Treatment of male hormone related diseases by cyclodextrins and their derivatives

Abstract: A use of a cyclodextrin or a derivative thereof for the manufacture of a medicament for treatment of diseases having an etiology based on or accompanied by excess male hormone.

Description: The present invention relates to a use of a cyclodextrin or a derivative thereof for the manufacture of a medicament for treating diseases having an etiology based on or accompanied by excess male hormone. Among various diseases having an etiology based on or accompanied by excess male hormone, diseases accompanied by enlargement of prostate such as prostatic hypertrophy and prostatic cancer, have conventionally been treated by administration of sex hormone such as estrogens. Since, however, sex hormones have well known side effects, there has been a continuous need of development of a medicament which has not such side effects. As a result of extensive studies about properties of non-hormone compounds, the present inventor discovered that cyclodextrin and their derivatives, which have been used only as a complexing agent in the pharmaceutical field, have beneficial action of relieving the disease having an etiology based on or accompanied by excess male hormone, for example action of reducing gain of prostate or testis. In a first aspect, the present invention provides the use of a cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for the treatment of diseases having an etiology based on or accompanied by excess male hormone. In a second aspect, the present invention provides the use of a cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for treatment of enlargement of testis. In a third aspect, the present invention provides the use of a cyclodextrin an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for lowering the serum level of testosterone. As used herein, the expression "diseases having an etiology based on or accompanied by excess mole hormone" is intended to all kinds of diseases insofar as they are proved or estimated from reliable bases to have at least an etiology based on or accompanied by excess male sex hormone e.g. due to excess secretion or to administration of such hormone. Said diseases include testicular hypertrophy, testicular cancer, prostatic hypertrophy, congenital or aquired adrenogenial syndrome (adrenal virilism following to adrenal hyperplasia, adrenal virilizing tumor which is a tumor having an androgen secreting function, etc.) and also urinary disturbance caused by prostatic hypertrophy (oligurea, ureteral stenosis, ureteral flexion etc.) vesical disturbance (cystitis, vesicoureteral reflux (VUR), etc.). Enlargement of prostate refers to all kinds of prostatic multiplication and prostatic hyperplasia including tumor and thickening, e.g. prostatic hypertrophy (i.e. adenoma of prostate including hypertrophy of bilateral lobes, median lobe, subcervical lobe, commisural, anterior commisural, subtriangle lobe, etc.), prostatic cancer, prostatic sarcoma, etc. The term "treatment" includes prevention, cure and relief of disease and arrest or relief of development of disease. The term "cyclodextrin" includes α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The term "derivatives" used in conjunction with the term cyclodextrin refers to etherified cyclodextrins, glucosyl cyclodextrins, maltosyl cyclodextrins, acylated cyclodextrins and sulfonated cyclodextrins. Said etherified cyclodextrins include (lower)alkylcyclodextrins such as methylcyclodextrin, ethylcyclodextrin, propylcyclodextrin, dimethylcyclodextrin, trimethylcyclodextrin, (lower)alkenylcyclodextrins, hydroxy(lower)alkylcyclodextrins such as hydroxyethylcyclodextrin, hydroxypropylcyclodextrin, (lower)alkoxy(lower)alkylcyclodextrins, aralkylcyclodextrins such as benzylcyclodextrin, halo(lower)alkylcyclodextrins such as chloroethylcyclodextrin, and cylodextrinepichlorohydrine copolymer. These may be etherified cyclodextrins in which one, two or three hydroxy groups in any of the glucose units of the cyclodextrin molecule are converted into ether. Said acylated cyclodextrins include (lower)alkanoylcyclodextrins such as formylcyclodextin, acetylcyclodextrin, aromatically or heterocyclically acylated cyclodextrins such as benzoylcyclodextrin, nicotinoylcyclodextrin. The derivatives of cyclodextrin include also derivatives in which two or more of derivatizations selected from etherification, branching, acylation and sulfuration are co-existing. These derivatives are known or can be prepared by a method similar to that for the known derivatives. While the dosage of cyclodextrin or derivatives thereof will vary depending on age, weight, condition of particular subject, desired therapeutic effect etc., satisfactory effects will generally be obtained with the dosage of 1 µg/kg to 500 mg/kg, preferably 10 µg/kg to 50 mg/kg, administered once a day or 2 to 4 divided doses a day or as a sustained form. Administration may be effected by injection etc. For administration, the compound used in the invention can be given in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as organic or inorganic, solid or liquid excipients suitable for the desired mode of administration such as injection. Such preparation may be in a solid form such as solid from which a solution can be made up before use, etc. or in a liquid form such as solution, emulsion, suspension, etc. Said carrier includes starch, lactose, glucose, sucrose, dextrin cellulose, paraffin, aliphatic glyceride, water, alcohol, acacia etc. The above preparation may also contain auxiliary substance, stabilizer, emulsifier, lubricant, binder, pH-adjuster, isotonic agent and other conventional additives added as necessary. The present invention is illustrated in more detail by way of the following Examples and Test Examples. Example 1 Dimethylcyclodextrin 100 mg Physiological saline q.s. to 10 ml The above ingredients are brought into solution by conventional way to form an injectable solution. Test Example 1 Male Crj-Wister rats (6 rats per group) intravenously received 5 mg/kg or 25 mg/kg dimethyl-α-cyclodextrin [a mixture mainly comprising hexakis(2,6-di-O-methyl)-α-cyclodextrin and pentakis[2,6-di-O-methyl)-mono(2, 3,5-tri-O-methyl)-α-cyclodextrin; hereinafter referred to as DMCD] or 25 mg/kg pentakis(2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl-α-cyclodextrin (purified from commercial DMCD; hereinafter referred to as Compound I, dissolved in 5 ml physiological saline for 2 weeks. Control group received the physiological saline alone. After the above period, body and testis were weighed for all animals of groups and a weight ratio testis/100 g body was calculated. The results are shown in Table 1. In addition, serum testosteron level was measured. The results are shown in Table 2. Group Testis (%) Mean SD Control 0.98 0.07 DMCD 5mg/kg 0.79 0.11 DMCD 25mg/kg 0.54 0.03 Compound I 25mg/kg 0.63 0.14 Group Testosteron (ng/dl) Mean SD Control 264 174 DMCD 5mg/kg 104 43 Compound I 25mg/kg 178 100 Test Example 2 Male rats (3 rats per group) were treated as Test Example 1 except that tetrakis(2,6-di-O-methyl)-bis(2,3,6-tri-O-methyl)-α-cyclodextrin (purified from DMCD as a mixture; hereinafter referred to as Compound II) was used as the test compound. Body and testis were weighed and a weight ratio testis/100 g body was calculated. The results are shown in Table 3. In addition, serum testosteron level was measured. The results are shown in Table 4. Group Testis (%) Mean SD Control 0.95 0.05 Compound II 5mg/kg 0.81 0.02 Group Teststeron (ng/dl) Mean SD Control 638 123 Compound II 5mg/kg 215 131 Test Example 3 Male rats (3 rats per groups were treated as Test Example 1 except that hexakis(2,6-di-O-methyl)-α-cyclodextrin (purified from DMCD as a mixture; hereinafter referred to as Compound III) was used as the test compound. Body and testis were weighed and a weight ratio testis/100 g body was calculated. The results are shown in Table 5. Group Testis (%) Mean SD Control 0.91 0.06 Compound III 5mg/kg 0.74 0.13 Compound III 25mg/kg 0.51 0.05 Test Example 4 Male rats (12 rats per group) intravenously received 125 mg/kg dimethyl-α-cyclodextrin [a mixture mainly comprising hexakis(2,6-di-O- methyl)-α-cyclodextrin and pentakis[2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl)-α-cyclodextrin (DMCD)] dissolved in 5 ml physilogical saline for 1 month. Control group received the physiological saline alone. After the above period, body and prostate were weighed for all animals of groups and a weight ratio testis/100 g body was calculated. The results are shown in Table 6. Group Prostate (%) Mean SD Control 0.13 0.018 Compound II 5mg/kg 0.10 0.022 The above results indicate that the compounds used in the invention have an action of inhibiting increase in weight of prostate.

Claims: The use of a cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for the treatment of diseases having an etiology based on or accompanied by excess male hormone. The use according to claim 1, in which an etherified cyclodextrin is used and is selected from the group consisting of dimethylcyclodextrin. The use according to claim 1, in which the disease is in consequence of testicular hypertrophy or testicular tumor. A use of cyclodextrin or a derivative thereof for the manufacture of a medicament for treatment of enlargement of prostate. The use according to claim 4 in which the enlargement is in consequence of prostatic hypertrophy. The use of a cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for treatment of enlargement of testis. The use of a cyclodextrin an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin or a sulfonated cyclodextrin for the manufacture of a medicament for lowering the serum level of testosterone.

Inventors: UENO RYUJI, UENO, RYUJI
Applicants: UENO SEIYAKU OYO KENKYUJO KK, KABUSHIKI KAISHA UENO SEIYAKU OYO KENKYUJO
Application year: 1990
Main classification: A61K31
IPC codes: A61K31