US3880995A - Treatment of arthritis with mycophenolic acid and derivatives - Google Patents

Treatment of arthritis with mycophenolic acid and derivatives Download PDF

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US3880995A
US3880995A US36029273A US3880995A US 3880995 A US3880995 A US 3880995A US 36029273 A US36029273 A US 36029273A US 3880995 A US3880995 A US 3880995A
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arthritis
mycophenolic acid
treatment
acid
derivatives
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E Linn Jones
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Eli Lilly and Co Ltd (GB)
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Eli Lilly and Co Ltd (GB)
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide

Abstract

Mycophenolic acid or its glucuronide is administered to patients suffering from inflammatory arthritis for the alleviation of their arthritic symptoms.

Description

United States Patent Jones Apr. 29, 1975 TREATMENT OF ARTHRITIS WITH [58] Field of Search 424/180; 260/210, 343.2 R

MYCOPIIENOLIC ACID AND DERIVATIVES [75] Inventor: E. Linn Jones, Indianapolis, Ind. Primary ExamInerQEIbert Roberts Attorney, Agent, or FzrmJames L. Rowe; Everet F. [73] Assrgnee: Eli Lilly and Company, Indianapolis, S i h Ind.

[22] Filed: May 14, 1973 [57] ABSTRACT [21] A N 360,292 Mycophenolic acid or its glucuronide is administered to patients suffering from inflammatory arthritis for th ll 'tfth th 't t 52 us. Cl 424/180; 260/210; 260/343.2 R e a em o ar Symp 0m [51] lm. Cl. A01N 9/00 4 Claims, N0 Drawings TREATMENT OF ARTHRITIS WITH MYCOPIIENOLIC ACID AND DERIVATIVES BACKGROUND OF THE INVENTION Mycophenolic acid is known to exhibit antifungal, antiviral and antibacterial activity. [See for example, J. Gen. Virol. 4, 629 (1969); J. Antibiotics 22, 297 (1969).]

Inflammatory arthritis is a fairly common problem 5 M h nolic acid fl-D-glucuronide is described by usually attacking the older segment of the pop l ion Ando et a]. in J. Antibiotics, 23, 408 (1970) and its analthough extremely severe cases of inflammatory arti-tumor activity is set forth in that same article. thritis are found, through infrequently, in younger per- It is an object of this invention to provide anew drug SOHS- for the treatment of arthritis and for the alleviation of lnflammatory arthritis may be classified into two 1() arthritic symptoms which is devoid ofcertain ofthe del based on the Presence of absence of a Serum ficiencies of other drugs employed in the past for these rheumatoid factor. The sero-positive group includes purposes rheumatoid arthritis and arthritis associated with connective tissue or collagen disease including systemic SUMMARY OF THE INVENTION lupus erythematosus and polyarteritis (periarteritis no- I f lfill f h above d other bj hi i The Seromegatlve group includes p' vention provides a method of treating inflammatory arthritis, ankylosing spondylitis and arthritis associated h i i comprising administering to a human suffering with ulcerative colitis, regional ileitis and Whipples h efrom an arthritic symptom relieving amount of a disease. Other forms of arthritis such as degenerative compound of the formula 9 joint disease (osteoarthritis) and arthritis caused by wherein M is hydrogen, potassium, sodium or ammometabolic or endocrine disorders, are also seronegative but are not classified with inflammatory arthritis. [For a discussion and classification of arthritis, see for example Harrisons Principles of lnternal Medicine, Ed. Wintrobe et al., 6th Edition (McGraw-Hill Book Co., New, NY. 1970) Section 13, particularly pages -l Inflammatory arthritis, generally, and rheumatoid and psoriatic arthritis in particular have been subject to more or less successful drug therapy for a number of years, the most acceptable of the drug treatments being either gold therapy or the use of the anti-inflammatory drugs aspirin, indomethacin and butazolidine. Neither of these treatment methods are free from defects. Gold therapy and aspirin administration are not uniformly successful and the two more recently introduced antiinflammatory drugs, indomethacin and butazolidine, are frequently toxic at therapeutic levels, usually necessitating a dose reduction, if not outright withdrawal, of the drug followed by a return of the arthritic symptoms. Other drug therapy of arthritis, such as the hormonal approach employing corticoids, has fallen into relative disuse, either for failure to alleviate the symptoms to the degree thought desirable or because of the extreme severity of the side effects accompanying their administration.

Mycophenolic acid is produced by various strains of fungi of th'e Penicillium brevicompactum, Penicillium stolomferum and Penicillium urtic/zae groups. The com; 60

pound was the first biologically-active compound iso-' lated from a mold. The initial isolation was carried out by Gosio in 1896 (Gosio, Rivista d lgiene e Sanita pubblica, Ann., 7 825, 869, 961 [1896]). Structure work was effected largely through the efforts of Raistrick et a]. from 1932 to 1935 (Raistrick et al., Biochem. .I. 26, 1441 [1932]; Biochem J. 27, 654 [1933]).

nium and R is hydrogen or B-D-glucuronidyl COOH When M is hydrogen and R is hydrogen, the above compound is named systematically as 6-[4-hydroxy-7- methyl-6-methoxy-3-oxo-5-phthalanyl]-4-methyl-4- hexenoic acid or mycophenolic acid. When R is B-D- glucuronidyl and M is hydrogen, the resulting compound is mycophenolic acid B-D-glucuronide or, systematically, 6-[ 4-( ,B-D-glucopyranosylglucuronate )-4- methyl-6-methoxy-3-oxo-5-phthalanyl]-4-methyl-4- hexenoic acid. Other non-toxic salts than those listed above can also be employed.

Mycophenolic acid, mycophenolic acid B-D- glucuronide or salts thereof are administered by the oral route to a human suffering from inflammatory arthritis, such as rheumatoid or psoriatic arthritis. For oral use, mycophenolic acid, its B-D-glucuronide, or salts thereof are administered in the form of tablets or capsules or as a liquid solution or suspension. A preferred mode for oral administration is via telescoping gelatin capsules. A typical useful formulation employing capsules is prepared as follows:

9.4 kg. of mycophenolic acid isolated from a fermentation medium is thoroughly mixed with 4.7 kg. of starch and the mixture loaded into empty telescoping gelatin capsules. Each capsule contains the following ingredients 400 mg. mycophenolic acid 200 mg. starch In the above formulation, mycophenolic acid [3-D- glucuronide, prepared by the method of Ando et al. (supra) can be substituted for mycophenolic acid.

In the above formulation it has been stated that it is preferred to employ the drug in the form of the free acid; however, the sodium, potassium or ammonium l salts are also effective. Formulations employed for the salts are substantially the same as those indicated above for the free acid.

In carrying out my novel treatment method, patients diagnosed as suffering from inflammatory arthritis are treated with from 2 to 5 g. of mycophenolic acid or an equivalent amount of its glucuronide or of a salt thereof per day. The daily dosage should be divided into either 2 or 3 doses.

An example of the use of the treatment method of this invention is as follows: A male subject 22 years old who had been diagnosed as suffering from psoriatic arthritis two years previously was found to have the following joints involved in his arthritis: shoulders, hips, right wrist, right hand, proximal interphalangial joints of third and fourth fingers and distal interphalangial joint of the thumb. The rheumatoid factor was negative indicating that the disease involved was psoriatic arthritis. Mycophenolic acid was administered to the patient at the rate of 1200 to 2400 mg every 12 hours over a 6 week period. Improvement was noticed at the end of 3 weeks as follows: The patient mentioned that there was improved comfort, decreased morning stiffness and he no longer needed to take aspirin.

A second, female patient of 46 years was diagnosed as suffering from psoriatic arthritis with hips, left wrist, and sacroiliac involved. She was given from 800 to 1600 mg of mycophenolic acid every eight hours for a 12-week period. Subjective improvement was noticed at the end of one week with the following comments: There was less pain in wrist and hips, less swelling of wrists (an objective improvement) and increased range of rotation. Again, in this instance, the need for aspirin was eliminated.

Mycophenolic acid B-glucuronide as well as cationic salts of mycophenolic acid can be employed in the treatment of inflammatory arthritis at dose levels equivalent to those specified above for mycophenolic acid itself. By equivalent dose levels is meant the same weight of mycophenolic acid per dose.

I claim:

I. The process of treating inflammatory arthritis in humans which comprises administering by the oral route to a human suffering therefrom an arthritis symptom relieving amount of mycophenolic acid or a derivative thereof represented by the following formula UNITED STATES PATENT AND TRADEMARK OFFICE CETHICATE OF CORRECTION PATENT N0. 5,880,995

DATED April 29, 1975 INVENTOR(S) E Linn Jones It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 8, "through" should read --though--,

Column 4, line 36, delete "[or B-D-glucuron1dyl].".

' Signed and Scaled this eighth Day of June 1976 ismu Arrest:

Claims (4)

1. A PROCESS OF TREATING INFLAMMATORY ARTHRITIS IN HUMANS WHICH COMPRISES ADMISTERING BY THE ORAL ROUTE TO A HUMAN SUFFERING THEREFROM AN ARTHRITIS SYMPTOM RELIEVING AMOUNT OF MYCOPHENLIC ACTA OR A DERIVATIVE THEREOR REPRESENTED BY THE FOLLOWING FORMULA
2. A process according to claim 1 in which the arthritis treated is rheumatoid arthritis.
3. A process according to claim 1 in which the arthritis treated is psoriatic arthritis.
4. A process according to claim 1 in which from 2-5 g. per day of drug is administered to the arthritic patient.
US3880995A 1973-05-14 1973-05-14 Treatment of arthritis with mycophenolic acid and derivatives Expired - Lifetime US3880995A (en)

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980000791A1 (en) * 1978-10-13 1980-05-01 Schwimmer A B-glucuronidase activity and/or ph-dependent pharmaceuticals and their methods of production and use for selective treatment of diseases
US4327074A (en) * 1978-10-13 1982-04-27 Adolf W. Schwimmer Method for diagnosis and selective treatment of infections of bacteria having β-glucuronidase activity
US4584368A (en) * 1978-10-13 1986-04-22 Adolf W. Schwimmer β-Glucuronidase activity and/or pH-dependent pharmaceuticals and thier methods of production
US4686234A (en) * 1985-11-27 1987-08-11 Syntex (U.S.A) Inc. Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622A (en) * 1986-01-23 1988-02-16 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4808592A (en) * 1987-01-30 1989-02-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholinoethylester of mycophenolic acid and derivatives thereof
US4868153A (en) * 1987-01-30 1989-09-19 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579A (en) * 1987-01-30 1990-08-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US4959387A (en) * 1986-01-23 1990-09-25 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4992467A (en) * 1987-01-30 1991-02-12 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with mycophenolic acid, and derivatives and formulations thereof
US5177072A (en) * 1987-01-30 1993-01-05 Syntex (U.S.A.) Inc. Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
WO1994001105A1 (en) * 1992-07-10 1994-01-20 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
US5346997A (en) * 1992-08-26 1994-09-13 Murphy James G Agents for complexing sodium under biological conditions
WO1995009626A1 (en) * 1993-10-01 1995-04-13 Syntex (U.S.A.) Inc. Mycophenolate mofetil high dose oral suspensions
US5472707A (en) * 1993-05-13 1995-12-05 Syntex (U.S.A.) Inc. High dose ranolazine formulations
US6025391A (en) * 1996-04-12 2000-02-15 Novartis Ag Enteric-coated pharmaceutical compositions of mycophenolate
US6471980B2 (en) 2000-12-22 2002-10-29 Avantec Vascular Corporation Intravascular delivery of mycophenolic acid
US20030139801A1 (en) * 2000-12-22 2003-07-24 Avantec Vascular Corporation Delivery of therapeutic capable agents
EP1349562A2 (en) * 2001-01-11 2003-10-08 Duke University Inhibiting gs-fdh to modulate no bioactivity
US20040127435A1 (en) * 2002-08-02 2004-07-01 Regents Of The University Of California Uses for inhibitors of inosine monophosphate dehydrogenase
US20050013859A1 (en) * 2001-10-17 2005-01-20 Dederichs Juergen Pharmaceutical compositions comprising mycophenolic acid or mycophenolate salt
US20050107869A1 (en) * 2000-12-22 2005-05-19 Avantec Vascular Corporation Apparatus and methods for controlled substance delivery from implanted prostheses
US20050125054A1 (en) * 2000-12-22 2005-06-09 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US20050203612A1 (en) * 2000-12-22 2005-09-15 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US20060106453A1 (en) * 2000-12-22 2006-05-18 Avantec Vascular Corporation Delivery of therapeutic capable agents
US20060212109A1 (en) * 2001-02-13 2006-09-21 Avantec Vascular Corporation Delivery of therapeutic capable agents
US20070032483A1 (en) * 2003-09-11 2007-02-08 Julia Greil Process for the production of mycophenolate mofetil
US20100010082A1 (en) * 2008-07-09 2010-01-14 Aspreva International Ltd. Formulations for treating eye disorders

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4327074A (en) * 1978-10-13 1982-04-27 Adolf W. Schwimmer Method for diagnosis and selective treatment of infections of bacteria having β-glucuronidase activity
US4584368A (en) * 1978-10-13 1986-04-22 Adolf W. Schwimmer β-Glucuronidase activity and/or pH-dependent pharmaceuticals and thier methods of production
WO1980000791A1 (en) * 1978-10-13 1980-05-01 Schwimmer A B-glucuronidase activity and/or ph-dependent pharmaceuticals and their methods of production and use for selective treatment of diseases
US4686234A (en) * 1985-11-27 1987-08-11 Syntex (U.S.A) Inc. Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622A (en) * 1986-01-23 1988-02-16 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4959387A (en) * 1986-01-23 1990-09-25 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US5177072A (en) * 1987-01-30 1993-01-05 Syntex (U.S.A.) Inc. Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
US4868153A (en) * 1987-01-30 1989-09-19 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579A (en) * 1987-01-30 1990-08-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US4992467A (en) * 1987-01-30 1991-02-12 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with mycophenolic acid, and derivatives and formulations thereof
US4808592A (en) * 1987-01-30 1989-02-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholinoethylester of mycophenolic acid and derivatives thereof
WO1994001105A1 (en) * 1992-07-10 1994-01-20 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
US5283257A (en) * 1992-07-10 1994-02-01 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
US5346997A (en) * 1992-08-26 1994-09-13 Murphy James G Agents for complexing sodium under biological conditions
US5472707A (en) * 1993-05-13 1995-12-05 Syntex (U.S.A.) Inc. High dose ranolazine formulations
WO1995009626A1 (en) * 1993-10-01 1995-04-13 Syntex (U.S.A.) Inc. Mycophenolate mofetil high dose oral suspensions
US5688529A (en) * 1993-10-01 1997-11-18 Syntex (U.S.A) Inc. Mycophenolate mofetil high dose oral suspensions
EP1475091A1 (en) * 1993-10-01 2004-11-10 Roche Palo Alto LLC Mycophenolate mofetil - high dose oral suspensions
US6025391A (en) * 1996-04-12 2000-02-15 Novartis Ag Enteric-coated pharmaceutical compositions of mycophenolate
US6172107B1 (en) 1996-04-12 2001-01-09 Novartis Ag Entric-coated pharmaceutical compositions
US6306900B1 (en) 1996-04-12 2001-10-23 Novartis Ag Enteric coated pharmaceutical compositions
US20050203612A1 (en) * 2000-12-22 2005-09-15 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US7077859B2 (en) 2000-12-22 2006-07-18 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
US7083642B2 (en) 2000-12-22 2006-08-01 Avantec Vascular Corporation Delivery of therapeutic capable agents
US6471980B2 (en) 2000-12-22 2002-10-29 Avantec Vascular Corporation Intravascular delivery of mycophenolic acid
US20060106453A1 (en) * 2000-12-22 2006-05-18 Avantec Vascular Corporation Delivery of therapeutic capable agents
US6858221B2 (en) 2000-12-22 2005-02-22 Avantec Vascular Corporation Intravascular delivery of mycophenolic acid
US20050107869A1 (en) * 2000-12-22 2005-05-19 Avantec Vascular Corporation Apparatus and methods for controlled substance delivery from implanted prostheses
US20050125054A1 (en) * 2000-12-22 2005-06-09 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US20050131532A1 (en) * 2000-12-22 2005-06-16 Avantec Vascular Corporation Apparatus and methods for controlled substance delivery from implanted prostheses
US20030139801A1 (en) * 2000-12-22 2003-07-24 Avantec Vascular Corporation Delivery of therapeutic capable agents
EP1349562A2 (en) * 2001-01-11 2003-10-08 Duke University Inhibiting gs-fdh to modulate no bioactivity
US8217006B2 (en) 2001-01-11 2012-07-10 Duke University Inhibiting GS-FDH to modulate no bioactivity
US20100015121A1 (en) * 2001-01-11 2010-01-21 Duke University Inhibiting gs-fdh to modulate no bioactivity
US20070111949A1 (en) * 2001-01-11 2007-05-17 Duke University Inhibiting GS-FDH to modulate no bioactivity
US7615535B2 (en) 2001-01-11 2009-11-10 Duke University Inhibiting GS-FDH to modulate no bioactivity
EP1349562A4 (en) * 2001-01-11 2008-08-06 Univ Duke Inhibiting gs-fdh to modulate no bioactivity
US20060212109A1 (en) * 2001-02-13 2006-09-21 Avantec Vascular Corporation Delivery of therapeutic capable agents
US20100210717A1 (en) * 2001-10-17 2010-08-19 Dederichs Juergen Pharmaceutical compositions comprising mycophenolic acid or mycophenolate salt
US20050013859A1 (en) * 2001-10-17 2005-01-20 Dederichs Juergen Pharmaceutical compositions comprising mycophenolic acid or mycophenolate salt
US20040127435A1 (en) * 2002-08-02 2004-07-01 Regents Of The University Of California Uses for inhibitors of inosine monophosphate dehydrogenase
US20070032483A1 (en) * 2003-09-11 2007-02-08 Julia Greil Process for the production of mycophenolate mofetil
US20100010082A1 (en) * 2008-07-09 2010-01-14 Aspreva International Ltd. Formulations for treating eye disorders

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