Albumin preparation, method for storing albumin preparation, and method for evaluating albumin preparation

Abstract

To provide an albumin preparation which is less likely to produce insoluble matter even when the volume is increased. A vial and an aqueous solution containing serum albumin sealed in the vial. wherein the vial has a body having an opening and a stopper that seals the opening, the inner surface of the body is subjected to an elution suppression treatment, and the surface of the stopper that comes into contact with an aqueous solution containing serum albumin is subjected to a laminate treatment.

Description

[Technical field]

[0001] The present disclosure relates to an albumin preparation, a method for storing an albumin preparation, and a method for evaluating an albumin preparation. [Background technology]

[0002] Serum albumin, a type of biopolymer, is a protein with a molecular weight of 66,000 Da and a molecule consisting of 585 amino acids. Serum albumin accounts for approximately 60% of plasma proteins in normal individuals and is the most abundant protein in the body. Serum albumin is formed in the liver.

[0003] Serum albumin is responsible for maintaining plasma oncotic pressure in blood and regulates circulating blood volume by retaining water (Non-Patent Document 1). Serum albumin can non-specifically bind to and transport various substances such as many drugs, fatty acids, and hormones.

[0004] Serum albumin has been formulated in the past. Formulated albumin preparations have been used to treat hypoalbuminemia or hemorrhagic shock caused by albumin loss due to burns, nephrotic syndrome, etc., or reduced albumin synthesis ability due to liver cirrhosis, etc. Such albumin preparations have been preserved, for example, by the preservation method described in Patent Document 1. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 4-210646 [Non-patent literature]

[0006] [Non-Patent Document 1] Tullis JL, JAMA, vol.237:355-360,1977 Summary of the Invention [Problem to be solved by the invention]

[0007] As albumin preparations, two types of preparations are manufactured: low-concentration isotonic albumin preparations and high-concentration hypertonic albumin preparations. Isotonic albumin preparations contain serum albumin at the same concentration as the plasma concentration of albumin, for example, 4.4 w / v% or 5 w / v%, while hypertonic albumin preparations contain serum albumin at a concentration of 20 w / v% or 25 w / v%. In particular, the administration of large amounts of hypertonic albumin preparations has been increasing, and studies are being conducted on albumin preparations with large volumes in order to reduce the need to exchange preparations during administration.

[0008] However, it has been found that when the volume of a hypertonic albumin preparation is increased, insoluble matter is generated in the albumin preparation (in the serum albumin-containing aqueous solution) during storage. As a result of intensive research, the present inventor has found an albumin preparation that can reduce this insoluble matter. That is, the present disclosure aims to provide an albumin preparation that is less likely to generate insoluble matter even when the volume is increased. In addition, the present disclosure aims to provide a method for storing an albumin preparation that is less likely to generate insoluble matter even when the volume is increased. Furthermore, the present disclosure provides an accelerated evaluation method for an albumin preparation. [Means for solving the problem]

[0009] This disclosure provides the following [1] to

[21] . [1] A vial and an aqueous solution containing serum albumin sealed in the vial. An albumin formulation comprising: The vial includes a body having an opening and a stopper for sealing the opening. having The inside of the body is treated to prevent leaching. The surface of the plug that comes into contact with the serum albumin-containing aqueous solution is laminated. Albumin preparations. [2] The albumin preparation according to [1], in which formation of insoluble matter in an aqueous solution containing serum albumin is suppressed. [3] The albumin preparation according to [1] or [2], wherein the entire surface of the plug which may come into contact with an aqueous solution containing serum albumin is laminated. [4] The albumin preparation according to any one of [1] to [3], wherein the lamination is carried out using a fluorine-based resin film. [5] The albumin preparation according to any one of [1] to [4], wherein the stopper contains butyl rubber or chlorinated butyl rubber. [6] The albumin preparation according to any one of [1] to [5], wherein the dissolution suppression treatment is at least one of a silicoat treatment and a sulfur treatment. [7] The albumin preparation according to [6], wherein the siliconizing treatment is a heat treatment using siliconizing gas. [8] The albumin preparation according to [6], wherein the sulfur treatment is a treatment using ammonium sulfate. [9] The albumin preparation according to any one of [1] to [8], wherein the concentration of the aqueous solution containing serum albumin is 20 to 25 w / v %.

[10] The albumin preparation according to any one of [1] to [9], wherein the amount of the albumin-containing aqueous solution is 75 mL or more.

[11] A method for preserving an aqueous solution containing serum albumin in a vial, comprising: The vial includes a body having an opening and a stopper for sealing the opening. having The inside of the body is treated to prevent leaching. The surface of the plug that comes into contact with the serum albumin-containing aqueous solution is laminated. How to save.

[12] The storage method according to

[11] , wherein the formation of insoluble matter in the aqueous solution containing serum albumin is suppressed.

[13] The method for preserving a serum albumin-containing aqueous solution according to

[11] or

[12] , wherein the entire surface of the stopper that may come into contact with the aqueous serum albumin-containing solution is laminated.

[14] The method for preservation according to any one of

[11] to

[13] , wherein the lamination is carried out using a fluorine-based resin film.

[15] The method for storage according to any one of

[11] to

[14] , wherein the stopper contains butyl rubber or chlorinated butyl rubber.

[16] The method for preservation according to any one of

[11] to

[15] , wherein the elution-suppressing treatment is at least one of a silicon coat treatment and a sulfur treatment.

[17] The preservation method according to

[16] , wherein the silicon coating treatment is a heat treatment using silicon coating gas.

[18] The preservation method according to

[16] , wherein the sulfur treatment is a treatment using ammonium sulfate.

[19] The method for preserving serum albumin according to any one of

[11] to

[18] , wherein the concentration of the aqueous solution containing serum albumin is 20 to 25 w / v %.

[20] The method for preserving serum albumin according to any one of

[11] to

[19] , wherein the amount of the aqueous solution containing serum albumin is 75 mL or more. [twenty one] A method for evaluating albumin preparations in which an albumin preparation containing an aqueous solution containing serum albumin is heated at 60°C for 1 to 2 weeks and the tendency for insoluble matter to form is evaluated. Effect of the Invention

[0010] According to the present disclosure, it is possible to provide an albumin preparation in which insoluble matter is unlikely to occur even when the volume is increased. In addition, according to the present disclosure, it is possible to provide a method for preserving an albumin preparation in which insoluble matter is unlikely to occur even when the volume is increased. Furthermore, according to the present disclosure, it is possible to provide a method for evaluating an albumin preparation with accelerated storage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In this specification, serum albumin may be abbreviated to "albumin."

[0012] In this specification, the term "insoluble matter" refers to a matter that can be visually confirmed in an albumin-containing aqueous solution. The insoluble matter has a shape such as a fiber or cotton-like shape. The insoluble matter is a modified product of albumin, such as a dimer or polymer of albumin.

[0013] [Albumin preparations] The albumin preparation of the present disclosure comprises a vial and an aqueous solution containing serum albumin sealed in the vial, the vial having a body with an opening and a stopper that seals the opening, the inner surface of the body has been treated to suppress elution, and the surface of the stopper that comes into contact with the aqueous solution containing serum albumin has been laminated.

[0014] The medical product has the above-mentioned configuration, and thus the formation of insoluble matters in the albumin-containing aqueous solution is suppressed.

[0015] [Vial] Main unit The main body is in a shape capable of containing an albumin-containing aqueous solution, and is typically in a bottle shape. The entire inner surface of the main body is subjected to an elution-suppressing treatment.

[0016] The body is preferably made of glass, which may be soft or hard glass.

[0017] An example of a body made of soft glass is an automatic bottle, which is manufactured by pouring molten soda-lime glass into a mold and blowing air into it to form the bottle.

[0018] An example of a body made of hard glass is a tube bottle. A tube bottle is manufactured by molding a tube of borosilicate hard glass by thermal processing without using a mold. A tube bottle can be processed at a lower temperature than the processing temperature when manufacturing an automatic bottle, so that the elution of alkaline components is small. In addition, the weight of a tube bottle is smaller than that of an automatic bottle, so that the load during transportation or use can be reduced.

[0019] The elution-preventing treatment is not particularly limited as long as it is a treatment method capable of reducing elution from the main body, for example, glass. For example, the elution-preventing treatment may be a silicon coating treatment or a sulfur treatment.

[0020] The silicon coating process is carried out by heat treatment using silicon coating gas such as tetraisocyanate silane. The heat treatment can be carried out by depositing silicon coating gas on the inner part and then carrying out heat treatment. This forms a thin SiO2 film on the inner part. The above-mentioned configuration makes it possible to suppress the elution of metals derived from glass, and improve the stability of the formulation. The silicon coating process is preferable because it can reduce production costs.

[0021] The sulfur treatment is carried out by a treatment using an ammonium sulfate aqueous solution. Specifically, the ammonium sulfate aqueous solution is injected into the main body, and then an annealing process is carried out. In the heat treatment during the annealing, the sulfur dioxide gas generated reacts with the alkali metals derived from the glass (e.g., borosilicate glass). This makes it possible to selectively remove the alkali components from the interior portion of the main body. By carrying out the sulfur treatment, for example, it becomes easier to control the pH, and the elution of the alkali metals can be reduced.

[0022] ·plug The plug is for sealing the opening of the main body. A hole can be made in the plug with a syringe needle or the like, and the albumin-containing aqueous solution present inside the main body can be taken out through this hole.

[0023] The stopper preferably contains butyl rubber or chlorinated butyl rubber, and more preferably the portion in contact with the body is made of the above rubber. The stopper is particularly preferably made of butyl rubber or chlorinated butyl rubber. By having the above configuration, the sealing performance of the vial is improved.

[0024] Preferably, the entire surface of the plug which may come into contact with the aqueous albumin-containing solution is laminated.

[0025] The lamination is preferably performed using a fluorine-based resin film. By having the above-mentioned constitution, the slipperiness and flexibility are improved, and the resealability after the injection needle inserted into the stopper is improved.

[0026] The lamination process can be carried out, for example, by placing a fluorine-based resin film on the rubber and applying heat and pressure. For example, the laminate can be heated to 100°C to 200°C and pressured to 10 to 100 kg / cm. 2 The pressure can be applied for 1 minute to 1 hour.

[0027] Examples of fluorine-based resin films include films of polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE), tetrafluoroethylene-perfluoroalkylvinyl ether copolymer (PFA), polyvinylidene fluoride (PVDF), polychlorofluoroethylene (PCTFE), and the like, such as PTFE.

[0028] The fluororesin film may be a porous film or a non-porous film.

[0029] ·cap The vial may further include a cap.

[0030] Preferably, a plug is provided on the opening of the body, and a cap is provided to sandwich the plug, and the cap is wound around the opening of the body. With the above-mentioned configuration, the sealing performance between the plug and the body is improved.

[0031] The material of the cap is not particularly limited, but may be, for example, a metal or a metal and a resin. Examples of metals include aluminum, etc. Examples of resins include polyethylene, polypropylene, etc.

[0032] The metal cap is attached to cover the mouth and stopper of the main body. The metal cap may be, for example, rolled onto the main body. An opening is present in the center of the metal cap, and the opening at least partially overlaps with the opening of the main body. At least a portion of the stopper is present in the opening of the metal cap. A hole is made in the stopper with a syringe needle or the like, and the albumin-containing aqueous solution present inside the main body can be taken out through the hole.

[0033] A resin cap may be used together with the metal cap. In this case, the resin cap is provided so as to cover the metal cap. That is, the resin cap exists as a cover that covers the metal cap. By removing the resin cap, the metal cap attached to the main body is exposed. When the albumin-containing aqueous solution is taken out, the resin cap is removed. By providing the resin cap, the metal cap can be protected.

[0034] The opening of the main body may be sealed only with a plug without using a cap.

[0035] 〔albumin〕 The albumin may be either plasma-derived albumin or recombinant albumin, preferably plasma-derived human serum albumin.

[0036] The albumin-containing aqueous solution may preferably contain 4 w / v% or more of albumin. The upper limit of the albumin content is not particularly limited, but is, for example, 30 w / v% or less. The albumin-containing aqueous solution may preferably contain 4.4 w / v% to 25 w / v% of albumin. The albumin-containing aqueous solution may, for example, contain 4.4 w / v% to 5 w / v% of albumin, for example, 20 w / v% to 25 w / v%.

[0037] Preferably, the albumin-containing aqueous solution contains 20 w / v % to 25 w / v % albumin. Even with a high concentration of albumin, insoluble matter is unlikely to form.

[0038] The amount of the albumin-containing aqueous solution is, for example, 75 mL or more, specifically, 100 mL or more. The upper limit of the amount of the albumin-containing aqueous solution is not particularly limited, but is, for example, 300 mL or less. The volume of the albumin-containing aqueous solution is preferably in the range of 75 to 300 mL, more preferably in the range of 100 to 250 mL. Even if the volume is increased as described above, insoluble matter is less likely to be generated.

[0039] Preferably, the albumin preparation of the present disclosure may contain an albumin-containing aqueous solution in a volume of 100 to 250 mL, and the albumin-containing aqueous solution may contain 20 w / v% to 25 w / v% albumin. Even when a large volume of a high-concentration albumin-containing aqueous solution is contained, insoluble matter is unlikely to be generated.

[0040] The albumin-containing aqueous solution may contain other ingredients such as additives. The other ingredients are not particularly limited as long as they do not inhibit the effect of albumin, and may be, for example, sodium acetyltryptophan, sodium caprylate, hydrochloric acid, sodium chloride, sodium hydroxide, etc.

[0041] The amount of other ingredients is not particularly limited as long as it is an amount that does not inhibit the effect of albumin, and may be contained in an amount of 0 to 5 wt % relative to albumin.

[0042] [Storage method for albumin-containing aqueous solution] The storage method of the present disclosure is characterized in that an albumin-containing aqueous solution is stored in a vial. In the present disclosure, the vial has a body having an opening and a stopper that seals the opening, the inner surface of the body is treated to suppress elution, and the surface of the stopper that comes into contact with the albumin-containing aqueous solution is laminated. By storing in the above manner, the generation of insoluble matter can be suppressed.

[0043] The albumin-containing aqueous solution and the vial are as described above.

[0044] [Evaluation method for albumin preparations] In the method for evaluating an albumin preparation disclosed herein, an albumin preparation containing an albumin-containing aqueous solution is heated at 60° C. for 1 to 2 weeks, and the tendency for insoluble matter to form is evaluated. Based on the results, it is possible to predict the formation of insoluble matter in the albumin preparation under normal storage conditions.

[0045] The evaluation of the tendency for insoluble matter to form is based on the total score of the visual evaluation by three people. The visual evaluation is judged by each person as follows: "No insoluble matter" is given a score of 0, "It is not clear to the naked eye whether this is insoluble matter, air bubbles, or the like, but insoluble matter is observed" is given a score of 1, and "Something that can be clearly identified as insoluble matter is observed to the naked eye" is given a score of 2.

[0046] In the evaluation method, an albumin preparation containing 50 mL of an aqueous solution containing albumin is used.

[0047] The albumin preparation, the method for storing the albumin preparation, and the method for evaluating the albumin preparation of the present disclosure are not limited to those exemplified above. EXAMPLES

[0048] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0049] Example 1: Determination of acceleration conditions A 50 mL portion of the product was used (Blood Donation Albumin 25% Intravenous Injection 12.5 g / 50 mL "KMB", manufactured by KM Biologics Co., Ltd.) The portion was heated to 60°C and visually evaluated by three observers over time. For the first 3 days: No insoluble matter was observed. One week after starting: Insoluble matter was confirmed. Two weeks after starting: It became cloudy. Size exclusion chromatography (SEC) revealed that the insoluble matter was albumin dimers and polymers.

[0050] Based on these results, the accelerated conditions for evaluating insoluble matter formation were determined to be leaving the mixture at 60°C for one week (7 days).

[0051] [Evaluation index under accelerated conditions] The evaluation results under accelerated conditions were scored based on visual evaluation. The score was the total value of the visual evaluations by three observers, and was evaluated as follows: "No insoluble matter" 0 points "It is not possible to clearly determine by visual inspection whether it is insoluble matter, air bubbles, or other substances, but insoluble matter is confirmed" 1 point "Insoluble matter is clearly identified by visual inspection" 2 points

[0052] Example 2: Evaluation of various combinations of container closure systems [Sample creation conditions] Albumin-containing aqueous solution: Small-aliquot product (Blood Donation Albumin 25% Intravenous Injection 12.5 g / 50 mL "KMB", manufactured by KM Biologics Co., Ltd.) Vials: Main body: One of the following 100 mL vials was used. Automatic bottle / sulfur treatment (manufactured by Daiichi Glass Co., Ltd.) Vial / sulfur treatment (manufactured by Fuji Glass Co., Ltd.) Vial / Silicoat treatment (manufactured by Fuji Glass Co., Ltd.) Stopper: Butyl rubber laminated with fluororesin (manufactured by Daikyo Seiko Co., Ltd.)

[0053] The contents of two small-sized products were transferred into a 100 mL vial, the opening was sealed (stoppered) with a rubber stopper, and a cap (F cap; manufactured by Hisa Kinzoku Kogyo Co., Ltd.) was then tightened. The vials were then heated for one week at 60° C. One vial was placed upside down with the stopper in contact with the albumin-containing aqueous solution, and the other was placed horizontally with part of the stopper in contact with the albumin-containing aqueous solution. After one week, each sample was visually evaluated, and the results are shown in Table 1.

[0054] Comparative Example 1: Evaluation of various combinations of container closure systems The measurement was carried out under the same conditions as in Example 2, except that a non-laminated butyl rubber was used as the plug.

[0055] [Table 1]

[0056] As shown in Table 1, the score was reduced by performing the lamination treatment. It was found that the lamination treatment made it difficult for insoluble matter to occur. [Industrial Applicability]

[0057] According to the present disclosure, insoluble matters are less likely to occur during storage of an albumin-containing aqueous solution, which is particularly effective in high-concentration hypertonic albumin preparations.

Claims

1. A vial and an aqueous solution containing serum albumin sealed in the vial. An albumin formulation comprising: The vial includes a body having an opening and a stopper for sealing the opening. having The inside of the body is treated to prevent leaching. The entire surface of the plug that can come into contact with the serum albumin-containing aqueous solution is laminated, The elution suppression treatment is at least one of a silicon coating treatment and a sulfur treatment, The lamination is performed using a fluorine-based resin film, The concentration of the serum albumin-containing aqueous solution is 20 to 25 w / v %, The amount of the serum albumin-containing aqueous solution is 75 mL or more, The formation of altered products of serum albumin in an aqueous solution containing serum albumin is inhibited. Albumin preparations.

2. 2. The albumin formulation of claim 1, wherein the stopper comprises butyl rubber or chlorinated butyl rubber.

3. The albumin preparation according to claim 1, wherein the silicoat treatment is a heat treatment using a silicoat gas.

4. 2. The albumin preparation according to claim 1, wherein the sulfur treatment is a treatment using ammonium sulfate.

5. A method for preserving an aqueous solution containing serum albumin, comprising the steps of: The vial includes a body having an opening and a stopper for sealing the opening. having The inside of the body is treated to prevent leaching. The entire surface of the plug that can come into contact with the serum albumin-containing aqueous solution is laminated, The elution suppression treatment is carried out by at least one of a silicon coating treatment and a sulfur treatment, The lamination is performed using a fluorine-based resin film, The concentration of the serum albumin-containing aqueous solution is 20 to 25 w / v %, The amount of the serum albumin-containing aqueous solution is 75 mL or more, The formation of altered products of serum albumin in an aqueous solution containing serum albumin is inhibited. How to save.

6. 6. The method of claim 5, wherein the stopper comprises butyl rubber or chlorinated butyl rubber.

7. 6. The method for preserving the food according to claim 5, wherein the silicon coating treatment is a heat treatment using a silicon coating gas.

8. 6. The method for preservation according to claim 5, wherein the sulfur treatment is a treatment using ammonium sulfate.

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