HK1000697B - Use of droloxifene for the treatment of cardiovascular diseases - Google Patents

Abstract

Use of dro'oxifene in the treatment of cardiovascular diseases.

Description

Treatment of cardiovascular diseases using droloxifene

This is a continuation-in-part application of U.S. patent application serial No. 08/276,969 filed on 7/19 of 1994.

The present invention relates to a medicament for the treatment of cardiovascular diseases comprising as active ingredient droloxifene having the following chemical formula:or a pharmaceutically acceptable salt thereof.

Droloxifene is a known compound disclosed in us patent 5,047,431, where droloxifene is an antineoplastic drug, especially for the treatment and prevention of breast cancer. Droloxifene is also useful for the relief of skeletal disorders due to estrogen or analog deficiency, which is common in women following menopause or hysterectomy. Us patent 5,254,594.

Reduction of the weight of the testis and secondary sexual organs in male mice using 200 and 400 mg/kg/day tamoxifen is disclosed in Gill-Sharma et al, j.

Neubauer et al, The protate 23: 245(1993) raloxifene treatment of male mice has been reported to cause regression of the ventral prostate.

The present invention provides a method of treating a condition or disease selected from cardiovascular disease or hypercholesterolemia in a mammal comprising administering to said mammal an amount of droloxifene or a pharmaceutically acceptable salt thereof effective to treat said condition or disease.

Methods for preparing droloxifene (1- [4 '- (2-dimethylaminoethoxy) phenyl ] -1- (3' -hydroxyphenyl) -2-phenylbut-1-ene) and pharmaceutically acceptable salts thereof are described in U.S. patent 5,047,431, which is incorporated herein by reference.

In the present specification, "prostate disease" means benign prostatic hyperplasia or prostate cancer. "cardiovascular disease" means hypercholesterolemia or atherosclerosis. "treating" or "treatment" refers to curing, alleviating, or preventing the onset of a disease or condition.

The inventive medicament for cardiovascular diseases, hypercholesterolemia or atherosclerosis comprises droloxifene and salts thereof as an active ingredient. Pharmaceutically acceptable salts of droloxifene are those of the non-toxic type commonly used, for example salts of organic acids such as formic acid, acetic acid, citric acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and salts of amino acids such as aspartic acid or glutamic acid. These salts can be prepared by methods known to the chemist skilled in the art.

The drugs for diseases and conditions of the present invention can be administered orally or parenterally to animals including humans, and the preparations can be in conventional forms such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, and syrups.

The drugs for diseases or conditions of the present invention can be prepared by a conventional method using conventional organic or inorganic additives, for example, excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methyl cellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, acacia, polyethylene glycol, sucrose or starch), disintegrators (e.g., starch, carboxymethyl cellulose, hydroxypropyl starch, lower-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavors (e.g., citric acid, methanol, glycine or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, sodium hydrogen sulfite, calcium phosphate or calcium carbonate), lubricants (e.g., gelatin, sodium stearate, sodium hydroxide, sodium lauryl sulfate, sodium chloride, Methyl or propyl parabens), stabilizers (such as citric acid, sodium citrate or acetic acid), suspending agents (such as methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents (such as hydroxypropylmethylcellulose), diluents (such as water) and base waxes (such as cocoa butter, white petrolatum or polyethylene glycol). In the pharmaceutical composition, the active ingredient may be present in an amount to achieve the desired therapeutic effect, for example, in a single dose of 1 to 100 mg for oral and parenteral administration.

The active ingredient is contained in an amount of 0.25 to 100 mg per single dose, and is usually administered to a patient one to four times per day, but the above dose may be suitably changed depending on the age, body weight, condition and administration form of the patient. Preferably one dose per day.

The following examples are intended to illustrate the invention and are not intended to limit the scope of the claims of the invention.

Example 1

Effect on prostate weight

Male Sprague-Dawley mice, three months of age, were injected subcutaneously with vehicle (10% ethanol in water), estradiol (30 μ g/kg), testosterone (1 mg/kg) or citrate of droloxifene (10 mg/kg) daily for 14 days (n ═ 6/group). After 14 days the animals were sacrificed and the prostate was removed and weighed wet. The mean weights were determined and statistical significance relative to vehicle treated groups was determined using Student's test method (p < 0.05).

The citrate salt of droloxifene at 10 mg/kg/day significantly reduced the weight of the prostate gland compared to the vehicle group (p < 0.05). The testosterone group had no effect, while estrogen at 30 μ g/kg significantly reduced prostate weight.

These data indicate that droloxifene citrate is useful in the treatment of benign prostatic hypertrophy and prostate cancer.

Example 2

Effect on Total Cholesterol level

The effect of the compounds of the present invention on total cholesterol levels in plasma was determined using the following method. Anesthetized 4-6 month old female Sprague-Dawley mice were ovariectomized bilaterally, treated with droloxifene citrate (5 mg/kg/day, oral) or vehicle for 28 days, or sham operated, and blood samples were obtained from the heart punctures of these mice. The blood samples were placed in a medium containing 30. mu.l of 5% EDTA (10. mu.l EDTA/1 ml blood). After centrifugation at 2500rpm at 20 ℃, plasma was removed and stored at-20 ℃ until analysis. Analysis of total cholesterol standard enzyme assay kits were used from Sigma Diagnostic, p.o. box 14508, st.louis MO 61378(Procedure No. 352). The following table shows the effect of droloxifene citrate on total cholesterol. When droloxifene citrate was administered (5 mg/kg/day, 28 days, orally), total plasma cholesterol was significantly reduced (30% reduction relative to vehicle-treated ovariectomized mice).

Effect of the citrate salt of droloxifene on the plasma Total Cholesterol levels in female mice

	Plasma Cholesterol (mg/dl)	Change% relative to sham surgery + vehicle group	% change from ovariectomy + vehicle group
				Sham surgery + vehicle group	57	-	-

Ovariectomy + vehicle group	112	96	-
				Droloxifene citrate (5 mg/kg/day, 28 days, oral)	78	+36	-30

Male Sprague-Dawley mice (3 months of age) were similarly tested by treating sham-operated and orchiectomized mice with vehicle and droloxifene citrate (10 mg/kg/day, 14 days, oral). As shown in the table below, droloxifene citrate significantly reduced plasma total cholesterol by 48% relative to sham operated, and 59% relative to orchiectomized vehicle treated animals.

Effect of the citrate salt of droloxifene on the plasma Total Cholesterol levels in Male mice

	Plasma Cholesterol (mg/dl)	Change%, sham surgery + vehicle group	Change%, testis excision + vehicle group
				Sham surgery + vehicle group	72	-	-
Testis excision plus excipient group	91	-	-
				Droloxifene citrate (10 mg/kg/day, 14 days, oral)	37	-48	-59

These data indicate that the citrate salt of droloxifene is effective in treating cardiovascular diseases such as hypercholesterolemia and atherosclerosis.

Example 3

Droloxifene citrate tablets

Droloxifene citrate 100 g

Lactose 1190 g

Lower substituted hydroxypropyl cellulose 250 g

Polyvinylpyrrolidone 50 g

Magnesium stearate 10 g

The above listed ingredients were mixed by a conventional method, and the mixture thus obtained was compressed into 10,000 tablets each containing 10mg of droloxifene citrate as an active ingredient.

Claims (2)

1. Use of droloxifene or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of atherosclerosis or hypercholesterolemia in a mammal.

2. The use of claim 1, wherein the pharmaceutically acceptable salt is citrate.