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

Abstract

To provide an albumin preparation that suppresses generation of insoluble matter even with an increased volume.SOLUTION: An albumin preparation comprises a vial and an aqueous solution containing serum albumin enclosed in the vial, wherein the vial has a main body having an opening and a stopper that seals the opening, an inner surface of the main body is subjected to elution suppression treatment, and a surface of the stopper that comes into contact with the aqueous solution containing serum albumin is subjected to laminate treatment.SELECTED DRAWING: None

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 is a molecule consisting of 585 amino acids. Serum albumin accounts for approximately 60% of plasma proteins in normal individuals, making it the most abundant in terms of quantity. Serum albumin is formed in the liver in the body.

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

[0004] Serum albumin has been formulated into pharmaceutical preparations. Formulated albumin preparations have been used to treat hypoalbuminemia or hemorrhagic shock caused by albumin loss due to burns, nephrotic syndrome, etc., or a decrease in 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] Two types of albumin 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 albumin concentration, 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 use of large doses of hypertonic albumin preparations is increasing, and studies are being conducted to develop large-volume albumin preparations to reduce the need for replacement of the preparation during administration.

[0008] However, it has been found that increasing the volume of a hypertonic albumin preparation results in the formation of insoluble matter in the albumin preparation (serum albumin-containing aqueous solution) during storage. After extensive research, the present inventors have discovered 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 produce insoluble matter even when the volume is increased. The present disclosure also aims to provide a method for storing an albumin preparation that is less likely to produce insoluble matter even when the volume is increased. Furthermore, the present disclosure provides an accelerated method for evaluating albumin preparations. [Means for solving the problem]

[0009] The present 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 comprises a body having an opening and a stopper that seals the opening. and 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 the 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 that can 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 comprises 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 siliconization 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 volume of the albumin-containing aqueous solution is 75 mL or more.

[11] A method for preserving a serum albumin-containing aqueous solution in a vial, comprising: The vial comprises a body having an opening and a stopper that seals the opening. and 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 storage method according to

[11] or

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

[14] The storage method according to any one of

[11] to

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

[15] The storage method according to any one of

[11] to

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

[16] The storage method according to any one of

[11] to

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

[17] The preservation method according to

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

[18] The preservation method according to

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

[19] The method for preservation 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 of serum albumin is heated at 60°C for 1 to 2 weeks and the tendency for insoluble matter to form is evaluated. [Effects of the Invention]

[0010] According to the present disclosure, it is possible to provide an albumin preparation that is less likely to produce insoluble matter even when the volume is increased. Also, according to the present disclosure, it is possible to provide a method for storing an albumin preparation that is less likely to produce insoluble matter even when the volume is increased. Furthermore, according to the present disclosure, it is possible to provide an accelerated method for evaluating an albumin preparation. DETAILED DESCRIPTION OF THE INVENTION

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

[0012] As used herein, the term "insoluble matter" refers to matter that can be visually confirmed in an albumin-containing aqueous solution. The insoluble matter has, for example, a fibrous or cotton-like shape. The insoluble matter is a modified product of albumin, such as an albumin dimer or polymer.

[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 having been treated to suppress elution, and the surface of the stopper that comes into contact with the aqueous solution containing serum albumin having been treated to laminate.

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

[0015] [Vial] Main unit The main body has a shape capable of containing an albumin-containing aqueous solution, and is typically bottle-shaped. The entire inner surface of the main body is treated to inhibit elution.

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

[0017] An example of a soft glass body 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 thermally molding a borosilicate hard glass tube without using a mold. A tube bottle can be processed at a lower temperature than the processing temperature used to manufacture an automatic bottle, so that the elution of alkaline components is minimal. Furthermore, the weight of a tube bottle is smaller than that of an automatic bottle, which can reduce the load during transportation or use.

[0019] The elution-preventing treatment is not particularly limited as long as it is a treatment method that can reduce elution from the main body, for example, glass. For example, elution-preventing treatment can include silicon coating treatment and sulfur treatment.

[0020] The siliconization treatment is carried out by heat treatment using siliconization gas such as tetraisocyanate silane. The heat treatment can be carried out by depositing siliconization gas on the inner lining portion, followed by heat treatment. This results in the formation of a thin SiO2 film on the inner lining portion. The above-mentioned configuration makes it possible to suppress the elution of metals derived from the glass, thereby improving the stability of the formulation. Siliconization treatment is preferred because it can reduce manufacturing costs.

[0021] Sulfurization is performed using an ammonium sulfate solution. Specifically, the ammonium sulfate solution is injected into the body, followed by an annealing process. The sulfur dioxide gas generated during the annealing heat treatment reacts with alkali metals derived from the glass (e.g., borosilicate glass). This allows for selective removal of alkaline components from the body's interior. Sulfurization, for example, facilitates pH control and reduces alkali metal elution.

[0022] ·plug The stopper is used to seal the opening of the main body. The stopper can be pierced with a syringe needle or the like, and the albumin-containing aqueous solution present inside the main body can be extracted through this hole.

[0023] The stopper preferably contains butyl rubber or chlorinated butyl rubber, and more preferably, the portion that comes into 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 that can come into contact with the albumin-containing aqueous solution is laminated.

[0025] The lamination is preferably carried out using a fluorine-based resin film. The above-mentioned structure improves the slipperiness and flexibility, and improves the resealability after the injection needle inserted into the stopper is withdrawn.

[0026] The lamination treatment can be carried out, for example, by placing a fluorine-based resin film on the rubber and applying heat and pressure. For example, the lamination treatment can be carried out by heating to 100°C to 200°C and applying a pressure of 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-perfluoroalkyl vinyl ether copolymer (PFA), polyvinylidene fluoride (PVDF), polychlorofluoroethylene (PCTFE), and the like, and an example of such a film is PTFE.

[0028] The fluorine-based resin 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 main body, and a cap is provided to sandwich the plug, and the cap is seamed around the opening of the main body. With the above configuration, the sealing performance between the plug and the main body is improved.

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

[0032] The metal cap is attached to cover the opening of the main body and the stopper. The metal cap may be, for example, seamed to 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 within the opening of the metal cap. A hole can be made in the stopper with a syringe needle or the like, and the albumin-containing aqueous solution present inside the main body can be removed through this hole.

[0033] A resin cap may be used together with the metal cap. In this case, the resin cap is provided 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 with only 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 preferably contains 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 preferably contains 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 less likely 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 produced.

[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 highly concentrated albumin-containing aqueous solution is contained, insoluble matter is less likely to form.

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

[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 by storing an albumin-containing aqueous solution in a vial. In the present disclosure, the vial has a body with 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 the albumin-containing aqueous solution in the above manner, the formation 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] The method for evaluating an albumin preparation disclosed herein involves heating an albumin preparation containing an albumin-containing aqueous solution at 60°C for 1 to 2 weeks and evaluating the tendency for insoluble matter to form. Based on these 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 evaluations by three people. Each person judges the visual evaluation as follows: "No insoluble matter" is given a score of 0; "It is not clear with the naked eye whether this is insoluble matter, air bubbles, or something else, but insoluble matter is observed" is given a score of 1; and "Something that can be clearly identified as insoluble matter is observed with the naked eye" is given a score of 2.

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

[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 aliquot product (25% donated blood albumin intravenous injection 12.5 g / 50 mL "KMB", manufactured by KM Biologics Co., Ltd.) was used. This aliquot product was heated to 60°C and visually evaluated by three people over time. For the first 3 days: No insoluble matter was observed. One week after starting: Insoluble matter was observed. Two weeks after starting: It became cloudy. The insoluble matter was found to be albumin dimers and polymers by size exclusion chromatography (SEC).

[0050] Based on the above 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 people, and each was evaluated as follows: "No insoluble matter" 0 points "It is not possible to clearly determine by visual inspection whether it is insoluble matter, bubbles, or other matter, but insoluble matter is confirmed" - 1 point "Insoluble matter is clearly visible to the naked eye" 2 points

[0052] Example 2: Evaluation of various combinations of container closure systems [Sample creation conditions] Albumin-containing aqueous solution: Small-aliquot product (Donated Blood Albumin 25% Intravenous Injection 12.5g / 50mL "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 (Fuji Glass Co., Ltd.) Stopper: butyl rubber laminated with fluororesin (manufactured by Daikyo Seiko Co., Ltd.)

[0053] The contents of two small-aliquot 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 1 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 Measurement was carried out under the same conditions as in Example 2, except that unlaminated butyl rubber was used as the stopper.

[0055] [Table 1]

[0056] As shown in Table 1, the score decreased when lamination was performed. This indicates that lamination makes it difficult for insoluble matter to occur. [Industrial Applicability]

[0057] According to the present disclosure, the formation of insoluble matter during storage of an albumin-containing aqueous solution is reduced, which is particularly effective for 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 comprises a body having an opening and a stopper that seals the opening. and 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 claim 1, which inhibits the formation of insoluble matter in an aqueous solution containing serum albumin.

3. 3. The albumin preparation according to claim 1, wherein the entire surface of the plug that can come into contact with an aqueous solution containing serum albumin is laminated.

4. The albumin preparation according to claim 1 or 2, wherein the lamination treatment is carried out using a fluorine-based resin film.

5. 3. The albumin preparation according to claim 1, wherein the stopper comprises butyl rubber or chlorinated butyl rubber.

6. 3. The albumin preparation according to claim 1, wherein the dissolution-suppressing treatment is at least one of a siliconizing treatment and a sulfur treatment.

7. The albumin preparation according to claim 6, wherein the siliconizing treatment is a heat treatment using siliconizing gas.

8. 7. The albumin preparation according to claim 6, wherein the sulfur treatment is a treatment using ammonium sulfate.

9. 3. The albumin preparation according to claim 1, wherein the concentration of the aqueous solution containing serum albumin is 20 to 25 w / v %.

10. 3. The albumin preparation according to claim 1, wherein the amount of the albumin-containing aqueous solution is 75 mL or more.

11. A method for preserving a serum albumin-containing aqueous solution in a vial, comprising: The vial comprises a body having an opening and a stopper that seals the opening. and 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 method for preserving serum albumin according to claim 11, wherein the formation of insoluble matter in the aqueous solution containing serum albumin is suppressed.

13. 13. The method for preserving serum albumin according to claim 11 or 12, wherein the entire surface of the stopper that can come into contact with the aqueous solution containing serum albumin is laminated.

14. 13. The method for preserving food according to claim 11 or 12, wherein the lamination treatment is carried out using a fluorine-based resin film.

15. 13. The method of claim 11 or 12, wherein the stopper comprises butyl rubber or chlorinated butyl rubber.

16. 13. The method for preservation according to claim 11 or 12, wherein the elution-suppressing treatment is at least one of a silicon coating treatment and a sulfur treatment.

17. The method for preserving the food product according to claim 16, wherein the siliconizing treatment is a heat treatment using siliconizing gas.

18. 17. The method for preservation according to claim 16, wherein the sulfur treatment is a treatment using ammonium sulfate.

19. 13. The method for preserving serum albumin according to claim 11 or 12, wherein the concentration of the aqueous solution containing serum albumin is 20 to 25 w / v %.

20. 13. The method for preserving serum albumin according to claim 11 or 12, wherein the amount of the aqueous serum albumin-containing solution is 75 mL or more.

21. A method for evaluating an albumin preparation, which comprises heating an albumin preparation containing an aqueous solution containing serum albumin at 60°C for 1 to 2 weeks and evaluating the tendency for insoluble matter to form.

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