AU709606B2 - Use of droloxifene for the treatment of prostatic diseases endometriosis and obesity - Google Patents

Description

-1- USE OF DROLOXIFENE FOR THE TREATMENT OF PROTASTIC DISEASES,

ENDOMETRIOSIS

AND OBESITY Field of the Invention This invention relates to remedies for prostate diseases, endometriosis and obesity comprising, as active ingredient, droloxifene having the chemical structure represented by the following formula, SCH3 0- CH CHCHN 3

C

OH

or a pharmaceutically acceptable salt thereof.

Background of the Invention SDroloxifene is a known compound disclosed in United States Patent 5,047,431 1 0 in which it is disclosed as an anti-tumor agent, particularly for treatment and prevention of cancer of the breast. Droloxifene is also useful for the relief of bone diseases caused by the deficiency of estrogen or the like, whichare often observed in women after menopause or those with the ovaries removed. U.S. Patent No. 5,254,594 Gil-Sharma, et al., roduction and Fertilit (1993) 99, 395, disclose that 9. 5 tamoxifen at 200 and 400 mg/kg/day reduces the weights of the testes and secondary sex organs in male rats.

Neubauer, et al., The Prostate 23:245 (1993) teach that raloxifene treatment of male rats produced regression of the ventral prostate.

Summary of the Invention This invention provides a method for treating a condition or disease selected from endometriosis, obesity and prostatic carcinoma in mammals which comprises administering to said mammal in need of such treatment an amount of droloxifene or a S pharmaceutically acceptable salt thereof which is effective in treating said condition or disease.

Detailed Description of the Invention The preparation of droloxifene 4 2 -dimethyaminoetloxy)phenyl] (3' hydroxyphenyl)-2-phenylbutl -ene) and pharmaceutically acceptable salts thereof is r0 described in United States Patent No. 5,047,431 which is incorporated herein by As used in this application, "prostatic disease" means benign prostatic hyperplasia ,.,s.easer means benign prostatic hyperplasia rprostatic carcinoma "Treating" means curing, alleviating the symptoms of or preventing the onset of a disease or condition.

The remedies for the prostatic disease, endometriosis and obesity of this invention comprise, as active ingredient, droloxifene or a salt thereof. The harmaceutically accptbl salts od xe aste pharaceutically cceptable salts of droloxifene are salts of non-toxic type commonly used, such as salts benzenesulfonic or toluenesulfonic acids), inorganic acids hydrochloric, .0 hydrobromic, sulfuric or phosphoric acids), and amino acids aspartic or glutamic acids). These salts may be prepared by the methods known the chemists of ordinary skill.

The remedies for the diseases and conditions of this invention may be administered to animals including humans orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, S 25 suppositories, injections, suspensions and syrups.

The remedies for the diseases and conditions of this invention can be prepared by the methods commonly employed using conventional, organic or inorganic additives, such as an excipient sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium, phosphate or calcium carbonate), a binder cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator starch, carboxymethylcellulose, hydroxypropylstarch, low substituted [R:VBH]00223.doc:KWW

I

-3hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent citric acid, menthol, glycine or orange powder), a preservative sodium benzoate, sodium bisulfite, methylparaben or propylparaben) a stabilizer citric acid, sodium citrate or acetic acid), a suspending agent (e.g methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent hydroxypropylmethylcellulose), a diluent water), and base wax cocoa butter, white petrolatum or polyethylene glycol). The amount of the active ingredient in the medical composition may be at a level that will exercise the desired therapeutical effect; for example, about 1 mg to 100 mg in unit dosage for both oral and parenteral administration.

The active ingredient may be usually administered once to four times a day with a unit dosage of 0.25 mg to 100 mg in human patients, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration. One dose per day is preferred.

S. The following Examples will serve to illustrate, but do not limit the invention which is defined by the claims.

EXAMPLE 1 Effect on Prostate Weight 20 Male Sprague-Dawley rats, three months of age were administered by subcutaneous injection either vehicle (10% ethanol in water), estradiol (30 pg/kg), testosterone (1 mg/kg) or droloxifene citrate (10 mg/kg) daily for 14 days (n=6/group).

After 14 days the animals were sacrificed, the prostate was removed and the wet prostate weight was determined. Mean weight was determined and statistical significance (p<0.05) was determined compared to the vehicle-treated group using Student's t-test.

Droloxifene citrate at 10 mg/kg/day significantly (P<0.05) decreased prostate Sweight compared to vehicle. Testosterone had no effect while estrogen at 30 pg/kg significantly reduces prostate weight.

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

EXAMPLE 2 Effect on Body Fat Mass Sprague-Dawley female rats at 10 months of age, weighing approximately 450 grams, were sham-operated (sham) or ovariectomized (OVX) and treated orally with vehicle, 1 7 a ethynyl estradiol at 30 pg/kg/day or droloxifene citrate at 1.0, 2.5 or mg/kg/day for 8 weeks. There were 6 to 7 rats in each sub group. On the last day of the study, body composition of all rats was determined using dual energy x-ray absorptiometry (Hologic QDR-1000/W) equipped with whole body scan software. See Faulkner, et al., Calcified Tissue 53, 7 (1993). Our results showed that ethynyl estradiol and all doses of droloxifene had no effect on lean body mass (in grams). However, the fat body mass (in grams) significantly decreased (40-60%) in OVX rats treated with ethynyl estradiol or droloxifene (at all dose levels) compared to sham or OVX controls.

These results demonstrated that droloxifene is a useful agent in treatment of obesity.

EXAMPLE 3 Control and Vention of Endometriosis b. The protocol for surgically inducing endometriosis is identical to that described o* by Jones, Acta Endocrinol (Copenh) 106:282-8. Adult Charles River Sprague-Dawley CD. e F s (C arle Ri e S ^ra ue Daw ey S..CD female rats (200-240 g) are used. An oblique ventral incision is made through the and musculature of the body wall. A segment of the right uterine horn is excised, 20 the myometrium is separated from the endometrium, and the segment is cut longitudinally. A 5x5 mm section of the endometrium, with the epithelial lining apposed to the body wall, is sutured at its four corners to the muscle using polyester braid Ethiflex, The criterion of a viable graft is the accumulation of fluid similar to that which occurs in the uterus as a result of oestrogen stimulation.

25 Three weeks after transplantation of the endometrial tissue weeks) the animals are laparotomized, the volume of the explant (length x width x height) in mm was measured with calipers, and treatment is begun. The animals are injected sc for 3 weeks with 10 to 1000 pg/kg/day of a compound of Formula I. Animals bearing Sndometrial explants are injected sc with 0.1 ml/day of corn oil for 3 weeks served a controls. At the end of 3 week treatment period weeks), the animals are laparotomized and the volume of the explant determined. Eight weeks after cessation of treatment (+14 weeks) the animals are sacrificed; the explant are measured again.

Statistical analysis of the explant volume is by an analysis of variance.

EXAMPLE 4 Droloxifene Citrate Tablets Droloxifene citrate 100 g Lactose 19 Low substituted hydroxypropycelluj 0 5 e 2590 g Polyvinylpyrrojli 0 d Magnesium stearate 1 The components listed above are mixed together by the usual method, and the mixture thus obtained is compressed into 10,000 tablets each containing 1 0 mg of droloxifene citrate.

The claims defining the invention are as follows: 1. A method of treating a disease or condition selected from endometriosis prostatic carcinoma and obesity in mammals which comprises administerin to a mammal in need of such treatment an amount of droloxifene or a pharmaceutically acceptable salt thereof which is effective in treating said disease or condition.

2. A method of claim 1 wherein said disease or condition is endometriosis.

3. A method of claim 1 wherein said disease or condition is prostatic carcinoma 4. A method of claim 1 wherein said disease or condition is obesity 5. A methdcceple of any one of clais to 4 wherein said Pharmaceutically Sacceptable salt is the citrate salt.

Dated 8 July, 1999 Pfizer Inc.

Patent Attorneys for the Applicant/Nominated Person SPRUSON

FERGUSON

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