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WO1997016193A1 - Composition pharmaceutique destinee au traitement de l'osteoporose - Google Patents

Composition pharmaceutique destinee au traitement de l'osteoporose Download PDF

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Publication number
WO1997016193A1
WO1997016193A1 PCT/EP1996/004532 EP9604532W WO9716193A1 WO 1997016193 A1 WO1997016193 A1 WO 1997016193A1 EP 9604532 W EP9604532 W EP 9604532W WO 9716193 A1 WO9716193 A1 WO 9716193A1
Authority
WO
WIPO (PCT)
Prior art keywords
osteoporosis
bone
pharmaceutical composition
calcium
vitamin
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/EP1996/004532
Other languages
English (en)
Inventor
John Joseph Nestor, Jr.
Milan Radoje Uskokovic
Brian Henry Vickery
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.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
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 F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to AU72956/96A priority Critical patent/AU7295696A/en
Publication of WO1997016193A1 publication Critical patent/WO1997016193A1/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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3

Definitions

  • This invention relates to a pharmaceutical composition for treating osteoporosis or for treating a medical condition characterized by a decrease in bone density, by restoring bone density to an asymptomatic level, without inducing hyper ⁇ calciuria, hypercalcemia, or nephrotoxicity, said composition containing the compound, l ⁇ -fluoro-25-hydroxy-16-ene-23-yne-
  • Osteoporosis is the most common form of metabolic bone disease and may be considered the symptomatic fracture stage of bone loss (osteopenia) . Although osteoporosis may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are at risk for idiopathic osteoporosis (postmenopausal or Type I osteoporosis) ; another particularly high risk group for idiopathic osteoporosis is the elderly of either sex (senile or Type II osteoporosis) .
  • Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemotherapy, hyper- prolactinemia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression, and oophorectomy.
  • Postmenopausal osteoporosis is characterized by fractures of the spine, while femoral neck fractures are the dominant features of senile osteoporosis.
  • osteoporotics The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) which then refill with new bone the cavity left by the osteoclasts.
  • bone remodeling It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells)
  • osteoclasts and osteoblasts function so that bone formation and bone resorption are in balance.
  • an imbalance in the bone remodeling process develops which results in bone being replaced at a slower rate than it is being lost.
  • this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in postmenopausal osteoporotics, following oophorectomy, or in iatrogenic situations such as those resulting from corticosteroid therapy or the immunosuppression practiced in organ transplantation.
  • parathyroid hormone to elevate the cyclic AMP levels of cultured rat fetal bone cells.
  • Vitamin D3 is a critical element in the metabolism of calcium, promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus, and stimulating flux of calcium into and out of bone.
  • the D vitamins are hydroxylated in vivo, with the resulting la,25-dihydroxy metabolite being the active material.
  • Animal studies with 1,25- (OH) 2 vitamin D have suggested bone anabolic activity.
  • Aerssens et al. in Calcif Tissue Int, 55:443-450 (1994) reported upon the effect of la- hydroxy Vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment.
  • human usage is restricted to antiresorption due to the poor therapeutic ratio (hypercalciuria and hypercalcemia as well as nephrotoxicity) .
  • 580,968 disclose fluorinated vitamin D3 analogs, including la- fluoro-25-hydroxy-16-ene-23-yne-26,27-hexafluorocholecalci ⁇ ferol, useful for the treatment of hyperproliferative disorders of the skin, for the treatment of cancer and leukemia, and for the treatment of sebaceous gland diseases. Use for the restoration of bone mass and/or density in osteoporosis is not suggested.
  • the compound, l ⁇ -fluoro-25-hydroxy-16-ene-23-yne-26,27- hexafluorocholecalciferol, hereinbelow l ⁇ F, may be prepared as taught by Baggiolini et al. in Example 3 of EP 580,968
  • compositions of this invention are useful for the prevention and treatment of a variety of mammalian conditions manifested by loss of bone mass.
  • l ⁇ F is indicated for the prophylaxis and therapeutic treatment of osteoporosis and osteopenia in mammals without inducing hypercalciuria, hypercalcemia, or nephrotoxocity.
  • hypercalciuria is excessive calcium in the urine, in humans corresponding to an excretion of greater than 4 mg/kg/day. This often results in nephrolithiasis (renal calculi) .
  • “Hypercalcemia” is an excessive concentration of calcium in the serum; in humans (and rats) this corresponds to greater than about 10.5 mg/dL.
  • Withinlerable hypercalcemia usually occurring at serum calcium concentrations greater than about 12 mg/dL, is associated with emotional lability, confusion, delirium, psychosis, stupor, and coma.
  • l ⁇ F may be administered in amounts between about 0.0002 and 0.5 ⁇ g compound/kg body weight per day, preferably from about 0.001 to about 0.1 ⁇ g/kg body weight per day, most preferably from about 0.002 to about 0.02 ⁇ g/kg body weight per day.
  • the daily dose of active ingredient l ⁇ F may be from about 0.01 to about 25 ⁇ gs, preferably from about 0.05 to about 5 ⁇ gs, most preferably from about 0.1 ⁇ g to about l ⁇ g per day.
  • This dosage may be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results, preferably once daily by mouth. In certain situations, alternate day dosing may prove adequate to achieve the desired therapeutic response.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will be influenced by, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient. In the treatment of corticosteroid induced osteopenia, it is expected that the requisite dose will be greater for higher doses of corticosteroids.
  • Representative delivery regimens include oral, parenteral (including subcutaneous, intramuscular and intravenous) , rectal, buccal (including sublingual) , pulmonary, transdermal, and intranasal, most preferably oral.
  • compositions of the present invention comprise as an active ingredient the compound l ⁇ F in admixture with a pharmaceutically acceptable, non-toxic carrier.
  • a pharmaceutically acceptable, non-toxic carrier such compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for pulmonary or intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA., (1985) .
  • Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray.
  • typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • Orally administrable compositions may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form, including, for example, tablets, coated tablets, capsules, lozenges, aqueous or oily suspensions, solutions, emulsions, elixirs, and powders suitable for reconstitution with water or another suitable liquid vehicle before use.
  • Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone
  • fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
  • lubricants such as magnesium stearate, talc, polyethylene glycol, or silica
  • surfactants such as sodium lauryl sulfate.
  • Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethylcellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) .
  • suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethylcellulose, or edible fats
  • emulsifying agents such as lecithin, or acacia
  • vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
  • preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) .
  • Liquid compositions may be encapsulated in, for example, gelatin to provide a
  • the pharmaceutical composition of the invention is expected to be useful in the treatment of Type I (postmenopausal), Type II (senile), and Type III (iatrogenic) osteoporosis, including that associated with immunosuppressive drugs used in organ transplantation, as well in the treatment of osteodystrophy due to renal dialysis and hyperparathyroidism.
  • test compound l ⁇ F is more effective than 1,25-dihydroxy vitamin D3, hereinbelow l,25-di(OH), at bone accretion and does not induce hypercalciuria, nephrotoxicity, or hypercalcemia at therapeutically effective doses.
  • Three month old rats were ovariectomized and administered either l,25-di(OH)) or l ⁇ F as test compound once a day by mouth for a period of 3 weeks starting at 3 weeks post- ovariectomy and continuing until final sacrifice at 6 weeks post-ovariectomy. Blood was drawn at 4 weeks post-ovariectomy and again at the 6 week mark. Urine samples were taken and final femoral calcium determined upon sacrifice 6 weeks post- ovariectomy.
  • Femoral calcium was measured on the excised right femur.
  • the femurs were cut in half, calcium extracted from the distal half femur (DHF) , measured with a Calcette® calcium analyzer, and expressed as mean bone calcium in mg/DHF.
  • DHF distal half femur
  • the compounds (l,25-di(OH) and l ⁇ F) were evaluated at 0.05, 0.1, and 0.2 ⁇ g/kg/day. The results are summarized in Table 1.
  • sham operated controls displayed femoral calcium of 41.2 mg/femur; ovariectomized rats 39.0 mg/femur.
  • Rats treated with 1,25- di(OH) showed statistically insignificant improvements in femur calcium levels relative to OVX controls after treatment with the three doses.
  • hyper ⁇ calciuria was observed, and, at the highest dose, intolerable hypercalcemia as well.
  • statistically significant improved femur calcium levels were obtained at the two higher doses without evidence of hypercalcemia. Only at the highest dose was there a marginal elevation in urinary calcium.
  • a capsule for oral administration is formulated under nitrogen in amber light from 0.01 to 25.0 ⁇ g of l ⁇ F in 150 mg of fractionated coconut oil, with 0.015 mg butylated hydroxytoluene (BHT) and 0.015 mg butylated hydroxyanisole (BHA) , filled in a soft gelatin capsule.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette composition pharmaceutique est destinée à traiter l'ostéoporose, ou un état médical caractérisé par une chute de la densimétrie osseuse, afin de restaurer cette densimétrie et que celle-ci atteigne un niveau asymptomatique, sans induction d'hypercalciurie, d'hypercalcémie ou de néphrotoxicité, ladite composition contenant en tant que principe actif le composé répondant à la formule 1α-fluoro-25-hydroxy-16-ène-23-yne-26,27-hexafluorocholécalciférol.
PCT/EP1996/004532 1995-10-27 1996-10-18 Composition pharmaceutique destinee au traitement de l'osteoporose Ceased WO1997016193A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72956/96A AU7295696A (en) 1995-10-27 1996-10-18 Pharmaceutical composition for treating osteoporosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US596695P 1995-10-27 1995-10-27
US60/005,966 1995-10-27

Publications (1)

Publication Number Publication Date
WO1997016193A1 true WO1997016193A1 (fr) 1997-05-09

Family

ID=21718613

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/004532 Ceased WO1997016193A1 (fr) 1995-10-27 1996-10-18 Composition pharmaceutique destinee au traitement de l'osteoporose

Country Status (4)

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AR (1) AR003089A1 (fr)
AU (1) AU7295696A (fr)
WO (1) WO1997016193A1 (fr)
ZA (1) ZA969021B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0808832A3 (fr) * 1996-05-23 1999-02-03 F. Hoffmann-La Roche Ag Dérivés fluorinés de Vitamine D3
US6329538B1 (en) 1996-05-23 2001-12-11 Hoffmann-La Roche Inc. Vitamin D3 analogs
WO2003055500A1 (fr) * 2002-01-04 2003-07-10 Italfarmaco, S.A. Compositions pharmaceutiques destinees au traitement ou a la prevention de l'osteoporose
CN114588176A (zh) * 2022-02-15 2022-06-07 许静宜 一种研究麦冬皂苷d促进骨质疏松h型血管方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326875A1 (fr) * 1988-01-20 1989-08-09 F. Hoffmann-La Roche Ag Dérivés de la didéhydro-vitamine D3
EP0580968A2 (fr) * 1992-05-20 1994-02-02 F. Hoffmann-La Roche Ag Derivés fluorinés de la vitamine D3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326875A1 (fr) * 1988-01-20 1989-08-09 F. Hoffmann-La Roche Ag Dérivés de la didéhydro-vitamine D3
EP0580968A2 (fr) * 1992-05-20 1994-02-02 F. Hoffmann-La Roche Ag Derivés fluorinés de la vitamine D3

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0808832A3 (fr) * 1996-05-23 1999-02-03 F. Hoffmann-La Roche Ag Dérivés fluorinés de Vitamine D3
US6329538B1 (en) 1996-05-23 2001-12-11 Hoffmann-La Roche Inc. Vitamin D3 analogs
WO2003055500A1 (fr) * 2002-01-04 2003-07-10 Italfarmaco, S.A. Compositions pharmaceutiques destinees au traitement ou a la prevention de l'osteoporose
ES2192136A1 (es) * 2002-01-04 2003-09-16 Italfarmaco Sa Composiciones farmaceuticas para el tratamiento o prevencion de la osteoporosis.
CN114588176A (zh) * 2022-02-15 2022-06-07 许静宜 一种研究麦冬皂苷d促进骨质疏松h型血管方法
CN114588176B (zh) * 2022-02-15 2024-01-23 许静宜 一种研究麦冬皂苷d促进骨质疏松h型血管方法

Also Published As

Publication number Publication date
ZA969021B (en) 1998-04-28
AR003089A1 (es) 1998-07-08
AU7295696A (en) 1997-05-22

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