CA2217388A1 - Composition of tyrosine and polymerised allergen - Google Patents
Composition of tyrosine and polymerised allergen Download PDFInfo
- Publication number
- CA2217388A1 CA2217388A1 CA002217388A CA2217388A CA2217388A1 CA 2217388 A1 CA2217388 A1 CA 2217388A1 CA 002217388 A CA002217388 A CA 002217388A CA 2217388 A CA2217388 A CA 2217388A CA 2217388 A1 CA2217388 A1 CA 2217388A1
- Authority
- CA
- Canada
- Prior art keywords
- allergen
- tyrosine
- solution
- polymerised
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/35—Allergens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/35—Allergens
- A61K39/36—Allergens from pollen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition comprising tyrosine and a polymerised allergen is prepared by (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier.
Description
W O 96/34626 PCT~EP96/01733 COMPOSITION OF TYROSINE AND POLYMERISED ALLERGEN
This invention relates to novel compositions for use in deseneitie~tion therapy 5 of allergy ~urrele,s.
GB-A- 1 4g2 973 describes a process for preparing coprecipitates of tyrosine ,~ having a modified allergen dispersed therein. The allergen has been modified by treatment with an agent, such as glutaraldehyde, which causes intra-molecular cross-linking and reduces the allergenicity of the product relative to the unmodified 10 allergen.
EP-A-0 367 306 and Nakada et al (Allergy, 54 ~1985~ 437 et seq.) describe processes for preparing polymerised allergens by prolonged treatment with a cross-linking agent to cause intermolecular cross-linking, followed by filtration or dialysis to remove unpolymerised product. The polymeAsed allergens are described as having 15 reduced allergenicity.
According to the present invention there is provided a pharm~ceutic~l composition comprising tyrosine and a polymerieed allergen. Typically. the allergen is coated with and /or adsorbed onto tyrosine, for example by co-precipitation.
The allergen may be derived from any allergy c~lleing substance, such as a 20 pollen (e.g. ragweed or birch pollen), food, insect venom, mould. animal fur, or house dust mite (D. farinae or D. pteronyssinus). In a particular aspect the allergen is derived from D. pteronyssinus. As used herein, "allergen" includes a mixture of allergens which may be from a single source or more than one source.
A further aspect of the invention provides a process for the preparation of a 25 pharm~eutic~l composition in accordance with the invention, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically accepta~le carrier.
Suitable physiologically acceptable carriers include phenol~ ne and sterile water.
The allergen is polymerised by treatment with a dialdehyde such as glutaraldehyde, in aqueous solution at a pH of 3 to 10, typically 7~1 ~nd a temperature of between 0 and lO0 ~C, typically between 4 and 37 ~C. for up to 10f 35 hours, for example about two hours at room temperature. The ratio of allergen to " glutaraldehyde is typically in the range 1:25 to 1:2, forexample about 1:4 w/w, although higher allergen ratios may be used in conjunction with a longer reaction time (see for instance EP-A-0 367 306, which uses ratios of about 3:l and a reaction time of about seven hours).
Low molecular weight product is then remQved by gel filtration or dialysis, for example, tangential flow dialysis, and the product freeze dried or used directly in the next stage. The molecular weight cut off is typically at least 100 kDaltons, for example at least 250 kDaltons, more preferably 300 kDaltons.
A solution of the polymerised allergen at pH 7+1, obtained either as the reaction mixture from the polymerisation process or from the solvation of a solid, is then mixed with a solution of tyrosine in a strong aqueous acid. The strong acid is ~-usually an inorganic acid, preferably hydrochloric acid. The solution of polymerised allergen used in this step typically contains between 0.1 ~g/ml and 100 ~lg/ml allergen protein. The ratio of allergen: tyrosine in the mixture is typically in the range 1:4 x 105 to 1:4 x 102 w/w.
The resulting mixture of solutions of allergen and tyrosine is neutralised. By neutralisation is meant an adjustment of pH to a value within the range 4.0 to 7.5. It is important that, at no time, or at least at no prolonged time, during the neutralisation does the pH of the solution rise appreciably above 7.5. This condition can be met by vigorous stirring of the solution and by the use only of the required amount of base, if desired. Various buffering agents can usefully be added to the solutions of allergen to assist in pH control during the mixing and neutr~li.cing stages.
A particularly useful method of carrying out the neutralisation is for separate streams of the solution of tyrosine in acid and the neutralising base to be run into the solution of allergen. The rates of flow of the added solutions are controlled by pH-state, that is by equipment which regulates the flow of one or both of the solutions so that the pH of the reaction mixture remains substantially constant at a predetermined level. We have found that optimum results are usually obtained by pH control within the range 6.5 to 7.5 though the precise pH may vary according to th~ nature of the allergen.
The result of the neutralisation is the immediate precipitation of the tyrosine,within and/or upon which the solution of allergen is occluded anli/or ~sorbed. After the precipitation the mixture is either washed immediately or allowed to stand for a period of from a few hours to a day or two prior to washing. Desir3t-ly the precipitate is obtained as fine as possible and this is achieved by rapid neutrallsat on of the solution coupled with vigorous agitation while this is being carried ou~.
The resulting precipitate may be removed from the solution hy centrifugation or filtration and washed, e.g. with phenol-saline, before being resuspcnded in aphysiologically-acceptable carrier such as phenol-saline, or sterile water. to produce ~yJ
an injectable composition suitable for use in desencitication therapy.
The following Example illustrates the present invention:
W O 96/34626 PCT~EP96/01733 Example A neutral solution of approximately 2.~ mg/ml D. pteronyssinus extract protein which had been partially purified by dialysis or fractionation was polymerised 5 by the addition of an equal volume of 1% w/v glutaraldehyde and the mixture stirred for approximately 2 hours at room temperature. The reaction was quenched by the addition of an equal volume of 2% w/v glycine and the mixture stirred for a further one hour at room temperature. Low molecular weight material was removed by diafiltration across a membrane with a molecular weight exclusion of 300 kDaltons.
10 The mixture was then sterile filtered and freeze dried.
A solution of the polymerised allergen was prepared either directly from the sterile filtered solution or by reconstitution of the freeze dried solid. This solution cont~inPd 10~1g/ml in phosphate buffer pH 7+1. The allergen solution was co-precipitated with tyrosine by the simultaneous addition of one volume of L-tyrosine in HCI (prepared by dissolving 24g L-tyrosine to 100ml with 3.4M HCI) and one volume of 3.2M NaOH, to four volumes of allergen solution, with vigorous agitation.
The suspension so formed was centrifuged, washed repeatedly with buffered saline to remove cont~min~nts and resuspended to the original volume in buffered saline pH6 +1.
This invention relates to novel compositions for use in deseneitie~tion therapy 5 of allergy ~urrele,s.
GB-A- 1 4g2 973 describes a process for preparing coprecipitates of tyrosine ,~ having a modified allergen dispersed therein. The allergen has been modified by treatment with an agent, such as glutaraldehyde, which causes intra-molecular cross-linking and reduces the allergenicity of the product relative to the unmodified 10 allergen.
EP-A-0 367 306 and Nakada et al (Allergy, 54 ~1985~ 437 et seq.) describe processes for preparing polymerised allergens by prolonged treatment with a cross-linking agent to cause intermolecular cross-linking, followed by filtration or dialysis to remove unpolymerised product. The polymeAsed allergens are described as having 15 reduced allergenicity.
According to the present invention there is provided a pharm~ceutic~l composition comprising tyrosine and a polymerieed allergen. Typically. the allergen is coated with and /or adsorbed onto tyrosine, for example by co-precipitation.
The allergen may be derived from any allergy c~lleing substance, such as a 20 pollen (e.g. ragweed or birch pollen), food, insect venom, mould. animal fur, or house dust mite (D. farinae or D. pteronyssinus). In a particular aspect the allergen is derived from D. pteronyssinus. As used herein, "allergen" includes a mixture of allergens which may be from a single source or more than one source.
A further aspect of the invention provides a process for the preparation of a 25 pharm~eutic~l composition in accordance with the invention, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically accepta~le carrier.
Suitable physiologically acceptable carriers include phenol~ ne and sterile water.
The allergen is polymerised by treatment with a dialdehyde such as glutaraldehyde, in aqueous solution at a pH of 3 to 10, typically 7~1 ~nd a temperature of between 0 and lO0 ~C, typically between 4 and 37 ~C. for up to 10f 35 hours, for example about two hours at room temperature. The ratio of allergen to " glutaraldehyde is typically in the range 1:25 to 1:2, forexample about 1:4 w/w, although higher allergen ratios may be used in conjunction with a longer reaction time (see for instance EP-A-0 367 306, which uses ratios of about 3:l and a reaction time of about seven hours).
Low molecular weight product is then remQved by gel filtration or dialysis, for example, tangential flow dialysis, and the product freeze dried or used directly in the next stage. The molecular weight cut off is typically at least 100 kDaltons, for example at least 250 kDaltons, more preferably 300 kDaltons.
A solution of the polymerised allergen at pH 7+1, obtained either as the reaction mixture from the polymerisation process or from the solvation of a solid, is then mixed with a solution of tyrosine in a strong aqueous acid. The strong acid is ~-usually an inorganic acid, preferably hydrochloric acid. The solution of polymerised allergen used in this step typically contains between 0.1 ~g/ml and 100 ~lg/ml allergen protein. The ratio of allergen: tyrosine in the mixture is typically in the range 1:4 x 105 to 1:4 x 102 w/w.
The resulting mixture of solutions of allergen and tyrosine is neutralised. By neutralisation is meant an adjustment of pH to a value within the range 4.0 to 7.5. It is important that, at no time, or at least at no prolonged time, during the neutralisation does the pH of the solution rise appreciably above 7.5. This condition can be met by vigorous stirring of the solution and by the use only of the required amount of base, if desired. Various buffering agents can usefully be added to the solutions of allergen to assist in pH control during the mixing and neutr~li.cing stages.
A particularly useful method of carrying out the neutralisation is for separate streams of the solution of tyrosine in acid and the neutralising base to be run into the solution of allergen. The rates of flow of the added solutions are controlled by pH-state, that is by equipment which regulates the flow of one or both of the solutions so that the pH of the reaction mixture remains substantially constant at a predetermined level. We have found that optimum results are usually obtained by pH control within the range 6.5 to 7.5 though the precise pH may vary according to th~ nature of the allergen.
The result of the neutralisation is the immediate precipitation of the tyrosine,within and/or upon which the solution of allergen is occluded anli/or ~sorbed. After the precipitation the mixture is either washed immediately or allowed to stand for a period of from a few hours to a day or two prior to washing. Desir3t-ly the precipitate is obtained as fine as possible and this is achieved by rapid neutrallsat on of the solution coupled with vigorous agitation while this is being carried ou~.
The resulting precipitate may be removed from the solution hy centrifugation or filtration and washed, e.g. with phenol-saline, before being resuspcnded in aphysiologically-acceptable carrier such as phenol-saline, or sterile water. to produce ~yJ
an injectable composition suitable for use in desencitication therapy.
The following Example illustrates the present invention:
W O 96/34626 PCT~EP96/01733 Example A neutral solution of approximately 2.~ mg/ml D. pteronyssinus extract protein which had been partially purified by dialysis or fractionation was polymerised 5 by the addition of an equal volume of 1% w/v glutaraldehyde and the mixture stirred for approximately 2 hours at room temperature. The reaction was quenched by the addition of an equal volume of 2% w/v glycine and the mixture stirred for a further one hour at room temperature. Low molecular weight material was removed by diafiltration across a membrane with a molecular weight exclusion of 300 kDaltons.
10 The mixture was then sterile filtered and freeze dried.
A solution of the polymerised allergen was prepared either directly from the sterile filtered solution or by reconstitution of the freeze dried solid. This solution cont~inPd 10~1g/ml in phosphate buffer pH 7+1. The allergen solution was co-precipitated with tyrosine by the simultaneous addition of one volume of L-tyrosine in HCI (prepared by dissolving 24g L-tyrosine to 100ml with 3.4M HCI) and one volume of 3.2M NaOH, to four volumes of allergen solution, with vigorous agitation.
The suspension so formed was centrifuged, washed repeatedly with buffered saline to remove cont~min~nts and resuspended to the original volume in buffered saline pH6 +1.
Claims (7)
1. A pharmaceutical composition comprising tyrosine and a polymerised allergen.
2. A composition according to claim 1 wherein the allergen is coated with and/or adsorbed onto tyrosine.
3. A composition according to claim 1 or 2 wherein the allergen is derived from D. pteronyssinus.
4. A process for the preparation of a pharmaceutical composition according to any one of the preceding claims, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier.
5. A composition according to any one of claims 1 to 3, for use in therapy.
6. A composition according to any one of claims 1 to 3, for use in desensitization therapy of allergy sufferers.
7. Use of a composition according to any one of claims 1 to 3 in the manufacture of a medicament for use in desensitization therapy of allergy sufferers.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9508785.4 | 1995-04-29 | ||
| GBGB9508785.4A GB9508785D0 (en) | 1995-04-29 | 1995-04-29 | Novel compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2217388A1 true CA2217388A1 (en) | 1996-11-07 |
Family
ID=10773769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002217388A Abandoned CA2217388A1 (en) | 1995-04-29 | 1996-04-25 | Composition of tyrosine and polymerised allergen |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0825874A1 (en) |
| JP (1) | JPH11504338A (en) |
| KR (1) | KR19990008120A (en) |
| CN (1) | CN1132629C (en) |
| AU (1) | AU705873B2 (en) |
| BG (1) | BG63990B1 (en) |
| BR (1) | BR9608123A (en) |
| CA (1) | CA2217388A1 (en) |
| CZ (1) | CZ288401B6 (en) |
| EA (1) | EA199700271A1 (en) |
| GB (1) | GB9508785D0 (en) |
| HK (1) | HK1010834A1 (en) |
| HU (1) | HUP9802237A3 (en) |
| NO (1) | NO974893L (en) |
| NZ (1) | NZ308080A (en) |
| PL (1) | PL183484B1 (en) |
| SK (1) | SK281877B6 (en) |
| TR (1) | TR199701265T1 (en) |
| WO (1) | WO1996034626A1 (en) |
| ZA (1) | ZA963340B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9706957D0 (en) * | 1997-04-05 | 1997-05-21 | Smithkline Beecham Plc | Formulation |
| GB9820525D0 (en) | 1998-09-21 | 1998-11-11 | Allergy Therapeutics Ltd | Formulation |
| GB0000891D0 (en) | 2000-01-14 | 2000-03-08 | Allergy Therapeutics Ltd | Formulation |
| GB201106802D0 (en) * | 2011-04-21 | 2011-06-01 | Allergy Therapeutics Ltd | Process for preparing vaccine composition |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1377074A (en) * | 1971-07-13 | 1974-12-11 | Beecham Group Ltd | Process for preparing injectable compositions |
| US4070455A (en) * | 1974-02-16 | 1978-01-24 | Beecham Group Limited | Process for preparing injectable desensitizing compositions and products thereof in microparticle form |
| EP0058021A3 (en) * | 1981-02-06 | 1982-10-27 | Beecham Group Plc | Pharmaceutical compositions |
| ES2013359A6 (en) * | 1988-11-04 | 1990-05-01 | Corporacion Biolog Farmaceutic | Procedure for polymerized allergenis production. |
-
1995
- 1995-04-29 GB GBGB9508785.4A patent/GB9508785D0/en active Pending
-
1996
- 1996-04-25 AU AU57616/96A patent/AU705873B2/en not_active Expired
- 1996-04-25 EA EA199700271A patent/EA199700271A1/en unknown
- 1996-04-25 WO PCT/EP1996/001733 patent/WO1996034626A1/en not_active Application Discontinuation
- 1996-04-25 KR KR1019970707645A patent/KR19990008120A/en not_active Application Discontinuation
- 1996-04-25 HU HU9802237A patent/HUP9802237A3/en unknown
- 1996-04-25 JP JP8532981A patent/JPH11504338A/en active Pending
- 1996-04-25 PL PL96323104A patent/PL183484B1/en unknown
- 1996-04-25 TR TR97/01265T patent/TR199701265T1/en unknown
- 1996-04-25 BR BR9608123A patent/BR9608123A/en not_active Application Discontinuation
- 1996-04-25 CA CA002217388A patent/CA2217388A1/en not_active Abandoned
- 1996-04-25 CZ CZ19973429A patent/CZ288401B6/en not_active IP Right Cessation
- 1996-04-25 CN CN96193592A patent/CN1132629C/en not_active Expired - Lifetime
- 1996-04-25 EP EP96914124A patent/EP0825874A1/en not_active Withdrawn
- 1996-04-25 SK SK1461-97A patent/SK281877B6/en not_active IP Right Cessation
- 1996-04-25 NZ NZ308080A patent/NZ308080A/en not_active IP Right Cessation
- 1996-04-26 ZA ZA963340A patent/ZA963340B/en unknown
-
1997
- 1997-10-23 NO NO974893A patent/NO974893L/en not_active Application Discontinuation
- 1997-10-29 BG BG102004A patent/BG63990B1/en unknown
-
1998
- 1998-11-20 HK HK98112143A patent/HK1010834A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1132629C (en) | 2003-12-31 |
| PL323104A1 (en) | 1998-03-16 |
| JPH11504338A (en) | 1999-04-20 |
| AU705873B2 (en) | 1999-06-03 |
| BG63990B1 (en) | 2003-09-30 |
| CZ288401B6 (en) | 2001-06-13 |
| BG102004A (en) | 1998-11-30 |
| CZ342997A3 (en) | 1998-03-18 |
| PL183484B1 (en) | 2002-06-28 |
| NZ308080A (en) | 1999-05-28 |
| NO974893D0 (en) | 1997-10-23 |
| HUP9802237A2 (en) | 1999-02-01 |
| TR199701265T1 (en) | 1998-02-21 |
| KR19990008120A (en) | 1999-01-25 |
| HK1010834A1 (en) | 1999-07-02 |
| CN1183046A (en) | 1998-05-27 |
| AU5761696A (en) | 1996-11-21 |
| SK146197A3 (en) | 1998-05-06 |
| SK281877B6 (en) | 2001-08-06 |
| GB9508785D0 (en) | 1995-06-21 |
| NO974893L (en) | 1997-10-23 |
| EA199700271A1 (en) | 1998-04-30 |
| WO1996034626A1 (en) | 1996-11-07 |
| ZA963340B (en) | 1997-03-27 |
| HUP9802237A3 (en) | 2000-06-28 |
| EP0825874A1 (en) | 1998-03-04 |
| BR9608123A (en) | 1999-02-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |