IL130820A - Pharmaceutical compositions for oral treatment of multiple sclerosis - Google Patents

Pharmaceutical compositions for oral treatment of multiple sclerosis

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Publication number
IL130820A
IL130820A IL130820A IL13082099A IL130820A IL 130820 A IL130820 A IL 130820A IL 130820 A IL130820 A IL 130820A IL 13082099 A IL13082099 A IL 13082099A IL 130820 A IL130820 A IL 130820A
Authority
IL
Israel
Prior art keywords
pharmaceutical composition
multiple sclerosis
medicament
glatiramer acetate
fed
Prior art date
Application number
IL130820A
Other languages
Hebrew (he)
Original Assignee
Yeda Res & Dev
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Yeda Res & Dev filed Critical Yeda Res & Dev
Priority to IL130820A priority Critical patent/IL130820A/en
Publication of IL130820A publication Critical patent/IL130820A/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/02Peptides of undefined number of amino acids; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Treatments Of Macromolecular Shaped Articles (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Materials For Medical Uses (AREA)
  • General Preparation And Processing Of Foods (AREA)

Abstract

The present invention relates to the treatment of multiple sclerosis by ingestion or inhalation of copolymer-1 and pharmaceutical compositions useful for such treatment.

Description

Pharmaceutical Compositions for oral treatment of multiple sclerosis Yeda Research and Development Company at the Weizman Institute of PO Box 95 Rehovot Israel FIELD OF THE INVENTION The present Invention relates to a pharmaceutical composition comprising used for the treatment of multiple wherein the imposition is for administration by ingestion or BACKGROUND OF THE INVENTION also known as acetate and marketed under the tradename comprises acetate of polypeptides and The average molar fraction of the amino acids are and and the average molecular weight of is between and It is a autoantigen which has been demonstrated to experimental allergic encephalomyelitis induced by various ehcephalitogens including mouse spinal cord homogenate which Includes all myelin such as myelin basic protein M et Bull Inst Pasteur 88 protein et 64 and myelin oligodendrocyte glycoprotein A et J Neurol 243 a variety of EAE an accepted for multiple has been demonstrated to be active when injected intravenously or intramuscularly Teitelbaum et Teitelbaum et In phase III clinical daily subcutaneous injections of were found to slow progression of disability and reduce the relapse rate g multiple sclerosis Neurology therapy is presently to its subcutaneous all specifically approved treatments of multiple sclerosis involve of the active Frequently observed problems include pain and even necrosis the case of at least one interferon β and a low level of patient an alternative method of administration is EP Patent discloses the treatment of autoimmune diseases by oral administration of it discloses the oral administration of for treatment of multiple Oral administration of an autoantigen has been termed PCT International Application Publication WO WO and WO disclose the treatment of other autoimmune diseases using the method with a variety of none of these references disclose the treatment of multiple sclerosis by the oral administration of The contents of all these patents and all literature references referred to above are hereby incorporated by reference in their An object of the present invention relates to the use of in the preparation of a medicament for the treatment of multiple The medicament is administrated through either ingestion or WO BRIEF DESCRIPTION OF THE FIGURES Figures 1 and 2 show the effect of on the immune response to guinea pig myelin basic protein in rats and mice as assessed by spleen cell Figures 3 and 4 show the effect of on cytokine Figure 5 shows the suppression of EAE in mice by mice were fed with PBS mg or Each dose was fed 7 times on days 4 and EAE was induced on day 0 by the injection of Figure 6 shows the proliferation and cytokine secretion by line derived from spleens of fed Cells were cultured with medium 1 or concavalin A The proliferation and cytokine secretion responses to these antigens were Figure 7 shows the inhibition of EAE by line derived from spleens of fed Cells were injected intraperitoneally 3 days after stimulation with followed by EAE Figure 8 shows the inhibition of EAE by line derived from spleens of fed Cells were injected intravenously 3 days after stimulation with followed by EAE 9 shows the Clinical Scores Days of Post EAE Disease Induction in three Rhesus 10 shows the Clinical Scores Days of Post EAE Disease Induction in six Rhesus a trial comparing uncoated pharmaceutical dosage Values at zero have been separated on the to better show the DETAILED DESCRIPTION OF THE INVENTION the present invention relates to the use of in the preparation of a medicament for the treatment of multiple The medicament is administrated through either ingestion or The present invention is further directed to a composition administered through ingestion or inhalation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of wherein the pharmaceutical composition is used to treat multiple As stated comprises the acetate salts of polypeptides and The average molar fraction of the amino acids are and the average molecular weight of is between and The present invention is based on the observation for the oral administration of is effective in suppressing has a therapeutic value for the treatment of multiple WO As the is brought into contact with those lymphoid tissues in the mucosal linings which are believed to be a primary source of immune system These mucosal finings may be found not necessarily in the bronchial passages they are known as the BALT or lymphoid and gastrointestinal linings as GALT or lymphoid the administration of is understood to include methods wherein is introduced into the body by way of ingestion or For may be administered by way of the mouth through through a stomach by inhalation into the bronchial passages or by nasal In one exemplary embodiment of the present is introduced orally in an amount of from to 1000 per which may be administered as a single dose or in multiple As understood by one skilled in the the therapeutically effective dosage is generally a function of a patients and physical as well as a function of other concurrent treatments being The determination of the therapeutically effective dosage is well within the scope of one skilled in the When is introduced it may be mixed with other food forms and consumed in or emulsion and it may be mixed with pharmaceutically acceptable including suspending emulsifying flavor and the like in one the oral composition is ente Use of enteric coatings are well known in the For Acrylic Coatings in Controlled Release Tablet Manufacturing Chemist and Aerosol 39 and Programmed Drug Release Oral Program 3 teach enteric coatings such as Eudragit S and Eudragit Handbook of Pharmaceutical 2nd also teaches Eudragit S and Eudragit L One Eudragit which may be used in the present invention is may also be administered nasally in certain of mentioned forms by inhalation or nose oral inhalation may be employed to deliver to the mucosal linings of the trachea and bronchial may be prepared by methods known in the for as disclosed in Patent wherein the of glutamate and trifiuoroacetylfysine are polymerized at ambient temperature in anhydrous dioxane with diethylamine as an The deblocking of the group of the glutamic acid is effected by hydrogen bromide in glacial acetic acid and is followed by the removal of the tnfluoroacetyl groups from the lysine residues by 1M As described in PCT having a desired average molecular weight of about kilodaltons may preferably be prepared by a method comprising reacting protected with hydrobromic acid to form tnfluoroacetyl treating the trifluoroacetyl with an aqueous piperidine solution to form and purifying the so as to result in having the desired average molecular The present invention will further be described in the examples the present invention should not be construed as being limited Unless otherwise all and the are by EXAMPLE 1 Antigens which was prepared according to the method described in PCT WO95 was obtained from Teva Pharmaceutical Industries GPBP was prepared from guinea pig spinal cord by acid extraction and ammonium sulfate precipitation as described in Hirshfeld H et Febs Lett 7 Animals F1 female mice weeks were obtained from Jackson Laboratories Female Lewis rats weeks were obtained from Induction and Assessment of EAE Mice were injected with 200 GPBP emulsified in an equal volume of complete adjuvant containing 4 mycobacterium tuberculosis The emufston at a total volume of ml was injected into ait four Immediately after and 24 hours pertussis toxin was injected Rats were immunized with 25 of GPBP emulsified in CFA containing 4 The emulsion at a total volume of 0 1 was injected the two hindfoot Animals were examined daily from day 10 post induction for signs of EAE was scored as limb of all four Induction of Oral Tolerance Mice were fed with 250 pg GPBP or dissolved in phosphate buffered saline on days 4 and 6 by gastric intubation with an stainless steei feeding needle EAE was induced on day Rats were fed with 1 GPBP or 1 dissolved in PBS by gastric intubation using a sterile feeding tube Rats were fed 5 times dose of 5 before disease induction at intervals of EAE was induced two days after the last Control mice and rats were mock fed with WO PCT Assay The proliferation response of spleen cells was tested days after EAE induction as described Cells from 3 animals in each group were pooled and cultured in triplicate mouse cells and 2x10s rat in plates with various antigen concentrations in a final volume of plates contained 1640 from Sigma culture medium supplemented with autologous After 72 of cells were pulsed with 1 18 hr then harvested onto fitter papers and radioactivity was Cytokine Secretion Assay Spleens were removed days after EAE induction and cells of 3 mice from each group were Cells were cultured in duplicates in 24 well plate in RPMI 1640 supplemented with FCS Calf in the presence or absence of antigen 100 Supematants were harvested after hr of Quantitative for and were performed using paired mAbs specific for the corresponding cytokines La according to the The efficacy of orally administered in preventing the clinical manifestations of EAE in Lewis rats was compared to that of when assayed under conditions previously reported to induce oral suppression by GPBP Higgins HL J Immunol 140 The results summarized in Table 1 below demonstrate that was more effective than GPBP and significantly decreased both the and severity of as compared to PBS fed rats which served as 6 Table Suppression of EAE in Rats by Oral Administration of Each figure represents the cumulative results of independent p values represent the statistical significance of difference from the control group exact Mean maximal score was calculated for the entire Effect of Feeding on the Immune Response to The effect of oral administration of and GPBP on the response to the disease inducing was tested in mice and The results are summarized in Figure 1 which shows the reduction in cell proliferation by each of the orally administered compounds or in a rat spleen cell suspension stimulated with GPBP 2 shows similar results from As can be oral administration of resulted almost complete inhibition of the proliferative responses to GPBP in these two In both 1 was more effective than GPBP inhibiting the response to Cytokine levels were measured in the supematants of spleen cell cultures derived from mice 3 and Control mice fed with PBS secreted WO and in response to In mice fed with GPBP the amounts of the Th1 proinflammatory cytokines and produced in response to GPBP stimuJation were lower than in control with 1 being a more effective suppressant and IL 10 were not detected with any group treatment The results demonstrate that is effective in suppressing EAE when given The clinically protective effect of orally administered is associated with down regulation of T cell immune responses to GPBP such as proliferation proinflammatory cytokines and EXAMPLE 2 Additional studies on the suppression of EAE by oral administration of 1 were performed in rats and These studies established the optimal dose for treatment in each In order to understand the mechanism underlying oral suppression of EAE by a 1 specific line was isolated from spleens of fed The in vitro reactivity of the lines and their in vivo effect on disease induction were Materials and Isolation of specific T cell lines Lewis rats were fed 5 times with 1 and J x mice 7 times with 250 at intervals of Four to twelve days after the last feeding animals were sacrificed and their spleens Spleen ceils of 3 animals were pooled and incubated x 06 with in medium containing autologous serum for 4 Every days cells x i were restimuiated by 3 days exposure to presented on syngeneic irradiated rat thymocytes x or mouse spienocytes x Stimulation was followed by propagation in supernatant of Con A activated normal mouse spleen ceils as T cell growth factor Proliferation Assay T cell lines x were cultured with irradiated thymocytes x or spienocytes 5 x and with the indicated antigens 1 Con in a final volume of ml in microliter At the end of 48 hours incubation cultures were pulsed with thymidine and harvested hours Cytokine Assay T cefls of rat line x were incubated with irradiated thymocytes x with or without the indicated antigen Con Cells were cultured for 24 hours in 1640 supplemented with FCS for T and and in serum free medium Kibbutz Beit for 72 hours for measurement Cytokine levels in supernatants were measured in a quantitative ELISA using pairs of monoclonal antibodies specific for the corresponding Induction of EAE mice were injected in all four footpads with 2mg mouse spinal cord homogenated emulsified in ratio in containing 1 H37Ra Pertussis toxin was twice injected once immediately after and again 48 hours Dose response study in rats and mice WO Rats were fed 5 times or 2 mg according to the established protocol Materials and and then challenged for EAE The results are summanzed in Table and indicate that the most effective dose was 1 mg mg or 2 mg were less efficient in suppressing mice were fed 7 times with or mg on days 4 and 6 by gastric EAE was induced on day 0 by the injection of The results summanzed in Figure 5 demonstrate that orat administration of could suppress the disease in mice and the most effective dose was mg mg of was less effective and a dose of mg was completely inactive the results in both rats and mice demonstrate that oral has an optimum dose response and exceeding the effective oral dose resulted in inefficient suppression of with specific established from fed animals specific T suppressor cell lines were isotated from spleens of rats and mice rendered unresponsive to EAE by feeding with The proliferation and cytokine secretion response of such line isolated from rats is demonstrated in Figure This line proliferated in response to and secreted some and TGFp but not or This cytokine profile is compatible with Th3 type cells which were shown to be induced by oral MBP et Science The ability of the specific lines to prevent EAE in vivo was Cell lines were injected 3 days in vivo stimulation with x injected and injected The animals were challenged for EAE induction immediately following cell The results illustrated in Figures 7 and 8 demonstrate that the disease was considerably inhibited WO the recipient both the rat and murine lines adoptively transferred the unresponsiveness to EAE induced by oral administration of These activeiy downreguLate the pathological immune response in Table Response Study of Oral Rats calculated by mean Each incidence figure represents the cumulative results of 2 individual Mean maximum clinical score was calculated for the whole Example 3 The effect of the oral administration of on the induction of EAE in Rhesus monkeys was Materials was provided by Teva Pharmaceutical Industries in an hard gelatin capsule comprising two dosage 1 of and 20 mg of Each dosage level was formulated using and coated with drag it Placebo or control capsules comprised capsules containing 5 mg of Bovine MBP was purchased Life Grand New This material represents a highly purified preparation that gives a single band at Kd following and Silver Feedino Protocol 3 Rhesus monkeys treated as One monkey served as control and was fed with placebo capsules 5mg glucose The second and third monkeys were fed with capsules at a dose of and 20mg Animals were fed every other day for a total of 10 5 times prior to disease induction on day and then 5 times after Disease Induction Disease was induced on day 0 an intradermal injection of 8mg bovine MBP and 3 H37Ra tuberculosis in FCA into the hind total injected volume between and ml per The animals were followed for clinical manifestations of a variety of serum and immunological markers and cord and cranial Clinical Scoring Symptom scores were given as normal neurological weight slow responses to irritability or mild neurological clumsiness using altered cry and disordered moderate neurological blindness do not react to leg or severe neurological lymphocytes Heparinized blood samples were diluted with Hanks balanced salt solution containing heat inactivated fetal calf serum and layered in a gradient Cenlrifugatfon for 20 minutes at room allowed recovery of diluted plasma and the separation of lymphocytes at the The recovered lymphocytes were washed three times in Hanks FCS and resuspended in RPMi 1β40 complete medium containing RPMI 1640 and of the following amino sodium and The recovered lymphocytes were counted and resuspended at a final concentration of 2 x Cultures containing 100 microliters of the ceil suspension and 100 microliters of MBP 100 microliters of micrograrrts or 100 microliters of Con A were set up in round bottom 96 well microliter The cultures were maintained at in for 6 On day 5 of each well was pulsed with of for 16 to 18 On day the cultures were harvested by an automatic ceil and counted by liquid scintillation Stimulation indices were determined as Experimental cpm Stimulation background cpm Clinical Results No animal exhibited clinical symptoms for 24 The animal 8374 developed disease on day due to severe manifestations of EAE on a scale of had to be sacrificed on day The treated animal treated with 20mg of did not show any significant clinical symptoms over the day observation The treated animal 18497 began to show minimal symptoms on day in contrast with the animal showed a much slower increase in clinical symptoms leveled off at 2 to from day 28 to day At this animal was fed with capsules 5 times on alternate days for a total of 10 As can be seen in within 3 days the clinical signs dropped to zero and remained there until the two fed animals and were sacrificed on day 60 for Flow Cytometry The Epics C flow cytometer was used to analyze both peripheral blood lymphocytes and cerebral spinal collected from each The red blood ceils were and the remaining white blood cells were washed and stained using standard methods with appropriate Tables 3 and 4 below show the data from PBL and CSF WBCs from the three animals in this number of cells staining was slightly greater in fed animals and than in the control animal The number of cells that are also appears to increase in both control animal and fed animal 18497 about the time both animals exhibited clinical symptoms to but remained fairly constant in the fed animal The number of staining cells decreased steadily in control animal 18374 and fed animal but increased slightly in fed animal the production of new The number of cells found in the CSF of the control animal 18374 increased steadily from day until day when the animal Analysis showed mat most of the cells were The number of cells collected from the CSF of animal were too few to count or The number of cells collected from animal were too few to count or stain except on day The cells collected then were predominantly WO Analysis of CGF obtained from Rhesus Monkeys immunized with Analysis For T cell suppressor factor inducer The analysis for Tsfi in the plasma of the three monkeys in this Example are seen in Tables 5 and 6 None of the animals produced Tsfi until day following EAE induction with Control animal 18374 did not produce any Tsfi until day and level produced thereafter was just above 1 fed animals 8497 and 18498 consistently produced significant levels of from day until day shortly before Table 6 shows that plasma samples which did not contain Tsfi did not react with Plasma which exhibited with 3C9 antibody also reacted the Recombinant human reacted with the but not 3C9 Table Assay for T suppressor inducer Data represents 00 at of plasma samples at a dilution ND Not Determined Table The association between and in plasma of Rhesus Monkeys treated with Represents OD405 nm of material tor MBP of and reacts with the human Tsfi antibody Represents of material bound to MBP and reacts with antibody Represents well coated with 100ng of recombinant human Example 4 Six monkeys were treated and subsequent analyses performed substantially according to the protocol described for Example 3 Control animal 18746 was fed with capsules containing Animal 18586 was fed with 1 mg in capsules with cracked enteric Animal 18639 was fed with 20 mg in capsules with cracked enteric Animal 18724 was fed with 1 mg in intact enteric coated Animal 18810 was fed with 10 mg in intact enteric coated Animal 18962 was fed with 20 mg in intact enteric coated The schedule of disease induction and were substantially the same as those of Example 3 described Results As can be seen with reference to control monkey 18746 developed acute disease beginning on day and died on day of disease Animals 18586 and 18639 treated with the enteric which opened in the stomach both were not protected from the disease and died within days of disease All the monkeys fed with in enteric coated capsule were fully protected from the and developed no signs of EAE until day when they were sacrificed for Any subject matter described in the present application that is not defined in the claims is not encompassed by the present insufficientOCRQuality

Claims (17)

130820/2
1. The use of copolymer-1 (glatiramer acetate) for the manufacture of a medicament for the treatment of multiple sclerosis, wherein said medicament is administered through ingestion or inhalation.
2. The use as claimed in claim 1, wherein the medicament comprises from 0.1 to 1000 mg/day of copolymer-1 (glatiramer acetate) .
3. The use according to claim 1 or 2, wherein the medicament is formulated for oral or nasal administration.
4. A. The use according to claim 3, wherein said administration is by inhalation.
5. The use according to claim 3, wherein the medicament is enterically-coated.
6. A pharmaceutical composition for the treatment of multiple sclerosis comprising a therapeutically effective amount of copolymer-1 (glatiramer acetate) and a pharmaceutically acceptable carrier, wherein said pharmaceutical composition is formulated for administration ■ by either ingestion or inhalation.
7. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is in solid form, liquid form, aerosol or inhalable powder.
8. The pharmaceutical composition of claim 7, wherein said solid form is enterically-coated. 130820/3
9. Use of glatiramer acetate in the manufacture of an ingestible enterically-coated solid medicament for. treating multiple sclerosis.
10. Use according to Claim 9, wherein glatiramer acetate is administered in an amount from 0.1 to 1000 mg.
11. An ingestible solid pharmaceutical composition comprising a ' therapeutically effective amount of glatiramer acetate to treat multiple sclerosis, a pharmaceutically acceptable carrier, and an enteric coating.
12. The pharmaceutical composition of Claim 11, wherein the enteric coating is Eudragit S or Eudragit L.
13. The pharmaceutical composition of Claim 12, wherein the enteric coating is Eudragit L.
14. '. The pharmaceutical composition of claim 13, wherein - the Eudragit L is L30D55.
15. The pharmaceutical composition of any one of claims 11-14, comprising glatiramer acetate in an amount of 0.1 to 1000 mg.
16. Use of glatiramer acetate for . the manufacture of a solid medicament for treating multiple sclerosis, wherein the medicament is administered by inhalation.
17. An inhalable, solid pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate to treat multiple sclerosis and a pharmaceutically acceptable carrier, wherein the 130820/2 pharmaceutical composition is formulated for administration by inhalation. For the Applicant: Sh ron Hausdorff, PhD
IL130820A 1997-01-10 1999-07-06 Pharmaceutical compositions for oral treatment of multiple sclerosis IL130820A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
IL130820A IL130820A (en) 1997-01-10 1999-07-06 Pharmaceutical compositions for oral treatment of multiple sclerosis

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IL11998997A IL119989A0 (en) 1997-01-10 1997-01-10 Pharmaceutical compositions for oral treatment of multiple sclerosis
PCT/US1998/000375 WO1998030227A1 (en) 1997-01-10 1998-01-12 Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1
IL130820A IL130820A (en) 1997-01-10 1999-07-06 Pharmaceutical compositions for oral treatment of multiple sclerosis

Publications (1)

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IL130820A true IL130820A (en) 2007-03-08

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IL130820A IL130820A (en) 1997-01-10 1999-07-06 Pharmaceutical compositions for oral treatment of multiple sclerosis

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KR (1) KR20000070058A (en)
CN (1) CN100528222C (en)
AT (1) ATE356608T1 (en)
AU (1) AU737287B2 (en)
BR (1) BRPI9807076B8 (en)
CA (1) CA2277365C (en)
CZ (1) CZ297983B6 (en)
DE (1) DE69837324T2 (en)
EA (1) EA003128B1 (en)
HK (1) HK1025737A1 (en)
HU (1) HU226612B1 (en)
IL (2) IL119989A0 (en)
NZ (1) NZ336690A (en)
PL (1) PL193300B1 (en)
SK (1) SK284029B6 (en)
WO (1) WO1998030227A1 (en)
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CN112649537B (en) * 2015-04-28 2024-03-29 深圳翰宇药业股份有限公司 High performance liquid chromatography analysis method for polypeptide mixture
US12097292B2 (en) 2016-08-28 2024-09-24 Mapi Pharma Ltd. Process for preparing microparticles containing glatiramer acetate
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ZA98214B (en) 1999-08-11
BR9807076A (en) 2000-05-02
EP0975351A4 (en) 2002-05-15
HK1025737A1 (en) 2000-11-24
EP0975351A1 (en) 2000-02-02
CZ243799A3 (en) 2000-06-14
DE69837324D1 (en) 2007-04-26
PL193300B1 (en) 2007-01-31
JP2001511121A (en) 2001-08-07
EA003128B1 (en) 2003-02-27
SK284029B6 (en) 2004-08-03
ATE356608T1 (en) 2007-04-15
CN100528222C (en) 2009-08-19
HUP0001917A2 (en) 2000-10-28
AU737287B2 (en) 2001-08-16
CN1249690A (en) 2000-04-05
HUP0001917A3 (en) 2001-12-28
BR9807076B1 (en) 2013-10-29
WO1998030227A1 (en) 1998-07-16
JP4216342B2 (en) 2009-01-28
AU5819598A (en) 1998-08-03
NZ336690A (en) 2001-05-25
KR20000070058A (en) 2000-11-25
EA199900621A1 (en) 2000-02-28
DE69837324T2 (en) 2007-11-29
CA2277365C (en) 2011-04-12
BRPI9807076B8 (en) 2021-05-25
PL334566A1 (en) 2000-03-13
CA2277365A1 (en) 1998-07-16
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IL119989A0 (en) 1997-04-15

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