AU5761696A - Composition of tyrosine and polymerised allergen - Google Patents
Composition of tyrosine and polymerised allergenInfo
- Publication number
- AU5761696A AU5761696A AU57616/96A AU5761696A AU5761696A AU 5761696 A AU5761696 A AU 5761696A AU 57616/96 A AU57616/96 A AU 57616/96A AU 5761696 A AU5761696 A AU 5761696A AU 5761696 A AU5761696 A AU 5761696A
- Authority
- AU
- Australia
- Prior art keywords
- allergen
- tyrosine
- solution
- composition according
- polymerised
- 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.)
- Granted
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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
Description
COMPOSITION OF TYROSINE AND POLYMERISED ALLERGEN
This invention relates to novel compositions for use in desensitisation therapy of allergy sufferers.
GB-A-1 492 973 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 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 polymerised allergens are described as having reduced allergenicity.
According to the present invention there is provided a pharmaceutical composition comprising tyrosine and a polymerised 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 causing substance, such as a 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 pharmaceutical 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 acceptable carrier. Suitable physiologically acceptable carriers include phenol-saline 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 and a temperature of between 0 and 100 °C, typically between 4 and 37 °C. for up to 10 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, for example 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 3:1 and a reaction time of about seven hours).
Low molecular weight product is then removed 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 μg ml and 100 μg/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 neutralising 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 the 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 and/or adsorbed. 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. Desirably the precipitate is obtained as fine as possible and this is achieved by rapid neutralisation of the solution coupled with vigorous agitation while this is being carried out.
The resulting precipitate may be removed from the solution by centrifugation or filtration and washed, e.g. with phenol-saline, before being resuspended in a physiologically-acceptable carrier such as phenol-saline, or sterile water, to produce an injectable composition suitable for use in desensitisation therapy.
The following Example illustrates the present invention:
Example
A neutral solution of approximately 2.5 mg/ml D. pteronyssinus extract protein which had been partially purified by dialysis or fractionation was polymerised 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. 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 contained lOμg/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 HCl (prepared by dissolving 24g L-tyrosine to 100ml with 3.4M HCl) 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 contaminants 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 (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9508785 | 1995-04-29 | ||
GBGB9508785.4A GB9508785D0 (en) | 1995-04-29 | 1995-04-29 | Novel compositions |
PCT/EP1996/001733 WO1996034626A1 (en) | 1995-04-29 | 1996-04-25 | Composition of tyrosine and polymerised allergen |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5761696A true AU5761696A (en) | 1996-11-21 |
AU705873B2 AU705873B2 (en) | 1999-06-03 |
Family
ID=10773769
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU57616/96A Expired AU705873B2 (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 CN CN96193592A patent/CN1132629C/en not_active Expired - Lifetime
- 1996-04-25 EA EA199700271A patent/EA199700271A1/en unknown
- 1996-04-25 HU HU9802237A patent/HUP9802237A3/en unknown
- 1996-04-25 SK SK1461-97A patent/SK281877B6/en not_active IP Right Cessation
- 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 EP EP96914124A patent/EP0825874A1/en not_active Withdrawn
- 1996-04-25 PL PL96323104A patent/PL183484B1/en unknown
- 1996-04-25 CZ CZ19973429A patent/CZ288401B6/en not_active IP Right Cessation
- 1996-04-25 CA CA002217388A patent/CA2217388A1/en not_active Abandoned
- 1996-04-25 TR TR97/01265T patent/TR199701265T1/en unknown
- 1996-04-25 KR KR1019970707645A patent/KR19990008120A/en not_active Application Discontinuation
- 1996-04-25 JP JP8532981A patent/JPH11504338A/en active Pending
- 1996-04-25 AU AU57616/96A patent/AU705873B2/en not_active Expired
- 1996-04-25 BR BR9608123A patent/BR9608123A/en not_active Application Discontinuation
- 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 |
---|---|
EA199700271A1 (en) | 1998-04-30 |
NZ308080A (en) | 1999-05-28 |
BG63990B1 (en) | 2003-09-30 |
EP0825874A1 (en) | 1998-03-04 |
ZA963340B (en) | 1997-03-27 |
KR19990008120A (en) | 1999-01-25 |
PL323104A1 (en) | 1998-03-16 |
CN1132629C (en) | 2003-12-31 |
HK1010834A1 (en) | 1999-07-02 |
NO974893D0 (en) | 1997-10-23 |
TR199701265T1 (en) | 1998-02-21 |
HUP9802237A2 (en) | 1999-02-01 |
CN1183046A (en) | 1998-05-27 |
AU705873B2 (en) | 1999-06-03 |
JPH11504338A (en) | 1999-04-20 |
WO1996034626A1 (en) | 1996-11-07 |
BG102004A (en) | 1998-11-30 |
SK281877B6 (en) | 2001-08-06 |
BR9608123A (en) | 1999-02-09 |
HUP9802237A3 (en) | 2000-06-28 |
CA2217388A1 (en) | 1996-11-07 |
CZ342997A3 (en) | 1998-03-18 |
GB9508785D0 (en) | 1995-06-21 |
CZ288401B6 (en) | 2001-06-13 |
NO974893L (en) | 1997-10-23 |
PL183484B1 (en) | 2002-06-28 |
SK146197A3 (en) | 1998-05-06 |
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