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WO1996039150A1 - Traitement par bisphosphonates de la deperdition osseuse associee a l'arthrite rhumatoide - Google Patents

Traitement par bisphosphonates de la deperdition osseuse associee a l'arthrite rhumatoide Download PDF

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Publication number
WO1996039150A1
WO1996039150A1 PCT/US1996/008361 US9608361W WO9639150A1 WO 1996039150 A1 WO1996039150 A1 WO 1996039150A1 US 9608361 W US9608361 W US 9608361W WO 9639150 A1 WO9639150 A1 WO 9639150A1
Authority
WO
WIPO (PCT)
Prior art keywords
alendronate
administered
rheumatoid arthritis
bone loss
dose
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1996/008361
Other languages
English (en)
Inventor
Anastasia G. Daifotis
Ashley J. Yates
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU59679/96A priority Critical patent/AU703887B2/en
Priority to EP96916971A priority patent/EP0831843A1/fr
Priority to JP9500987A priority patent/JPH11506750A/ja
Publication of WO1996039150A1 publication Critical patent/WO1996039150A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • 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

Definitions

  • This invention relates to the use of bisphosphonates, particularly alendronate, to prevent bone loss associated with rheumatoid arthritis.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • 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.
  • 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.
  • bisphosphonates can prevent and treat bone loss associtated with rheumatoid arthritis when administered in either a prophylactically or therapeutically effective amount.
  • alendronate (4-amino- 1 -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 rheumatoid arthritis comprising administering an effective amount of a bisphosphonate selected from the group consisting of: alendronate, etidronate (1-hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino- 1 -hydroxypropyildiene- 1 , 1 -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(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
  • the patient undergoing treatment for rheumatoid arthritis will be receiving one or more of: an immunosuppressive drug, cyclosporine, methotrexate, or glucocorticoids.
  • “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.
  • 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 inco ⁇ orated by reference.
  • the pharmaceutically acceptable salts of alendronate include salts of alkali metals (e.g., Na, K), alkaline earth metals (e.g. Ca), salts of inorganic acids, such as HCl and salts of organic acids such as citric acid and amino acids.
  • Sodium salt forms are preferred, particularly the monosodium salt trihydrate form.
  • the bisphosphonate compounds of the present invention can be administered in oral dosage forms 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 non ⁇ toxic 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 and 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 5, 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 abso ⁇ tion.
  • 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 practices.
  • 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 practices.
  • the active ingredient can be combined with an oral, non ⁇ toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like;
  • an oral, non ⁇ toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated 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 inco ⁇ orated by reference.
  • the compounds used in the instant method may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran co-polymer, polyhydroxylpropyl-methacrylamide and the like.
  • Patients suffering from rheumatoid arthritis may be male or female of any age. Women may be pre-or post-menopausal.
  • 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 5 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.
  • the bone mineral density (BMD) of the spine, hip and total body are measured.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les bisphosphonates, et en particulier l'alendronate, peuvent prévenir ou traiter la déperdition osseuse liée à l'arthrite rhumatoïde.
PCT/US1996/008361 1995-06-06 1996-06-03 Traitement par bisphosphonates de la deperdition osseuse associee a l'arthrite rhumatoide Ceased WO1996039150A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU59679/96A AU703887B2 (en) 1995-06-06 1996-06-03 Bisphosphonate therapy for bone loss associated with rheumatoid arthritis
EP96916971A EP0831843A1 (fr) 1995-06-06 1996-06-03 Traitement par bisphosphonates de la deperdition osseuse associee a l'arthrite rhumatoide
JP9500987A JPH11506750A (ja) 1995-06-06 1996-06-03 慢性関節リウマチに係わる骨欠損に対するビスホスホネート療法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47146495A 1995-06-06 1995-06-06
US08/471,464 1995-06-06

Publications (1)

Publication Number Publication Date
WO1996039150A1 true WO1996039150A1 (fr) 1996-12-12

Family

ID=23871729

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/008361 Ceased WO1996039150A1 (fr) 1995-06-06 1996-06-03 Traitement par bisphosphonates de la deperdition osseuse associee a l'arthrite rhumatoide

Country Status (5)

Country Link
EP (1) EP0831843A1 (fr)
JP (1) JPH11506750A (fr)
AU (1) AU703887B2 (fr)
CA (1) CA2221416A1 (fr)
WO (1) WO1996039150A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033473A1 (fr) * 1997-12-25 1999-07-08 Toray Industries, Inc. Remedes contre les maladies intramedullaires
WO2000021541A1 (fr) * 1998-10-09 2000-04-20 F. Hoffmann-La Roche Ag Procede de preparation de compositions pharmaceutiques orales comprenant des biphosphonates
WO2001013922A1 (fr) * 1999-08-19 2001-03-01 The Royal Alexandra Hospital For Children Medicament pour traiter des fractures
AU741818B2 (en) * 1997-07-22 2001-12-13 Merck Sharp & Dohme Corp. Method for inhibiting bone resorption
US6548042B2 (en) 2000-08-07 2003-04-15 Arstad Erik Bis-phosphonate compounds
SG109478A1 (en) * 1997-07-22 2005-03-30 Merck & Co Inc Method for inhibiting bone resorption
AU781068B2 (en) * 1999-08-19 2005-05-05 Sydney Children's Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), The Drug for treating fractures
US20060009413A1 (en) * 2000-05-01 2006-01-12 Frey William H Ii Methods and compositions for protecting or treating muscarinic receptors through administration of pyrophosphate analog in subjects exposed to toxic or carcinogenic metals or metal ions
WO2016054056A1 (fr) * 2014-10-01 2016-04-07 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Procedes de traitement de pxe avec des inhibiteurs de tnap

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010043119A (ja) * 2009-10-16 2010-02-25 Gador Sa 骨の代謝病の予防および／または治療のための組成物、その組成物の調製方法およびその使用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5462932A (en) * 1994-05-17 1995-10-31 Merck & Co., Inc. Oral liquid alendronate formulations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5462932A (en) * 1994-05-17 1995-10-31 Merck & Co., Inc. Oral liquid alendronate formulations

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG109478A1 (en) * 1997-07-22 2005-03-30 Merck & Co Inc Method for inhibiting bone resorption
AU741818C (en) * 1997-07-22 2003-01-09 Merck Sharp & Dohme Corp. Method for inhibiting bone resorption
AU741818B2 (en) * 1997-07-22 2001-12-13 Merck Sharp & Dohme Corp. Method for inhibiting bone resorption
US6555529B1 (en) 1997-12-25 2003-04-29 Toray Industries, Inc. Remedies for intramedullary diseases
WO1999033473A1 (fr) * 1997-12-25 1999-07-08 Toray Industries, Inc. Remedes contre les maladies intramedullaires
WO2000021541A1 (fr) * 1998-10-09 2000-04-20 F. Hoffmann-La Roche Ag Procede de preparation de compositions pharmaceutiques orales comprenant des biphosphonates
EP0998933A1 (fr) * 1998-10-09 2000-05-10 Boehringer Mannheim Gmbh Procédé pour la préparation de compositions pharmaucetiques contenant des diphosphonates pour administration orale
US6419955B1 (en) 1998-10-09 2002-07-16 Hoffmann-La Roche Inc. Process for making bisphosphonate compositions
AU781068B2 (en) * 1999-08-19 2005-05-05 Sydney Children's Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), The Drug for treating fractures
WO2001013922A1 (fr) * 1999-08-19 2001-03-01 The Royal Alexandra Hospital For Children Medicament pour traiter des fractures
US8772263B2 (en) * 2000-05-01 2014-07-08 Healthpartners Research Foundation Methods and compositions for protecting or treating muscarinic receptors through administration of pyrophosphate analog in subjects exposed to toxic or carcinogenic metals or metal ions
US20060009413A1 (en) * 2000-05-01 2006-01-12 Frey William H Ii Methods and compositions for protecting or treating muscarinic receptors through administration of pyrophosphate analog in subjects exposed to toxic or carcinogenic metals or metal ions
US6548042B2 (en) 2000-08-07 2003-04-15 Arstad Erik Bis-phosphonate compounds
WO2016054056A1 (fr) * 2014-10-01 2016-04-07 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Procedes de traitement de pxe avec des inhibiteurs de tnap

Also Published As

Publication number Publication date
AU5967996A (en) 1996-12-24
JPH11506750A (ja) 1999-06-15
AU703887B2 (en) 1999-04-01
EP0831843A1 (fr) 1998-04-01
CA2221416A1 (fr) 1996-12-12

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