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WO1998025623A1 - Procedes et compositions destines a prevenir et a traiter la perte osseuse - Google Patents

Procedes et compositions destines a prevenir et a traiter la perte osseuse Download PDF

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Publication number
WO1998025623A1
WO1998025623A1 PCT/US1997/022344 US9722344W WO9825623A1 WO 1998025623 A1 WO1998025623 A1 WO 1998025623A1 US 9722344 W US9722344 W US 9722344W WO 9825623 A1 WO9825623 A1 WO 9825623A1
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WO
WIPO (PCT)
Prior art keywords
bone
disease
finasteride
bisphosphonic acid
subject
Prior art date
Application number
PCT/US1997/022344
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English (en)
Inventor
Vivian L. Fuh
Keith D. Kaufman
Joanne Waldstreicher
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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 claimed from GBGB9700221.6A external-priority patent/GB9700221D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU55943/98A priority Critical patent/AU5594398A/en
Publication of WO1998025623A1 publication Critical patent/WO1998025623A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention provides for a novel method of preventing and/or treating bone loss. Further, the present invention is directed to methods of treating and/or preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the present invention also provides for a method of manufacture of a medicament useful for inhibiting bone loss, and for preventing and/or treating osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the present invention also provides for compositions useful in the methods of inhibiting bone loss and treating and/or preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the mechanism of bone loss is not well understood, but in practical effect, the disorder arises from an imbalance in the formation of new healthy bone and the resorption of old bone, with the result being a net loss of bone tissue.
  • This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of, predominantly, femoral bones and bones in the forearm and vertebrae. These fractures, in turn, lead to an increase in general morbidity, a marked loss of stature and mobility, and, in many cases, an increase in mortality resulting from complications.
  • Bone loss occurs in a wide range of subjects including aging men and women, post-menopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patents having gonadal dysgenesis.
  • Osteopenia is reduced bone mass due to a decrease in the rate of osteoid synthesis to a level insufficient to compensate normal bone lysis.
  • Osteoporosis is a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume, producing porosity and fragility.
  • osteoporosis One on the most common types of osteoporosis is found in post-menopausal women affecting an estimated 20 to 25 million women in the United States alone.
  • a significant feature of post-menopausal osteoporosis is the large and rapid loss of bone mass due to the cessation of estrogen production by the ovaries. Indeed, estrogens have been shown to limit the progression of osteoporotic bone loss, and estrogen replacement is a recognized treatment for postmenopausal osteoporosis in the United States and many other countries.
  • estrogens Although the administration of estrogens have beneficial effects on bone when given even at very low levels, long-term estrogen therapy has been implicated in a variety of disorders such as an increase in the risk of uterine and breast cancer, vaginal bleeding, and endometrial hyperplasia, causing many women to avoid this treatment. Recently suggested therapeutic regimens which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, may be linked to negative cardiovascular effects. Concerns over the significant undesirable effects associated with estrogen therapy, and the limited ability of estrogens to reverse existing bone loss, support the need to develop alternative therapy for bone loss that generates the desirable effects on bone but does not cause undesirable effects.
  • antiestrogens which interact with the estrogen receptor
  • these compounds have had limited success, perhaps due to the fact that these compounds generally display a mixed agonist/antagonist effect. That is, although these compounds can antagonize estrogen interaction with the receptor, the compounds themselves may cause estrogenic responses in those tissues having estrogen receptors. Therefore, some antiestrogens, when administered alone, are subject to the same adverse effects associated with estrogen therapy. Osteoporosis and osteopenia are present in both aging men and women, due to age-related bone loss.
  • Treatments used for bone loss in men include vitamin and mineral supplementation with calcium and vitamin D. This has limited effectiveness in treating advanced disease and regular disease. The effectiveness of this treatment is limited in treating and preventing bone loss.
  • bone loss in men is treated with androgens such as testosterone.
  • Treatment with testosterone can lead to baldness, acne, lowering of HDL cholesterol (the "good” cholesterol) and raising of LDL cholesteroal (the “bad” cholesterol), and it may be associated with an increased risk of prostate cancer and benign prostatic hyperplasia.
  • U.S. 5,550,134 issued August 27, 1996, describes methods for inhibiting the loss of bone with benzoquinolin-3-ones known to be inhibitors of the enzyme 5 ⁇ -reductase type 1.
  • U.S. 5,550,134 describes that the type 1 isoform of the 5 ⁇ -reductase enzyme is the form of the enzyme which is active in one of the processes which affect the formation/resorption of bone.
  • the present invention relates to methods of inhibiting bone loss without the associated adverse effects of hormone replacement therapy, and thus, serves as an effective acceptable treatment for osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • Paget's disease malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease
  • a 5 ⁇ -reductase type 2 inhibitor is useful for the inhibition of bone loss and the treatment of the associated clinical conditions.
  • the present invention relates to the use of the 5 -reductase type 2 inhibitor finasteride for the inhibition of bone loss and the treatment and prevention of osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the inhibition of bone loss contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
  • the enzyme 5 -reductase catalyzes the reduction of testosterone (T) to the more potent androgen, 5 -dihydrotestosterone (dihydrotestosterone" or DHT), as shown below:
  • isozymes There are two isozymes of 5 -reductase in humans. Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44 (1990); Andersson, et al., Nature, 354, 159-61 (1991).
  • the isozymes usually called Type 1 and Type 2, exhibit differences in their biochemical properties, genetics, and pharmacology. Both isozymes are now the subject of considerable research and it has been found one isozyme (type 1) predominates in the sebaceous glands of facial skin and skin tissue and that the other (type 2) predominates in the prostate.
  • Finasteride 17 ⁇ -(N-tert-butylcarbamoyl)-3-oxo-4-aza-5 ⁇ - androst-l-en-3-one is a potent inhibitor of the human type 2 enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride's usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published 5 October 1988, EP 0 285 383, published 5 October 1988 and Canadian patents 1,302,277 and 1,302,276.
  • BPH benign prostatic hyperplasia
  • Finasteride has been reported to have no effect on bone density. Tollin et al. "Finasteride therapy does not alter bone turnover in men with benign prostatic hyperplasia ⁇ A clinical research center study" (J. Clin Endocrin. & Metab. 81(3):1031-1034, 1996), report that finasteride had no effect on bone and mineral metabolism. Matzkin et al. "Prolonged treatment with finasteride (a 5 ⁇ -reductase inhibitor) does not affect bone density and metabolism” (Clin. Endocrin. 37:432-436, 1992) also conclude that in elderly men, finasteride had no effect on bone density or mineral metabolism except for an increase in serum 1,25- dihydroxy vitamin D. Rosen et al. "Bone density is normal in male rats treated with finasteride (Endocrinology 136(4):1381-1387, 1995) reported that bone development and density were normal in rats treated with finasteride.
  • the present invention provides for a method of inhibiting bone loss in a subject in need of such treatment comprising administration of a therapeutically effective amount of the 5 ⁇ -reductase type 2 inhibitor finasteride to the subject.
  • the present invention further provides for a method for treating and preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease as well as reducing the risk of fractures, both vertebral and nonvertebral, comprising administration of therapeutically effective amount of the 5 ⁇ - reductase type 2 inhibitor finasteride to the subject.
  • the present invention provides for compositions useful in the methods of the present invention, as well as a method of manufacture of a medicament useful for inhibiting bone loss and treating or preventing osteoporosis and osteopenia.
  • the present invention is directed to a method for inhibiting bone loss in a subject in need thereof by administering an effective amount of a 5 -reductase type 2 inhibitor to the subject.
  • the present invention is directed to a method for inhibiting bone loss in a subject in need thereof by administering an effective amount of the 5 ⁇ -reductase type 2 inhibitor finasteride to the subject.
  • Still a further aspect of the present invention is a method of preventing diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject in need thereof by administering an effective amount of the 5 -reductase type 2 inhibitor finasteride to the subject.
  • Still another aspect of the present invention is the method of reducing the risk of diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject at risk therefor by administering an effective amount of the 5 -reductase type 2 inhibitor finasteride to a subject.
  • Yet a further aspect of the present invention is the method of treating diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject in need thereof by administration of an effective amount of the 5 ⁇ -reductase type 2 inhibitor finasteride to the subject.
  • Still another aspect of the present invention is the use of the 5 ⁇ -reductase type 2 inhibitor finasteride for the manufacture of a medicament useful to reduce the risk of diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject at risk therefor.
  • Yet a further aspect of the present invention is the use of the 5 ⁇ -reductase type 2 inhibitor finasteride for the manufacture of a medicament useful to treat diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • Also useful in the present invention are pharmaceutically acceptable salts of the 5 -reductase type 2 inhibitor finasteride.
  • the subject treated in the methods above is a mammal, preferably a human being, male or female, at risk of developing a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the subject treated is a mammal, or preferably a human being, who has developed a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • a subject in need of the present invention may also be identified as possessing bone fractures.
  • terapéuticaally effective amount means the amount of 5 -reductase type 2 inhibitor finasteride that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • the instant method of administering the 5 ⁇ -reductase type 2 inhibitor finasteride is useful in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases can be divided into two categories: 1. Abnormal (ectopic) depositions of calcium salts, mostly calcium phosphate, pathological hardening of tissues and bone malformations.
  • a reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation.
  • a reduction in bone resorption can aleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions.
  • osteoporosis including estrogen defficiency, immobilization, glucocorticoid induced and senile
  • osteodystrophy Paget's disease
  • myositis ossificans Bechterew's disease
  • malignant hypercalcemia metastatic bone disease
  • peridontal disease cholelithiasis
  • nephrolithiasis nephrolithiasis
  • urolithiasis urinary calculus
  • hardening of the arteries (sclerosis) arthritis
  • bursitis neuritis and tetany, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the administration of finasteride in order to practice the present methods of therapy is carried out by administering an effective amount of finasteride to the patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment. It will be observed that finasteride is active at very low concentrations, and hence at low dosage levels, thereby allowing effective bone loss inhibition with slight probability of side effects or cross-reactions with other treatments or drugs.
  • the daily dosage of the 5 ⁇ -reductase type 2 inhibitor finasteride may be varied over a wide range from 0.01 to 10 mg per adult human per day.
  • finasteride is administered at a dose of 1 to 5 mg per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.02, 0.05, 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, and 10.0 milligrams of active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Formulations of the 5 ⁇ -reductase inhibitor employed in the present method for medical use comprise the 5 ⁇ -reductase type 2 inhibitor finasteride together with an acceptable carrier thereof and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient subject of the formulation.
  • the present invention therefor further provides a pharmaceutical formulation comprising the 5 ⁇ -reductase type 2 inhibitor finasteride together with a pharmaceutically acceptable carrier thereof.
  • the formulations include those suitable for oral, rectal, intravaginal, topical or parenteral (including subcutaneous, intramuscular and intravenous administration). Preferred are those suitable for oral administration.
  • the formulations may be presented in a unit dosage form and may be prepared by any of the methods known in the art of pharmacy. All methods include the step of bringing the active compound in association with a carrier which constitutes one or more ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound in association with a liquid carrier, a waxy solid carrier or a finely divided solid carrier, and then, if needed, shaping the product into desired dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the active compound, preferably in powdered form, with a suitable carrier.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, 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, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Oral liquid forms such as syrups or suspensions in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like may be made by adding the active compound to the solution or suspension. Additional dispersing agents which may be employed include glycerin and the like.
  • Formulations for rectal administration may be presented as a suppository with a conventional carrier, i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with the 5 ⁇ - reductase type 2 inhibitor finasteride, and is stable in storage and does not bind or interfere with the release of the finasteride.
  • Suitable bases include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax and polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, and hydrogenated vegetable oils.
  • cocoa butter theobroma oil
  • polyethylene glycols such as carbowax and polyglycols
  • glycol-surfactant combinations such as polyoxyl 40 stearate
  • polyoxyethylene sorbitan fatty acid esters such as Tween, Myrj, and Arlacel
  • glycerinated gelatin When glycerinated gelatin suppositories are used, a preservative such as methylparaben or propylparaben may be employed.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamidephenol, or polyethylene-oxide polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Formulations suitable for parenteral administration include formulations which comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Such formulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject.
  • Such formulations may contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceutically and pharmacologically acceptable acid addition salt of the active compound that has appropriate solubility for the solvents employed.
  • Useful salts include the hydrochloride isothionate and methanesulfonate salts.
  • Useful formulations also comprise concentrated solutions or solids comprising the active compound which on dilution with an appropriate solvent give a solution suitable for parenteral administration.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro- pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro- pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance vitamin D2 and D3 and hydroxylated derivatives, e.g. l ⁇ -hydroxy-vitamin D3, l ⁇ -hydroxy-vitamin D2, l ⁇ -25-dihydroxy- vitamin D3, l ⁇ -25-dihydroxy- vitamin D£, dehydroepiandrosterone, calcitonin (human, porcine or salmon), mitramycin, sodium fluoride, estrogens, estrogen mimetics, including reloxafine and other compounds within the oxefine class, non-steroid antiinflammatory drugs, such as acetylsalicyclic acid, indomethacin, naprosyn, and timegadine, growth hormone secretagogues, growth hormone, growth hormone releasing hormone and insulin-like growth factor and bisphosphonates such as alendronate.
  • vitamin D2 and D3 and hydroxylated derivatives e.g. l ⁇ -hydroxy-
  • One aspect of the present invention provides a method for inhibiting bone loss comprising administering to a mammal in need of treatment an effective amount of the 5 ⁇ -reductase type 2 inhibitor, finasteride.
  • Bone antiresportive agents are those agents which are known in the art to inhibit the resorption of bone and include, for example, estrogen in which estrogen includes steroidal compounds having estrogenic activity such as, for example, 17 ⁇ -estradiol, estrone, conjugated estrogen (PREMARIN®), equine estrogen, 17 ⁇ -ethynyl estradiol, and the like.
  • Bisphosphonate compounds may also be employed in combination with the 5 ⁇ -reductase type 2 inhibitor finasteride of the present invention include:
  • antiestrogenic compounds such as raloxifene (see, e.g., U.S. Pat. No. 5,393,763) clomiphene, zuclomiphene, enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27,Mer-25, U-ll, 555A, U-100A, and salts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and 4,894,373) may be employed in combination with the 5 ⁇ - reductase type 2 inhibitor finasteride in the methods and compositions of the present invention.
  • Bone anabolic agents are those agents which are known in the art to build bone by increasing the production of the bone protein matrix.
  • Such anabolic agents include, for example, the various forms of parathyroid hormone (PTH) such as naturally occurring PTH (1-84), PTH (1-34), analogs thereof, growth hormone secretagogues, growth hormone, growth hormone releasing hormone and insulin- like growth factorand the like.
  • PTH parathyroid hormone
  • Representative growth hormone secretagogues are disclosed in U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; U.S.
  • Preferred growth hormone secretagogues for use in the present invention include:
  • Especially preferred growth hormone secretagogues specifically include:
  • dosages of 2.5 to 100 mg/day are appropriate for treatment, more preferably 5 to 20 mg/day, especially about 10 mg/day.
  • doses of about 2.5 to about 10 mg/day and especially about 5 mg/day should be employed.
  • the compounds of the methods of the present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal, and such compounds are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of finasteride or a pharmaceutically acceptable salt thereof, a bone antiresorptive or anabolic agent, and a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • EXAMPLE 1 Effect of the 5 ⁇ -reductase type 2 inhibitor finasteride on bone mineral density in men Sixty- three healthy, young men entered the study and were randomized to treatment with 1 mg/day finasteride or placebo for 48 weeks.
  • the placebo group contained 29 men and the treatment group contained 34 men.
  • Lumbar spine bone mineral density measured by dual energy X-ray absorptiometry (DXA), and indices of bone metabolism, including Cross-Linked N-Telopeptides of Type 1 Collagen (NTX) measured in urine and serum Bone-Specific Alkaline Phosphatase (BSAP) were measured at weeks 12, 24, 36 and 48.
  • DXA dual energy X-ray absorptiometry
  • NTX Cross-Linked N-Telopeptides of Type 1 Collagen
  • BSAP Bone-Specific Alkaline Phosphatase
  • Table 1A Median Analysis Results for Percent Change from Baseline to Week 48 in Cross-Linked N-Telopeptides of Type 1
  • BSAP bone specific alkaline phosphatase
  • EXAMPLE 2 One-hundred-fifty older men with benign prostatic hyperplasia are enrolled as part of a large (3014 patients), 4-year, double- blind, placebo-controlled trial. Bone density is measured at baseline, years 2, 3, and 4. Biochemical markers of bone are also measured at these time points.
  • finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 0.5 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 2.5 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • finasteride 17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one
  • an oral composition of a compound of this invention 6 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • the silicone fluid and finasteride are mixed together and the colloidal silicone dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate.
  • the resulting laminated sheet is then cut into 10 cm ⁇ patches. For 100 Patches.
  • the finasteride and buffering agents are dissolved in the propylene glycol at about 50°C.
  • the water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving. For 1000 Ampules.
  • the finasteride, magnesium sulfate heptahydrate and buffering agents are dissolved in the water for injection with stirring, and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving. For 1000 Ampules.
  • an oral composition of a compound of this invention 3 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) and 2.5 mg of alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 0.5 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) and 10.0 mg of alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate )is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 2.5 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) and 5.0 mg of alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate )is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 6 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) and 2.5 mg of alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • EXAMPLE 15 6 mg of finasteride (17 ⁇ -(N-tert- butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l-en-3-one) and 2.5 mg of alendronate (4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate
  • the silicone fluid alendronate and finasteride are mixed together and the colloidal silicone dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate.
  • the resulting laminated sheet is then cut into 10 cm ⁇ patches. For 100 Patches.
  • the reaction mixture for the type 1 5 ⁇ -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7- 3 H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 ⁇ L of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 rpm in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC (10 cm Whatman Partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1-9.7 min).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ Autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5 ⁇ -reductase type 1 and type 2 inhibition.
  • a compound referred to herein as a 5 -reductase 2 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • the compounds are tested in the above-described assay for 5 ⁇ -reductase type 1 and type 2 inhibition, and were found to have IC50 values under about 100 nM for inhibition of the type 1 isozyme.
  • Compounds found to have IC50 values of under about 50 nM for inhibition of the type 1 isozyme are called type 1 inhibitors.
  • Compounds called "dual inhibitors" additionally had IC ⁇ o's under about 200 nM for inhibition of the type 2 isozyme.

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Abstract

La présente invention concerne un procédé destiné à empêcher la perte osseuse chez un sujet nécessitant une tel traitement. Ce procédé comprend l'administration audit sujet d'une dose thérapeutiquement efficace de l'inhibiteur de la 5'alpha'-réductase de type 2 tel que le finastéride. La présente invention concerne également un procédé destiné à traiter et à prévenir l'ostéoporose et l'ostéopénie ainsi que d'autre maladies dans lesquelles il peut être utile d'empêcher la perte osseuse, notamment la maladie de Paget, l'hypercalcémie maligne, la maladie parodontal, le relâchement des articulations, et la maladie osseuse métastatique. Un tel procédé comprend l'administration au sujet d'une dose thérapeutiquement efficace de l'inhibiteur de la 5'alpha'-réductase de type 2 tel que le finastéride. La présente invention concerne enfin des compositions destinées à être utilisées dans les procédés susmentionnés, ainsi qu'un procédé de fabrication d'un médicament conçu pour empêcher la perte osseuse et traiter ou prévenir l'ostéoporose et l'ostéopénie.
PCT/US1997/022344 1996-12-09 1997-12-05 Procedes et compositions destines a prevenir et a traiter la perte osseuse WO1998025623A1 (fr)

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US6043026A (en) * 1997-05-01 2000-03-28 Merck & Co., Inc. Combination therapy for the prevention and treatment of osteoporosis
WO2000076529A3 (fr) * 1999-06-11 2001-07-12 Karobio Ab Recepteur d'oestrogenes
WO2003029268A1 (fr) 2001-10-03 2003-04-10 Merck & Co., Inc. Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
US7605152B2 (en) * 2002-01-15 2009-10-20 Merck & Co., Inc. 17-hydroxy-4-aza-androstan-3-ones as androgen receptor modulators
EP1485095A4 (fr) * 2002-03-13 2009-11-18 Merck & Co Inc Derives de 4-azasteroide fluore en tant que modulateur de recepteur androgenique
EP1501512A4 (fr) * 2002-04-30 2009-11-18 Merck & Co Inc Derives de 4-azasteroide utilises comme modulateurs du recepteur de l'androgene
EP1771179A4 (fr) * 2004-07-21 2010-03-17 Gtx Inc Compositions contenant des inhibiteurs de la 5-alpha reductase, et des modulateurs selectifs de recepteur d'oestrogene et leurs methodes d'utilisation
WO2018005608A1 (fr) * 2016-06-28 2018-01-04 Northeast Ohio Medical University Compositions et procédés de prévention de la perte osseuse et/ou de stimulation de la guérison osseuse
WO2019084503A1 (fr) * 2017-10-27 2019-05-02 Victor Hasson Formulations topiques destinées au traitement d'affections dermatologiques comprenant la calvitie hippocratique
US10874638B2 (en) * 2014-01-17 2020-12-29 Ligand Pharmaceuticals Incorporated Methods and compositions for modulating hormone levels

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US5578724A (en) * 1994-09-20 1996-11-26 Eli Lilly And Company Process for preparation of benzo[f]quinolinones
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043026A (en) * 1997-05-01 2000-03-28 Merck & Co., Inc. Combination therapy for the prevention and treatment of osteoporosis
WO2000076529A3 (fr) * 1999-06-11 2001-07-12 Karobio Ab Recepteur d'oestrogenes
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1420796A4 (fr) * 2001-07-31 2007-07-11 Merck & Co Inc Modulateurs du recepteur des androgenes et leurs procedes d'utilisation
WO2003029268A1 (fr) 2001-10-03 2003-04-10 Merck & Co., Inc. Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
US7402577B2 (en) * 2001-10-03 2008-07-22 Merck & Co., Inc. Androstane 17-beta-carboxamides as androgen receptor modulators
EP1434786A4 (fr) * 2001-10-03 2009-03-25 Merck & Co Inc Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
US7605152B2 (en) * 2002-01-15 2009-10-20 Merck & Co., Inc. 17-hydroxy-4-aza-androstan-3-ones as androgen receptor modulators
EP1485095A4 (fr) * 2002-03-13 2009-11-18 Merck & Co Inc Derives de 4-azasteroide fluore en tant que modulateur de recepteur androgenique
KR100938136B1 (ko) * 2002-03-13 2010-01-22 머크 앤드 캄파니 인코포레이티드 안드로겐 수용체 조정자로서의 불화된 4-아자스테로이드 유도체 및 이를 포함하는 약제학적 조성물
EP1501512A4 (fr) * 2002-04-30 2009-11-18 Merck & Co Inc Derives de 4-azasteroide utilises comme modulateurs du recepteur de l'androgene
EP1771179A4 (fr) * 2004-07-21 2010-03-17 Gtx Inc Compositions contenant des inhibiteurs de la 5-alpha reductase, et des modulateurs selectifs de recepteur d'oestrogene et leurs methodes d'utilisation
US10874638B2 (en) * 2014-01-17 2020-12-29 Ligand Pharmaceuticals Incorporated Methods and compositions for modulating hormone levels
WO2018005608A1 (fr) * 2016-06-28 2018-01-04 Northeast Ohio Medical University Compositions et procédés de prévention de la perte osseuse et/ou de stimulation de la guérison osseuse
WO2019084503A1 (fr) * 2017-10-27 2019-05-02 Victor Hasson Formulations topiques destinées au traitement d'affections dermatologiques comprenant la calvitie hippocratique
US11786466B2 (en) 2017-10-27 2023-10-17 XYON Health Inc. Topical formulations for treating dermatological disorders including male pattern baldness

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