WO2002072135A1 - LIQUID INTERFERON α PREPARATIONS FOR INJECTION AND METHOD OF STABILIZING THE SAME - Google Patents

Abstract

It is intended to provide liquid preparations for injection which contain interferon α and can be stored over a long time owing to the high stability. Liquid preparations for injection which contain interferon α, a recombinant human serum albumin and a nonionic surfactant and have a pH value of 6.5 to 7.5; and a method of stabilizing interferon α characterized by adding a recombinant human serum albumin to a liquid preparation for injection which contains interferon α and a nonionic surfactant and has a pH value of 6.5 to 7.5.

Description

Description Interfluon _α liquid preparation for injection and method for stabilizing the same

 The present invention relates to a liquid preparation for injection containing interferon α and a method for stabilizing the liquid preparation. Background art

 Interferon (IFN) is a type of glycoprotein produced in vivo and is also called site force protein. It has the physiological activity of inhibiting the replication of virus in cells and the proliferation of cells, and has been implicated in immune responses. 1 to 1 ^ are roughly classified into three types: 0: type, type, and γ type. IFNα is produced in vivo mainly by leukocytes after virus infection.

 There are two types of IFNa formulations: freeze-dried and liquid. The former has excellent long-term storage stability as a formulation, but has drawbacks such as the labor of freeze-drying in the manufacturing process and the labor of redissolving with water for injection at the time of use (at the time of administration to patients). The latter is due to the fact that IFNa, like other proteins, can be used in aqueous solutions in aqueous solutions, for chemical effects such as proteolysis, oxidation, disulfide exchange, oligomerization, deamidation or elimination, as well as for aggregation and precipitation. The focus is on how to improve long-term storage stability due to physical susceptibility such as adsorption.

As a method of liquid preparation of the IFN _alpha for injection, as a method of adding a stabilizing agent, such as polysorbate (trade name "glycocalyx over emissions", JP 6 1 - 2 7 7 6 3 3 JP, Japanese Patent Publication No. 7-5 4 7 9 and Japanese Patent Publication No. 10-5 06 9 12) have been reported. Also, IFN is known to stabilize at a specific ρ 、, and 巿 In many freeze-dried IFN preparations on the market, 5-6 is selected as the pH during dissolution. Also, a method of adjusting the pH to 4.5 to 5.5 in a liquid preparation of IFN (Japanese Patent Application Laid-Open No. 8-28316, Japanese Patent No. 2758154), etc. Have been reported. It also contains IFN o (derived from Namalva cells), plasma-derived human serum albumin (HSA), tromethamol, glycine and sodium chloride, and has a pH of 7.1 which is a liquid preparation for injection. Commercially available (trade name “Sumifuron”, Sumitomo Pharma). .

 Japanese Patent Application Laid-Open No. Sho 63-2955513 discloses a lyophilized preparation comprising IFN, plasma-derived HSA, a nonionic surfactant, an isotonic agent and a buffer. However, lyophilized products are not intended to be stored in a solution state for a long time (for example, 1 to 3 years), and do not guarantee long-term stability as a liquid preparation. Disclosure of the invention

An object of the present invention is to provide a liquid preparation for injection containing human IFN, which can be stored for a long period of time and has excellent stability. The present inventors have conducted research in consideration of the above circumstances, and as a result, have confirmed that the use of recombinant HSA suppresses a decrease in IFN titer. However, since this formulation causes aggregation due to long-term storage, further studies have shown that the combined use of recombinant HSA and nonionic surfactants can suppress the decrease in IFNa titer, and that it does not cause agglomeration, has an excellent long-term storage stability, and found that can be prepared for injection liquid preparations I FN _alpha, and have completed the present invention.

That is, the present invention 1. Recombinant human serum containing a recombinant human serum albumin and a nonionic surfactant, and: a liquid preparation for injecting interferon α having an H of 6.5 to 7.5. A method for stabilizing interface alpha, comprising adding albumin.

 2. The method for stabilizing interferon α according to item 1 before adding a stabilizer for recombinant human serum albumin to the preparation.

3. amount of recombinant human serum albumin is, LXL 0 per ⁶ IU of interferon, 0.0 5: first or second term stabilization method Intaferonhi according before a L mg.

4. The addition amount of the nonionic surfactant, lx 1 0 per ⁶ IU of Intaferonhi, 0. 0 0 1~; L 0 Intafuyuron according to any one of mg first to third terms before a α Stabilization method.

5. nonionic surfactant, stabilizing method of polyoxyethylene Intafe port emissions of paragraph 4, wherein before a sorbitan fatty acid ester alpha ₀

 6. The method for stabilizing interferon ο; according to the above item 5, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.

7. amount of recombinant human serum albumin in stabilizers, interferon Eron 1 X 1 0 per ⁶ IU of alpha, 0. 0. 1 to: either before of the second to item 6 is L 0 mg 2. The method for stabilizing an interface a according to the item 1.

8. The stabilizing agent for recombinant human serum albumin is selected from acetyltryptophan or a salt thereof, caprylic acid or a salt thereof, and used alone or in combination as described in Item 7 above. Interferon _α stabilization method.

9. The method for stabilizing an interfacial α according to the first to eighth aspects, wherein the pH is adjusted to 6.8 to 7.1.

10. Interferon injectable liquid preparation prepared by introducing the method of stabilizing interferon according to any one of Items 1 to 9 above. 1 1. A liquid preparation for injection of interferon containing interferon, recombinant human serum albumin and a non-ionic surfactant, and having a pH of 6.5 to 7.5.

 1 2. The liquid preparation for injecting interferon-α according to the above-mentioned item 11, which contains a stabilizer for recombinant human serum albumin.

 1 3. The liquid preparation for injecting interferon α according to item 11 above, wherein the preparation is filled in a vial or a syringe.

It is about. The details will be described below. BEST MODE FOR CARRYING OUT THE INVENTION

 I F Ν α

The interferon (IFN a) used in the present invention may be either a natural type or a recombinant type, but preferably a natural human IFNα. IFNa has the effect of inhibiting virus replication and cell growth and modulating the immune response. IFNa has 20 or more subtypes due to partial substitution or deletion of the amino acid sequence, or binding to a sugar chain or the like. Representative IFN a subtypes include IFN o! 2a and a 2 ba 2c, but also IFN al, α4, α5, α6, and a7 a ^ ί b ^ a 7 c, α 8, a 1 0 s Q! l 3, α 1 4, a 1 7 a Ν α 1 b N α 1 7 c s a 2 1, a 7 8, a 8 8, 2 , etc. Numerous subtypes exist due to differences in sugar chains. In the present invention, IFN a containing any of the above subtypes can be used. It is possible to use IFNa containing preferably at least 5 subtypes, more preferably at least 10 subtypes, particularly preferably at least 20 subtypes. Native IFN Hiniwa Namalwa cell-derived or BALL - 1 thing of the cell - derived (Mochida Pharmaceutical Co., Ltd. of "I FN _a Mochida," Otsuka "Oai F)) and so on. Recombinant IF No: may include recombinant IFN a 2a ("Canada Feron A" by Takeda Pharmaceutical Co., Ltd., "Mouth Feron A" by Roche Nippon) or recombinant IFN α2b (Schering-Plough). Company's “Intron A”). Particularly, purified mixture of natural I FN _alpha of Namalwa fine胞由come are preferred.

In injectable liquid preparations of the present invention, the concentration of I FN a is ^{1 X 1 0 6 2 0 X} 1 0 of about ⁶ IU / mL range is preferred. Recombinant HSA

The recombinant human serum albumin (recombinant HSA) used in the present invention is prepared using a genetic recombination technique and is sufficiently purified to be usable as a pharmaceutical (injection). If so, it is not particularly limited, and known ones can be used. Recombinant HSA (rHSA) is not particularly limited as long as it is HSA produced by an HSA-producing host prepared through genetic manipulation. Preferably, contaminant components derived from the production host (eg, proteins, polysaccharides, etc.) After the rHSA-producing host is cultured by a known means, the culture filtrate or the cells and the cells collected and purified by known separation means and purification means are used. Can be In addition, transgenic animals and transgenic plants can also be used (Japanese Patent Application Laid-Open Nos. Hei 9-1509565 and No. 10-504289). Specific examples include the following methods. The host for obtaining rHSA used in the present invention is not particularly limited as long as it is prepared through genetic manipulation, and may be any of those already described in the known literature. However, even those that will be developed in the future can be used as appropriate. Specific examples include bacteria (eg, Escherichia coli, yeast, Bacillus subtilis, etc.) and animal cells that have been made rHSA-producing through genetic manipulation. You. In particular, yeasts, preferably Saccharomyces genus [eg, Saccharomyces cerevisiae], or Pichia genus [eg, Pichiaastoris] are used as hosts. An auxotrophic strain or an antibiotic-sensitive strain may also be used. More preferably, Saccharomyces' Celepiche AH22 strain (a, his4, leu2, can1) and Pichia's Nostris GTS115 strain (his4) are used.

 A method for preparing these rHSA-producing hosts, a method for producing rHSA by culturing the host, and a method for separating and collecting rHSA from a culture are known and employ methods based on them. Can be implemented. For example, as a method for preparing an rHSA-producing host, for example, a method using a normal HSA gene (JP-A-58-56684, JP-A-58-90515, JP-A-58-115) — 15050517 publication), a method using a novel HSA gene (JP-A-62-29985, JP-A-11-96486), a synthetic signal sequence (Japanese Unexamined Patent Application Publication No. Hei 1-204191), a method using a serum albumin signal sequence (Japanese Unexamined Patent Publication No. Hei 2-16795), integration of a recombinant plasmid into a chromosome. Method (Japanese Patent Application Laid-Open No. 3-72889), a method of fusing hosts (Japanese Patent Application Laid-Open No. 3-58777), a method of causing mutation in a medium containing methanol, and a mutant AO X A method using a two-port motor (Japanese Unexamined Patent Application Publication Nos. Hei 6-09768 and No. 4-299984), the expression of HSA by Bacillus subtilis (Japanese Unexamined Patent Publication No. Sho 62-251) No. 33), Expression of HSA by yeast (Japanese Unexamined Patent Publication No. Sho 60-41487, No. 63-395976, No. 63-374493) ) And HSA expression by Pichia yeast (Japanese Patent Application Laid-Open No. 2-140290).

Among them, the method of causing mutation in a methanol-containing medium is concrete. Is performed as follows. That is, first, a suitable host, preferably a Pichia yeast, specifically, the AOX1 gene region of the GTS115 strain (NRRL accession number Y-185581) is controlled by the AOX1 promoter in a conventional manner. Then, a plasmid having a transcription kit expressing HSA is introduced into the transformant to obtain a transformant (see JP-A-2-104290). This transformant has a low ability to grow in a methanol medium. Then, this transformant is cultured in a methanol-containing medium to cause mutation, and only a viable strain is recovered. At this time, the methanol concentration is, for example, about 0.001 to 5%. The medium may be an artificial medium or a natural medium. Examples of the culture conditions include 15 to 40 ° C. and 1 to 1000 hours.

 In addition, in addition to the methods described in each of the above publications, a high-batch high-concentration glucose or methanol, etc., may be added in small amounts by fed batch culture (half-batch culture) in addition to the methods described in the above publications. A method of obtaining a high concentration of cells and a product by avoiding high concentration substrate inhibition on the producing cells (Japanese Patent Application Laid-Open No. 3-83595). (JP-A-4-293495), and the like.

Various methods have been proposed for isolating and purifying rHSA produced by the culture treatment from components derived from host cells and cultured components with sufficient accuracy. For example, as a conventional method, a yeast culture solution containing rHSA is subjected to squeezing → ultrafiltration membrane treatment-heating treatment → ultrafiltration membrane treatment, followed by cation exchanger treatment and hydrophobic chromatography treatment. , Anion exchanger treatment, etc. (Japanese Unexamined Patent Publication No. Heisei 5-3-1790; Biotechnological Gio'Blad Blood Proteins, Vol. 227, 293-2) 98 pages, published in 1993). In addition, a method has been reported in which the above-mentioned conventional method is further subjected to a chelate resin treatment or a boric acid salt treatment step. (JP-A-6-56883, JP-A-6-245789). Further, after the yeast culture solution is subjected to heat treatment, a stream line method using an adsorption fluidized bed technique (Japanese Patent Application Laid-Open No. 8-116985) or the like can also be used. The rHSA thus prepared / purified can be subjected to a known method, for example, sterilization heating, ultrafiltration membrane treatment, addition of a stabilizer, sterilization filtration, dispensing, freeze-drying, etc. .

Recombinant HSA is I FNa 1 X 1 0 ⁶ IU per 0.1 05～: it is preferable to add a degree Lmg, adding 0 0 8 to 0 5 mg approximately per ^{I FN a 1 X 1 0 6} IU.. Is more preferable. Nonionic surfactant

 Examples of the nonionic surfactant used in combination with the recombinant HS A in the present invention include a polyoxyalkylene derivative or a polyoxyalkylene copolymer. Specifically, polyoxyethylene sorbitan fatty acid ester (polysorbate, trade name "Twin"), polyoxyethylene anolyl ether, polyoxyethylene alkyne ^ / furether (trade name "Triton"), polyoxyethylene polyoxypropylene glycol Coal (trade name “Pull mouth nick”), polyoxyethylene hydrogenated castor oil (trade name “HCO”), lunar fatty acid monoglyceride, and the like. Among them, a preferred nonionic surfactant is polyoxyethylene sorbitan fatty acid ester. There are monooleate (polysorbate 20), monolaterate (40), monostearate (60), monopass remitate (80), etc., with polysorbate 80 being particularly preferred.

The concentration of the nonionic surfactant to be added is, for example, about 0.001 to 10 mg mL. It is preferably about 0.01 to lmg /: mL, and particularly preferably about 0.1 to 0.1 SmgZmL. . The amount of addition, Ru More in ^{I FN a 1 X 1 0 6} I UZm 1 per value. H ■ buffer

 Although the pH of the liquid preparation for injection obtained according to the present invention is in the range of 6.5 to 7.5, it is possible to stabilize IFNo; more preferably, the pH is 6.8 to 7.1. It is about.

 The liquid preparation for injection obtained by the present invention may contain a buffer. The buffer is not particularly limited as long as it can be used for injections and has a buffering ability in the above pH range, and conventional ones can be used. After the addition of the buffer, the pH can be adjusted to the above-mentioned pH range using a conventional pH adjuster. Buffers used in the present invention include, for example, trometamol, glycine, phosphate buffers (combinations of mono- and di-phosphates, such as sodium dihydrogen phosphate and disodium hydrogen phosphate) ) Are shown. Preferably, tromethamol and glycine are used. The concentration of the buffer added is not particularly limited as long as the pH can be maintained within a desired range, but is about 1-2 mg / mL for trometamol, and 0.5-lm gZmL for glycine. The degree is exemplified. Tonicity agent

The liquid preparation for injection obtained by the present invention may contain an isotonic agent. The tonicity agent is not particularly limited as long as it is pharmaceutically acceptable and can be used for injections, and conventional ones can be used. Examples thereof include inorganic salts such as sodium chloride, polyols such as glycerin, monosaccharides such as glucose, disaccharides such as sucrose, and sugar alcohols such as mannitol. Preferably, sodium chloride Is used. The tonicity agent is added at a concentration that maintains the osmotic pressure ratio of the liquid preparation for injection at about 1 to 2. The osmotic pressure ratio refers to the ratio of the osmotic pressure of a solution to the osmotic pressure of 0.9 w / v ° / o sodium chloride (physiological saline). Other additives

Another embodiment of the present invention may include a known additive for stabilizing recombinant HSA. For example, acetyltryptophan or a salt thereof, caprylic acid or a salt thereof, and the like are preferably exemplified. The addition concentration is preferably about 0.01 to: about 0 mg ZniL (or about 1 to 10 mM in terms of mole), and these are used alone or in combination. This amount is also a ^{I FN a 1 X 1 0 6} IU / m 1 per value. Preparation method

 The liquid preparation for injection obtained by the present invention can be produced, for example, by the following method. That is, an aqueous solution containing IFNa (preferably containing an isotonic agent such as sodium chloride, a buffer such as trometamol and glycine, etc.) is added to recombinant HSA and a nonionic surfactant (eg, polysorbate). 80) to a specified concentration, adjust the pH, and then dilute IFNo! To a specified concentration. Thereafter, the liquid preparation for injection of the present invention can be obtained by filtering under sterile conditions and filling the mixture in a sealed container such as a vial.

The liquid preparation for injection obtained according to the present invention is prepared without undergoing lyophilization, and unlike the lyophilized preparation, it does not need to be dissolved in a solvent such as distilled water for injection at the time of use, and the patient Can be administered by injection. Dosage and indications

The IFN a liquid preparation for injection obtained according to the present invention includes kidney cancer, multiple myeloma, leukemia, chronic and acute hepatitis B and ZC, subacute sclerosing panencephalitis, ^ 1 It is effective for treating various diseases such as HAM). Usually 1 day ^{3 XI 0 6 ~ 9 X 1} 0 6 IU is administered subcutaneously or intramuscularly. Example

 In order to explain the present invention in more detail, examples and experimental examples will be given, but the present invention is not limited thereto.

 The IFN o; (from Namalba cells, Sumitomo Pharmaceutical) used in the experimental examples was a subtype α1, 2, a5, a7, α8, a88, λ2h, etc. Contains (more than 16 types due to differences in sugar chains, etc.). MU means 1,000,000 IU. Example 1

 1.5 mg of IFNα3MU, rHSA and 800.1 mg of polysorbate were dissolved in an appropriate amount of water for injection, the pH was adjusted to 7.1, and the total amount was adjusted to 1 mL. This was filled into a 1 mL glass vial to prepare a liquid preparation for IFN injection. Examples 2 to 4

In the same manner as in Example 1, a liquid formulation for injection of IFNα having the formulation shown in Table 1 was prepared. 【table 1】

Experimental example 1

Aggregate liquid formulation containing 1.5 or 3 mg of I.FN a 3MU r HSA per mL and pH adjusted to 6.8 or 7.1 with Tris / glycine buffer after long-term storage Was observed. Table 2 shows the results. [Table 2]

 □ Cut r H S A P H H Aggregation rate

 (mg / ml) 10 ° C 3 months 25 ° C 2 months

A 1 .5 7 .1 2 1/3 1 1 4/1 5

 B 1.5 .1 2 2/3 5 1 5/1 5

 C 1.5 7 .1 25/3 8 1 4/1 5

 D 3 7. 1 28/3 5 1 3/1 5

 E 1.5 6. 8 1 3/3 5 1 1/1 5

It was found that aggregation was caused when rHSA was added to the IFNa liquid preparation for injection and stored for a long time. Experimental example 2

The I FN _alpha injectable liquid preparations lot A~C of Example 1 was measured I FN _alpha content after storage for 1 year at 1 0 ° C. Table 3 shows the results. [Table 3]

 □ Cut I F N α content (M U / ml)

 Immediately before storage 1 0 ° C 1 year

 A 3.5 3.5

 B 3.7.3.3

 C 3.5 5 3.1

r HSA was found to be effective as a stabilizer for maintaining IFN activity. Experiment 3 Includes IFN a 3MU / mL HSA 1.5 mg / mL, various additives, trometamol 1.22 mg, sodium chloride 8.8 mg and glycine 0.76 mg, pH 7.1 The IFN liquid preparation for injection prepared in Example 1 was filled into a 1-mL glass vial, and stored at 10 ° C for 2 power months to observe the presence or absence of aggregation. Table 4 shows the results. [Table 4]

The I FN _alpha injectable liquid preparation, by adding § cetyl trypsinogen xanthohumol An'natoriumu and caprylate sodium © beam with r HSA, it was possible to suppress the aggregation of the long-term storage. The effect of sodium oleate was weak. Experiment 4

I FN a 3MU per mL, 1.5 mg r HSA, 800 or 0.10 mg polysonorate, 1.2 mg tromethamole / re, 8.8 mg sodium chloride and 0.7 glycine A 1 mL glass vial was filled with an IFN liquid preparation containing 6 mg and adjusted to pH 7.1. After storage for 10 months at 10 ° C, the presence or absence of aggregation was observed. Table 5 shows the results. [Table 5]

By adding polysorbate together with rHSA to the liquid formulation for IFNα injection, aggregation during long-term storage could be suppressed. Experimental example 5

 per mL contains 3 MU IFN, 1.5 mg rHSA, 800-0.3 mg polysonorate, 1.22 mg tromethanore, 8.8 mg sodium chloride and 0.76 mg glycine, The IFN liquid preparation for injection adjusted to pH 7.1 was filled into a 1-mL glass vial. After storage at room temperature under shaking for 50 days, the presence or absence of aggregation was observed. Table 6 shows the results.

 [Table 6]

It was found that the effect of adding polysorbate was best when the concentration was 0.1 to 0.1 SmgZniL. Experiment 6

I FN o per mL: 3 or 6 MU, r HSA 5 mg, polysonolate 800.l mg, tromethanore 22 m g, sodium chloride, 8.8 mg, and glycine 0.76 mg, and a pH adjusted to 7.1 IFNα liquid injection solution was filled into a 1 mL glass vial or syringe. After long-term storage, the presence or absence of aggregation was observed. Table 7 shows the results.

 [Table 7]

It was found that the formation of agglomeration could be suppressed regardless of the content of IFN and the type of dosage form. Reference Example (Preparation of rHSA)

 Acquisition of the rHSA-producing yeast Pichia pastoris and cultivation thereof were performed according to the method described in Japanese Patent Application Laid-Open No. 5-317,795. Recovery and purification of rHSA from the obtained culture solution was performed according to the method described in JP-A No. 8-116985.

Adjust the purified rHSA to a 25% solution, add sodium caprylate and acetyltributophan sodium to a final concentration of 0.02M, and then add 60 ° C for 30 minutes. The heat-sterilization treatment of this product can be used as an injection by filtering bacteria using a 0.22 μπι filter (Millipore). As for the composition, the sodium chloride content was 3.7 mgZ: mL or less, the pH was 6.4: to 7.4, and the osmotic pressure ratio was about 1 (ratio to physiological saline). The properties of the purified rHSA (containing composition) were confirmed.

HP LC analysis: r HSA was analyzed by HPLC gel filtration. Gel filtration analysis was performed under the following conditions. The column is TSK gel G 3 000 SW (Tosoichi). The developing solution is 0.1 M KH ₂ PO ₄ /0.3 MNaCl buffer. Detection is absorbance at a wavelength of 280 nm.

 Analysis of yeast-derived components: A supernatant of HS A non-producing yeast was roughly purified by the above-described method, and immunized to rabbits. Purified using the obtained antiserum r Yeast contaminating in HS A-containing composition Originated components were detected. The measurement was performed by enzyme immunoassay (EIA method). r The measurement was performed using the HSA concentration adjusted to 25%. Molecular weight: According to the aforementioned HP LC gel filtration method.

Isoelectric point: The isoelectric point was measured using a thin-layer polyatarylamide gel according to the method of Allen et al. (J. Cromomatog., 146, pl, 1978).

Coloration: Measure absorbance at wavelengths of 280 nm, ₃₅₀ nm, ₄₅₀ nm and 500 nm, A _35Q / A ₂₈ . A ₄₅ . No A ₂₈ . , A _5. . Were each calculated ZA _280.

Pyrogens: Seikagaku's Endoscopy was used. Table 8 shows all the measurement results.

[Table 8] J¾

 Π 1 L then π A ττ

 Yeast-derived component (protein equivalent) 0.1 ng or less

 (Polysaccharide conversion) Less than 1 ng / mL

 Molecule about 6/000

 R @ »about 4.9

 'c ix. \ 3 5 o / A 2 8 0' About 0.0 1 5

(A ₄₅₀ A approx.0.0 1

(A ₅ o 0 ^ A 2 go) About 0.002

Pyrogen less than 0.5 E U

 (per r H S A 250 mg)

The rHSA-containing composition was used in Examples and Experimental Examples of the present invention. Industrial applicability

According to the present invention, recombinant HSA and a nonionic surfactant are added to a liquid preparation for injection of IFN to adjust the pH to a specific range (pH 6.5 to 7.5). However, it is possible to suppress a decrease in the IFNα titer over a long period of time and maintain a high degree of stability. In particular, it suppresses the formation of aggregates or precipitates during long-term storage, and solves the problems specific to IFNa-injectable liquid preparations supplemented with recombinant HS. The preparation of the present invention is a stable liquid preparation for injection that can be stored for a long period of time and has the advantage that it does not need to be dissolved in a solvent before use and can be easily administered to patients. According to the present invention, it is possible to provide a stable liquid preparation for injection containing IFN containing the same subtype as that produced in a human body, and which can be stored for a long period of time. In addition, recombinant HSA is expected to be suitable in terms of both quantity and quality, as recombinant HSA can be supplied more uniformly and more uniformly than plasma-derived HSA. Is done.

Claims

The scope of the claims

1. In a liquid preparation for injection of interferon α containing recombinant human serum albumin and a nonionic surfactant and having a pH of 6.5 to 7.5, recombinant human serum albumin was used. A method for stabilizing interferon.

 2. The method for stabilizing interferon alpha according to claim 1, wherein a stabilizer for recombinant human serum albumin is added to the preparation.

3. amount of recombinant human serum albumin, LXL 0 per ⁶ IU of interferon, 0.0 5: I centers interferon α method for stabilizing the range first or second claim of claim is L mg .

4. The addition amount of the nonionic surfactant, interferon Hino 1 X 1 0 per ^{6 IU, 0. 0 0 1~ 1} 0 mg a according to any one of claims the first to third term is How to stabilize the interface α.

5. The method according to claim 4, wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester.

 6. The method for stabilizing interferon α according to claim 5, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.

7. The addition amount of the stabilizer of recombinant human serum albumin, interferon Eron 1 X 1 0 per ⁶ IU of α, 0, 0 1~; L 0 mg a is according range囲第2 of 6 Section Stabilization method of interfuron α according to any one of the above.

8. The method according to claim 7, wherein the stabilizing agent for the recombinant human serum albumin is selected from acetyltryptophan or a salt thereof, caprylic acid or a salt thereof and used alone or in combination. A method for stabilizing interferon α.

9. The method for stabilizing interferon according to claims 1 to 8, wherein the pH is adjusted to 6.8 to 7.1.

 10. A liquid preparation for injection of interferon sp. Prepared by introducing the method of stabilizing interferon sp. According to claims 1 to 9.

1 1. A liquid preparation for injection of interferon, which comprises interferon, recombinant human serum albumin and a non-ionic surfactant, and has an H of 6.5 to 7.5.

 1 2. The liquid preparation for injection of interferon α according to claim 11, which contains a stabilizer for recombinant human serum albumin.

 1 3. The liquid preparation for injecting interferon according to claim 11, wherein said preparation is filled in a vial or a syringe.