WO1995031990A1 - Copolymer-1 improvements in compositions of copolymers - Google Patents

Copolymer-1 improvements in compositions of copolymers Download PDF

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Publication number
WO1995031990A1
WO1995031990A1 PCT/US1995/006551 US9506551W WO9531990A1 WO 1995031990 A1 WO1995031990 A1 WO 1995031990A1 US 9506551 W US9506551 W US 9506551W WO 9531990 A1 WO9531990 A1 WO 9531990A1
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copolymer
molecular weight
fraction
kilodaltons
species
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PCT/US1995/006551
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French (fr)
Inventor
Eliezer Konfino
Michael Sela
Dvora Teitelbaum
Ruth Arnon
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Yeda Research And Development Co., Ltd.
Lemmon Company
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Priority to DE69525340T priority Critical patent/DE69525340T2/en
Priority to UA96114382A priority patent/UA62908C2/en
Priority to SI9530577T priority patent/SI0762888T1/en
Priority to CA002191088A priority patent/CA2191088C/en
Priority to HU9603243A priority patent/HU223473B1/en
Priority to EP95920632A priority patent/EP0762888B1/en
Priority to AU26021/95A priority patent/AU2602195A/en
Priority to CNB200410064296XA priority patent/CN1310673C/en
Priority to BRPI9507758-8A priority patent/BRPI9507758B1/en
Priority to TJ96000421A priority patent/TJ392B/en
Priority to BR9507758A priority patent/BR9507758A/en
Priority to DK95920632T priority patent/DK0762888T3/en
Priority to NZ287335A priority patent/NZ287335A/en
Priority to JP7530519A priority patent/JPH10500955A/en
Priority to AT95920632T priority patent/ATE212857T1/en
Priority to KR1019960706612A priority patent/KR100403750B1/en
Priority to DE2002199030 priority patent/DE10299030I1/en
Priority to SK1493-96A priority patent/SK283699B6/en
Priority to MD97-0024A priority patent/MD1443G2/en
Priority to EE9600170A priority patent/EE03423B1/en
Priority to PL95317331A priority patent/PL181026B1/en
Application filed by Yeda Research And Development Co., Ltd., Lemmon Company filed Critical Yeda Research And Development Co., Ltd.
Publication of WO1995031990A1 publication Critical patent/WO1995031990A1/en
Priority to FI964600A priority patent/FI120236B/en
Priority to NO19964976A priority patent/NO324528B1/en
Priority to HK98108818A priority patent/HK1008657A1/en
Priority to NL300096C priority patent/NL300096I2/en
Priority to LU90987C priority patent/LU90987I2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Polyamides (AREA)

Abstract

The present invention relates to an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.

Description

COPOLYMER-1 IMPROVEMENTS IN COMPOSITIONS OF COPOLYMERS
This application is a continuation-in-part of U.S.S.N. 08/344,248, filed November 23, 1994, which is a continuation of U.S.S.N. 08/248,037, filed May 24, 1994.
Background of the Invention
Copolymer-l is a synthetic polypeptide analog of myelin basic protein (MBP) , which is a natural component of the myelin sheath. It has been suggested as a potential therapeutic agent for multiple sclerosis (Eur. J. Immunol. [1971] 1:242; and J. Neurol. Sci. [1977] 31:433) . All references cited herein are hereby incorporated by reference in their entirety. Interest in copolymer-l as an immunotherapy for multiple sclerosis stems from observations first made in the 1950's that myelin components such as MBP prevent or arrest experimental autoimmune encephalomyelitis (EAE) . EAE is a disease resembling multiple sclerosis that can be induced in susceptible animals.
Copolymer-l was developed by Drs. Sela, Arnon, and their co-workers at the Weizmann Institute (Rehovot, Israel) . It was shown to suppress EAE (Eur. J. Immunol. [1971] 1:242; U.S. Patent No. 3,849,550) . More recently, copolymer-l was shown to be beneficial for patients with the exacerbating-remitting form of multiple sclerosis (N. Engl. J. Med. [1987] 317:408) . Patients treated with daily injections of copolymer-l had fewer exacerbations and smaller increases in their disability status than the control patients.
Copolymer-l is a mixture of polypeptides composed of alanine, glutamic acid, lysine, and tyrosine in a molar ratio of approximately 6:2:5:1, respectively. It is synthesized by chemically polymerizing the four amino acids forming products with average molecular weights of 23,000 daltons (U.S. Patent No. 3,849,550).
It is an object of the present invention to provide an improved composition of copolymer-l.
Summary of the Invention The present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) .
The invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
In addition, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa.
Moreover, the invention relates to a pharmaceutical composition and a method for the treatment of multiple sclerosis, using the above-discussed copolymer-l.
Brief Description of the Drawings
Figure 1 displays the molecular weight distribution of three batches of copolymer-l, showing the proportion of species with molecular weight above 0KDa. Figure 2 shows similar data relating to the molar fraction.
Detailed Description of the Invention The present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) . Preferably, the composition contains less than 5% of species of copolymer-l having a molecular weight of 40 KDa or more. More preferably, the composition contains less than 2.5% of species of copolymer-l having a molecular weight of 40 KDa, or more.
The invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
In addition, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa. In particular, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8 KDa and a copolymer-l having an average molecular weight of about 6.25 to about 8.4 KDa.
Copolymer-l, according to the present invention, may be prepared by methods known in the art, for example, the process disclosed in U.S. Patent 3,849,550, wherein the N-carboxyanhydrides of tyrosine, alanine, y-benzyl glutamate and E-N-trifluoro-acetyllysine are polymerised at ambient temperature in anhydrous dioxane with diethylamine as initiator. The deblocking of the y- carboxyl group of the glutamic acid is effected by hydrogen bromide in glacial acetic acid and is followed by the removal of tr-i trifluoroacetyl groups from the lysine residues by 1M piperidine. For the purposes of the application, the terms "ambient temperature" and "room temperature" should be understood to mean a temperature ranging from about 20 to about 26 °C.
The copolymer-l with the required molecular weight profile can be obtained either by methods known per se. Such methods include chromatography of copolymer-l containing high molecular weight species and collecting the fractions without the undesired species or by partial acid or enzymatic hydrolysis to remove the high molecular weight species with subsequent purification by dialysis or ultrafiltration. A further method to obtain copolymer-l with the desired molecular weight profile is by preparing the desired species while the amino acids are still protected and then obtain the correct species directly upon removing the protection. The compositions of the present invention may be formulated by conventional methods known in the art. Preferably, the composition is lyophilized and formed into an aqueous solution suitable for sub-cutaneous injection. Alternatively, copolymer-l may be formulated in any of the forms known in the art for preparing oral, nasal, buccal, or rectal formulations of peptide drugs.
Typically, copolymer-l is administered daily to patients suffering from multiple sclerosis at a dosage of 20mg.
The invention will be exemplified but not necessarily limited by the following Examples.
EXAMPLE 1
Chromato raphic method of preparation of low-toxicity copolymer-l Two batches of copolymer-l were prepared according to the methods known in the art, for example, U.S. Patent No. 3,849,550.
One batch was then subjected to chromatographic separation, as described below.
A column for gel filtration, FRACTOGEL TSK HW55 (600 x 26mm) was prepared in a Superformance 26 Merck cartridge according to the manufacturer's instructions. The column was equilibrated with water and acetone solution was injected for total volume determination. The column was equilibrated with' 0.2M ammonium acetate buffer pH 5.0. 30 ml copolymer-l samples (20mg/ml, in 0.2M ammonium acetate pH 5.0) were loaded on the column and fractions were collected every 10 minutes. A fraction having an average molecular weight of 7-8 KDa was isolated between 120-130 minutes (Batch A) .
Molecular Weight Analysis
UV absorbance at 275 nm was determined in a UVIKON 810 spectrophotometer. Samples were diluted to obtain a UV absorbance lower than 1 Absorption Unit. The molecular distribution of the 2 batches was determined on a calibrated gel filtration column (Superose 12) .
Copolymer-l batch A was found to have an average molecular weight of 7-8 KDa. 2.5% of this batch had a molecular weight above 32 KDa, but no copolymer-l species present in this batch had a molecular weight of over 40 KDa.
The other batch of copolymer-l which was not subjected to chromatography, had an average molecular weight of 12 KDa. 2.5% of the batch had a molecular weight above 42KDa and 5% of the total copolymer-l species in this batch had a molecular weight of over 40 KDa.
EXAMPLE 2
Toxicity Analysis A: In Vivo
Three batches of copolymer-l having an average molecular weight of 7.3 and 8.4 KDa (less than 2.5% copolymer-l species over 40KDa) and 22KDa (more than 5% copolymer-l species over 40KDa) were subjected to the toxicity test described below. In each case 5 mice were used in each experimental group.
Method
Copolymer-l was dissolved in distilled water to yield a solution of 2mg/ml of the active ingredient. Each mouse was injected with 0.5ml of the test solution into the lateral tail vein. Mice were observed for mortality and relevant clinical signs over a 48 hour period. Observations were recorded 10 minutes, 24 hours and 48 hours post-injection. If, at the end of 48 hours, all the animals were alive and no adverse signs had been observed, then the batch was designated "non-toxic". If, however, one or more of the mice had died or had shown adverse signs, then the batch was designated "toxic".
The batches with the average molecular weight of 7.3 and 8.4 KDa were both designated "non-toxic", whereas in the batch with the average molecular weight of 22KDa, 3 out of 5 mice had died at the end of 48 hours, and it was consequently designated "toxic".
B: In Vitro
RBL - Decrranulation test
I. Introduction
Histamine (or serotonin) release from basophile is an in vitro model for immediate hypersensitivity. The Rat Basophilic Leukemia cell line (RBL-2H3) was developed and characterized as a highly sensitive, uniform, easy to maintain in culture and reproducible system (E.L. Basumian, C. Isersky, M.G. Petrino and R.P. Siraganian. Eur. J. Immunol. 11, 317 (1981)). The physiological stimulus for histamine release involves binding of the antigen to membrane-bound IgE molecules, resulting in the latter's cross-linking and the consequent triggering of an intricate biochemical cascade. Beside these physiological, immunoglobulin-mediated triggers, degranulation can be induced by different non-IgE- mediated stimuli. Among these are various peptides and synthetic polymers, e.g. polylysine (R.P. Siraganian. Trends in Pharmacological Sciences, October 432 (1983)). The RBL degranulation test is, therefore, used in order to screen out those batches of copolymer-l which evoke substantial degranulation and thus might elicit undesirable local and/or systemic side effects. II. Principle of the test method
Rat Basophilic Leukemia cells (RBL-2H3) , are loaded with [3H] -serotonin, followed by incubation with 100 μg of the copolymer-l to be tested. Batches of copolymer-l which induce non-specific degranulation, release [3H] -serotonin into the medium. The radioactivity in the medium is counted by a scintillation counter and the total radiolabeled serotonin incorporated into the cells is determined in the pelleted cells. Percent degranulation is calculated as the percentage of serotonin released out of the total incorporated.
III. Results
Four batches of copolymer-l, with average molecular weight between 6,250-14,500 were analyzed for both % of the species with molecular weight over 40KDa and for degranulation of RBL's. Results are summarized in the following table.
Average % of species with % Serotonin M.W. (Daltons) M.W. over 40KDa Release
6,250 < 2.5 12.4
7,300 < 2.5 21.0
13,000 > 5 66.9
14,500 > 5 67.8
As can be seen, when the % of high molecular weight species is low (< 2.5), the % release of serotonin, indicative of toxicity, is low, and vice versa.
EXAMPLE 3
Preparation of Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , y-benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
The polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine. The reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water. The product (protected copolymer- 1) is filtered, washed with water and dried. The removal of the gamma-benzyl blocking groups from the glutamate residue is carried out by treating the protected copolymer-l with 33% hydrobromic acid in glacial acetic acid at room temperature for 6-12 hours with stirring. The product is poured into excess water, filtered, washed and dried, yielding the trifluoroacetyl-copolymer-l.
EXAMPLE 4
Preparation of Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , τ-benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
The polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine. The reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water. The product (protected copolymer- 1) is filtered, washed with water and dried.
Protected copolymer-l is treated with 33% HBr in acetic acid which removes the omega benzyl protecting group from the 5-carboxylate of the glutamate residue and cleaves the polymer to smaller polypeptides. The time needed for obtaining copolymer-l of molecular weight 7,000±2,000 Da depends on the reaction temperature and the size of protected copolymer-l. At temperatures of between 20- 28°C a test reaction is performed on every batch at different time periods for example, from 10-50 hours. The results concerning the molecular weights of these small scale reactions are calculated and a curve of molecular weight against time is drawn. The time needed for obtaining molecular weight 7,000±2,000 Da is calculated from the curve and performed ι larger scale reaction. On average, working at 26°C trie time period is 17 hours. The product is poured into excess water, filtered, washed and dried, yielding the trifluoroacetyl- copolymer-l. Preparation of low-toxicity copolymer-l
20g of trifluoroacetyl-copolymer-l are dispersed in 1 liter of water to which lOOg piperidine are added. The mixture is stirred for 24 hours at room temperature and filtered. The solution of crude copolymer-l is distributed into dialysis bags and dialyzed at 10°-20°C against water until a pH = 8 is attained. It is then dialyzed against about 0.3% acetic acid and again water until a pH = 5.5-6.0 is obtained. This solution is then concentrated and lyophilized to dryness.

Claims

1. A copolymer-l fraction substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons.
2. A copolymer-l fraction, wherein said fraction contains less than 5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
3. The copolymer-l fraction according to claim 2, wherein the fraction contains less than 2.5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
4. The copolymer-l fraction according to claim 2, wherein over 75% of said fraction is within a molecular weight range from about 2 kilodaltons to about 20 kilodaltons.
5. A copolymer-l fraction, wherein said copolymer-l has an average molecular weight of about 4 to about 8 kilodaltons.
6. A copolymer-l fraction, wherein said copolymer-l has an average molecular weight of about 6.25 to about 8.4 kilodaltons.
7. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said fraction contains less than 5% of species of copolymer-l having a molecular weight of over 40 kilodaltons, and a pharmaceutically acceptable carrier.
8. The composition according to claim 7, wherein the copolymer-l fraction contains less than 2.5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
9. The composition according to claim 7, wherein over 75% of said copolymer-l in said fraction is within a molecular weight range of about 2 kilodaltons to about 20 kilodaltons.
10. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said copolymer-l in said fraction has an average molecular weight of about 4 to about 8 kilodaltons, and a pharmaceutically acceptable carrier.
11. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said copolymer-l in said fraction has an average molecular weight of about 6.25 to about 8.4 kilodaltons, and a pharmaceutically acceptable carrier.
PCT/US1995/006551 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers WO1995031990A1 (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
NZ287335A NZ287335A (en) 1994-05-24 1995-05-23 Copolymer-1 composition substantially free of species of copolymer -1 with a mw of from 4 kda to 8 kda, in particular 6.25 kda to 8.4 kda
EE9600170A EE03423B1 (en) 1994-05-24 1995-05-23 Copolymer-1, a process for its preparation and compositions comprising it
SI9530577T SI0762888T1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
CA002191088A CA2191088C (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
HU9603243A HU223473B1 (en) 1994-05-24 1995-05-23 Copolymer-1 fraction having low toxicity for treating multiple sclerosis, process for producing it and pharmaceutical compositions comprising same
EP95920632A EP0762888B1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
AU26021/95A AU2602195A (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
CNB200410064296XA CN1310673C (en) 1994-05-24 1995-05-23 Composition of multiple scattered mixture contg.polypeptide and its pharm compsn.
BRPI9507758-8A BRPI9507758B1 (en) 1994-05-24 1995-05-23 copolymer fraction-1; composition for the treatment of multiple sclerosis; pharmaceutical composition
TJ96000421A TJ392B (en) 1994-05-24 1995-05-23 Fraction of copolymer-1 and method prodaction of it, composition for the treatment of multiple sclerosis, farmaceutical composition, method for the t reatment of multiple sclerosis.
BR9507758A BR9507758A (en) 1994-05-24 1995-05-23 Copolymer-1 fraction and composition for the treatment of multiple sclerosis
DK95920632T DK0762888T3 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in copolymer preparations
JP7530519A JPH10500955A (en) 1994-05-24 1995-05-23 Copolymer 1
DE69525340T DE69525340T2 (en) 1994-05-24 1995-05-23 IMPROVEMENTS IN COMPOSITIONS CONTAINING COPOLYMERS KOPOLYMER-1
MD97-0024A MD1443G2 (en) 1994-05-24 1995-05-23 Copolymer-1 fraction, process for preparation thereof and compositions on base thereof for cerebrospinal sclerosis treatment
KR1019960706612A KR100403750B1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
DE2002199030 DE10299030I1 (en) 1994-05-24 1995-05-23 Improvements in compositions of copolymers containing copolymer-1
SK1493-96A SK283699B6 (en) 1994-05-24 1995-05-23 Fraction of copolymer-1, composition comprising this fraction, process for its preparation and use for production of medicament for treatment of disseminated sclerosis
AT95920632T ATE212857T1 (en) 1994-05-24 1995-05-23 IMPROVEMENTS IN COMPOSITIONS OF COPOLYMERS CONTAINING COPOLYMER-1
UA96114382A UA62908C2 (en) 1994-05-24 1995-05-23 Fractions of copolymer-1, methods for preparation thereof, compositions and a method for treatment of disseminated sclerosis
PL95317331A PL181026B1 (en) 1994-05-24 1995-05-23 Copolymer-1 of an improvement in composition of copolymers
FI964600A FI120236B (en) 1994-05-24 1996-11-15 Copolymer-1 Improvements in Copolymer Mixtures
NO19964976A NO324528B1 (en) 1994-05-24 1996-11-22 Copolymer-1 fraction, process for its preparation, use, composition and scavenger for preparing a composition for the treatment of multiple sclerosis and copolymer-1 preparation
HK98108818A HK1008657A1 (en) 1994-05-24 1998-07-02 Copolymer-1 improvements in compositions of copolymers
NL300096C NL300096I2 (en) 1994-05-24 2002-07-29 Improvements of copolymer-1 in compositions of copolymers.
LU90987C LU90987I2 (en) 1994-05-24 2002-08-05 Copaxone and its pharmaceutically acceptable derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US24803794A 1994-05-24 1994-05-24
US34424894A 1994-11-23 1994-11-23
US08/248,037 1994-11-23
US08/344,248 1994-11-23

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EP (1) EP0762888B1 (en)
JP (2) JPH10500955A (en)
KR (1) KR100403750B1 (en)
CN (2) CN1174753C (en)
AT (1) ATE212857T1 (en)
AU (1) AU2602195A (en)
BR (2) BRPI9507758B1 (en)
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