WO1998025628A1 - Pharmaceutical compositions containing alendronate and an agent promoting gastric emptying - Google Patents

Pharmaceutical compositions containing alendronate and an agent promoting gastric emptying Download PDF

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Publication number
WO1998025628A1
WO1998025628A1 PCT/US1997/022554 US9722554W WO9825628A1 WO 1998025628 A1 WO1998025628 A1 WO 1998025628A1 US 9722554 W US9722554 W US 9722554W WO 9825628 A1 WO9825628 A1 WO 9825628A1
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WO
WIPO (PCT)
Prior art keywords
alendronate
gastric
cisapride
salt
propulsive
Prior art date
Application number
PCT/US1997/022554
Other languages
French (fr)
Inventor
Richard C. Fuisz
Original Assignee
Fuisz Technologies Ltd.
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 Fuisz Technologies Ltd. filed Critical Fuisz Technologies Ltd.
Priority to EP97950904A priority Critical patent/EP0938319A1/en
Priority to JP52689398A priority patent/JP2001508769A/en
Publication of WO1998025628A1 publication Critical patent/WO1998025628A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis

Definitions

  • This invention is related to the field of reducing side effects of a drug. In particular it related to reducing side effects of drugs which reduce calcium loss. Description of the Prior Art
  • Alendronate is an agent for reducing calcium resorption and thereby treating loss of calcium.
  • Alendronate sodium is sold under the trademar Fosamax® by Merck & Cop., Inc., West Point, PA 19486.
  • Fosamax® has a side effect of producing severe gastric and esophageal distress.
  • U. S. Patent 4,705,651 describes the preparation of alendronate.
  • U. S. Patent 4,705,651 is incorporated herein by reference in its entirety. The pharmacological properties and dosage of Fosamax® is described in detail in the 1996 Supplement to Physicians Desk Reference. That reference is incorporated herein by reference.
  • Alendronate sodium, ( 4-amino-l-hydroxybutylidene) bis- phosphonic acid, monosodium salt has the following structure:
  • Cisapride is sold under the brand name PROPULSID® as an agent to promote gastric emptying.
  • Cisapride Cis 4-amino- 5-chloro-N- [1- (3-p-flurophenylpropyl] 3-methoxy-4- piperndinyl) -O-asisamide, has the following structure:
  • This invention encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of alendronate salt for reducing calcium loss and an effective amount of gastric propulsive agent to relieve and prevent esophageal and gastric distress.
  • the invention also encompasses a method for relieving and preventing esophageal and gastric distress caused by an alendronate salt which comprises administering to a patient treated with alendronate salt a gastric reflux inhibiting amount of a gastric propulsive agent, preferably cisapride, at or about the time of administering the alendronate salt.
  • a gastric reflux inhibiting amount of a gastric propulsive agent preferably cisapride
  • an alendronate formulation which has a therapeutically effective amount of an alendronate salt to reduce calcium resorption and at the same time to have a therapeutically effective amount of a gastric propulsive agent to overcome the gastric reflux side effect of alendronate.
  • gastric propulsive agents other than cisapride and compounds related to cisapride are also useable by separate administration or in combination with alendronate.
  • Alendronate is an agent for reducing calcium loss and is sold under the trademark Fosamax® by Merck & Co. This product has a side effect of producing severe esophagitis due to gastric reflux.
  • the recommended daily dose of Fosamax® is about 10 mg/day.
  • For Paget's disease the recommended dose is 40 mg/day.
  • the present invention contemplates unit dose of between about 10 mg to 40 mg of alendronate salt.
  • Cisapride is available in 10 mg or 20 mg tablets under the tradename of PROPULSID®. A detailed description of this material is found in 1995 Physicians Desk Reference (PDR) at pages 1300-1301 which is incorporated herein by reference. Cisapride is combined with alendronate salt to reduce the side effect of gastric reflux. Analogs of cisapride and closely related compounds described in U. S. Patent 4,962,115 are suitable gastric propulsive agents. Those skilled in the pharmaceutical arts will recognize a wide variety of formulations and techniques for combining alendronate and a gastric propulsive drug such as cisapride to achieve pharmaceutical formulations which meet the objects of this invention. For example, tablets containing 10 mg of cisapride and 10 mg of alendronate in a suitable pharmaceutical carrier are preferred.
  • a preferred dose is a tablet of 10 mg of alendronate sodium and 10 mg of cisapride in inactive carriers of microcrystallin cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.

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

Abstract

This invention encompasses a pharmaceutical composition comprising an effective amount of alendronate salt for reducing calcium loss and an effective amount of a gastric propulsive agent, preferably cisapride, to prevent gastric reflux caused by the alendronate salt.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING ALENDRONATE AND AN AGENT PROMOΗNG GASTRIC EMPTYING
Field of the Invention
This invention is related to the field of reducing side effects of a drug. In particular it related to reducing side effects of drugs which reduce calcium loss. Description of the Prior Art
Alendronate is an agent for reducing calcium resorption and thereby treating loss of calcium. Alendronate sodium is sold under the trademar Fosamax® by Merck & Cop., Inc., West Point, PA 19486. Fosamax® has a side effect of producing severe gastric and esophageal distress. U. S. Patent 4,705,651 describes the preparation of alendronate. U. S. Patent 4,705,651 is incorporated herein by reference in its entirety. The pharmacological properties and dosage of Fosamax® is described in detail in the 1996 Supplement to Physicians Desk Reference. That reference is incorporated herein by reference.
Alendronate sodium, ( 4-amino-l-hydroxybutylidene) bis- phosphonic acid, monosodium salt has the following structure:
Figure imgf000003_0001
U. S. Patent 4,962,115 describes cisapride and related gastric propulsive compounds. The entire specification of U. S. Patent 4,962,115 is incorporated herein by reference. Cisapride is sold under the brand name PROPULSID® as an agent to promote gastric emptying. Cisapride, Cis 4-amino- 5-chloro-N- [1- (3-p-flurophenylpropyl] 3-methoxy-4- piperndinyl) -O-asisamide, has the following structure:
Figure imgf000004_0001
SUMMARY OF THE INVENTION
This invention encompasses a pharmaceutical composition comprising an effective amount of alendronate salt for reducing calcium loss and an effective amount of gastric propulsive agent to relieve and prevent esophageal and gastric distress.
The invention also encompasses a method for relieving and preventing esophageal and gastric distress caused by an alendronate salt which comprises administering to a patient treated with alendronate salt a gastric reflux inhibiting amount of a gastric propulsive agent, preferably cisapride, at or about the time of administering the alendronate salt. DETAILED DESCRIPTION OF THE INVENTION The inventor believes that the esophageal and gastric distress caused by alendronate is due to gastric reflux. Therefore, it is an object of this invention to provide an alendronate formulation which has a therapeutically effective amount of an alendronate salt to reduce calcium resorption and at the same time to have a therapeutically effective amount of a gastric propulsive agent to overcome the gastric reflux side effect of alendronate. Those skilled in the pharmaceutical arts will recognize that other gastric propulsive agents other than cisapride and compounds related to cisapride are also useable by separate administration or in combination with alendronate.
Alendronate is an agent for reducing calcium loss and is sold under the trademark Fosamax® by Merck & Co. This product has a side effect of producing severe esophagitis due to gastric reflux. The recommended daily dose of Fosamax® is about 10 mg/day. For Paget's disease the recommended dose is 40 mg/day. The present invention contemplates unit dose of between about 10 mg to 40 mg of alendronate salt.
Cisapride is available in 10 mg or 20 mg tablets under the tradename of PROPULSID®. A detailed description of this material is found in 1995 Physicians Desk Reference (PDR) at pages 1300-1301 which is incorporated herein by reference. Cisapride is combined with alendronate salt to reduce the side effect of gastric reflux. Analogs of cisapride and closely related compounds described in U. S. Patent 4,962,115 are suitable gastric propulsive agents. Those skilled in the pharmaceutical arts will recognize a wide variety of formulations and techniques for combining alendronate and a gastric propulsive drug such as cisapride to achieve pharmaceutical formulations which meet the objects of this invention. For example, tablets containing 10 mg of cisapride and 10 mg of alendronate in a suitable pharmaceutical carrier are preferred.
A preferred dose is a tablet of 10 mg of alendronate sodium and 10 mg of cisapride in inactive carriers of microcrystallin cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising an effective amount of alendronate salt for reducing calcium loss and an affective amount of gastric propulsive agent to prevent gastric reflux caused by alendronate salt.
2. A pharmaceutical composition, according to claim 1, wherein the gastric propulsive drug is cisapride.
3. A pharmaceutical composition, according to claim 1, which contains 10 to 40 mg of alendronate sodium and 10 to 20 mg of cisapride.
4. A pharmaceutical composition, according to claim 3, which contains about 10 mg of alendronate sodium and about 10 mg of cisapride.
5. A method for preventing esophageal or gastric distress caused by an alendronate salt comprising administering to a patient treated with alendronate salt a gastric reflux inhibiting amount of a gastric propulsive drug at or about the time of administering the alendronate salt.
6. A method according to claim 5 wherein the gastric propulsive drug is cisapride.
PCT/US1997/022554 1996-12-11 1997-12-08 Pharmaceutical compositions containing alendronate and an agent promoting gastric emptying WO1998025628A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP97950904A EP0938319A1 (en) 1996-12-11 1997-12-08 Pharmaceutical compositions containing alendronate and an agent promoting gastric emptying
JP52689398A JP2001508769A (en) 1996-12-11 1997-12-08 Pharmaceutical composition comprising alendronate and an agent for promoting gastric emptying

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/762,672 US5773429A (en) 1996-12-11 1996-12-11 Drug combination for treating calcium loss
US08/762,672 1996-12-11

Publications (1)

Publication Number Publication Date
WO1998025628A1 true WO1998025628A1 (en) 1998-06-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (5)

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US (1) US5773429A (en)
EP (1) EP0938319A1 (en)
JP (1) JP2001508769A (en)
CA (1) CA2250221A1 (en)
WO (1) WO1998025628A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003043641A1 (en) * 2001-11-19 2003-05-30 Nobel Ilaç Sanayii Ve Ticaret A.S. New pharmaceutical combinations prepared with alginates and biphosphonates in order to prevent gastroesophageal reflux during use of oral biphoshonates

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010031244A1 (en) * 1997-06-13 2001-10-18 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
US6432932B1 (en) 1997-07-22 2002-08-13 Merck & Co., Inc. Method for inhibiting bone resorption
US5994329A (en) 1997-07-22 1999-11-30 Merck & Co., Inc. Method for inhibiting bone resorption
EE05627B1 (en) * 1998-12-23 2013-02-15 Pfizer Inc. Human monoclonal antibodies to CTLA-4
CA2480814A1 (en) * 2002-04-05 2003-10-23 Merck & Co., Inc. Method for inhibiting bone resorption with an alendronate and vitamin d formulation
TR200300510A2 (en) * 2003-04-18 2004-11-22 Sanovel �La� Sanay� Ve T�Caret A.�. Dispersing alendronate microparticle formulation
US20050261250A1 (en) * 2004-05-19 2005-11-24 Merck & Co., Inc., Compositions and methods for inhibiting bone resorption
US20060134190A1 (en) * 2004-12-16 2006-06-22 Banner Pharmacaps Inc. Formulations of bisphosphonate drugs with improved bioavailability

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US4962115A (en) * 1981-10-01 1990-10-09 Janssen Pharmaceutica N.V. Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives
IT1196315B (en) * 1984-10-29 1988-11-16 Gentili Ist Spa PROCEDURE FOR THE PREPARATION OF DIPHOSPHONIC ACIDS
US5464632C1 (en) * 1991-07-22 2001-02-20 Prographarm Lab Rapidly disintegratable multiparticular tablet
US5270365A (en) * 1991-12-17 1993-12-14 Merck & Co., Inc. Prevention and treatment of periodontal disease with alendronate

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANDRE L. BLUM ET AL.: "Long-term treatment of gastro-esophageal reflux disease: experience with cisapride", TODAY'S THER. TRENDS, vol. 11, no. 4, 1994, pages 219 - 247, XP002056401 *
G.MACONI ET AL.: "Multiple ulcerative esophagitis caused by alendronate", AM.J.GASTROENTEROL., vol. 90, no. 10, 1995, pages 1889 - 1890, XP002056397 *
G.N.J.TYTGAT ET AL.: "Reflux esophagitis", SCAND.J.GASTROENTEROL., vol. 25, no. suppl. 175, 1990, pages 1 - 12, XP002056399 *
PIET C. DE GROEN ET AL.: "Esophagitis associated with the use of alendronate", N.ENGL.J.MED., vol. 335, no. 14, 3 October 1996 (1996-10-03), pages 1016 - 1021, XP002056398 *
RICHARD W. MCCALLUM ET AL: "Cisapride", DRUGS, vol. 36, no. 6, 1988, pages 652 - 681, XP002056400 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003043641A1 (en) * 2001-11-19 2003-05-30 Nobel Ilaç Sanayii Ve Ticaret A.S. New pharmaceutical combinations prepared with alginates and biphosphonates in order to prevent gastroesophageal reflux during use of oral biphoshonates

Also Published As

Publication number Publication date
EP0938319A1 (en) 1999-09-01
US5773429A (en) 1998-06-30
JP2001508769A (en) 2001-07-03
CA2250221A1 (en) 1998-06-18

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