Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1997-06-23
2002-06-04
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S182000
Reexamination Certificate
active
06399592
ABSTRACT:
FIELD OF THE INVENTION
The instant invention relates generally to the combination of estrogen and bisphosphonates and their use in bone growth and maturation. Specifically, the invention relates to the use of estrogen and bisphosphonates to inhibit bone resorption and promote net bone formation. This therapeutic combination will result in a decreased rate of bone resorption with either an increase or stabilization of bone mass.
BACKGROUND OF THE INVENTION
The normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of maintenance of a constant mineral balance. The dual process is commonly called “bone turnover”. In normal growing bones, the mineral deposition exceeds the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition, for instance due to malignancy or primary hyperparathyroidism, or in osteoporosis. In other pathological conditions the calcium deposition may take place in undesirable amounts and areas leading to e.g. heterotopic calcification, osteoarthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens, act by reducing bone resorption in the osteoporotic patient. See the review article, British Medical Bulletin 46 (1), p. 94-112 (1990).
Bisphosphonates are also known in the art as bone resorption inhibitors.
Alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, is described as a composition, method of use and synthesis in U.S. Pat. Nos. 4,621,077 (Gentili); 4,922,007 and 5,019,651 (Merck).
Clodronate, (dichloromethylene)bisphosphonic acid disodium salt (Proctor and Gamble, is described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967) for its preparation.
Tiludronate, ([(4-chlorophenyl)thiomethylene]-bisphosphonic acid) (Sanofi) is described in U.S. Pat. No. 4,876,248 issued Oct. 24, 1989.
YM 175 ([(cycloheptylamino)methylene]bisphosphonic acid, disodium salt) by Yamanouchi is described in U.S. Pat. No. 4,970,335 issued Nov. 13, 1990.
BM 210995 (1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonate) by Boehringer-Mannheim—is described in U.S. Pat. No. 4,927,814 issued May 22, 1990.
A study by Proctor and Gamble (Norwich Eaton Pharmaceuticals) using risendronate, whose chemical name is sodium trihydrogen [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in combination with estrogen showed a positive effect on bone loss in ovaricetomized rats (published in Abstracts 731 and 732 at the Fall 1992 ASBMR meeting in Minnesota.
The article, J. Clin. Invest., Jan. 1992, 89 (1), p. 74-78 by J. Chow et al., describes the effect of estrogen on ovariectomized rats in which bone resorption was suppressed by pamidronate. They concluded that estrogen inhibits bone resorption and also stimulates bone formation.
The article, J. Bone Miner. Res. (USA) 1991, p. 387-394 by T. J. Wronski et al., describes studies in rats with estrogen and the bisphosphonates etidronate and risedronate. The studies showed that etidronate, (1-hydroxyethylidene)bisphosphonic acid, disodium salt, (Proctor and Gamble) has long term adverse effects on bone mineralization.
However, these studies did not suggest the use of other bisphosphonates including alendronate.
There are situations where a female patient is undergoing estrogen therapy for a menopausal or postrnenopausal-related condition, (e.g., vasomotor symptoms, atrophy of the vaginal mucosa, increased cardiovascular risk, etc.) and is also discovered to be suffering from osteoporosis (i.e. rarefaction of bone) or to be at risk for developing osteoporosis.
Although estrogens/hormone replacement therapy (HRT) are known to help prevent the development of osteoporosis, there are instances, which are not at all uncommon, where HRT or a weak estrogen is prescribed at dosages which do not provide adequate protection against osteoporosis. There are also some women who continue to lose bone mass despite treatment with higher estrogen/HRT doses or who have established osteoporosis but fail to increase their bone mass on estrogen/HRT alone.
What is desired in these cases is a therapy to optimally treat both the menopausal and postmenopausal-related conditions and the development of osteoporosis or osteoporosis risk concurrently.
SUMMARY OF THE INVENTION
The present invention discloses a combination method for treating and/or preventing bone loss in a subject by the combination therapy of pharmaceutically effective amounts of estrogen and of a bisphosphonate selected from: alendronate, clodronate, tiludronate, YM 175, BM 210995, or mixture thereof.
Also described is a pharmaceutical composition containing the combination described above in a pharmaceutically acceptable carrier.
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Bone, Henry G., et al., “Alendronate and Estrogen Effects in Postmenopausal Women with Low Bone Mineral Density”, J. Clinical Endocrinology & Metabolism, vol. 85, No. 2, pp 720-726, 2000.
Lindsay, Robert, et al., “Addition of Alendronate to Ongoing Hormone Replacement Therapy in the Treatment of Osteoporosis: A Randomized, Controlled Clinical Trial”, J. Clinical Endocrinology & Metabolism, vol. 84, No. 9, pp. 3076-3081, 2000.
Fleisch, Bisphosphonates in Bone Disease (2nd ed. 1995), p. 35.
British Med. Bull. 46 (1), pp. 94-112 (1990).
J. Org. Chem., 32, pp. 4111-4114 (1967).
Abstr. 732 and 732, ASBMR Mtg., Minn. (Fall 1992).
Ciminera, N., et al., Ann. Ostet. Ginecol. Med. Perinat., vol. 113, No. 5, pp. 232-237, 1992.
Criares Theodore J.
Daniel Mark R.
Merck & Co. , Inc.
Wallinger Nicole M.
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