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Publication numberUS3880995 A
Publication typeGrant
Publication dateApr 29, 1975
Filing dateMay 14, 1973
Priority dateMay 14, 1973
Publication numberUS 3880995 A, US 3880995A, US-A-3880995, US3880995 A, US3880995A
InventorsJones E Linn
Original AssigneeLilly Co Eli
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Treatment of arthritis with mycophenolic acid and derivatives
US 3880995 A
Mycophenolic acid or its glucuronide is administered to patients suffering from inflammatory arthritis for the alleviation of their arthritic symptoms.
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Description  (OCR text may contain errors)

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:

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4327074 *Feb 12, 1979Apr 27, 1982Adolf W. SchwimmerMethod for diagnosis and selective treatment of infections of bacteria having β-glucuronidase activity
US4584368 *Oct 13, 1978Apr 22, 1986Adolf W. Schwimmerβ-Glucuronidase activity and/or pH-dependent pharmaceuticals and thier methods of production
US4686234 *Nov 27, 1985Aug 11, 1987Syntex (U.S.A) Inc.Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622 *Jan 23, 1986Feb 16, 1988Syntex (U.S.A.) Inc.Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4808592 *Sep 4, 1987Feb 28, 1989Syntex (U.S.A.) Inc.Method of treating diseases by administering morpholinoethylester of mycophenolic acid and derivatives thereof
US4868153 *Aug 17, 1988Sep 19, 1989Syntex (U.S.A.) Inc.Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793 *Jun 29, 1989Aug 14, 1990Syntex (U.S.A.) Inc.Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579 *Nov 14, 1988Aug 28, 1990Syntex (U.S.A.) Inc.Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US4959387 *Nov 24, 1987Sep 25, 1990Syntex (U.S.A.) Inc.Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4992467 *Mar 28, 1990Feb 12, 1991Syntex (U.S.A.) Inc.Treatment of autoimmune diseases with mycophenolic acid, and derivatives and formulations thereof
US5177072 *Dec 9, 1991Jan 5, 1993Syntex (U.S.A.) Inc.Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
US5283257 *Jul 10, 1992Feb 1, 1994The Board Of Trustees Of The Leland Stanford Junior UniversityMethod of treating hyperproliferative vascular disease
US5346997 *Aug 26, 1992Sep 13, 1994Murphy James GAgents for complexing sodium under biological conditions
US5472707 *May 9, 1994Dec 5, 1995Syntex (U.S.A.) Inc.High dose ranolazine formulations
US5688529 *Mar 29, 1995Nov 18, 1997Syntex (U.S.A) Inc.Mycophenolate mofetil high dose oral suspensions
US6025391 *Apr 10, 1997Feb 15, 2000Novartis AgEnteric-coated pharmaceutical compositions of mycophenolate
US6172107Dec 22, 1999Jan 9, 2001Novartis AgEntric-coated pharmaceutical compositions
US6306900Oct 23, 2000Oct 23, 2001Novartis AgEnteric coated pharmaceutical compositions
US6471980Feb 13, 2001Oct 29, 2002Avantec Vascular CorporationIntravascular delivery of mycophenolic acid
US6858221Sep 11, 2002Feb 22, 2005Avantec Vascular CorporationIntravascular delivery of mycophenolic acid
US7077859Dec 14, 2001Jul 18, 2006Avantec Vascular CorporationApparatus and methods for variably controlled substance delivery from implanted prostheses
US7083642Jul 25, 2002Aug 1, 2006Avantec Vascular CorporationDelivery of therapeutic capable agents
US7615535Dec 29, 2006Nov 10, 2009Duke UniversityInhibiting GS-FDH to modulate no bioactivity
US8217006Sep 24, 2009Jul 10, 2012Duke UniversityInhibiting GS-FDH to modulate no bioactivity
US20040127435 *Aug 1, 2003Jul 1, 2004Regents Of The University Of CaliforniaUses for inhibitors of inosine monophosphate dehydrogenase
US20050013859 *Oct 16, 2002Jan 20, 2005Dederichs JuergenPharmaceutical compositions comprising mycophenolic acid or mycophenolate salt
US20050107869 *Dec 9, 2004May 19, 2005Avantec Vascular CorporationApparatus and methods for controlled substance delivery from implanted prostheses
US20050125054 *Nov 19, 2004Jun 9, 2005Avantec Vascular CorporationDevices delivering therapeutic agents and methods regarding the same
US20070032483 *Sep 10, 2004Feb 8, 2007Julia GreilProcess for the production of mycophenolate mofetil
EP1349562A2 *Dec 14, 2001Oct 8, 2003Duke UniversityInhibiting gs-fdh to modulate no bioactivity
EP1475091A1 *Sep 27, 1994Nov 10, 2004Roche Palo Alto LLCMycophenolate mofetil - high dose oral suspensions
WO1980000791A1 *Oct 2, 1979May 1, 1980Schwimmer AB-glucuronidase activity and/or ph-dependent pharmaceuticals and their methods of production and use for selective treatment of diseases
WO1994001105A1 *Jul 7, 1993Jan 20, 1994Univ Leland Stanford JuniorMethod of treating hyperproliferative vascular disease
WO1995009626A1 *Sep 27, 1994Apr 13, 1995Syntex IncMycophenolate mofetil high dose oral suspensions
U.S. Classification514/27, 549/310, 536/18.1, 514/456
International ClassificationA61K31/34
Cooperative ClassificationA61K31/34, A61K31/70
European ClassificationA61K31/34, A61K31/70