a different closing member 2.

[0041] According to the drug-containing container of the present invention, in the container body (i.e., in the closed space) in which the opening is closed by the closing member, the drug and the auxiliary agent are separated and present, and by mixing both substances in the coexistence of an aqueous solvent such as water or an aqueous solution, the above-mentioned drug and the above-mentioned auxiliary agent can be dissolved or diluted to prepare a mixed solution. Therefore, it is possible to omit the labor involved in preparing and storing and managing the auxiliary agent solution when preparing a mixed solution containing the drug and the auxiliary agent. Further, since the operation of introducing the auxiliary agent solution into the container body can be omitted, an accident due to misappropriation of the auxiliary agent solution can be prevented. Therefore, according to the drug-containing container of the present invention, a mixed solution containing a drug and an auxiliary agent can be easily and surely prepared at the time of use by a single mixing operation. Also, since the drug-containing container of the present invention has the drug and the auxiliary agent separated and present in the closed space before the preparation of the mixed solution, it is possible to prevent the storage stability of the drug from being reduced due to the presence of the auxiliary agent.

[0042] The following is an explanation of each component of the drug container of the present invention.

[0043] A. Drug and adjuvant In the drug container of the present invention, the drug and the adjuvant are separately present in the container main body (closed space) with the opening closed by the above-mentioned closing member.

[0044] The fact that the drug and the adjuvant "are separately present" in the closed space means that the drug and the adjuvant are not mixed and each exists independently.

[0045] It is preferable that the above-mentioned drug or the above-mentioned adjuvant is detachably held by the above-mentioned closing member, and it is more preferable that the above-mentioned adjuvant is detachably held by the above-mentioned closing member. By holding one of the above-mentioned drug and the above-mentioned adjuvant by the above-mentioned closing member and making the other exist in the above-mentioned container main body, it becomes easy to separately present the above-mentioned drug and the above-mentioned adjuvant in the above-mentioned closed space, and it is possible to prevent the decrease in the storage stability of the above-mentioned drug due to the presence of the adjuvant. Further, when preparing the mixed solution, the mixed solution can be easily prepared by detaching the substance held by the above-mentioned closing member. When the above-mentioned adjuvant is detachably held by the above-mentioned closing member, the above-mentioned drug may exist in the above-mentioned container main body or may be held by the above-mentioned container main body. Incidentally, the "detachable" and the specific modes in which the drug and the adjuvant are separately present in the closed space will be described in detail later.

[0046] The above-mentioned drug and the above-mentioned adjuvant can be appropriately selected and combined according to the mixed solution to be prepared. For example, when preparing a pharmaceutical such as a biological preparation, the above-mentioned drug and the above-mentioned adjuvant are not particularly limited, but the above-mentioned drug may be a pharmaceutical such as a drug substance of a pharmacologically active substance or a preparation containing the same. Among them, it is preferable that the above-mentioned drug is a protein or a protein preparation. At this time, the above-mentioned adjuvant may be a substance added to the drug substance in order to obtain a pharmaceutical composition suitable for administration to animals including humans. Among them, it is preferable that the above-mentioned adjuvant is an adjuvant containing at least one selected from solubilizers, isotonic agents, and soothing agents as adjuvant components, or an adjuvant containing a buffer as an adjuvant component. This is because a pharmaceutical such as a biological preparation can be prepared simply and reliably using the drug-containing container of the present invention.

[0047] When preparing a reagent solution for microbial contaminant inspection or a measurement sample, it is preferable that the above-mentioned drug is a Limulus reagent, and it is preferable that the above-mentioned adjuvant is an adjuvant containing a buffer as an adjuvant component. This is because the above-mentioned reagent solution or measurement sample can be prepared simply and reliably using the drug-containing container of the present invention. In addition, after the preparation of the above-mentioned reagent solution or simultaneously with the preparation of the mixed solution containing the drug and the adjuvant, the measurement sample can be prepared simply and reliably in the same closed space only by the operation of directly introducing the subject into the drug-containing container of the present invention.

[0048] Hereinafter, the drug and the adjuvant will be described.

[0049] 1. Drug The drug is a substance showing the main function of the mixed solution prepared using the drug-containing container of the present invention and contains at least one active ingredient.

[0050] The type of the active ingredient contained in the above agent is not particularly limited, and can be appropriately selected according to, for example, the usage mode of the mixed solution containing the above agent. The active ingredient contained in the above agent may be only one kind, or may be two or more kinds. Further, the amount of the active ingredient contained in the above agent is not particularly limited, and can be appropriately set according to, for example, the usage mode of the mixed solution containing the above agent.

[0051] As the above agent, for example, the active ingredient's raw drug or a preparation containing the above active ingredient can be used. In the present invention, the active ingredient refers to, for example, a component having pharmacological activity in the body of an animal including a human, a component that causes a physical or chemical change in the other substance or the active ingredient itself when contacting other substances such as microbial contaminants, etc. Further, the physical or chemical changes mentioned here include binding, transfer, rearrangement, addition, elimination, decomposition, cleavage, oxidation, reduction, labeling, color development, luminescence, etc.

[0052] Examples of the above agent in the present invention include pharmaceuticals used for the diagnosis, treatment, treatment, prevention, etc. of diseases of animals including humans, reagents used for tests, tests, research, etc. including clinical tests, etc.

[0053] (1) Pharmaceutical Examples of the above pharmaceutical include, for example, the raw drug of a pharmacologically active substance. Examples of the raw drug of the above pharmacologically active substance include, for example, proteins. Further, examples of the above pharmaceutical include, for example, a preparation containing a pharmacologically active substance as an active ingredient. Examples of the preparation containing the above pharmacologically active substance include, for example, a protein preparation having a protein as an active ingredient. The above protein preparation can be the same as known ones, and examples include collagen, serum albumin, fibrinogen, various hormones, erythropoietin, interferon, interleukin, etc. Further, examples of the raw drug of the above pharmacologically active substance include those that are difficult to store in liquid form among vaccines and antibody pharmaceuticals (monoclonal antibodies against cytokines / tumor antigens / various receptors, etc.) and are stored by lyophilization.

[0054] (2) Reagent Examples of the above-mentioned reagent include the Limulus reagent. The Limulus reagent may be the hemocyte extract (lysate reagent) of horseshoe crab itself, or it may be obtained by appropriately fractionating and / or purifying the above hemocyte extract. Further, the Limulus reagent may be obtained, for example, from horseshoe crab hemocytes according to a conventional method.

[0055] The type of the above horseshoe crab is not particularly limited, and may be any horseshoe crab belonging to the order Xiphosura, for example. Examples of the horseshoe crab include those belonging to the family Limulidae. The horseshoe crab is preferably a horseshoe crab belonging to the genus Tachypleus, the genus Limulus, or the genus Carcinoscorpius. Specifically, examples of the horseshoe crab include Tachypleus tridentatus, Tachypleus gigas, Limulus polyphemus, and Carcinoscorpius rotundicauda.

[0056] Examples of the above Limulus reagent include a reagent containing one or more Limulus factors that react with microbial contaminants, which are the substances to be measured in the Limulus test, among the respective factors (factor C, factor B, factor G, proclotting enzyme, hereinafter individually or collectively referred to as "Limulus factors") that are protease precursors involved in the coagulation cascade reaction of horseshoe crab (hereinafter simply referred to as "cascade reaction"). The Limulus reagent may be, for example, a Limulus reagent (hereinafter referred to as "reconstituted Limulus reagent") artificially reconstituted to contain only an arbitrary Limulus factor. The "reaction with microbial contaminants" as used herein means a reaction in which the precursor of the Limulus factor in contact with the microbial contaminants is activated and changes to have protease activity.

[0057] When the above reconstituted Limulus reagent measures endotoxin as a microbial contaminant, for example, it may contain at least factor C as a Limulus factor, and may or may not contain other Limulus factors (factor B, factor G, proclotting enzyme). Also, when the above reconstituted Limulus reagent measures (1→3)-β-D-glucan as a microbial contaminant, for example, it may contain at least factor G as a Limulus factor, and may or may not contain other Limulus factors (factor C, factor B, proclotting enzyme).

[0058] When measuring endotoxin as a microbial contaminant, it is preferable that the above reconstituted Limulus reagent contains factor C as a Limulus factor. More preferably, it contains factor B in addition to factor C. Even more preferably, it contains factor B and proclotting enzyme in addition to factor C. Also, when measuring endotoxin as a microbial contaminant, it is preferable that the above reconstituted Limulus reagent does not contain factor G.

[0059] When measuring (1→3)-β-D-glucan as a microbial contaminant, it is preferable that the above reconstituted Limulus reagent contains factor G as a Limulus factor. More preferably, it contains proclotting enzyme in addition to factor G. Also, when measuring (1→3)-β-D-glucan as a microbial contaminant, it is preferable that the above reconstituted Limulus reagent does not contain factor C, and more preferably, it does not contain factor C and factor B.

[0060] The above reconstituted Limulus reagent can be prepared, for example, by performing purification or fractionation to remove any Limulus factor from the Limulus reagent. Also, for example, one kind of Limulus factor isolated from the Limulus reagent may be used as the above reconstituted Limulus reagent, or a mixture of two or more kinds of isolated Limulus factors may be used as the above reconstituted Limulus reagent.

[0061] The preparation of the above-mentioned reconstituted Limulus reagent can be carried out by appropriately combining known methods. For example, it can be carried out with reference to the method disclosed in "Nakamura T, Horiuchi T, Morita T, Iwanaga S. J Biochem. 1986 Mar; 99(3): 847-57."

[0062] The Limulus factor contained in the above-mentioned reconstituted Limulus reagent may be a natural Limulus factor obtained from horseshoe crabs or a recombinant Limulus factor obtained by genetic recombination technology.

[0063] The above-mentioned natural Limulus factor can be obtained, for example, from the hemocyte extract of horseshoe crabs as described above. Further, the above-mentioned recombinant Limulus factor can be obtained, for example, by expressing the Limulus factor in a host cell transformed with a nucleic acid encoding the Limulus factor. The type of the host cell is not particularly limited, and may be, for example, a mammalian cell or an insect cell. The host cell is preferably a mammalian cell. This is because a reconstituted Limulus reagent that is less susceptible to reaction inhibition due to the presence of salts (ions) can be provided (International Publication No. 2014 / 92079). Examples of the mammalian cells include a Chinese hamster ovary-derived cell line (CHO cells) and a human fetal kidney-derived cell line (HEK cells). Examples of the HEK cells include HEK293 cells.

[0064] The expression of the recombinant limulus factor by the above host cell can be carried out according to a conventional method. For example, it can be carried out with reference to the method disclosed in International Publication No. WO 2014 / 92079. The amino acid sequence of the limulus factor and the nucleotide sequence of the gene encoding the same can be obtained from known databases. Examples of known databases include, for example, the databases provided by the National Center for Biotechnology Information (NCBI). The expressed recombinant limulus factor may be, for example, the culture solution obtained by culturing the above host cell used directly as the above limulus factor, or, if necessary, the one purified to a desired degree may be used as the above limulus factor.

[0065] All of the limulus factors contained in the above reconstituted limulus reagent may be natural limulus factors, may all be recombinant limulus factors, or may be an appropriate combination of natural limulus factors and recombinant limulus factors. Further, the above reconstituted limulus reagent may be, for example, the limulus reagent itself, or a product obtained by appropriately fractionating and / or purifying the limulus reagent, in appropriate combination with natural and / or recombinant limulus factors.

[0066] The limulus reagent described above may be a commercially available limulus reagent. Examples of the above commercially available limulus reagents include, for example, Pyrosmart (Seikagaku Corporation), Endospecy (Seikagaku Corporation), Pyrochrome (Associates of Cape Cod, Inc.), Pyrotell-T (Associates of Cape Cod, Inc.), Pyrotell Single Test (Associates of Cape Cod, Inc.), Limulus ES-II Single Test (Wako Pure Chemical Industries, Ltd.), Kinetic-QCL (Lonza Walkersville, Inc.), Endochrome-K (Charles River Laboratories, Inc.), and the like. These can be used as the agents in the present invention.

[0067] (3) Others The above-mentioned agent may be composed of only the active ingredient of the above-mentioned medicine or reagent, or may be composed of a composition containing the above-mentioned active ingredient and other ingredients. For example, the above-mentioned Limulus reagent may be a reagent composed of only the above-mentioned Limulus factor as the active ingredient, or may be a reagent containing the above-mentioned Limulus factor and other components other than that. Examples of the above-mentioned other components include the above-mentioned host cell expressing the above-mentioned Limulus factor or components other than the above-mentioned Limulus factor possessed by the above-mentioned horseshoe crab (specifically, carbohydrates such as nucleic acids, proteins, lipids, and saccharides). Further, the above-mentioned Limulus reagent may contain a detection substrate used in the Limulus test as the above-mentioned other component. The detection substrate will be described later.

[0068] The mass concentration (w / w%) of the above-mentioned active ingredient contained in the above-mentioned agent may be, for example, 0.01 w / w% or more, 0.1 w / w% or more, 1 w / w% or more, 10 w / w% or more, 25 w / w% or more, 50 w / w% or more, 75 w / w% or more, 90 w / w% or more, 95 w / w% or more, 99 w / w% or more, or 100 w / w%. Further, the mass concentration (w / w%) of the above-mentioned active ingredient contained in the above-mentioned agent may be, for example, 99.9 w / w% or less, 99 w / w% or less, 95 w / w% or less, 90 w / w% or less, 75 w / w% or less, 50 w / w% or less, 25 w / w% or less, 10 w / w% or less, or 1 w / w% or less. Note that "w / w%" is synonymous with the ratio calculated as "predetermined material (component) (g) / total amount (g)". The same shall apply hereinafter.

[0069] 2. Auxiliary agent An auxiliary agent is a substance containing one or more auxiliary agent components that impart other functions different from the function of the agent in the mixed solution containing the above-mentioned agent.

[0070] The type of the auxiliary agent component contained in the above auxiliary agent is not particularly limited, and can be appropriately selected according to the usage mode of the mixed solution containing the above auxiliary agent, the type of the above drug to be used, etc. The above auxiliary agent component contained in the above auxiliary agent may be only one type, or may be two or more types. Further, the amount of the above auxiliary agent component contained in the above auxiliary agent is not particularly limited, and can be appropriately set according to, for example, the usage mode of the mixed solution containing the above auxiliary agent.

[0071] When the above drug is a pharmaceutical, it is preferable that the above auxiliary agent contains an auxiliary agent component added to the active ingredient in order to obtain a pharmaceutical composition suitable for administration to animals including humans, and it is preferable that the above auxiliary agent component contains at least one selected from solubilizing agents, isotonic agents, and soothing agents. The solubilizing agent, isotonic agent, and soothing agent can be the same as the materials used in known biological preparations. Also, in the above case, the above auxiliary agent may contain, as the above auxiliary agent component, a buffer, a diluent, a diuretic, an antibiotic, a nutrient, an antioxidant, etc. Among them, it is preferable that the above auxiliary agent contains a buffer as the above auxiliary agent component. This is because it is possible to adjust the pH of a pharmaceutical such as a biological preparation obtained by using the pharmaceutical container of the present invention. The type of the above buffer and the content of the above buffer in the above auxiliary agent will be described later.

[0072] When the above drug is a reagent, it is preferable that the above auxiliary agent contains a buffer as the above auxiliary agent component. This is because it is possible to adjust the pH of the above reagent solution or the sample for measurement. Also, the above auxiliary agent may contain, in addition to the above auxiliary agent component, a detection substrate used in the Limulus test, etc. The detection substrate will be described later.

[0073] Here, examples of the buffer include amino acids such as citric acid, malic acid, lactic acid, ascorbic acid, maleic acid, gluconic acid, phosphoric acid, boric acid, glycine, and glutamic acid, tris(hydroxymethyl)aminomethane (Tris), 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES), N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), 2-hydroxy-3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid, monohydrate (HEPPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), N,N-bis(2-hydroxyethyl)glycine (Bicine), imidazole, phosphates, and the like.

[0074] The content of the buffer in the above auxiliary agent can be appropriately set according to the type and amount of the mixed solution to be prepared. Among them, it is preferable that the above auxiliary agent contains an amount of the buffer such that the pH becomes neutral when mixed with a predetermined aqueous solvent. Since the pH of the obtained mixed solution can be made neutral by a single mixing operation of the above drug and the above auxiliary agent, a separate pH adjustment operation is not required, and the mixed solution can be used immediately after preparation. For example, when preparing a pharmaceutical such as a biological preparation, the pH of the above pharmaceutical can be adjusted to a pH suitable for administration to animals including humans. Also, for example, when preparing a reagent solution or a measurement sample for microbial contaminant inspection, the pH can be adjusted to a pH suitable for preferably promoting a reaction or a cascade reaction in which a protease precursor (limulus factor) is activated by microbial contaminants.

[0075] Here, the content of the buffer in the above auxiliary agent may be an amount that makes the pH neutral in consideration of the buffering capacity and the like of these substances according to the type and amount of the above drug and the above aqueous solvent.

[0076] The aqueous solvent to be mixed with the above-mentioned agent and the above-mentioned adjuvant is not particularly limited. Here, the aqueous solvent means a solvent that can be miscible with water. Examples of the above-mentioned "aqueous solvent" include water such as water for injection, an aqueous solution containing water and other components, a liquid specimen, and the like. Examples of the above-mentioned "other components" include inorganic components such as sodium chloride and organic components such as surfactants. Examples of the above-mentioned "liquid specimen" include a specimen to be subjected to a Limulus test. Specifically, examples include water for injection, injections, specimens derived from animals including humans, and the like. Examples of the above-mentioned "specimen derived from an animal" include blood, serum, plasma, and the like. Examples of the above-mentioned "specimen derived from an animal" also include a specimen (such as a dialysate) obtained by collecting a liquid that has come into direct or indirect contact with the body of an animal.

[0077] The above-mentioned aqueous solvent may contain an organic solvent, may substantially contain no organic solvent, or may contain no organic solvent at all. The phrase "substantially free of an organic solvent" as used herein means that even if it is contained, it is contained only in an amount such that the function of the agent in the mixed solution is not lost and the desired effect can be achieved. As the volume concentration (v / v%), for example, it may be within the range of more than 0 v / v% and 20 v / v% or less, more than 0 v / v% and 10 v / v% or less, more than 0 v / v% and 5 v / v% or less, more than 0 v / v% and 2 v / v% or less, or more than 0 v / v% and 1 v / v% or less.

[0078] The amount of the aqueous solvent to be mixed with the above adjuvant is not particularly limited. The amount of the aqueous solvent to be mixed with the above adjuvant can be an amount that does not require dilution and has a neutral pH when mixed with the adjuvant, and can be, for example, 0.1 mL or more, or 0.2 mL or more. Also, the amount of the aqueous solvent to be mixed with the above adjuvant can be, for example, 1 L or less, 100 mL or less, 10 mL or less, 1 mL or less, or 0.5 mL or less. Therefore, examples of the range of the amount of the aqueous solvent to be mixed with the above adjuvant include within the range of 0.1 mL to 1 L, within the range of 0.1 mL to 100 mL, within the range of 0.1 mL to 10 mL, within the range of 0.1 mL to 1 mL, within the range of 0.2 mL to 1 mL, within the range of 0.2 mL to 0.5 mL, etc. When the above drug is a Limulus reagent, the range of the amount of the aqueous solvent to be mixed with the above adjuvant is preferably within the range of 0.1 mL to 1 mL, and more preferably within the range of 0.2 mL to 0.5 mL.

[0079] In the above, the pH being neutral means that the pH measured at room temperature (24 - 26 °C) is neutral. For example, the pH that is neutral at 25 °C can be, for example, 6 or more, 6.2 or more, 6.4 or more, 6.6 or more, or 6.8 or more. Also, the neutral pH can be, for example, 8 or less, 7.9 or less, 7.8 or less, 7.6 or less, or 7.4 or less. That is, examples of the range of the neutral pH include within the range of 6 - 8, within the range of 6.4 - 8, within the range of 6.8 - 8, within the range of 6.8 - 7.9, within the range of 6.4 - 7.8, within the range of 6.8 - 7.8, within the range of 6.4 - 7.4, within the range of 6.8 - 7.4, etc. When the above drug is a Limulus reagent, it is preferable that the pH when the above adjuvant containing the above buffer as the above adjuvant component is mixed with the above predetermined aqueous solvent is within the range of 6.8 - 7.9. The above pH means the pH shown when the above drug, the above adjuvant, and the above predetermined aqueous solvent are mixed and the above drug and the above adjuvant are dissolved.

[0080] The content of the buffer in the above-mentioned auxiliary agent can also be defined by the molar concentration of the buffer (hereinafter referred to as "final concentration of the buffer") when the above-mentioned drug, the above-mentioned auxiliary agent, and the above-mentioned predetermined aqueous solvent are mixed. The amount at which "the pH becomes neutral when the auxiliary agent is mixed with the predetermined aqueous solvent" may be the amount at which the final concentration of the buffer is within a predetermined range when the above-mentioned auxiliary agent is mixed with the above-mentioned drug and the above-mentioned predetermined aqueous solvent. Specifically, the final concentration of the buffer may be, for example, 1 mM or more, 5 mM or more, 10 mM or more, or 20 mM or more. The final concentration of the buffer may be, for example, 1 M or less, 500 mM or less, 250 mM or less, or 100 mM or less. Therefore, examples of the range of the final concentration of the buffer include within the range of 1 mM to 1 M, within the range of 1 mM to 500 mM, within the range of 1 mM to 250 mM, within the range of 1 mM to 100 mM, within the range of 5 mM to 500 mM, within the range of 5 mM to 250 mM, within the range of 5 mM to 100 mM, within the range of 10 mM to 500 mM, within the range of 10 mM to 250 mM, within the range of 10 mM to 100 mM, within the range of 20 mM to 250 mM, within the range of 20 mM to 100 mM, etc. When the above-mentioned drug is a Limulus reagent, the final concentration of the buffer is preferably within the range of 20 mM to 100 mM. Note that mM = mmol / L.

[0081] 3. Other components The above-mentioned drug and the above-mentioned auxiliary agent may contain other components. Hereinafter, other components will be described.

[0082] (1) Substrate for detection At least one of the above-mentioned drug and the above-mentioned auxiliary agent may contain a substrate for detection (hereinafter simply referred to as "substrate"). The above-mentioned substrate is a component used in the Limulus test. The above-mentioned substrate is not particularly limited as long as it is a substance that can be used for measuring the presence or amount of activated Limulus factor, the progress of the cascade reaction, etc., and examples include proteins, polypeptides, peptides, and their derivatives. The above-mentioned substrate may be a natural protein or the like, a recombinant protein or the like, or a chemically synthesized protein or the like.

[0083] The above substrate may be a substrate for detecting a clotting enzyme that is the final product of a cascade reaction, or may be a substrate for detecting an activated Limulus factor (specifically, factor C, factor B, or factor G) present in an intermediate stage of the cascade reaction.

[0084] Examples of the above substrate include coagulogen, which is a substrate for a clotting enzyme that is the final product of a cascade reaction. For example, natural coagulogen can be prepared from a hemocyte extract of a horseshoe crab. Also, for example, recombinant coagulogen can be prepared with reference to the method described in, for example, "Miyata et al., Protein, Nucleic Acid, Enzyme, Separate Volume No. 29; P30-43; 1986".

[0085] The above substrate is preferably a derivative of a peptide (hereinafter referred to as a "peptide substrate"). This is because, in addition to the relatively low production cost, the detection sensitivity is excellent. Examples of the above peptide substrate include derivatives of peptides represented by the general formula Y-X-Z (wherein X is a peptide, Y is a protecting group, and Z is a labeling substance). In the above peptide substrate, the protecting group (Y) is bonded via the α-amino group of the amino acid residue at the N-terminus of the peptide (X), and the labeling substance (Z) is bonded via the carboxy group of the amino acid residue at the C-terminus of the peptide (X). The specific forms of each component (X, Y, and Z) in the above peptide substrate are not particularly limited as long as the bond between X and Z is cleaved by the activated Limulus factor to release the labeling substance (Z). The bond between X and Z in the above peptide substrate is preferably an amide bond. Also, in the above general formula, the protecting group (Y) may not be present, and examples of the above peptide substrate also include derivatives of peptides represented by the general formula X-Z (wherein X is a peptide and Z is a labeling substance).

[0086] The above protecting group (Y) is not particularly limited, and known protecting groups applicable to peptides can be used. Examples of such protecting groups include benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group, benzoyl group, acetyl group, and the like.

[0087] The above peptide (X) is not particularly limited as long as it has a sequence recognized by an activated Limulus factor. Examples of the above peptide (X) include Asp-Pro-Arg (DPR), Val-Pro-Arg (VPR), Leu-Thr-Arg (LTR), Met-Thr-Arg (MTR), Leu-Gly-Arg (LGR), Ile-Glu-Gly-Arg (IEGR) (SEQ ID NO: 1), Glu-Gly-Arg (EGR), and the like.

[0088] The above labeling substance (Z) is not particularly limited, and known labeling substances applicable to peptides can be used. Such a labeling substance may be a substance detected by ultraviolet light or visible light, a fluorescent dye, or a substance detected by electrochemical measurement. Examples of the above labeling substance (Z) include p-nitroaniline (pNA), 7-methoxycoumarin-4-acetic acid (MCA), 2,4-dinitroaniline (DNP), Dansyl dyes, Rhodamine dyes, Cyanine dyes, phenylenediamine (PDA) and its derivatives, and the like.

[0089] As the above substrate, a suitable one can be appropriately selected and used according to the type of the above Limulus factor to be detected. For example, from the viewpoint of substrate specificity, a substrate containing the peptide sequence of LGR or IEGR is preferably used for the measurement of clotting enzyme, a substrate containing the peptide sequence of LTR or MTR is preferably used for the measurement of active factor B, a substrate containing the peptide sequence of VPR or DPR is preferably used for the measurement of active factor C, and a substrate containing the peptide sequence of EGR is preferably used for the measurement of active factor G.

[0090] It is preferable that the above drug and the above adjuvant substantially do not contain microbial contaminants. This is because the mixed solution obtained by mixing the above drug and the above adjuvant can be directly administered to animals including humans or used for the preparation of a measurement sample for microbial contaminant inspection. Here, "substantially free of microbial contaminants" means that the amount of microbial contaminants detected from the above-mentioned drug and the above-mentioned adjuvant is less than the limit of quantification or less than the limit of detection.

[0091] (2) Others The above-mentioned drug and the above-mentioned adjuvant may generally contain known materials contained in drugs and adjuvants. For example, when the above-mentioned drug and the above-mentioned adjuvant are lyophilized products described below, inorganic components such as sodium chloride and organic components such as surfactants contained in the aqueous solvent in which the above-mentioned drug or the above-mentioned adjuvant was dissolved before lyophilization may be included.

[0092] 4. Dosage form The shapes of the above-mentioned drug and the above-mentioned adjuvant are not particularly limited, and may be solid, liquid (liquid), or in a state where the liquid (liquid) is frozen. In the following description, the above-mentioned liquid drug may be referred to as a drug solution, and the above-mentioned solid drug may be referred to as a solid drug in some cases. Also, the above-mentioned liquid adjuvant may be referred to as an adjuvant solution, and the above-mentioned solid adjuvant may be referred to as a solid adjuvant in some cases.

[0093] Examples of the above-mentioned drug solution or the above-mentioned adjuvant solution include a mixed solution (dissolved) in which the above-mentioned drug or the above-mentioned adjuvant is mixed in the above-mentioned aqueous solvent. The aqueous solvent is as described above. The above-mentioned mixed solution is appropriately prepared so as to be able to indicate the above-mentioned pH and the molar concentration of the buffer.

[0094] On the other hand, examples of the above-mentioned solid drug or the above-mentioned solid adjuvant include a lyophilized product of the above-mentioned drug or the above-mentioned adjuvant, a lyophilized product of the above-mentioned mixed solution, and a solid preparation containing the above-mentioned drug or the above-mentioned adjuvant. Among them, the above-mentioned solid preparation containing the above-mentioned drug or the above-mentioned adjuvant is preferable because it can stabilize the dosage form. Examples of the above-mentioned solid preparation include a solid preparation containing the above-mentioned drug or the above-mentioned adjuvant and a molding agent, and a capsule preparation in which the above-mentioned drug or adjuvant is filled in a known capsule or encapsulated and molded with a capsule coating.

[0095] Examples of the solid preparation containing the above-mentioned drug or auxiliary agent and the above-mentioned molding agent include, in addition to a single molded product obtained by molding a mixture of the above-mentioned drug or auxiliary agent and the above-mentioned molding agent into a desired dosage form such as a tablet or powder, a capsule preparation obtained by filling the above-mentioned drug or auxiliary agent or the above-mentioned molded product into a known capsule or coating and molding it with a capsule film. Examples of the dosage form of the solid preparation include tablets, pills, capsules, powders, granules, etc. Among them, tablets, pills, and capsules are preferable, and particularly tablets are preferable. Here, the "molding agent" is a substance directly mixed with the drug or auxiliary agent, and those not mixed with the drug or auxiliary agent, such as the molding agent contained in the capsule of the "capsule preparation", are not included.

[0096] When the solid preparation contains a molding agent, the drug or auxiliary agent and the molding agent are dispersed and present in one unit (one tablet) of the solid preparation. When the auxiliary agent contained in the solid preparation contains two or more kinds of the above-mentioned auxiliary agent components, the solid preparation can be considered to contain two or more kinds of the above-mentioned auxiliary agent components and the molding agent dispersed in one unit (one tablet).

[0097] As the molding agent, known materials usually used in the production of solid preparations can be used. Examples of the molding agent include excipients, binders, etc. Specifically, cellulose such as crystalline cellulose; starch; dextrin; dextran; sugar alcohols such as mannitol, erythritol, xylitol, maltose, maltitol, sorbitol; saccharides such as lactose, sucrose, trehalose, glucose; phosphates such as calcium phosphate and sodium phosphate; sodium chloride; calcium carbonate; kaolin; silicic acid, etc. can be exemplified. These materials can be used alone or in combination of two or more.

[0098] When the solid preparation contains a molding agent, the content of the molding agent contained in the solid preparation may be an amount that enables the above-mentioned drug and auxiliary agent to be formed into a desired dosage form, and can be appropriately set according to the dosage form of the solid preparation, the content of the drug or auxiliary agent in the solid preparation, etc. Among them, it is preferable that the content of the molding agent is an amount that enables the dosage form of the solid preparation to be a tablet. The content of the molding agent in the solid preparation can be, for example, 1 w / w% or more, 5 w / w% or more, 10 w / w% or more, 25 w / w% or more, or 50 w / w% or more as a mass concentration (w / w%). Further, the content of the molding agent can be, for example, 99.9 w / w% or less, 99 w / w% or less, 95 w / w% or less, 90 w / w% or less, 80 w / w% or less, 70 w / w% or less, or 60 w / w% or less as a mass concentration (w / w%).

[0099] It is preferable that at least one of the above-mentioned drug and auxiliary agent is in a solid state, and it is more preferable that both the above-mentioned drug and auxiliary agent are in a solid state. This is because it becomes easier to separate and store the above-mentioned drug and auxiliary agent in a closed space.

[0100] When the above-mentioned drug is a solid drug, it is preferable that the solid drug substantially does not contain an aqueous solvent. This is because the active ingredient of the drug can be stored stably compared to the case where it contains an aqueous solvent. "Substantially does not contain an aqueous solvent" means that the water content (w / w%) in the solid drug is, for example, in the range of 20 w / w% to 0 w / w%, preferably in the range of 10 w / w% to 0 w / w%, more preferably in the range of 5 w / w% to 0 w / w%, still more preferably in the range of 2 w / w% to 0 w / w%, and particularly preferably in the range of 1 w / w% to 0 w / w%.

[0101] When the above-mentioned agent is a solid agent, the solid agent may be a lyophilized product or a solid preparation. However, when the agent is held by the above-mentioned closing member, the solid agent is preferably a solid preparation. This is because it is easier to hold the agent on the closing member. On the other hand, when the agent is present in the above-mentioned container body (other than the above-mentioned closing member), the solid agent is preferably a lyophilized product. This is because it can prevent the inactivation of the agent.

[0102] Similarly, when the above-mentioned auxiliary agent is a solid auxiliary agent, the solid auxiliary agent may be a lyophilized product or a solid preparation. However, when the auxiliary agent is held by the above-mentioned closing member, the solid auxiliary agent is preferably a solid preparation. This is because it is easier to hold the auxiliary agent on the closing member. On the other hand, when the auxiliary agent is present in the above-mentioned container body (other than the above-mentioned closing member), the solid auxiliary agent may be either a solid preparation or a lyophilized product.

[0103] When the above-mentioned auxiliary agent is a solid auxiliary agent containing a buffer as an auxiliary component, the amount of the buffer contained in the solid auxiliary agent is preferably such that the molar concentration of the buffer when mixed with a predetermined aqueous solvent is within the range described in the section of "2. Auxiliary agent" above. As the content of the buffer in the solid preparation, it can be 0.01 w / w% or more, 0.05 w / w% or more, 0.1 w / w% or more, 1 w / w% or more in terms of mass concentration (w / w%). Also, the above content can be 50 w / w% or less, 20 w / w% or less, 10 w / w% or less, 5 w / w% or less, 1 w / w% or less in terms of mass concentration (w / w%).

[0104] B. Closing member The closing member in the present invention is a member that closes the opening of the above-mentioned container body. Here, "closing the opening of the container body" means closing the opening of the container body and preventing the entry of other materials (solids) from the opening of the container body by the closing member. In the state where the opening of the container body is closed, the closing member may or may not seal the container body, but it is preferably sealed. "Sealing" means that there is no leakage of the agent and the auxiliary agent in the container body, and there is substantially no gas permeation.

[0105] The above-mentioned closing member may be integrally connected to the container body or may be a separate body separated from the container body.

[0106] The above-mentioned closing member is not particularly limited as long as it can close the opening of the container body, and can be appropriately selected according to the type of the container body and the form of the opening. Examples of the above-mentioned closing member include a lid, a pot lid, a cap, a stopper, a composite of these, etc. Examples of the cap include a screw cap, a hinge cap, etc. Examples of the stopper include a plug-in type stopper, a covering type stopper, etc.

[0107] The above-mentioned closing member is not particularly limited as long as it has a shape capable of closing the opening of the container body. For example, the opening side of the closing member may be flat, and as illustrated in FIGS. 4(a) to (e), it can have a top plate portion 2a and a convex portion T located at a position overlapping the opening O on the surface of the top plate portion 2a on the side of the closing member 1 in plan view. When the opening of the container body is closed with the above-mentioned closing member, the convex portion is inserted into the opening and located inside the container body, and the solid preparation can be held on the surface of the convex portion (FIG. 4(a)), or the solid preparation can be held between the convex portion and the inner wall of the container body (FIG. 4(b)). As illustrated in FIG. 4(c), when the closing member 2 has two or more convex portions T, the solid preparation may be sandwiched by the two or more convex portions T. Further, as illustrated in FIG. 4(d), the convex portion T may have a protruding portion 2d protruding in a direction intersecting the direction of insertion into the opening. If the solid preparation is a perforated tablet, the solid preparation can be hooked and held by passing the protruding portion through the hole of the solid preparation. Furthermore, as illustrated in FIG. 4(e), the convex portion T may have a concave portion P on the side surface or on a surface intersecting the insertion direction. This is because the solid preparation can be held in the concave portion.

[0108] Also, as illustrated in FIG. 5, the above-mentioned closing member may have a top plate portion 2a and a concave portion P located at a position overlapping the opening O on the surface of the top plate portion 2a on the side of the closing member 1 in plan view. This is because the solid preparation can be held in the concave portion. The concave portion preferably exists on a surface intersecting the opening central axis of the opening of the container body.

[0109] It is preferable that the closing member can be fitted into the opening of the container body. This is because when the closing member is fitted inside or outside the opening of the container body, the drug and the adjuvant can be stored in a sealed state. Among the closing members, a closing member that can be fitted to the opening of the container body may be particularly referred to as a sealing member. That the closing member can be fitted to the opening of the container body means that the closing member may be fitted inside the opening of the container body or may be fitted outside.

[0110] Examples of the closing member that can be fitted inside the opening of the container body include those having a plug portion that fits inside the opening of the container body. Examples of the closing member that can be fitted outside the opening of the container body include those having a top plate portion and a rib formed on the surface of the top plate portion on the side of the closing member 1 and fitting with the peripheral edge of the opening of the container body, and those having a top plate portion and a cylindrical peripheral wall portion that hangs down from the peripheral edge of the top plate portion and fits outside the opening.

[0111] Among them, it is preferable that the closing member has a plug portion that fits inside the opening of the container body. The closing member 2 in FIGS. 1(a), (b) and FIGS. 2(a), (b) has a plug portion (2b in FIGS. 1 and 2) that fits inside the opening O of the container body 1.

[0112] When the closing member has a plug portion, as shown in FIGS. 2(a), (b), the closing member 2 may have a top plate portion 2a and a plug portion 2b on the surface of the top plate portion 2a on the side of the closing member 2, or as shown in FIG. 3, the entire closing member 2 may be the plug portion 2b.

[0113] The planar shape of the above-mentioned plug portion is not particularly limited as long as it can be fitted into the above-mentioned opening of the container body, and for example, it can be circular, square, or the like. In FIG. 2, a plug portion having a circular planar shape is shown. Further, the longitudinal sectional shape of the above-mentioned plug portion in the insertion direction is not particularly limited, and examples thereof include a triangular shape, a square shape, a tapered shape, and the like. Further, the tip of the plug portion may have a pointed shape, a flat shape, or a shape having a curved surface.

[0114] The height (vertical length in the insertion direction) of the above-mentioned plug portion is appropriately designed so as to be fitted into the above-mentioned opening of the container body and be capable of being sealed. Among them, it is preferably a height having a temporary plug portion that enables temporary fitting when being fitted into the above-mentioned opening.

[0115] The above-mentioned plug portion can have a recess for fitting a solid agent containing a drug or an adjuvant. The position of the recess P is not particularly limited, and for example, as illustrated in FIG. 6, it can be provided on the side surface of the plug portion 2b. In this case, a solid agent can be fitted into the above-mentioned recess to hold the solid agent between the plug portion and the inner wall of the container body. Further, as shown in FIGS. 2(a) and (b), the above-mentioned plug portion can have a recess P on a surface intersecting the insertion direction Y. When the above-mentioned plug portion has a recess on a surface intersecting the insertion direction, the recess is formed such that the above-mentioned insertion direction is the depth direction of the recess. By the above-mentioned plug portion having the above-mentioned structure, for example, a solid agent containing a drug or an adjuvant can be fitted and held in the above-mentioned recess.

[0116] The above-mentioned recess preferably has a shape capable of holding the above-mentioned solid agent. When the above-mentioned plug portion has a recess P on a surface intersecting the insertion direction Y, the planar shape of the above-mentioned recess is not particularly limited, and examples thereof include a linear shape (FIG. 7(a)), a circular shape (FIG. 7(b)), polygons such as a triangle and a square (FIGS. 7(c) and (d)), and the like.

[0117] When the plug portion has a concave portion on a surface intersecting the insertion direction, it is preferable that the concave portion has a depth such that a part thereof can be exposed from the opening portion of the container body when the plug portion is temporarily fitted into the opening portion of the container body. At this time, it is more preferable that a part of the concave portion penetrates the side surface of the plug portion. In the manufacturing process of the drug storage container of the present invention, in a state where the opening portion of the container body is temporarily fitted with the closing member, when freeze-drying a liquid substance that is separated from the solid agent held by the closing member in the container body (inside the closed space), the concave portion can function as a degassing path for the air in the container body, and thus the liquid substance can be freeze-dried with high efficiency.

[0118] Examples of the shape of the concave portion penetrating the side surface of the plug portion include, for example, as shown in FIG. 7(a), the planar shape of the concave portion is linear, and both ends in the longitudinal direction of the linear concave portion penetrate the side surface of the plug portion; as shown in FIG. 7(d), the planar shape of the concave portion is quadrangular, and the four corners of the quadrangular concave portion penetrate the side surface of the plug portion, and the like.

[0119] As illustrated in FIG. 8(a), the plug portion can further have one or more convex portions T on a surface intersecting the insertion direction Y. When having two or more convex portions T, the solid agent can be sandwiched by the two or more convex portions T. Further, the convex portion may have a protruding portion t protruding in a direction intersecting the insertion direction at the end on the side opposite to the plug portion. If the solid agent is a perforated tablet, as illustrated in FIG. 8(a), the protruding portion t can be hooked and held through the hole of the solid agent 12. FIG. 8(b) shows an example in which the closing member 2 has two convex portions T on a surface intersecting the insertion direction Y of the plug portion 2b, one of the convex portions T further has a protruding portion t, and the solid agent 12 is held by the two convex portions T.

[0120] The material of the closure member is not particularly limited as long as it is a material capable of closing the opening of the container body, and can be appropriately selected according to the shape of the closure member, the shape of the opening of the container body, etc. Examples of the material of the closure member include metals such as aluminum, resins, rubber, etc. Furthermore, when the closure member has a plug portion, the material of the plug portion is preferably an elastic body such as resin or rubber. This is because it is possible to maintain a state of fitting with the opening of the container body and to increase the airtightness in the closed space.

[0121] The closing member may be used as it is in the state of the processed material, or may be used after being treated by coating or the like, because this makes it possible to more reliably retain and release the solid agent from the closing member.

[0122] The closure member is preferably penetrable by a hollow needle such as a syringe needle, although this depends on the material of the closure member. This is because it is possible to introduce the aqueous solvent into the container body using a syringe or the like without opening and closing the closure member, and it is possible to prevent impurities from being mixed into the container body due to opening and closing of the closure member. In addition, when a solid agent is releasably held in the closure member, particularly when the solid agent is physically releasably held, the hollow needle that penetrates the closure member when introducing the aqueous solvent can press the solid agent held in the closure member to remove it from the closure member.

[0123] When the closure member has the stopper portion, by penetrating a hollow needle at a position that overlaps in a planar view with the recess of the stopper portion, as shown in Figure 9, for example, the auxiliary agent 12 (in Figure 9, a solid agent containing auxiliary agent 12) held in the recess P of the stopper portion 2b can be pressed when the aqueous solvent is introduced, thereby removing the auxiliary agent 12 from the recess P, and the auxiliary agent 12 can be efficiently mixed into the aqueous solvent together with the drug (not shown) that is present separately in the container body 1.

[0124] The above-mentioned closing member may have an area (puncture area) through which a hollow needle can penetrate in part. Even if the closing member is made of a material that is difficult for the hollow needle to penetrate, since the hollow needle can penetrate in the above-mentioned puncture area, it is possible to introduce an aqueous solvent without opening and closing the closing member. Further, when a solid agent is detachably held on the above-mentioned closing member, especially when the solid agent is physically detachably held, the solid agent held on the closing member can be pressed by the hollow needle that has penetrated the above-mentioned puncture area during the introduction of the aqueous solvent and detached from the above-mentioned closing member. As the closing member having a puncture area, for example, as shown in FIG. 10, a structure having a puncture area 2c formed of rubber, resin, or the like and a casing part 2d formed of metal that surrounds the puncture area 2c can be mentioned.

[0125] When the above-mentioned closing member has a plug part, it is preferable that the above-mentioned puncture area is located at a position overlapping with the recess provided in the above-mentioned plug part in a plan view. This is because the solid agent held in the above-mentioned recess can be pressed by the hollow needle that has penetrated the above-mentioned puncture area during the introduction of the aqueous solvent and detached from the above-mentioned closing member.

[0126] C. Container body The container body in the present invention has an opening at one end.

[0127] The above-mentioned container body is not particularly limited as long as it has at least one opening, and it may have a shape with two or more openings. Further, the above-mentioned container body is not particularly limited as long as it has an opening at at least one end. For example, it may have a shape having another opening (second opening) at a position different from the opening (first opening) at the above-mentioned one end.

[0128] Specific examples of the shape of the above-mentioned container body include a cylindrical shape, a cup shape, a bag shape, and the like. Specific examples of the above-mentioned container body having such a shape include a vial, a syringe, an infusion bag, and the like.

[0129] When the container body has two or more openings, each opening is closed by a closing member. When the container body has two or more openings, among the plurality of closing members for closing the openings, it is sufficient that one or two or more closing members hold a drug or an adjuvant. When the container body has two or more closing members, the same drug or adjuvant may be held in each of the two or more closing members, or different drugs or adjuvants may be held for each closing member. Further, when the container body has two or more closing members, each of the two or more closing members may have the same form or different forms.

[0130] The material of the container body is not particularly limited, and examples thereof include metal, resin, and glass. Among them, glass is preferable from the viewpoint of high gas barrier properties.

[0131] The container body may be transparent, translucent, or opaque, but is preferably transparent or translucent because the contents of the container body can be easily visually recognized.

[0132] The inside of the container body may be pressurized or depressurized. The degree of pressurization or depressurization can be appropriately adjusted according to the type and amount of the drug or adjuvant present in the container body, the purpose of use of the container body, and the like. Further, the gas inside the container body may be air, but may be replaced with nitrogen. This is because deterioration of the drug and adjuvant inside the container body can be prevented.

[0133] D. Others In the drug storage container of the present invention, the drug and the adjuvant are separated and present in the closed space formed by closing the opening of the container body with the closing member. In the drug storage container of the present invention, it is preferable that the drug and the adjuvant are enclosed in the container body (that is, in the closed space) in which the container body is sealed by the closing member. Note that "sealing" is as described above.

[0134] The modes in which the drug and the auxiliary agent are separately present are not particularly limited. For example, the above drug and the above auxiliary agent are separately held in the container body, or one of the above drug or the above auxiliary agent is detachably held by the closing member, etc. can be mentioned. As the mode in which the above drug and the above auxiliary agent are separately held in the container body, for example, one of the above drug or the above auxiliary agent may be held on the wall surface inside the container body, and the other may be held at another position on the wall surface inside the container body, or may not be held on the wall surface. Also, as the mode in which one of the above drug or the above auxiliary agent is detachably held by the closing member, for example, one of the above drug or the above auxiliary agent is detachably held by the closing member, and the other may be present inside the container body other than the closing member. "Detachable" will be described later.

[0135] Of the above drug and the above auxiliary agent, the other substance not held on the closing member or the wall surface inside the container body may be present in a liquid state (liquid), a solid state, or a state in which the liquid (liquid) is frozen. From the viewpoint of long-term storage, it is preferable that there is no moisture in the closed space, and a solid state is preferable. Also, when used as a mode of storing the container body in a frozen state, the other substance may be present in a liquid state or a solid state. The other substance in a solid state may or may not be held at a desired position inside the container body.

[0136] Among them, the mode in which the above drug or the above auxiliary agent is detachably held by the closing member is preferable. By adopting such a mode, it becomes easy to separate and present the above drug and the above auxiliary agent in the closed space, and by detaching the above drug or the above auxiliary agent held by the closing member, the preparation of the mixed solution can be easily performed.

[0137] Here, "detachable" means that the substance held by the closing member may be physically detachable by receiving a force or the like, or the substance held by the closing member may be chemically detachable due to a reaction such as dissolution by contact with another substance. Physically detachable means, for example, when a hollow needle such as an injection needle penetrates the closing member and a substance such as a tablet can be detached by the pushing force of the hollow needle, or when the drug container is centrifuged or the drug container is shaken by snapping the wrist, a substance such as a tablet can be detached. Also, chemically detachable means, for example, when the drug container is inverted and stirred or shaken up and down, and as a result of a reaction such as dissolution by contact with the aqueous solvent in the container body, a substance such as a tablet can be detached.

[0138] The drug or the adjuvant detachably held by the closing member is preferably in a solid state, and among them, a solid preparation is more preferably used. This is because using a solid preparation makes it easy to hold the drug or the adjuvant on the closing member and to detach it from the closing member. At this time, the solid preparation preferably has a tablet dosage form. Among the drug and the adjuvant, it is more preferable that the adjuvant is held by the closing member.

[0139] The drug or the adjuvant may be held on the surface of the closing member located on the opening side among the surfaces of the closing member when the opening of the container body is closed by the closing member. The mode of holding the drug or the adjuvant in the closing member is not particularly limited as long as it is a mode that allows detachment from the closing member, and can be appropriately selected according to the dosage form of the drug or the adjuvant and the shape of the closing member.

[0140] As a mode of holding a drug or an adjuvant in a drug storage container in which an opening is closed by a closing member, for example, in one aspect, the closing member has a convex portion inserted inside the opening of the container body, and the drug or the adjuvant may be held on the convex portion of the closing member. Further, in one aspect, the closing member has a concave portion inside the container body (inside the closed space), and the drug or the adjuvant may be held in the concave portion of the closing member.

[0141] Although not particularly limited as a specific mode of holding a drug or an adjuvant at a convex portion or a concave portion, for example, a mode of attaching to the surface of the convex portion or the concave portion of the closing member via an adhesive substance, a mode of sandwiching a solid preparation containing a drug or an adjuvant by two or more convex portions of the closing member, a mode of fitting a solid preparation containing a drug or an adjuvant into the concave portion of the closing member, etc. may be mentioned. At this time, it is preferable that the drug or the adjuvant exists on a plane intersecting the central axis of the opening of the container body.

[0142] When the convex portion further has a protruding portion, as illustrated in FIG. 4(d), for example, a perforated tablet of the adjuvant 12 can be held on the protruding portion t. Further, as illustrated in FIG. 8(b), for example, a solid preparation of the adjuvant 12 can be sandwiched between the protruding portion t of one convex portion T and the other convex portion T. Further, the closing member may have the concave portion on the convex portion, and the drug or the adjuvant may be held in the concave portion. This is because the state in which the solid preparation is held can be easily maintained in the closing member. The concave portion of the closing member preferably exists on a plane intersecting the central axis of the opening of the container body when the container body is closed by the closing member.

[0143] In addition, when the closing member has a plug portion that fits into the opening of the container body, the holding mode of the drug or adjuvant in the drug storage container with the opening closed by the closing member is not particularly limited as long as it can be detached from the closing member. For example, the drug or the adjuvant may be held on a surface intersecting the insertion direction of the plug portion of the closing member, or may be held on the side surface of the plug portion. At this time, the drug or the adjuvant may be fitted and held in a recess provided on a surface or side surface intersecting the insertion direction of the plug portion. Among them, it is preferable that the plug portion of the closing member has a recess on a surface intersecting the insertion direction, and the drug or the adjuvant is detachably held in the recess of the plug portion. This is because it facilitates detachment from the closing member.

[0144] As a preferable mode in which the drug and the adjuvant are separated and present, the closing member has a plug portion that fits into the opening of the container body, the plug portion has a recess on a surface intersecting the insertion direction, the lyophilized product of the drug is present on the inner wall or bottom surface of the container body, and a solid agent (solid adjuvant) containing the adjuvant is detachably held in the recess of the plug portion. The above mode is preferable in that it prevents the mixing of the drug and the adjuvant and the inactivation of the drug, and further facilitates the detachment of the solid agent (solid adjuvant) containing the adjuvant.

[0145] E. Mixed solution The mixed solution obtained by the present invention can be, for example, a reagent solution for microbial contamination inspection (reagent solution), a sample for measurement, or a pharmaceutical such as a biological preparation, depending on the types of the drug, the adjuvant, and the aqueous solvent introduced into the container body.

[0146] The mixed solution obtained by the present invention can be prepared by performing an operation of coexisting the above-mentioned drug and the above-mentioned adjuvant in an aqueous solvent in the container body (in a closed space). Here, "coexist" means that the objects are in a state where they can come into contact with each other. The method of coexisting the above-mentioned drug and the above-mentioned adjuvant in an aqueous solvent is not particularly limited. For example, when using a drug solution, a method of performing an operation of detaching a solid adjuvant held by a closing member and adding it to the drug solution in the container body can be mentioned. Further, when using a solid drug and a solid adjuvant, a method of performing an operation of directly introducing an aqueous solvent to be mixed with the solid drug and the solid adjuvant into the container body from the opening of the container body or indirectly through a closing member can be mentioned. Since the above-mentioned aqueous solvent is the same as the content described in the section of "A. Drug and Adjuvant 2. Adjuvant", the description here is omitted.

[0147] In addition, the mixed solution obtained by the present invention can also be used as a measurement sample containing a drug, an adjuvant, and a test subject by further introducing a test subject into a reagent solution prepared by mixing the drug and the adjuvant.

[0148] F. Use and Method of Use The drug storage container of the present invention can be used for preparing a mixed solution containing a drug and an adjuvant. The use and method of use of the drug storage container of the present invention will be described.

[0149] 1. Use for Microbial Contaminant Inspection The drug storage container of the present invention can be used for preparing a reagent solution for microbial contaminant inspection (reagent solution) or a measurement sample. The drug storage container of the present invention can, for example, prepare a measurement sample by introducing a test subject into the drug storage container containing the reagent solution after preparing the reagent solution. Further, the drug storage container of the present invention can, for example, directly prepare a measurement sample without performing the operation of preparing a reagent solution by introducing only the test subject into the drug storage container. The inspection of microbial contaminants can be carried out using the above-mentioned measurement sample. That is, the drug storage container of the present invention can also be used as a container for microbial contaminant inspection.

[0150] FIG. 11 is a schematic diagram showing an example of a method of using the drug container of the present invention, and shows an example of a method for preparing a reagent solution for microbial contamination inspection and a method for inspecting microbial contamination using the same. First, as shown in FIG. 11(a), an aqueous solvent 13 is introduced into the container body 1 of the drug container 10 of the present invention. In FIG. 11(a), a hollow needle 31 such as an injection needle is passed through the closing member 2, and the aqueous solvent 13 is introduced into the container body 1 from the hollow needle 31. The drug 11 and the adjuvant 12 in the container body 1 are mixed with the aqueous solvent 13 to prepare a mixed solution (reagent solution) 20. When mixing the drug 11, the adjuvant 12 and the aqueous solvent 13, it is preferable to perform shaking or stirring using a stirrer or the like.

[0151] Next, as shown in FIG. 11(b), a test specimen 21 is introduced into the container body 1 of the drug container 10 and mixed with the mixed solution (reagent solution) 20 to prepare a measurement sample containing the drug, the adjuvant, and the test specimen. The amount of microbial contaminants in the test specimen can be calculated, for example, by measuring turbidity, color development by a chromogenic group, or fluorescence by a fluorescent group using an optical detector. Specifically, for example, the amount of coagulin generated from coagulogen by cleavage with an activated Limulus factor or the amount of a chromogenic group released from a detection substrate is measured by absorbance or transmittance, or the amount of a fluorescent group released from a detection substrate is measured by fluorescence intensity, thereby determining the presence or absence of microbial contaminants or calculating the amount of microbial contaminants.

[0152] In the example shown in FIG. 11, after preparing a reagent solution containing the drug 11 and the adjuvant 12, a test specimen is introduced to prepare a measurement sample. However, it is also possible to directly prepare a measurement sample without preparing a reagent solution by introducing a liquid test specimen without introducing the aqueous solvent 13. The above-described embodiment in which the preparation of the measurement sample is completed by introducing only the liquid test specimen can be used as a preferred embodiment for microbial contamination inspection in the present invention. This is because the measurement of microbial contaminants can be performed simply and reliably.

[0153] 2. Use for pharmaceutical preparation The drug storage container of the present invention can be used for the preparation of pharmaceuticals such as biological preparations. Further, the drug storage container of the present invention can also be used as an injector or syringe for enemas, etc., for example, by attaching a nozzle or injection needle to one end of the drug storage container after the preparation of pharmaceuticals such as biological preparations. When using the drug storage container as a syringe, it is preferable to attach a plunger rod or the like to the other end and use it.

[0154] 3. Others The drug storage container of the present invention may be provided singly according to the use, or may be provided as a kit including the same. The kit can have other articles as components according to its use. For example, if the use is for the inspection of microbial contaminants, the kit may have, as components, distilled water, an injection needle, a syringe, a standard product of microbial contaminants, an attached document with product information, etc., in addition to the drug storage container of the present invention.

[0155] II. Closing member The closing member of the present invention is a closing member used for the above-mentioned drug storage container, and is characterized by detachably holding the solid agent containing the above-mentioned drug or the above-mentioned auxiliary agent.

[0156] According to the closing member of the present invention, when the closing member of the present invention is used for the above-mentioned drug storage container, even when there are other substances in the container body for which premixing is contraindicated or not preferable, at the stage before the preparation of the mixed solution, they can be individually separated and present in the container body. Further, since the closing member detachably holds the solid agent, by detaching the solid agent and introducing an aqueous solvent as necessary, it becomes possible to prepare a mixed solution with another substance present in the main body container at the time of use, and it is possible to easily prepare a mixed solution containing a drug or auxiliary agent with poor storage stability in an aqueous solvent.

[0157] The closing member of the present invention can have, for example, the structure described in the section of "I. Drug storage container B. Closing member" above. The closing member of the present invention is used as a member for closing the opening of a container body having an opening at one end. In the present invention, for example, a solid preparation is detachably held by the closing member. Since the details of the closing member of the present invention have been described in the section of "I. Drug storage container B. Closing member" above, the description here is omitted.

[0158] In the present invention, the solid preparation contains a drug or an adjuvant. Since the details of the drug and the adjuvant, as well as the dosage form of the solid preparation, have been described in the section of "I. Drug storage container A. Drug and adjuvant" above, the description here is omitted.

[0159] Further, the solid preparation is preferably a solid adjuvant containing a buffer as an adjuvant component, and contains the buffer in an amount such that the pH becomes neutral when mixed with a predetermined aqueous solvent. Since the reasons, specific pH ranges, amounts of the buffer, etc., the details of the buffer in the solid preparation have been described in the section of "I. Drug storage container A. Drug and adjuvant" above, the description here is omitted.

[0160] Since the holding mode of the solid preparation in the present invention has been described in the section of "I. Drug storage container D. Others" above, the description here is omitted.

[0161] III. Manufacturing method of drug storage container The manufacturing method of the drug storage container of the present invention is the method for manufacturing the above-mentioned drug storage container, and the following three modes can be cited. The manufacturing method of the drug storage container of the present invention will be described for each mode.

[0162] A. First mode The manufacturing method of the drug storage container in this mode is roughly classified into the first example and the second example shown below. The first example of the method for manufacturing the drug-containing container of this aspect includes an introduction step of introducing the drug from the opening of the container body, and a closing step of closing the container body with the closing member having the auxiliary agent held thereon, with the surface of the closing member holding the auxiliary agent facing the opening side of the container body. Further, the second example of the method for manufacturing the drug-containing container of this aspect includes an introduction step of introducing the auxiliary agent from the opening of the container body, and a closing step of closing the container body with the closing member having the drug held thereon, with the surface of the closing member holding the drug facing the opening side of the container body.

[0163] According to the first aspect of the method for manufacturing the drug-containing container of the present invention, it is possible to easily obtain a drug-containing container in which the drug and the auxiliary agent are separated and present inside the container body (inside the closed space) closed by the closing member.

[0164] Hereinafter, each step of the method for manufacturing the drug-containing container of this aspect will be described.

[0165] 1. Introduction step The introduction step in this aspect is a step of introducing the drug from the opening of the container body (first example), or a step of introducing the auxiliary agent from the opening of the container body (second example).

[0166] Since the container body used in this step has been described in the section of "I. Drug-containing container C. Container body", the description here is omitted.

[0167] The drug or the auxiliary agent introduced into the container body in this step may be in a solid state or a liquid state. In the first example of this step, the drug is preferably a solid drug, and more preferably a freeze-dried product. Also, in the second example of this step, the auxiliary agent may be a solid auxiliary agent or an auxiliary agent solution, but a solid auxiliary agent is preferred. The reason for this has been described above. Details of the drugs, adjuvants, and their dosage forms used in this process are described in the section "I. Drug Containers", so the description here is omitted.

[0168] In this process, the method of introducing the drug or adjuvant into the container body is not particularly limited and can be appropriately selected according to various conditions such as the dosage form of the drug or adjuvant. For example, if it is a drug solution or adjuvant solution, an injection method using a syringe or the like can be mentioned. Also, for example, if it is a solid drug or solid adjuvant, a charging method or the like can be mentioned.

[0169] 2. Closing process The closing process in this embodiment is a process of closing the container body with the surface of the closing member that holds the adjuvant facing the opening side of the container body with the adjuvant held by the closing member (first example), or closing the container body with the surface of the closing member that holds the drug facing the opening side of the container body with the drug held by the closing member (second example).

[0170] Regarding the closing member used in this process, since it is described in the section "I. Drug Containers B. Closing Member", the description here is omitted.

[0171] The adjuvant or drug held by the closing member may be in a shape that can exist separately from the drug or adjuvant introduced into the container body, preferably in a solid state, more preferably a solid preparation containing the drug or adjuvant, even more preferably a solid preparation containing the drug or adjuvant and a molding agent, and particularly preferably a tablet containing the adjuvant and the molding agent. Since the reason and the specific method of holding the adjuvant or drug on the closing member are described in the section "I. Drug Containers", the description here is omitted. Regarding the drugs, adjuvants, and solid preparations containing the drugs or adjuvants used in this process, since they are described in the section "I. Drug Containers", the description here is omitted.

[0172] In this project, it is only necessary that the opening of the container body is closed by the above-mentioned closing member, and the container body may be sealed according to the shape of the above-mentioned closing member.

[0173] 3. Other processes In this aspect, in addition to the above-mentioned introduction process and the above-mentioned closing process, it may further have other processes. For example, in this aspect, after the above-mentioned closing process, it may further have a sealing process of sealing the container body. This is because the airtightness of the drug storage container can be enhanced by the above-mentioned sealing process, and the entry of impurities and the like into the container body can be prevented. The above-mentioned sealing process may be, for example, a process of sealing the container body by sealing the part where the opening of the container body and the closing member are in contact.

[0174] B. Second aspect The manufacturing method of the drug storage container of this aspect is roughly classified into the following first example and second example. The first example of the manufacturing method of the drug storage container of this aspect includes an introduction process of introducing the liquid drug from the opening of the container body, and a closing process of closing the container body with the surface of the closing member that holds the auxiliary agent facing the opening side of the container body while the closing member holds the auxiliary agent. It is characterized by having a drying process of freeze-drying and solidifying the liquid drug in the container body. Also, the second example of the manufacturing method of the drug storage container of this aspect includes an introduction process of introducing the liquid auxiliary agent from the opening of the container body, and a closing process of closing the container body with the surface of the closing member that holds the drug facing the opening side of the container body while the closing member holds the drug. It is characterized by having a drying process of freeze-drying and solidifying the liquid auxiliary agent in the container body.

[0175] According to the second aspect of the method for manufacturing a drug-containing container of the present invention, in a state where the opening of the container body is closed with a closing member holding a drug or an adjuvant, the liquid adjuvant or drug in the container body is freeze-dried and solidified, so that mixing of the adjuvant and the drug can be surely prevented. Thereby, a drug-containing container in which the drug and the adjuvant are separated and present can be easily obtained. Further, by performing freeze-drying by the above method, it is possible to prevent a decrease in the storage stability of the drug before preparing the mixed solution.

[0176] Hereinafter, each step of the method for manufacturing a drug-containing container of this aspect will be described.

[0177] 1. Introduction step The introduction step in this aspect is a step of introducing the liquid drug from the opening of the container body (first example) or introducing the liquid adjuvant from the opening of the container body (second example). Regarding the details of this step, it can be the same as the introduction step in the above-mentioned "A. First Aspect" except that the drug is a drug solution or the adjuvant is an adjuvant solution.

[0178] 2. Closing step The closing step in this aspect is a step of closing the container body with the surface of the closing member holding the adjuvant facing the opening side of the container body in a state where the closing member holds the adjuvant (first example), or closing the container body with the surface of the closing member holding the drug facing the opening side of the container body in a state where the closing member holds the drug (second example).

[0179] Regarding the details of this step, it can be the same as the closing step in the above-mentioned "A. First Aspect". In this aspect, since degassing from the inside of the container body is required in the drying step described later, it is preferable that the container body is not sealed by the closing member.

[0180] 3. Drying step In this embodiment, the drying step is a step of freeze-drying and solidifying the liquid drug in the container body (Example 1), or a step of freeze-drying and solidifying the liquid auxiliary agent in the container body (Example 2).

[0181] In this step, the method of freeze-drying the drug solution or auxiliary agent solution in the container body is not particularly limited and can be the same as a general freeze-drying method. For example, after freezing the drug solution or auxiliary agent solution in the container body with liquid nitrogen or the like, the drug or auxiliary agent can be dried and solidified by vaporizing and removing the aqueous solvent under non-heating and reduced pressure conditions using a freeze-dryer. The freeze-drying conditions and the like only need to be conditions under which the aqueous solvent contained in the drug solution or auxiliary agent solution can be sufficiently vaporized, and can be appropriately set according to the type of the aqueous solvent.

[0182] 4. Other steps In this embodiment, in addition to the introduction step, the closing step, and the drying step, other steps may further be included. For example, in this embodiment, after the drying step, a closing step of closing the container body may further be included. The details of the sealing step can be the same as the details described in the section of "A. First Embodiment 4. Other steps" above.

[0183] C. Third Embodiment The method for manufacturing the drug-containing container of this embodiment is roughly classified into Example 1 and Example 2 shown below. Example 1 of the method for manufacturing the drug-containing container of this embodiment includes an introduction step of introducing the liquid drug from the opening of the container body, and a closing step of temporarily fitting the plug portion of the closing member to the opening of the container body in a state where the auxiliary agent is held on the plug portion of the closing member to close the container body, and a drying step of freeze-drying and solidifying the liquid drug in the container body in a temporarily fitted state. Further, a second example of the method for manufacturing the drug-containing container of this aspect includes an introduction step of introducing the liquid auxiliary agent from the opening of the container body, and in a state where the drug is held on the plug portion of the closing member, temporarily fitting the plug portion of the closing member into the opening of the container body to close the container body, and a drying step of freeze-drying and solidifying the liquid auxiliary agent in the container body in a temporarily fitted state. It is characterized by having these steps.

[0184] FIG. 12 is a process diagram showing an example of the method for manufacturing the drug-containing container of this aspect, and specifically illustrates the first example. First, a drug solution 11a is introduced from the opening O of the container body 1 (FIG. 12(a), introduction step). Next, with the solid agent containing the auxiliary agent 12 held on the plug portion 2b of the closing member 2, the plug portion 2b of the closing member 2 is temporarily fitted into the opening O of the container body 1 to close the container body 1 (the left diagram in FIG. 12(b), closing step). Subsequently, the drug solution 11a in the container body 1 is freeze-dried and solidified in a temporarily fitted state (the right diagram in FIG. 12(b), drying step). After that, the plug portion 2b of the closing member 2 is inserted into the opening O of the container body 1 to seal the container body 1 (FIG. 12(c), sealing step). The drug-containing container 10 illustrated in FIG. 1 is obtained, for example, through the above operations shown in FIGS. 12(a) to (c). For the reference numerals not described in FIG. 12, they are the same as the reference numerals described in FIGS. 1 to 11.

[0185] According to the third aspect of the method for manufacturing the drug-containing container of the present invention, the drug or the auxiliary agent is held on the plug portion of the closing member. With the opening of the container body temporarily fitted with the plug portion, the liquid auxiliary agent or the drug in the container body is freeze-dried and solidified, so that the mixing of the auxiliary agent and the drug can be reliably prevented. As a result, a drug-containing container in which the drug and the auxiliary agent are separated can be easily obtained. Further, by performing freeze-drying by the above method, a decrease in the storage stability of the drug before preparing the mixed solution can be prevented. Furthermore, since the opening of the container body is temporarily fitted by the plug portion in the drying step, air in the container body can be easily degassed from the gap at the temporarily fitted position, and freeze-drying can be efficiently performed, and at the same time, the entry of impurities from the outside can be prevented.

[0186] The following describes each step of the method for manufacturing the drug container of this embodiment.

[0187] 1. Introduction Step The introduction step in this embodiment is a step of introducing the liquid drug from the opening of the container body (First Example), or introducing the liquid auxiliary agent from the opening of the container body (Second Example). Regarding the details of this step, it can be the same as the introduction step in the above-mentioned "B. Second Embodiment".

[0188] 2. Closing Step The closing step in this embodiment is a step of temporarily fitting the plug portion of the closing member to the opening of the container body with the auxiliary agent held on the plug portion of the closing member to close the container body (First Example), or temporarily fitting the plug portion of the closing member to the opening of the container body with the drug held on the plug portion of the closing member to close the container body (Second Example).

[0189] In this step, "temporarily fitting the plug portion of the closing member to the opening of the container body" means that a part of the plug portion closes the opening of the container body, but the inside of the container body is not sealed and air can enter and exit the inside of the container body.

[0190] Regarding the details of this step, it can be the same as the closing step in the above-mentioned "B. Second Embodiment".

[0191] The above-mentioned closing member used in this project has a plug portion that fits into the opening of the above-mentioned container body. The plug portion preferably has the above-mentioned recess on a plane intersecting the insertion direction. Among them, it is preferable that when the recess is temporarily fitted into the opening of the container body in the above-mentioned drying process, a part of it has a depth that can be exposed from the opening of the container body. When freeze-drying the pharmaceutical solution or auxiliary agent solution in the container body in the temporarily fitted state by the above-mentioned closing member in the drying process described later, a part of the recess of the plug portion of the above-mentioned closing member is exposed from the opening of the container body, thereby functioning as a degassing path for air from the container body, and freeze-drying can be performed more efficiently. At this time, the method of holding the above-mentioned drug or the above-mentioned auxiliary agent on the closing member is not particularly limited. Among them, it is preferable that the above-mentioned drug or the above-mentioned auxiliary agent is held in the above-mentioned recess of the plug portion.

[0192] Details of the above-mentioned closing member and the method of holding the above-mentioned drug or the above-mentioned auxiliary agent on the closing member having a plug portion have been described in the section of "I. Pharmaceutical Containers", so the description here is omitted.

[0193] 3. Drying Process The drying process in this aspect is a process of freeze-drying and solidifying the above-mentioned liquid drug in the container body in a temporarily fitted state (Example 1), or freeze-drying and solidifying the above-mentioned liquid auxiliary agent in the container body in a temporarily fitted state (Example 2). Details of this process can be the same as those of the drying process in the above-mentioned "B. Second Aspect".

[0194] 4. Other Processes In this embodiment, in addition to the above-introduction step, the above-closure step, and the above-drying step, there may further be other steps. For example, in this embodiment, after the above-drying step, there may further be a sealing step of sealing the above container body. This is because the airtightness of the drug-containing container can be enhanced by the above-sealing step, and it is possible to prevent impurities and the like from entering the container body. The above-sealing step may be, for example, a step of inserting the above plug portion of the above-closure member into the above-opening of the above-container body to seal the above-container body.

[0195] IV. Method for inspecting microbial contaminants The method for inspecting microbial contaminants of the present invention is a method for inspecting microbial contaminants using the above-described drug-containing container, comprising: an introduction step of introducing a test specimen into the above container body of the above drug-containing container; and a preparation step of preparing a sample (measurement sample) for use in measuring microbial contaminants including the above drug, the above adjuvant, and the above test specimen; and a detection step of detecting the above microbial contaminants in the above sample.

[0196] According to the method for inspecting microbial contaminants of the present invention, by introducing a test specimen into the container body of the above-described drug-containing container, a measurement sample containing a drug, an adjuvant, and a test specimen can be prepared collectively in the above container body. That is, according to the present invention, the measurement sample can be easily prepared in a single step without the need for steps such as preparing and weighing an adjuvant solution, and introducing the above adjuvant solution into the container body containing the drug to prepare a reagent solution. Then, microbial contaminants can be detected using the drug-containing container in which the measurement sample has been prepared. Thus, the method for inspecting microbial contaminants of the present invention enables easy preparation of a measurement sample, and can simply and reliably measure the presence or absence and amount of microbial contaminants in the test specimen contained in the measurement sample, and can simply and reliably measure the degree of microbial contamination.

[0197] The effects of the present invention will be described in more detail. Usually, when detecting microbial contaminants, in the preparation process, in the preparation step, a necessary amount of buffer solution is weighed and introduced into the container body containing the drug and stirred to prepare a reagent solution (mixed solution), and the sample to be measured for use in the detection step of detecting microbial contaminants by introducing the test sample into the reagent solution in the container body and stirring is prepared. At least these operations are required. Thus, there has been a problem that the preparation process becomes complicated in the conventional method. In contrast, in the present invention, since the drug storage container in which the drug and the auxiliary agent are separated in advance in a sealed space is used, by only the operation of introducing the test sample into the drug storage container, a measurement sample containing the drug, the auxiliary agent, and the test sample can be prepared collectively in the drug storage container, and the preparation process can be simplified.

[0198] Hereinafter, each step in the method for inspecting microbial contaminants of the present invention will be described.

[0199] A. Preparation step The preparation step in the present invention is a step of introducing a test sample into the container body of the drug storage container to prepare a measurement sample.

[0200] Details of the drug storage container used in this step have been described in the section of "I. Drug storage container" above, so the description here is omitted. The drug storage container used in this step is preferably a solid auxiliary agent in which a solid auxiliary agent is detachably held by the closing member, and the solid auxiliary agent is a solid auxiliary agent containing a buffer agent in an amount such that the pH becomes neutral when mixed with the test sample as an auxiliary agent component. The reason and specific embodiments have been described in the section of "I. Drug storage container" above, so the description here is omitted.

[0201] The type and introduction amount of the test sample in this step are not particularly limited as long as it is possible to detect microbial contaminants in the test sample, and can be set as appropriate.

[0202] In the above preparation process, the subject is introduced into the container body of the drug-containing container directly or indirectly through a closing member from the opening of the container body. As a method for introducing the subject into the container body of the drug-containing container, for example, a method of removing the closing member from the drug-containing container and directly introducing the subject from the opening of the container body, a method of passing a hollow needle through the closing member that closes the opening of the container body, and indirectly introducing the subject from the opening of the container body through the hollow needle without removing the closing member, etc. can be mentioned. If a solid agent is held by the closing member, a method of passing a hollow needle through the closing member that closes the opening of the container body and introducing the subject through the hollow needle is preferable. This is because the solid agent can be detached from the closing member simultaneously with passing the hollow needle through the closing member.

[0203] In this process, in the drug-containing container, the introduced subject, as well as the drug and the auxiliary agent, are mixed, and a measurement sample is prepared.

[0204] This process is preferably carried out in the presence of an aqueous solvent. This is because the drug, the auxiliary agent, and the subject can be dissolved in the aqueous solvent and mixed. If at least one of the drug and the auxiliary agent is liquid, the subject may be solid or may be in a liquid state mixed with the aqueous solvent. On the other hand, if the drug and the auxiliary agent are solid, the subject is preferably a subject solution (liquid subject). This is because the aqueous solvent in the subject solution dissolves the drug and the auxiliary agent and enables them to be mixed with each other. Since the above aqueous solvent has been described in the section of "I. Drug-containing container A. Drug and auxiliary agent" above, the description here is omitted.

[0205] In this process, after introducing the subject, it is preferable to perform stirring by a test tube mixer, a shaker, a stirring device, etc. so that the drug, the auxiliary agent, and the subject are uniformly mixed in the container body.

[0206] B. Detection process The detection step in the present invention is a step of detecting the microbial contaminants in the above-mentioned specimen. Specifically, this step is a step of detecting the microbial contaminants contained in the measurement sample prepared in the above-mentioned preparation step as the microbial contaminants in the specimen.

[0207] The microbial contaminants are not particularly limited as long as they are substances derived from microorganisms, but are preferably endotoxin or (1→3)-β-D-glucan. This is because detection using Limulus reagent is possible.

[0208] The method for detecting microbial contaminants in a specimen is not particularly limited, and a method corresponding to the type of microbial contaminants can be used. When using Limulus reagent as a drug, examples of the detection method include optical measurement methods such as turbidimetry, colorimetry, and fluorescence method, electrochemical measurement methods, and gelation methods. Since the details of these various detection methods are the same as those in known Limulus tests, the description here is omitted.

[0209] The optical detector used in the optical measurement method of microbial contaminants can be appropriately selected according to the type of the optical measurement method and the like, and specifically, examples include fluorescence measuring instruments such as spectrophotometers and luminometers. Examples of the electrochemical measurement method of microbial contaminants include amperometry and voltammetry. When detecting microbial contaminants by the gelation method, the presence or absence of microbial contaminants can be determined by visually confirming the presence or absence of gel formation.

[0210] V. Solid Agent for Buffer Preparation The solid agent for buffer preparation of the present invention (hereinafter, may be referred to as the solid agent of the present invention) is a solid agent for buffer preparation containing at least a buffer and a molding agent, and is characterized in that it contains an amount of the buffer that makes the pH neutral when mixed with a predetermined aqueous solvent.

[0211] According to the solid preparation of the present invention, since the pH becomes neutral when mixed with a predetermined aqueous solvent, a buffer solution showing a predetermined pH can be easily prepared. Further, when preparing a mixed solution containing a drug and an adjuvant, and a sample using the above mixed solution, by using the solid preparation of the present invention, the pH of the mixed solution and the sample can be easily adjusted.

[0212] Specifically, when preparing a measurement sample used for the inspection of microbial contaminants, by mixing the solid preparation of the present invention with a predetermined aqueous solvent, a buffer solution with a neutral pH that does not require dilution can be obtained. By mixing the above buffer solution with a liquid or solid Limulus reagent (drug) as an adjuvant solution, a measurement sample with a neutral pH can be obtained. Further, by mixing the Limulus reagent and the solid preparation of the present invention together in an aqueous solvent, a measurement sample with a neutral pH can be obtained without preparing a buffer solution.

[0213] The solid preparation of the present invention contains the above buffer in an amount such that the pH becomes neutral when mixed with a predetermined aqueous solvent. Regarding the specific range of the pH that is neutral, since it is the same as the content described in the section of "I. Drug container", the description is omitted.

[0214] The content of the above buffer in the solid preparation of the present invention can be 0.01 w / w% or more, 0.05 w / w% or more, 0.1 w / w% or more, 1 w / w% or more in terms of mass concentration (w / w%). Further, the above content can be 50 w / w% or less, 20 w / w% or less, 10 w / w% or less, 5 w / w% or less, 1 w / w% or less in terms of mass concentration (w / w%). The mass concentration (w / w%) indicating the content of the above buffer in the solid preparation is the ratio (%) of the mass (g) of the buffer to the mass (g) of the entire solid preparation.

[0215] The content of the above-mentioned shaping agent in the solid preparation of the present invention can be, for example, 1 w / w% or more, 5 w / w% or more, 10 w / w% or more, 25 w / w% or more, or 50 w / w% or more in terms of mass concentration (w / w%). Also, the content of the above-mentioned shaping agent can be, for example, 99.9 w / w% or less, 99 w / w% or less, 95 w / w% or less, 90 w / w% or less, 80 w / w% or less, 70 w / w% or less, or 60 w / w% or less in terms of mass concentration (w / w%). Note that the mass concentration (w / w%) indicating the content of the above-mentioned shaping agent in the solid preparation is the ratio (%) of the mass (g) of the shaping agent to the mass (g) of the entire solid preparation.

[0216] As the final concentration of the above-mentioned buffer in the buffer solution obtained by mixing the solid preparation of the present invention with a predetermined aqueous solvent, it can be, for example, 1 mM or more, 5 mM or more, 10 mM or more, or 20 mM or more. The final concentration of the above-mentioned buffer can be, for example, 1 M or less, 500 mM or less, 250 mM or less, or 100 mM or less. Therefore, examples of the range of the final concentration of the above-mentioned buffer include within the range of 1 mM to 1 M, within the range of 1 mM to 500 mM, within the range of 1 mM to 250 mM, within the range of 1 mM to 100 mM, within the range of 5 mM to 500 mM, within the range of 5 mM to 250 mM, within the range of 5 mM to 100 mM, within the range of 10 mM to 500 mM, within the range of 10 mM to 250 mM, within the range of 10 mM to 100 mM, within the range of 20 mM to 250 mM, within the range of 20 mM to 100 mM, etc.

[0217] Details of the buffer, shaping agent, and aqueous solvent in the present invention are the same as those described in the section of "I. Drug-containing container", so the description here is omitted.

[0218] The solid preparation of the present invention preferably contains substantially no microbial contaminants. This is because the solid preparation of the present invention can be used as it is for the preparation of a mixed solution for administration to animals including humans and for the preparation of a sample for measuring microbial contaminants. "Substantially free of microbial contaminants" means that the amount of microbial contaminants (endotoxin, (1→3)-β-D-glucan) detected from the buffer solution obtained by mixing the solid preparation of the present invention with a predetermined aqueous solvent is less than the quantification limit value or the detection limit value.

[0219] The solid preparation of the present invention contains at least a buffering agent and a molding agent. The buffering agent only needs to be contained in an amount such that the pH becomes neutral when the solid preparation of the present invention is mixed with a predetermined aqueous solvent, and can contain any other optional components. Examples of the optional components include the materials of the drugs and auxiliaries described in the section of "I. Drug storage container A. Drugs and auxiliaries" described above.

[0220] Specifically, when the solid preparation of the present invention contains a predetermined amount of a buffering agent and a molding agent, and further contains at least one or more selected from a solubilizing agent, an isotonic agent, and an anesthetic agent, by mixing the solid preparation of the present invention with a predetermined aqueous solvent, a buffer solution with a neutral pH that does not require dilution can be obtained. By mixing the above buffer solution with a liquid or solid protein preparation (drug) as an auxiliary solution, a biological preparation with a neutral pH can be obtained. Further, by directly mixing the protein preparation and the solid preparation of the present invention in a batch into an aqueous solvent, a biological preparation with a neutral pH can be obtained without the need for preparing a buffer solution.

[0221] The dosage form of the solid preparation of the present invention is not particularly limited, and examples include tablets, pills, capsules, powders, granules, and the like. Among them, tablets, pills, and capsules are preferred, and tablets are particularly preferred. Tablets have high strength as a solid preparation, and it is easy to hold them in the above-described closing member of the present invention and maintain the holding state. If the solid preparation of the present invention is a tablet for preparing a buffer solution containing at least a buffering agent and a molding agent, it contains the buffering agent in an amount such that the pH becomes neutral when one tablet is mixed with a predetermined aqueous solvent.

[0222] The solid preparation of the present invention can be produced using a general method for producing solid preparations. For example, it can be produced by biaxially kneading 0.2 w / w% fine powder PBS into endotoxin-free (injection grade) mannitol under aseptic conditions, producing granules with a granulating device, and tableting. Finer PBS powder can be similarly produced by previously micronizing it with a jet mill and adding it equivalently. As a method for granulating more uniformly, a method such as dissolving PBS in endotoxin-free injection water and producing granules finely dispersed in mannitol using a spray drying type kneading / granulating device can be used. If the dosage form is a tablet, a direct tableting method, a granule compression method, etc. can be used.

[0223] The solid preparation of the present invention can adjust the pH to neutral without dilution when preparing a buffer solution. The amount of the aqueous solvent required for preparing the buffer solution using the solid preparation of the present invention can be an amount that does not require dilution and has a neutral pH when mixed with the solid preparation. Although it also depends on the amount of the buffer agent contained in the above solid preparation, for example, it may be 0.1 mL or more, or 0.2 mL or more. Also, the amount of the aqueous solvent mixed with the above solid preparation may be, for example, 1 L or less, 100 mL or less, 10 mL or less, 1 mL or less, or 0.5 mL or less. Therefore, examples of the range of the amount of the aqueous solvent mixed with the above solid preparation include within the range of 0.1 mL to 1 L, within the range of 0.1 mL to 100 mL, within the range of 0.1 mL to 10 mL, within the range of 0.1 mL to 1 mL, within the range of 0.2 mL to 1 mL, within the range of 0.2 mL to 0.5 mL, etc. For example, in the case of a lysate reagent, it can be within the range of 0.1 mL to 10 mL, and preferably within the range of 0.2 mL to 1 mL.

[0224] Note that the present disclosure is not limited to the above embodiments. The above embodiments are examples, and any structure that has a structure substantially the same as the technical idea described in the claims of the present invention and exhibits the same operational effects is included in the technical scope of the present invention. Also, all documents, patent applications, and technical standards described in this specification are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually indicated to be incorporated by reference.

Explanation of Signs

[0225] 1 … Container body 2 … Sealing member 2b … Plug portion 10 … Drug storage container 11 … Solid protein preparation 12 … Solid auxiliary 13 … Aqueous solvent 20 … Mixed solution 21 … Subject O … Opening P … Recess

Claims

1. A container body having an opening at one end, and a closing member for closing the opening of the container body, and it is a drug storage container in which a drug and an adjuvant are separated and present in the container body with the opening closed by the closing member, wherein the drug and the adjuvant are in a solid state, the container body is a vial, and the closing member is configured to seal the container body and allow a hollow needle to penetrate therethrough. A drug storage container.

2. The drug storage container according to claim 1, wherein the drug is a medicine.

3. The drug storage container according to claim 1 or claim 2, wherein the container body is made of glass.

4. The drug storage container according to any one of claims 1 to 3, wherein the drug is a lyophilized product disposed in the container body, and the adjuvant is a solid agent held by the closing member.

5. The drug storage container according to any one of claims 1 to 4, wherein the adjuvant contains at least one selected from a solubilizing agent, an isotonic agent, and a pain reliever as an adjuvant component.

6. The drug storage container according to claim 1, wherein the drug is a limulus reagent.

7. The drug storage container according to any one of claims 1 to 6, wherein the adjuvant contains a buffer as an adjuvant component.

8. The drug storage container according to claim 7, wherein the adjuvant contains an amount of the buffer such that the pH becomes neutral when mixed with a predetermined aqueous solvent.

9. The drug storage container according to any one of claims 1 to 8, wherein one of the drug and the adjuvant is detachably held by the closing member.

10. The drug storage container according to claim 9, wherein the closing member has a plug portion that fits into the opening of the container body, and one of the drug and the adjuvant is detachably held by the plug portion.

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