CN1132629C - Composition of tyrosine and polymerised allergen - Google Patents
Composition of tyrosine and polymerised allergen Download PDFInfo
- Publication number
- CN1132629C CN1132629C CN96193592A CN96193592A CN1132629C CN 1132629 C CN1132629 C CN 1132629C CN 96193592 A CN96193592 A CN 96193592A CN 96193592 A CN96193592 A CN 96193592A CN 1132629 C CN1132629 C CN 1132629C
- Authority
- CN
- China
- Prior art keywords
- tyrosine
- anaphylactin
- solution
- allergen
- compositions
- 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.)
- Expired - Lifetime
Links
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title claims abstract description 21
- 239000013566 allergen Substances 0.000 title claims abstract description 14
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 title description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 25
- 239000000243 solution Substances 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- 241000238740 Dermatophagoides pteronyssinus Species 0.000 claims description 5
- 238000006116 polymerization reaction Methods 0.000 claims description 5
- 238000000975 co-precipitation Methods 0.000 claims description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 3
- 230000036783 anaphylactic response Effects 0.000 claims description 3
- 208000003455 anaphylaxis Diseases 0.000 claims description 3
- 238000000586 desensitisation Methods 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 abstract description 2
- 239000011260 aqueous acid Substances 0.000 abstract 1
- 229960004441 tyrosine Drugs 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 235000003932 Betula Nutrition 0.000 description 1
- 241000219429 Betula Species 0.000 description 1
- 235000000509 Chenopodium ambrosioides Nutrition 0.000 description 1
- 244000098897 Chenopodium botrys Species 0.000 description 1
- 235000005490 Chenopodium botrys Nutrition 0.000 description 1
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 230000000774 hypoallergenic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
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
Landscapes
- 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
The present invention relates to be used for the new compositions of anaphylaxis patient's desensitization treatment.
GB-A-1492973 has described and has prepared a kind of method that is dispersed with the tyrosine coprecipitate of modification anaphylactin.This anaphylactin has used a kind of reagent (for example glutaraldehyde) to handle and modification, makes interior molecules crosslinked and reduced the anaphylaxis of product with respect to unmodified anaphylactin.
People such as EP-A-0367306 and Nakada (Allergy, 54[1985] 437 et seq.) has described the method for preparing polymeric anaphylactin.Thereby these methods are prolongations makes intermolecular cross-linking with the cross-linking agent processing time, and then unpolymerized product is removed in filtration or dialysis.This polymeric anaphylactin has hypoallergenic.
The invention provides a kind of pharmaceutical composition that contains tyrosine and polymerised allergen.This anaphylactin is for example used coprecipitation method usually with the tyrosine coating or be adsorbed on the tyrosine.
This anaphylactin can cause that material hypersensitive derives from any, for example from pollen (as Ambrosia or Betula pollen), food, insecticide venom, mycete, and animal skin, or house dust small worm (D.farnae or dermatophagoides pteronyssinus (D.pteronyssinus)).This anaphylactin is particularly deutero-from D.pteronyssinus.Here said " anaphylactin " comprises it can being single source or more than a kind of anaphylactin mixture of source.
Another aspect of the present invention provides the method for preparing pharmaceutical composition of the present invention, this method comprises: (a) with the anaphylactin polymerization, (b) aqueous solution of this anaphylactin is mixed with tyrosine solution in moisture strong acid, (c) with this solution mixture neutralization, make tyrosine and polymerised allergen co-precipitation therefrom and (d) randomly this product is mixed with the physiology acceptable carrier.
Suitable physiology acceptable carrier comprises phenol saline and sterilized water.
By at pH3-10, general 7 ± 1 and 0-100 ℃, under general 4-37 ℃ the temperature, reach 10 hours with dialdehyde (for example glutaraldehyde) processing, for example at room temperature handled about 2 hours, with this anaphylactin polymerization.The ratio of anaphylactin and glutaraldehyde generally is 1: 25-1: 2 scope, for example about 1: 4 (w/w), but can use higher anaphylactin ratio (for example seeing EP-A-0367306) with the longer response time, it is about 7 hours that the document has been used about 3: 1 ratio and response time).
By gel filtration or dialysis, low molecular weight product is removed in for example slipstream dialysis then.This product lyophilization or be directly used in next stage.Molecular weight is generally limit at least 100 kilodaltons, for example at least 250 kilodaltons, more preferably 300 kilodaltons.
Then, with obtain as reactant mixture in the polymerization process or to be 7 ± 1 polymerised allergen solution from the pH that solid solvation obtains mix with tyrosine solution moisture strong acid.This strong acid is mineral acid normally, preferred hydrochloric acid.The anaphylactin albumen that generally contains 0.1 μ g/ml-100 μ g/ml at the polymerised allergen solution of this step use.Anaphylactin in this mixture: the ratio of tyrosine is generally 1: 4 * 10
5-1: 4 * 10
2Scope (w/w).
The mixture of resulting anaphylactin and tyrosine solution neutralizes." neutralization " is meant pH regulator in the scope of 4.0-7.5.Importantly, during neutralizing, the pH of this solution can not or can not be elevated to more than 7.5 in for a long time any time at least significantly.By stirring this solution tempestuously, and if desired, can satisfy this condition by the alkali that only uses requirement.Various buffer agents can be joined in the anaphylactin solution effectively, mix and neutralization stage control pH so that help.
Carrying out neutral useful especially method is that tyrosine solution and neutralization bases liquid stream in acid are separately flow in the solution of anaphylactin.With the speed of pH control adding liquid stream, promptly regulate the flow of one or two solution by an equipment, cause the pH of reactant mixture to be substantially constant on the scheduled volume.We find, by obtaining optimum usually in the scope that pH is controlled at 6.5-7.5, although accurate pH can change according to the character of anaphylactin.
Neutral result is that the anaphylactin solution that is mingled with in tyrosine and/or adsorbs on tyrosine precipitates immediately.Post precipitation perhaps washs this mixture immediately, perhaps allows it leave standstill several hours-1 or 2 day time before washing.Preferably obtain thin as far as possible precipitate, this can realize by cooperating vigorous stirring and quick this solution of neutralization.
Thereby it is resuspended in the physiology acceptable carrier for example produce in phenol saline or the sterilized water be applicable to the injectable compositions of desensitization treatment before, by centrifugalize or filtration and washing (for example using phenol saline), can from solution, isolate resulting precipitation.
The following examples explanation the present invention.
Embodiment
With by dialysis or fractional distillation and the D.pteronyssinus of partially purified about 2.5mg/ml extracts proteic neutral solution by adding isopyknic 1% (w/v) glutaraldehyde and making its polymerization in about 2 hours at this mixture of stirring at room.This reaction is by adding isopyknic 2% (w/v) glycine and at room temperature this mixture restir being made reaction stop in 1 hour.Remove by filter low molecular weight substance by the film dialysis that can get rid of 300 kilodalton molecular weight.Then with this mixture filtration sterilization and lyophilization.
Perhaps, perhaps, prepare this polymerised allergen solution again by this cryodesiccated solid directly from the solution of sterilising filtration.This solution contains 10 μ g/ml in the phosphate buffer of pH7 ± 1.Under vigorous stirring, simultaneously L-tyrosine (by L-tyrosine with 24g with 3.4M HCl be dissolved into 100ML preparation) and the 3.2M NaOH of 1 volume of 1 volume in HCl joined in the anaphylactin solution of 4 volumes, make this anaphylactin solution and tyrosine co-precipitation.Form suspension like this, centrifugalize, repeatedly wash, so that remove impurity and resuspending in the buffer saline of pH6 ± 1 of beginning volume with buffer saline.
Claims (6)
1. pharmaceutical composition that contains tyrosine and polymerised allergen, wherein the molecular weight of polymerised allergen is at least 100kD.
2. according to the compositions of claim 1, wherein this anaphylactin is with the tyrosine coating and/or be attracted on the tyrosine.
3. according to the compositions of claim 1 or 2, wherein this anaphylactin is deutero-from dermatophagoides pteronyssinus.
4. each compositions among the claim 1-3 that is used for the treatment of.
5. method for preparing each pharmaceutical composition in the aforementioned claim, this method comprises: (a) with the anaphylactin polymerization, (b) aqueous solution of this anaphylactin is mixed with tyrosine solution in moisture strong acid, (c) with this solution mixture neutralization, make tyrosine and polymerised allergen co-precipitation therefrom and (d) randomly this product is mixed with the physiology acceptable carrier.
6. each compositions is used for the purposes of the medicine of anaphylaxis patient desensitization treatment among the claim 1-4 in preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9508785.4A GB9508785D0 (en) | 1995-04-29 | 1995-04-29 | Novel compositions |
| GB9508785.4 | 1995-04-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1183046A CN1183046A (en) | 1998-05-27 |
| CN1132629C true CN1132629C (en) | 2003-12-31 |
Family
ID=10773769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96193592A Expired - Lifetime CN1132629C (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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070455A (en) * | 1974-02-16 | 1978-01-24 | Beecham Group Limited | Process for preparing injectable desensitizing compositions and products thereof in microparticle form |
| EP0058021A2 (en) * | 1981-02-06 | 1982-08-18 | Beecham Group Plc | Pharmaceutical compositions |
| EP0367306A2 (en) * | 1988-11-04 | 1990-05-09 | Corporacion Biologica Farmaceutica, Sa (C.B.F. , S.A.) | Procedure for polymerized allergenis production |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1377074A (en) * | 1971-07-13 | 1974-12-11 | Beecham Group Ltd | Process for preparing injectable compositions |
-
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 TR TR97/01265T patent/TR199701265T1/en unknown
- 1996-04-25 SK SK1461-97A patent/SK281877B6/en not_active IP Right Cessation
- 1996-04-25 JP JP8532981A patent/JPH11504338A/en active Pending
- 1996-04-25 EA EA199700271A patent/EA199700271A1/en unknown
- 1996-04-25 CZ CZ19973429A patent/CZ288401B6/en not_active IP Right Cessation
- 1996-04-25 BR BR9608123A patent/BR9608123A/en not_active Application Discontinuation
- 1996-04-25 EP EP96914124A patent/EP0825874A1/en not_active Withdrawn
- 1996-04-25 WO PCT/EP1996/001733 patent/WO1996034626A1/en not_active Application Discontinuation
- 1996-04-25 NZ NZ308080A patent/NZ308080A/en not_active IP Right Cessation
- 1996-04-25 CN CN96193592A patent/CN1132629C/en not_active Expired - Lifetime
- 1996-04-25 CA CA002217388A patent/CA2217388A1/en not_active Abandoned
- 1996-04-25 KR KR1019970707645A patent/KR19990008120A/en not_active Application Discontinuation
- 1996-04-25 PL PL96323104A patent/PL183484B1/en unknown
- 1996-04-25 HU HU9802237A patent/HUP9802237A3/en unknown
- 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
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070455A (en) * | 1974-02-16 | 1978-01-24 | Beecham Group Limited | Process for preparing injectable desensitizing compositions and products thereof in microparticle form |
| EP0058021A2 (en) * | 1981-02-06 | 1982-08-18 | Beecham Group Plc | Pharmaceutical compositions |
| EP0367306A2 (en) * | 1988-11-04 | 1990-05-09 | Corporacion Biologica Farmaceutica, Sa (C.B.F. , S.A.) | Procedure for polymerized allergenis production |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9608123A (en) | 1999-02-09 |
| JPH11504338A (en) | 1999-04-20 |
| SK146197A3 (en) | 1998-05-06 |
| BG102004A (en) | 1998-11-30 |
| HK1010834A1 (en) | 1999-07-02 |
| AU5761696A (en) | 1996-11-21 |
| EA199700271A1 (en) | 1998-04-30 |
| CZ288401B6 (en) | 2001-06-13 |
| TR199701265T1 (en) | 1998-02-21 |
| CN1183046A (en) | 1998-05-27 |
| PL323104A1 (en) | 1998-03-16 |
| AU705873B2 (en) | 1999-06-03 |
| NO974893D0 (en) | 1997-10-23 |
| BG63990B1 (en) | 2003-09-30 |
| KR19990008120A (en) | 1999-01-25 |
| CA2217388A1 (en) | 1996-11-07 |
| WO1996034626A1 (en) | 1996-11-07 |
| PL183484B1 (en) | 2002-06-28 |
| NO974893L (en) | 1997-10-23 |
| NZ308080A (en) | 1999-05-28 |
| HUP9802237A3 (en) | 2000-06-28 |
| GB9508785D0 (en) | 1995-06-21 |
| SK281877B6 (en) | 2001-08-06 |
| CZ342997A3 (en) | 1998-03-18 |
| ZA963340B (en) | 1997-03-27 |
| EP0825874A1 (en) | 1998-03-04 |
| HUP9802237A2 (en) | 1999-02-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term |
Granted publication date: 20031231 |
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| EXPY | Termination of patent right or utility model |