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WO1996038156A1 - Use of alendronate for the prevention of osteoporosis - Google Patents

Use of alendronate for the prevention of osteoporosis Download PDF

Info

Publication number
WO1996038156A1
WO1996038156A1 PCT/US1996/007912 US9607912W WO9638156A1 WO 1996038156 A1 WO1996038156 A1 WO 1996038156A1 US 9607912 W US9607912 W US 9607912W WO 9638156 A1 WO9638156 A1 WO 9638156A1
Authority
WO
WIPO (PCT)
Prior art keywords
alendronate
osteoporosis
years
bone
aln
Prior art date
Application number
PCT/US1996/007912
Other languages
English (en)
French (fr)
Inventor
Ashley J. Yates
Original Assignee
Merck & 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
Priority to EE9700308A priority Critical patent/EE03306B1/xx
Priority to EA199700449A priority patent/EA000677B1/ru
Priority to NZ308935A priority patent/NZ308935A/en
Priority to HU9900659A priority patent/HUP9900659A3/hu
Priority to SK1595-97A priority patent/SK159597A3/sk
Priority to JP8536616A priority patent/JPH10506648A/ja
Priority to EP96920553A priority patent/EP0828496A1/en
Priority to AU58824/96A priority patent/AU709196B2/en
Priority to BR9609020A priority patent/BR9609020A/pt
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO1996038156A1 publication Critical patent/WO1996038156A1/en
Priority to IS4617A priority patent/IS4617A/is
Priority to BG102060A priority patent/BG63103B1/bg
Priority to NO975527A priority patent/NO975527L/no

Links

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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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 alendronate, an amino- bisphosphonate, for the prevention of osteoporosis in early post- menopausal women.
  • Alendronate, 4-amino- 1 -hydroxybuty lidene- 1,1 - bisphosphonic acid, and its pharmaceutically acceptable salts has been found to be useful in the treatment of osteoporosis.
  • Alendronate is a specific inhibitor of bone resorption. It has a high affinity for bone mineral and is taken up into the bone selectively where it inhibits osteoclast activity. While alendronate has been shown to be useful in restoring lost bone, there has been no indication that it can prevent the loss of bone in otherwise healthy individuals.
  • Peak bone mass in women is achieved at around 30-35 years of age, after which bone mass is lost progressively throughout life. The rate of loss is accelerated during the early post menopausal period, especially at sites with a high component of trabecular bone.
  • the only approved therapy for prevention of osteoporosis is estrogen replacement therapy.
  • administration of estrogen can help reduce post menopausal symptoms such as vasomotor instability, vaginal atrophy, and an improvement in the lipid profile with a probable reduction in cardiovascular problems.
  • estrogen treatment is also associated with some serious risks, including endometrial carcinoma, symptomatic gall bladder disease, and a possible increase in the incidence of breast cancer. Although some of these risks can be lowered by addition of progestins to the therapeutic regimen or by yearly endometrial biopsies, a large proportion of women will not accept long-term estrogen treatment mainly because of poor tolerability and safety concerns.
  • This invention relates to a method of preventing osteoporosis in women having a normal bone mineral density comprising administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficient amount of time.
  • a further aspect of this invention is a method of reducing the risk of fracture in women by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a substantial period of time.
  • Yet another aspect of this invention is a method of preventing osteoporosis in early postmenopausal women by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.
  • a further aspect of this invention is a method of preserving normal bone microstructure and bone strength by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.
  • “Prophylactically effective amount” an amount of alendronate or a pharmaceutically acceptable salt thereof which is sufficient to prevent osteoporosis in women not currently suffering from osteoporosis. This amount may or may not be a pharmaceutically acceptable amount, i.e. sufficient to treat osteoporosis, i.e. restore bone mass in a patient who is currently suffering from osteoporosis.
  • Substantial period of time a sustained period, i.e. at least about three years, and preferably longer.
  • Ostoporosis a condition wherein a person's bone mineral density is more than about 2 standard deviations below the peak bone mineral density.
  • 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 (e.g., Na, K), alkali 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 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 compound desired can be used as a osteoporosis-preventing agent.
  • the dosage regimen utilizing the claimed method is selected in accordance with a variety of factors including age, weight, sex, and medical condition of the patient; 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 osteoporosis.
  • Oral dosages of the present invention 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 2.5-20 mg/day over the effective treatment period, and a preferred prophylactic amount is 2.5, 5, or 10 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.
  • 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, cros-carmellose sodium, magnesium stearate, mannitol, sorbitol and the like;
  • an oral, non- toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, cros-carmellose sodium, magnesium stearate, mannitol, sorbitol 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 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 stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • a particularly preferred tablet formulation 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.
  • Women enrolled in this study are in good general health and are between 45-59 years old and have been selected randomly from a target population who live in a defined geographical area. The majority are early postmenopausal. Fewer than 15 percent of the participants have any incidence of osteoporosis evident on baseline spinal dual-energy X-ray densitometry.
  • each subject is randomized to ether placebo, alendronate low dose (ALN 2.5 mg per day), alendronate high dose (ALN 5 mg per day) or open labeled estrogen/progestin (E/P).
  • the estrogen/progestin group in the United States will receive the conjugated estrogen PREMARIN® (0.625 mg per day) and the medroxyprogesterone acetate PROVERA® (5 mg per day) taken continuously throughout the calendar month. Outside the United States, the estrogen/progestin group will receive micronized 17b-estradiol and norethisterone acetate (Trisequens) as a cyclical regimen. All subjects who have a calcium intake of less than 500 mg per day will be advised to increase their calcium intake (either by diet or supplements) to above this level. Distribution of the groups is shown in TABLE 1. The duration of treatment in each of the groups is given in TABLE 2.
  • the study is double blind (for women receiving either alendronate or placebo) for the first two years, at the end of which a first analysis is performed.
  • the study remains double blind until each subject reaches the end of the fourth year of study, when the blind is broken for each subject individually.
  • Subjects are informed only whether or not they received active treatment with alendronate, and, if so, whether they were treated for two or four years. Subjects will not be informed of the dose of the study drug. Those subjects who remain in the blinded study for years 5 and 6, and the investigators remain blinded to their treatment allocation during the extension period.
  • Subjects in Group "A” continue to take blinded placebo for four years. At the end of four years these women will be informed that they had received placebo during Years 1 to 4. They are then given the option to be further randomized (1 : 1) between blinded placebo and alendronate and the "optimal" dose or to exit the study.
  • Groups Bl and C2 receive the 2.5 or 5 mg of alendronate, respectively for six years.
  • Groups B2 and C2 will remain on the 2.5 and 5 mg of alendronate, respectively for four years before switching to placebo for the final two years of the study.
  • Those subjects who remain in the study for Years 5 and 6 will be blinded (double blind) regarding their allocation to active drug or placebo for Years 5 and 6.
  • Groups B3 and C3 remain on the 2.5 and 5 mg alendronate, respectively for only two years before switching to placebo for the third and fourth years of the study. They will discontinue study drug after the fourth year.
  • Subjects in Group D continue the open-label estrogen/progestin treatment for four years, after which they will discontinue the study drug after the fourth year.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US1996/007912 1995-06-02 1996-05-29 Use of alendronate for the prevention of osteoporosis WO1996038156A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
AU58824/96A AU709196B2 (en) 1995-06-02 1996-05-29 Use of alendronate for the prevention of osteoporosis
NZ308935A NZ308935A (en) 1995-06-02 1996-05-29 Use of Alendronate for the prevention of osteoporosis
HU9900659A HUP9900659A3 (en) 1995-06-02 1996-05-29 Use of alendronate for prevention of osteoporosis
SK1595-97A SK159597A3 (en) 1995-06-02 1996-05-29 Use of alendronate for the prevention of osteoporosis
JP8536616A JPH10506648A (ja) 1995-06-02 1996-05-29 骨粗鬆症予防へのアレンドロネートの使用
EE9700308A EE03306B1 (et) 1995-06-02 1996-05-29 Alendronaadi kasutamine osteoporoosi vältimiseks
EA199700449A EA000677B1 (ru) 1995-06-02 1996-05-29 Способ предотвращения остеопороза
EP96920553A EP0828496A1 (en) 1995-06-02 1996-05-29 Use of alendronate for the prevention of osteoporosis
BR9609020A BR9609020A (pt) 1995-06-02 1996-05-29 Processo para evitar a osteoporose em mulheres com pós-menopausa precoce
IS4617A IS4617A (is) 1995-06-02 1997-11-19 Notkun alendrónats til að fyrirbyggja beingisnun
BG102060A BG63103B1 (bg) 1995-06-02 1997-11-20 Използуване на алендронат за профилактика на остеопороза
NO975527A NO975527L (no) 1995-06-02 1997-12-01 Anvendelse av alendronat til forhindring av osteoporose

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45819595A 1995-06-02 1995-06-02
US08/458,195 1995-06-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US08952830 A-371-Of-International 1997-11-25
US09/794,722 Continuation US20010046977A1 (en) 1997-11-25 2001-02-27 Use of alendronate for the prevention of osteoporosis

Publications (1)

Publication Number Publication Date
WO1996038156A1 true WO1996038156A1 (en) 1996-12-05

Family

ID=23819759

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/007912 WO1996038156A1 (en) 1995-06-02 1996-05-29 Use of alendronate for the prevention of osteoporosis

Country Status (21)

Country Link
EP (1) EP0828496A1 (cs)
JP (1) JPH10506648A (cs)
KR (1) KR19990022436A (cs)
CN (1) CN1192685A (cs)
AU (1) AU709196B2 (cs)
BG (1) BG63103B1 (cs)
BR (1) BR9609020A (cs)
CA (1) CA2222318A1 (cs)
CZ (1) CZ381197A3 (cs)
EA (1) EA000677B1 (cs)
EE (1) EE03306B1 (cs)
HU (1) HUP9900659A3 (cs)
IL (1) IL118422A0 (cs)
IS (1) IS4617A (cs)
NO (1) NO975527L (cs)
NZ (1) NZ308935A (cs)
PL (1) PL323669A1 (cs)
SK (1) SK159597A3 (cs)
TR (1) TR199701482T1 (cs)
WO (1) WO1996038156A1 (cs)
ZA (1) ZA964465B (cs)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061111A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate
US7601336B2 (en) 1997-06-13 2009-10-13 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100317935B1 (ko) * 1999-10-20 2001-12-22 유승필 대사성 골질환 치료용 약제조성물 및 이의 제조방법
BR0209360A (pt) * 2001-05-02 2004-06-08 Novartis Ag Método de administração de bisfosfonatos por inalação no tratamento ou prevenção de reabsorção óssea e osteoporose
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
KR102472749B1 (ko) * 2022-01-18 2022-12-02 주식회사 위엔씨 유해가스제거 및 항균탈취기능을 함유한 흡착소재 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366965A (en) * 1993-01-29 1994-11-22 Boehringer Mannheim Gmbh Regimen for treatment or prophylaxis of osteoporosis
US5462932A (en) * 1994-05-17 1995-10-31 Merck & Co., Inc. Oral liquid alendronate formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366965A (en) * 1993-01-29 1994-11-22 Boehringer Mannheim Gmbh Regimen for treatment or prophylaxis of osteoporosis
US5462932A (en) * 1994-05-17 1995-10-31 Merck & Co., Inc. Oral liquid alendronate formulations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. LOMBARDI, ET AL.: "clinical trials with bisphosphonates", ANN. ITAL. MED. INT., vol. 7, no. 3(suppl.), July 1992 (1992-07-01) - September 1992 (1992-09-01), pages 158s - 165s, XP000579314 *
MASSIMO DE GREGORIO, GIOVANNI DE GREGORIO: "I bisfosfonati nel trattamento dell' osteoporosi e nella prevenzione delle fratture correlate", CLIN. TER., vol. 146, no. 2, February 1995 (1995-02-01), ROME, pages 123 - 132, XP000579317 *
N.B. WATTS: "treatment of osteoporosis with bisphosphonates", RHEUM. DIS. CLIN. NORTH. AM (UNITED STATES), vol. 20, no. 3, August 1994 (1994-08-01), EMORY UNIVERSITY SCHOOL OF MEDICINE ATLANTA, GEORGIA, pages 717 - 734, XP000579259 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601336B2 (en) 1997-06-13 2009-10-13 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
US8420058B2 (en) 1997-06-13 2013-04-16 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
WO2000061111A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate

Also Published As

Publication number Publication date
EE03306B1 (et) 2000-12-15
IS4617A (is) 1997-11-19
NO975527D0 (no) 1997-12-01
AU709196B2 (en) 1999-08-26
ZA964465B (en) 1996-12-11
KR19990022436A (ko) 1999-03-25
HUP9900659A3 (en) 2002-12-28
EP0828496A1 (en) 1998-03-18
BG102060A (en) 1998-07-31
PL323669A1 (en) 1998-04-14
CZ381197A3 (cs) 1998-06-17
JPH10506648A (ja) 1998-06-30
AU5882496A (en) 1996-12-18
BG63103B1 (bg) 2001-04-30
TR199701482T1 (xx) 1998-03-21
CA2222318A1 (en) 1996-12-05
BR9609020A (pt) 1999-07-06
SK159597A3 (en) 1998-06-03
IL118422A0 (en) 1996-09-12
EA000677B1 (ru) 2000-02-28
HUP9900659A2 (hu) 2001-04-28
NO975527L (no) 1997-12-01
CN1192685A (zh) 1998-09-09
NZ308935A (en) 2000-07-28
EA199700449A1 (ru) 1998-06-25

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