LONG-ACTING FATTY ACID-CONJUGATED GnRH DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

Abstract

An aspect of the present disclosure pertains to a novel long-acting fatty acid-conjugated gonadotrophin-releasing hormone (GnRH) derivative and a pharmaceutical composition containing the same. A GnRH derivative of the present invention is expected to greatly contribute, through excellent bioavailability, increased half-life in blood, and remarkably high therapeutic effects on sex hormone-dependent disease, to the reduction in drug dosing frequency and dosage and the like in the treatment of sex hormone-dependent diseases. Particularly, the GnRH derivative can overcome the disadvantages of existing GnRH sustained-release preparations, which have the side effects of residual feeling and pain at the injection site.

What is claimed is: 
     
         1 . A long-acting fatty acid-conjugated gonadotropin-releasing hormone (GnRH) derivative in which the gonadotropin-releasing hormone (GnRH) derivative is conjugated with a fatty acid;
 or a pharmaceutically acceptable salt thereof,   wherein the fatty acid is not palmitic acid.   
     
     
         2 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1 , wherein the fatty acid is a C 6  to C 30  fatty acid. 
     
     
         3 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 2 , wherein the fatty acid is selected from the group consisting of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, linolenic acid, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linoleic acid, dihomo gamma-linoleic acid, arachidonic acid, oleic acid, vaccenic acid, elaidic acid, eicosanoic acid, erucic acid, and nervonic acid. 
     
     
         4 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1 , wherein the fatty acid is conjugated to the amino terminus of the GnRH derivative. 
     
     
         5 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1 , wherein the GnRH derivative is a GnRH agonist. 
     
     
         6 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 5 , wherein the GnRH agonist is selected from the group consisting of Leuprolide, Goserelin, Triptorelin, Nafarelin, Buserelin, Histrelin, Deslorelin, Meterelin, and Gonadorelin. 
     
     
         7 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1 , wherein the GnRH derivative comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 10, and SEQ ID NO: 11. 
     
     
         8 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic acids, organic acids, ammonium salts, alkali metal salts, and alkaline earth metal salts. 
     
     
         9 . The long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 8 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, phosphate, metaphosphate, nitrate, sulfate, acetate, sulfonate, benzoate, citrate, ethanesulfonate, furmarate, lactate, maleate, malate, succinate, tartrate, sodium salt, calcium salt, potassium salt, and magnesium salt. 
     
     
         10 . A method for preventing or treating a sex hormone-dependent disease comprising:
 administering a pharmaceutical composition to a patient in need thereof,   wherein the pharmaceutical composition comprises the long-acting fatty acid-conjugated GnRH derivative or salt thereof according to  claim 1  as an active ingredient.   
     
     
         11 . The method of  claim 10 , wherein the sex hormone-dependent disease is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary disease, central precocious puberty, hypertrichosis, gonadotroph pituitary adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and contraception. 
     
     
         12 . The method of  claim 10 , wherein the pharmaceutical composition further comprises a biodegradable polymer. 
     
     
         13 . A method for preventing or treating a sex hormone-dependent disease, comprising administering a pharmaceutical composition to a patient in need thereof,
 wherein the pharmaceutical composition comprising:   a long-acting fatty acid-conjugated gonadotropin-releasing hormone (GnRH) derivative in which the gonadotropin-releasing hormone (GnRH) derivative is conjugated with a fatty acid, or a pharmaceutically acceptable salt thereof as an active ingredient; and   cyclodextrin.   
     
     
         14 . The method of  claim 13 , wherein the fatty acid is a C 6  to C 30  fatty acid. 
     
     
         15 . The method of  claim 14 , wherein the fatty acid is selected from the group consisting of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, linolenic acid, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linoleic acid, dihomo gamma-linoleic acid, arachidonic acid, oleic acid, vaccenic acid, elaidic acid, eicosanoic acid, erucic acid, and nervonic acid. 
     
     
         16 . The method of  claim 13 , wherein the fatty acid is conjugated to the amino terminus of the GnRH derivative. 
     
     
         17 . The method of  claim 13 , wherein the GnRH derivative is a GnRH agonist. 
     
     
         18 . The method of  claim 17 , wherein the GnRH agonist is selected from the group consisting of Leuprolide, Goserelin, Triptorelin, Nafarelin, Buserelin, Histrelin, Deslorelin, Meterelin, and Gonadorelin. 
     
     
         19 . The method of  claim 13 , wherein the GnRH derivative comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 2, and SEQ ID NOS: 4 to 11. 
     
     
         20 . The method of  claim 13 , wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic acids, organic acids, ammonium salts, alkali metal salts, and alkaline earth metal salts. 
     
     
         21 . The method of  claim 20 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, phosphate, metaphosphate, nitrate, sulfate, acetate, sulfonate, benzoate, citrate, ethanesulfonate, furmarate, lactate, maleate, malate, succinate, tartrate, sodium salt, calcium salt, potassium salt, and magnesium salt. 
     
     
         22 . The method of  claim 13 , wherein the sex hormone-dependent disease is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary disease, central precocious puberty, hypertrichosis, gonadotroph pituitary adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and contraception. 
     
     
         23 . The method of  claim 13 , wherein the cyclodextrin is methyl-β-cyclodextrin. 
     
     
         24 . The method of  claim 13 , wherein the fatty acid-conjugated GnRH derivative and the cyclodextrin exist together as an inclusion complex. 
     
     
         25 . The method of  claim 13 , wherein the cyclodextrin and the fatty acid-conjugated GnRH derivative are used at a molar ratio of 7:1 to 1:1. 
     
     
         26 . The method of  claim 13 , wherein the pharmaceutical composition further comprises a biodegradable polymer.