Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-12-19
2002-04-23
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S170000
Reexamination Certificate
active
06376477
ABSTRACT:
SUMMARY OF THE INVENTION
This invention is concerned with a novel method for the prevention and/or treatment of diseases involving calcium or phosphate metabolism. In particular it is concerned with the prevention and/or treatment of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, by the administration of an agent that binds to the androgen receptor to produce a beneficial effect on bone and a bisphosphonic acid or a pharmaceutically acceptable salt thereof either combined in a single pharmaceutical formulation or as separate entities administered more or less concurrently.
This invention is also concerned with a pharmaceutical formulation in which an agent that binds to the androgen receptor and a bisphosphonic acid or pharmaceutically acceptable salt thereof are combined.
In the remainder of this specification the term “bisphosphonic acid” is meant to refer to the acid or the pharmaceutically acceptable salt thereof. Similarly, the expression, “agent that binds to the androgen receptor” refers to such agents that produce a beneficial effect on bone and includes androgen antagonists, agonists and partial agonist/antagonist agents.
BACKGROUND OF THE INVENTION
Several bisphosphonic acids are known in the art and known to be effective in the treatment of diseases involving bone resorption. Unfortunately they also inhibit overall bone formation. Attempts have been made to stimulate bone formation that has been inhibited by a bisphosphonic acid such as with injections of growth hormone, IGF-1, parathyroid hormone or transforming growth factor (TGF
b
) which is described in U.S. Pat. No. 5,118,667. None of these attempts has been successful or widely used in patients and have been only partially successful in animals. Most importantly use of these agents involves daily injections with compounds that have multiple effects. Combination of a bisphosphonic acid and a growth hormone secretogogue also has been reported in WO95/11029.
Combinations of estrogen, which is also known to prevent bone resorption, and androgens to stimulate bone formation, have been tried (Davis et al, 1996 Maturittas 21:227-236; Raisz et al., 1996 J. Clin. Endocrinol. Metab. 81: 37-43; and Watts et al., 1995 Obstet-Gynecol. 85: 529-537). However, it is not obvious from the results of these studies that androgens would stimulate the formation of bone in the presence of a strong non-hormonal inhibitor of bone formation. As a matter of fact, it has been reported that the bisphosphonic acid, tiludronate, inhibits the anabolic effect of parathyroid hormone (Delmas, Bone, 16(6), 603-610 (1995)).
Now, with the present invention there is provided a novel method for the prevention and/or treatment of disease involving bone resorption comprising the administration of a bisphosphonic acid and an agent that binds to the androgen receptor whereby bone resorption is prevented without compromising normal bone formation induced by the androgen.
DETAILED DESCRIPTION OF THE INVENTION
The novel method of prevention and/or treatment of diseases involving bone resorption of this invention comprises the administration to a patient in need thereof of an effective amount of a bisphosphonic acid and an effective amount of an agent that binds to the androgen receptor.
The disease states involving bone resorption that can be prevented and/or treated by the novel combination of this invention are osteoporosis, Paget's disease, malignant hypercalcemia, periodontal disease, joint prostheses loosening and metastatic bone disease, especially osteoporosis.
Examples of the bisphosphonic acids that may be used as an active ingredient in the novel method and formulation of this invention include:
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;
3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;
(dichloromethyene)-bisphosphonic acid;
[1-hydroxy-3-(1-pyrrolidinyl)-propylidene] bisphosphonic acid;
(1-hydroxyyethylidene)-bisphosphonic acid;
[(cycloheptylamino) methylene] bisphosphonic acid;
(6-amino-1-hydroxyhexylidene) bisphosphonic acid;
[[(4-chloropheny) thio] methylene] bisphosphonic acid;
[1-hydroxy-2-imidazo-(1,2a) pyridin-3-ylethylidene] bisphosphonic acid;
[1-hydroxy-2-(1H-imidazole-1-yl) ethyledene] bisphosphonic acid;
1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and
4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;
or their pharmaceutically acceptable salts.
Methods for the preparation of bisphosphonic acids may be found in, e.g., U.S. Pat. No. 3,962,432: U.S. Pat. No. 4,054,598: U.S. Pat. No. 4,267,108: U.S. Pat. No. 4,327,039: U.S. Pat. No. 4,407,761: U.S. Pat. No. 4,621,077: U.S. Pat. No. 4,624,947: U.S. Pat. No. 4,746,654: U.S. Pat. No. 4,922,077: and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,077, respectively.
The pharmaceutically acceptable salts of bisphosphonic acids may also be employed in the instant invention. Examples of basic salts of bisphosphonic acids include ammonium salts, alkali metal salts such as potassium and sodium (including mono-, di- and tri-sodium) salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth. The non-toxic, physiologically acceptable salts are preferred. The salts may be prepared by methods known in the art, such as in U.S. Pat. No. 4,922,077.
In the present invention it is preferred that the bisphosphonic acid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. It is even more preferred that the bisphosphonic acid is a sodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, in particular, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.
Examples of agents that bind to the androgen receptor that may be used as an active ingredient in the novel method and formulation of this invention include but not limited to danazol, 5a-dihydrotestosterone, testosterone, nandrolane decanoate, methyltestosterone, methanadrostenolone, stanozolol, fluoxymesterone, oxymetholone, oxandrolone, oxymethol, norethandrolone, ethylestranol, 4-androsten-19-al-3,17-dione, 19-nortestosterone, norethandrone, norethisterone, dehydroepiandrosterone, epiandrosterone sulfate, androstenedione and androstenediol, testosterone propionate, testosterone cytpionate, and testosterone enanthate, preferably testosterone.
The bisphosphonic acid and the agent that binds to the androgen receptor can be administered combined in a single dosage form, which forms another aspect of the present invention, or as separate entities administered more or less concurrently. In either method of administration, the active ingredients are provided in doses that are the same as would be administered if given as sole medicament. In the case of the bisphosphonic acid, oral doses of 2.5 to 100 mg/day are approprate. Prophylactically, doses of about 2.5 to about 10 mg/day, and especially about 5 mg/day should be employed. For the treatment of bone disease involving bone resorption daily doses of about 5 to 20 mg/day may be used, especially about 10 mg/day. In the case of the agent that binds to the androgen receptor, doses of about 0.1-100 mg/day are recommended and preferably about 0.1-10 mg/day, depending on the potency of the agent.
In the combination of the present invention the bisphosphonic acid and the agent binds to the adrog
Harada Shun-Ichi
Rodan Gideon
Schmidt Azriel
Merck & Co. , Inc.
Sabatelli Anthony D.
Wallinger Nicole M.
Winokur Melvin
LandOfFree
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