Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1997-12-03
1998-12-15
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
A61K 3166
Patent
active
058497269
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The instant invention relates to the use of the anhydrous crystal form of alendronate sodium, i.e., 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, hereinafter referred to as "anhydrous alendronate sodium" or "AAS", to inhibit bone resorption in human patients.
BACKGROUND OF THE INVENTION
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 is in equilibrium with 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.
U.S. Pat. No. 4,621,077 to Istituto Gentili discloses a method of treating urolithiasis and inhibiting bone reabsorption by the use of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (also named 4-amino-1-hydroxybutane-1,1-bisphosphonic acid) and its salts with an alkali metal, an organic base or a basic amino acid. The compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is described as being between 100 and 300 times more active than dichloromethane-biphosphonic acid in inhibiting bone reabsorption.
Alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, is an agent for combating bone resorption in bone diseases including osteoporosis and is described as a composition, method of use and synthesis along with other pharmaceutically acceptable salts in U.S. Pat. Nos. 4,922,007 and 5,019,651 (both assigned to Merck).
However, new crystalline forms of alendronate sodium are constantly being searched for to enable ease of formulation and better pharmacokinetics, e.g., desirable crystal habit, good flow properties, higher solubility, longer duration or quicker onset of action, and improved bioavailability. Particularly what is desired is a new formulation to overcome the gastric irritability associated with the administration of the free acid form of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. This is of particular importance in cases where the patient has a history of gastrointestinal problems prior to recommended alendronate therapy.
SUMMARY OF THE INVENTION
The present invention provides a method for treating and/or preventing bone loss in a subject by the administering to said patient a pharmaceutically effective amount of the anhydrous form of alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt. Because the aqueous pH of the monosodium salt is about 4.4, as compared to the free acid which is about 2.6, there is substantially less gastric irritability associated with the administration of the anhydrous monosodium salt to a human patient.
Also provided is a pharmaceutical composition comprising a pharmaceutically effective amount of anhydrous alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt, in a pharmaceutically acceptable excipient mixture.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The method disclosed herein can be used to treat humans, particularly females who are post-menopausal, with an osteogenically effective amount of anhydrous alendronate sodium to inhibit bone resorption in need of such treatment. Such need arises locally in cases of bone fracture, non-union, defect, and the like. Such need also arises in cases of systemic bone disease, as in osteoporosis, osteoarthritis, Paget's disease, osteomalacia, multiple myeloma and other forms of cancer, steroid therapy, and age-related loss of bone mass.
The term "inhibition of bone reso
REFERENCES:
patent: 4621077 (1986-11-01), Rosini et al.
patent: 4922007 (1990-05-01), Kieczykowski et al.
patent: 5019651 (1991-05-01), Kieczykowski
Brenner Gerald S.
Oberholtzer, Jr. Earl R.
Ostovic Drazen
Thies J. Eric
Henley III Raymond
Merck & Co. , Inc.
Minokur Melvin
Sabatelli Anthony D.
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