AU703887B2

AU703887B2 - Bisphosphonate therapy for bone loss associated with rheumatoid arthritis

Info

Publication number: AU703887B2
Application number: AU59679/96A
Authority: AU
Inventors: Anastasia G. Daifotis; Ashley J Yates
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1995-06-06
Filing date: 1996-06-03
Publication date: 1999-04-01
Anticipated expiration: 2016-06-03
Also published as: JPH11506750A; WO1996039150A1; CA2221416A1; AU5967996A; EP0831843A1

Description

WO 96/39150 PCT/US96/08361 TITLE OF THE INVENTION BISPHOSPHONATE THERAPY FOR BONE LOSS ASSOCIATED WITH RHEUMATOID ARTHRITIS SUMMARY OF THE INVENTION This invention relates to the use of bisphosphonates, particularly alendronate, to prevent bone loss associated with rheumatoid arthritis.

BACKGROUND OF THE INVENTION Rheumatoid arthritis (RA) is a chronic, multisystemic disease of unknown cause. The characteristic feature of RA is persistent inflammatory synovitis, usually involving peripheral joints. One hallmark of the disease is cartilage destruction and periarticular bone erosion caused by synovial inflammation, resulting in joint deformities.

The cell believed to be responsible for the erosive process in the osteoclast. In patients with RA, therapy often includes glucocorticoid administration, immobilization of joints, cyclosporine or methotrexate, all of which may potentiate bone loss and deformity.

It would be desirable to prevent or treat generalized and periarticular bone loss associated with RA.

DETAILED DESCRIPTION OF THE INVENTION It has been found in accordance with this invention that bisphosphonates can prevent and treat bone loss associtated with rheumatoid arthritis when administered in either a prophylactically or therapeutically effective amount.

In particular, alendronate (4-amino-l-hydroxybutylidene- 1,1-bisphosphonate) or a pharmaceutically effective salt thereof, can prevent and treat bone loss associated with rheumatoid arthritis when administered either in a prophylactically or therapeutically effective amount.

A further aspect of this invention is a method of preventing or treating generalized and/or periarticular bone loss associated with

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WO 96/39150 PCT/US96/08361 -2rheumatoid arthritis comprising adr'nistering an effective amount of a bisphosphonate selected from the group consisting of: alendronate, etidronate (1-hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino-l-hydroxypropyildiene-I,l -diphosphanate), risedronate (2-(3-pyridinyl)-l-hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4phenylthio-methylidene-bisphosphonic acid), ibandronic acid (1hydroxy-3(methylpenty-lamino)-propylidene-bisphosphonic acid, and pharmaceutically acceptible salts of any of the foregoing, and mixtures of any of the acids and any of the salts to a patient suffering from rheumatoid arthritis. All of the foregoing compounds are well known in the art.

Generally the patient undergoing treatment for rheumatoid arthritis will be receiving one or more of: an immunosuppressive drug, cyclosporine, methotrexate, or glucocorticoids.

As used throughout the specification and claims, the following definitions apply: "Prophylactically effective amount"--the amount of alendronate needed to prevent or lessen the severity of bone loss associated with rheumatoid arthritis.

"Therapeutically effective amount"--the amount of alendronate needed to treat bone loss associated with rheumatoid arthritis.

In a preferred aspect of this invention, the patient will receive alendronate. Alendronate may be prepared according to any of the processes described in U.S. Patents 5,019,651, 4,992,007, and U.S.

Application Serial No. 08/286,151, filed August 4, 1994, each of which is hereby incorporated by reference. The pharmaceutically acceptable salts of alendronate include salts of alkali metals Na, alkaline earth metals Ca), salts of inorganic acids, such as HCI and salts of organic acids such as citric acid and amino acids. Sodium salt forms are preferred, particularly the monosodium salt trihydrate form.

WO 96/39150 PCT/US96/08361 -3- Many of the bisphosphonate compounds of the present invention can be administered in oral dosage formn such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, paste, tinctures, suspensions, syrups, emulsions, and zydis. Likewise they may be administered in an intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but nontoxic amount of the bisphosphonate compound desired can be used as a an agent which treats or prevents bone loss associated with RA.

The dosage regime utilizing the claimed method is selected in accordance with a variety of factors including type, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent alid or treat bone loss.

Oral dosages of the present invention when alendronate is the bisphosphonate will range from between 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day. Preferred oral dosages in humans may range from daily total dosages of about 2.5-50 mg/day over the effective treatment period, and a preferred amount is 10 or 20 mg/day.

Alendronate may be administered in a single daily dose or in a divided dose. It is desirable for the dosage to be given in the absence of food, preferably from about 30 minutes to 2 hours prior to a meal, such as breakfast to permit adequate absorption.

In the methods of the present invention, the active ingredient is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier materials") suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical WO 96/39150 PCT/US96/08361 -4practices. For example, for oral administration in the form of a tablet or capsule, the active ingredient can be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of active ingredient(s) and inert carrier materials. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium sterate, sodium benzoate, sodium acetate, sodium chloride and the like.

A particularly preferred tablet formulation of alendronate is that described in U.S. Patent 5,358,941, which is hereby incorporated by reference.

The compounds used in the instant method may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran co-polymer, polyhydroxylpropyl-methacrylamide and the like.

Patients suffering frcm rheumatoid arthritis may be male or female of any age. Women may be pre-or post-menopausal.

The following non-limiting examples are presented to better illustrate the invention.

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WO 96/39150 PCT/US96/08361 EXAMPLE 1 Alendronate for the treatment and prevention of bone loss in patients with rheumatoid arthritis 220 men and women with active rheumatoid arthritis (as defined by the 1987 ARA Diagnostic Criteria), ages 18-80 are studied in a randomized double-blind clinical trial. Patients are randomized into groups which receive either placebo, 2.5, 5, 10, or 20 mg/day alendronate orally each day for one year. In addition to standard RA therapy, patients are also given 1000 mg calcium and 250 IU Vitamin D daily.

After one year, the bone mineral density (BMD) of the spine, hip and total body are measured. In addition, the hand erosion score is assessed using standard techniques.

It is found that patients who receive daily oral alendronate at doses of 5-20 mg/day increase spine and hip BMD relative to both their baseline scores and to patients receiving placebo. The increase is statistically significant. Also, in patients receiving alendronate, hand erosion scores are decreased relative to baseline and placebo.

Claims

1. A method of preventing or treating generalised and/or periarticular bone loss associated with rheumatoid arthritis (RA) in an animal suffering from RA, which method comprises administering to the animal an effective amount of a bisphosphonatc selected from the group consisting of: alendronate (4-amino-l-hydroxybutylidene-1,1- bisphosphonic acid), etidronate (1-hydroxy-ethidene-bisphosphonic acid), pamidronate (3- amino- 1-hydroxy-propyildiene- 1,1-diphosphanate), risedronate (2-(3-pyridinyl)-1- hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio-methylidene-bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid, and pharmaceutically acceptable salts of any of the forgoing, and mixtures of any of the acids and any of the salts.

2. A compound which is a bisphosphonate selected from the group consisting of: alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid), etidronate (1- hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino-l -hydroxy-propyildiene- 1,1- diphosphanate), risedronate (2-(3-pyridinyl)-1 -hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio- methylidene-bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpentylamino)- propylidene-bisphosphonic acid, and pharmaceutically acceptable salts of any of the forgoing, and mixtures of any of the acids and any of the salts, when used to prevent or treat generalised and/or periarticular bone loss associated with RA in an animal suffering from RA.

3. Use of a bisphosphonate selected from the group consisting of: alendronate (4- amino-1-hydroxybutylidene-1,1-bisphosphonic acid), etidronate (1-hydroxy-ethidene- bisphosphonic acid), pamidronate (3-amino-l-hydroxy-propyildiene-l,l-diphosphanate), risedronate (2-(3-pyridinyl)-l-hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio-methylidene- bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpentylamino)-propylidene- bisphosphonic acid, and pharmaceutically acceptable salts of any of the forgoing, and mixtures of any of the acids and any of the salts, in the manufacture of a medicament for preventing or treating generalised and/or periarticular bone loss associated with RA in an animal suffering from RA.

4. A method according to claim 1, a compound according to claim 2 or a use according to claim 3 wherein the bisphosphonate is alendronate.

5. A method, compound or use according to claim 4 wherein the alendronate is in the form of monosodium salt trihydrate.

6. A method according to claim 4 or claim 5 wherein the alendronate is administered orally.

7. A method according to any one of claims 4 to 6 wherein the alendronate is o administered in a dose of from 2.5 to 50 mg per day. Ai4 C V '-2 Ijn\lhbaalO I 486:t ab

8. A method according to claim 7 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.

9. A method according to any one of claims 1 or 4 to 8 or the compound according to any one of claims 2, 4 or 5 wherein the bisphosphonate or compound is combined, with a pharmaceutically acceptable carrier or diluent, in the form of a composition.

A method of treating bone loss associated with rheumatoid arthritis (RA) in an animal suffering from RA, which method comprises administering to the animal a therapeutically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

11. A compound which is alendronate or a pharmaceutically acceptable salt thereof when used to treat bone loss associated with RA in an animal suffering from RA.

12. Use of alendronate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bone loss associated with RA in an animal suffering from RA.

13. A method according to claim 10, a compound according to claim 11 or a use according to claim 12 wherein the alendronate or compound is in the form of monosodium salt trihydrate.

14. A method according to claim 10 or claim 13 wherein the alendronate is administered orally.

A method according to any one of claims 10, 13 or 14 wherein the alendronate is administered in a dose of from 2.5 to 50 mg per day.

16. A method according to claim 15 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.

17. A method according to any one of claims 10 or 13 to 16, or a compound according to claim 11 or claim 13, wherein the alendronate or compound is combined, with a pharmaceutically acceptable carrier or diluent, in the form of a composition.

18. A method of preventing bone loss associated with rheumatoid arthritis (RA), in an animal suffering from RA, which method comprises administering to the animal a prophylatically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

19. A compound which is alendronate or a pharmaceutically acceptable salt thereof when used to prevent bone loss associated with RA in an animal suffering from RA.

20. Use of alendronate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing bone loss associated with RA in an animal suffering from RA.

21. A method according to claim 18, a compound according to claim 19 or a use according to claim 20 wherein the alendronate or compound is in the form of 'o monosodium salt trihydrate. a O I nhaa 486: tab

22. A method according to claim 18 or claim 21 wherein the alendronate is administered orally.

23. A method according to any one of claims 18, 21 or 22 wherein the alendronate is administered in a dose of from 2.5 to 50 mg per day.

24. A method according to claim 23 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.

A method according to any one of claims 18 or 21 to 24, or a compound according to claim 19 or claim 21, wherein the alendronate or compound is combined, with a pharmaceutically acceptable carrier or diluent, in the form of a composition.

26. A method according to any one of claims 1, 4 to 10, 13 to 18 or 21 to 25, a compound according to any one of claims 2, 4, 5, 11, 13, 19 or 21, a composition according to claim 25 or a use according to any one of claims 3, 4 5. 12, 13. 20 or 21, wherein the animal is a mammal.

27. A method, compound or use according to claim 26, wherein the mammal is human. Dated 27 January, 1999 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON r e o e i L- c r 2 uT C,~ In; \hlaj014 itab I -I