WO1998053827A1 - Traitement de l'osteoporose - Google Patents

Traitement de l'osteoporose Download PDF

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Publication number
WO1998053827A1
WO1998053827A1 PCT/IL1998/000246 IL9800246W WO9853827A1 WO 1998053827 A1 WO1998053827 A1 WO 1998053827A1 IL 9800246 W IL9800246 W IL 9800246W WO 9853827 A1 WO9853827 A1 WO 9853827A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
ghs
osteoporosis
pharmaceutical composition
treatment
Prior art date
Application number
PCT/IL1998/000246
Other languages
English (en)
Inventor
Zvi Laron
Original Assignee
Ramot University Authority For Applied Research And Industrial Development 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 Ramot University Authority For Applied Research And Industrial Development Ltd. filed Critical Ramot University Authority For Applied Research And Industrial Development Ltd.
Priority to AU75459/98A priority Critical patent/AU7545998A/en
Publication of WO1998053827A1 publication Critical patent/WO1998053827A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin

Definitions

  • the present invention relates to a novel combination of drugs for the treatment of osteoporosis.
  • Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus resorption during the ongoing remodeling process. Bone mass increases during the first two decades of life reaching a peak bone mass, and then steadily declines, especially after menopause. OSP is a major public health concern of increasing magnitude as the population ages (1). OSP can also occur in children (2), and some investigators believe that the seeds of OSP are sown during the first 20 years of life (3).
  • Anti-osteoporosis therapy falls into two classes: anti-resorptive agents and bone restorative (or anabolic) agents.
  • Anti-resorptive therapy targets bone resorption, reducing bone turnover and thereby preventing bone loss. It has been the major focus until now and current therapies fall into this class. More recently, the focus has shifted onto bone restoration, which seeks to restore bone to osteopenic skeletons thereby reducing the likelihood of skeletal fracture.
  • Anti-resorptive therapy is preventative while bone restoration is an active treatment of OSP (1).
  • Antiresorptrve agents include bisphosphonates, estrogens, estrogen agonists and antagonists, calcitonin and vitamin D. Bone restorative approaches include the use of parathyroid hormone, growth hormone (GH), GH secretagogues (GHS) and sodium fluoride. Currently, estrogen replacement therapy, calcitonin and the bisphosphonate alendronate are the only approved therapies for OSP in the United States (1).
  • Vitamin D and its metabolites are hormones that participate in the regulation of calcium homeostasis and bone metabolism (4).
  • a deficiency of vitamin D or its precursors in humans can result in abnormalities in calcium and phosphate metabolism.
  • overly high dosages of vitamin D can lead to undesirable side effects such as hypercalcemia and nephrocalcinosis.
  • Numerous vitamin D analogs have been synthesized, some of which have been tested for their effect on OSP. However, their use for treating OSP remains experimental (1).
  • GHS appear to act both on the hypothalamus and on the pituitary to increase the secretion of endogenous pituitary growth hormone (GH), which in turn increases the level of endogenous IGF-I, the hormone which acts on protein and bone metabolism.
  • GH pituitary growth hormone
  • IGF-I endogenous endogenous growth hormone
  • the specific effects on bone metabolism result from a combination of the renotropic effect of IGF-I as well as from the protein anabolic effect and cell multiplication effect.
  • Both peptide and nonpeptide GHS exist.
  • Various hepta-, hexa-, penta-, tetra-, tri- and di-peptide analogs have been synthesized (5).
  • Administration of pharmacological doses of GH as a single daily bolus have resulted in several objectionable side effects (1).
  • U.S. 5,069,905 to Lidor discloses a composition comprising a vitamin
  • D 3 derivative for local, topical application to a site of bone fracture or osteotomy, or for application to solid or semi-solid bone implants.
  • auxiliary substances listed in this patent is GH.
  • Novel therapeutic agents would be useful for the prevention and active treatment of OSP.
  • a method for the treatment of osteoporosis comprising systemically administrating to a subject a combination of:
  • a pharmaceutical composition for the treatment of osteoporosis comprising a combination of:
  • treatment encompasses both preventive treatment in subjects who have not as yet developed OSP, but may have nascent osteoporosis (such as in chronic recipients of glucocorticoids), as well as therapy for patients already suffering from active OSP.
  • the effects of the treatment are systemic as opposed to the local effects of the aforementioned U.S. Patent No. 5,069,905.
  • the present invention provides a combination of two different classes of compounds which act by different mechanisms to combat OSP, as explained above. The combination of the compounds is expected to result in a synergistic action enabling the use of smaller doses of each compound. It is thus possible to avoid undesirable side effects observed with each compound alone at optimal or maximal effective doses.
  • GHS comprise any compound which stimulates the release of endogenous pituitary GH, including both peptide and non-peptide agents.
  • Peptide GHS include but are not limited to GHRP-1, GHRP-2, GHRP-6, G-7509, G-7039, EP41614, EP41615, EP41616, EP41617, EP50886, EP 50477, tetrarelin and hexarelin (6).
  • Non-peptide GHS include but are not limited to benzo-lactam derivatives such as L-692,429, and MK-677.
  • GHS can be obtained, for example, from Pharmacia-Upjohn, Merck, Europeptide, Genentech and Wyeth-Ayerst.
  • Vitamin D compounds comprise both the various types of vitamin D (vitamin D . , vitamin D 2 [calciferol], vitamin D 3 [cholecalciferol], as well as vitamin D analogs which include but are not limited to calcitriol, 24,25-dihydroxycholecalciferol, 1 -vitamin D 3 and 1 -hydroxyvitamin D.
  • Vitamin D can be obtained from standard commercial suppliers.
  • Vitamin D analogs can be obtained from various suppliers, as detailed in the following table (7):
  • the pharmaceutical composition of the invention may be manufactured both in dry or in fluid form.
  • a pharmaceutically acceptable excipient will usually be included in the formulation.
  • the dry form may include tablets or capsules, while the fluid form may include a nasal spray, an injectable fluid or an orally administered fluid.
  • the composition may be administered orally, intra-nasally or by injection.
  • the optimal dosage of GHS and vitamin D compound in the composition of the invention may be readily determined as a function of age, sex, manner of preparation, administration technique, and whether the composition is used for therapeutic of preventive treatment.
  • the dosage of vitamin D is usually adjusted according to the blood calcium level.
  • Typical vitamin D dosages in tablet form for treatment of OSP are 125-500 I.U./day.
  • Dosages of vitamin D analogs such as alphacalcidol and calcitriol in the treatment of postmenopausal OSP are generally in the range of 0.25-2 g/day (8).
  • the dosage level also depends on the level of exposure of the patient to the sun, as greater exposure results in increased production of endogenous vitamin D. It is to be expected that in accordance with the method of the invention, lower dosages will be effective in view of the synergistic effect of the composition of the invention.
  • the dosage of GHS is usually adjusted by following the serum IGF-I level, and will depend, inter alia, on the activity of the secretagogue. Typical dosage ranges for some of the GHS are 400-600 mg/day p.o. for GHRP-2, 100-150 g/kg/day i.n. or 250-500 mg/day p.o. for hexarelin, and 15-30 mg/day p.o. for MK-677. Adolescents will usually receive higher doses than adults, due to their increased growth rate.
  • the level of GHS in the composition of the invention are expected to be lower than when administered alone.
  • the pharmaceutical composition of the invention may be tested in various groups at risk for OSP. These include adolescents, young adults receiving large doses of corticosteroids, and postmenopausal women. Among the parameters which may be followed in a clinical trial are IGF-I level, calcium and phosphate levels, alkaline phosphatase, procollagens and bone mineral density.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé et une composition pharmaceutique destinés au traitement systémique de l'ostéoporose. Le procédé consiste à administrer à un sujet un mélange combinant 1) un sécrétagogue d'hormone de croissance (GHS) et 2) un complexe vitaminique D. Ledit procédé s'applique aussi bien au traitement de l'ostéoporose évolutive qu'au traitement préventif de l'ostéoporose naissante.
PCT/IL1998/000246 1997-05-30 1998-05-28 Traitement de l'osteoporose WO1998053827A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75459/98A AU7545998A (en) 1997-05-30 1998-05-28 Treatment of osteoporosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL12095597A IL120955A0 (en) 1997-05-30 1997-05-30 Treatment of osteoporosis
IL120955 1997-05-30

Publications (1)

Publication Number Publication Date
WO1998053827A1 true WO1998053827A1 (fr) 1998-12-03

Family

ID=11070199

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL1998/000246 WO1998053827A1 (fr) 1997-05-30 1998-05-28 Traitement de l'osteoporose

Country Status (3)

Country Link
AU (1) AU7545998A (fr)
IL (1) IL120955A0 (fr)
WO (1) WO1998053827A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027913A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Compositions pharmaceutiques et methodes de traitement consistant en des associations d'un derive de la 2-alkylidene-19-nor-vitamine d et d'un secretagogue de l'hormone de croissance
WO2017147420A1 (fr) * 2016-02-25 2017-08-31 The University Of Florida Research Foundation, Inc. Procédés et compositions avec des composés de vitamine d pour le traitement de la fibrose kystique et de troubles respiratoires
CN113181193A (zh) * 2021-05-08 2021-07-30 黄彬 卡泊三醇作为预防和治疗老年性骨质疏松的皮肤外用药的用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4330537A (en) * 1977-12-07 1982-05-18 The Procter & Gamble Company Compositions for inhibiting mobilization of calcium phosphate in animal tissue
US5069905A (en) * 1985-03-15 1991-12-03 Yeda Research And Development Company Limited Method and compositions comprising a vitamin d derivatives for the local treatment of bone fractures
US5317017A (en) * 1992-09-30 1994-05-31 Merck & Co., Inc. N-biphenyl-3-amido substituted benzolactams stimulate growth hormone release
GB2273046A (en) * 1992-12-02 1994-06-08 Merck & Co Inc Synergistic combination to improve secretion of endogenous growth hormone
US5606054A (en) * 1993-12-14 1997-02-25 Merck & Co., Inc. Heterocyclic-fused lactams promote release of growth hormone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4330537A (en) * 1977-12-07 1982-05-18 The Procter & Gamble Company Compositions for inhibiting mobilization of calcium phosphate in animal tissue
US5069905A (en) * 1985-03-15 1991-12-03 Yeda Research And Development Company Limited Method and compositions comprising a vitamin d derivatives for the local treatment of bone fractures
US5317017A (en) * 1992-09-30 1994-05-31 Merck & Co., Inc. N-biphenyl-3-amido substituted benzolactams stimulate growth hormone release
GB2273046A (en) * 1992-12-02 1994-06-08 Merck & Co Inc Synergistic combination to improve secretion of endogenous growth hormone
US5606054A (en) * 1993-12-14 1997-02-25 Merck & Co., Inc. Heterocyclic-fused lactams promote release of growth hormone

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027913A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Compositions pharmaceutiques et methodes de traitement consistant en des associations d'un derive de la 2-alkylidene-19-nor-vitamine d et d'un secretagogue de l'hormone de croissance
WO2017147420A1 (fr) * 2016-02-25 2017-08-31 The University Of Florida Research Foundation, Inc. Procédés et compositions avec des composés de vitamine d pour le traitement de la fibrose kystique et de troubles respiratoires
CN113181193A (zh) * 2021-05-08 2021-07-30 黄彬 卡泊三醇作为预防和治疗老年性骨质疏松的皮肤外用药的用途

Also Published As

Publication number Publication date
IL120955A0 (en) 1997-09-30
AU7545998A (en) 1998-12-30

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