Gnrh analogue formulations

Abstract

The present invention relates to topical bioadhesive formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and/or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid for use in therapy. The invention additionally relates to the use of a preformulation of the invention in a method for the manufacture of a medicament.

1 - 37 . (canceled) 
     
     
         38 . A pre-formulation comprising a low viscosity mixture of:
 a) at least one diacyl glycerol comprising at least 50% glycerol dioleate (GDO);   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent;   d) at least one peptide GnRH analogue comprising 12 or fewer amino acids;   wherein the ratio of a:b (w/w) is in the range of 40:60 to 70:30;   wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid.   
     
     
         39 . A pre-formulation as claimed in  claim 38  wherein the ratio of a:b (w/w) is in the range of 45:55 to 60:40. 
     
     
         40 . A pre-formulation as claimed in  claim 38  wherein component b) comprises soy PC. 
     
     
         41 . A pre-formulation as claimed in  claim 38  wherein component c) is a single solvent. 
     
     
         42 . A pre-formulation as claimed in  claim 38  wherein component c) is a mixture of solvents. 
     
     
         43 . A pre-formulation as claimed in  claim 38  wherein component c) is a single solvent or mixture of solvents, having a viscosity of no more than 18 mPas at 20° C. 
     
     
         44 . A pre-formulation as claimed in  claim 38  wherein component c) is a single solvent or mixture of solvents, having a viscosity of no more than 10 mPas at 20° C. 
     
     
         45 . A pre-formulation as claimed in  claim 38  wherein component c) comprises at least one solvent selected from alcohols, ketones, esters, ethers, amides, and sulfoxides. 
     
     
         46 . A pre-formulation as claimed in  claim 38  wherein component c) comprises at least one solvent selected from ethanol, N-methyl pyrrolidone (NMP), and dimethylsulphoxide (DMSO). 
     
     
         47 . A pre-formulation as claimed in  claim 38  wherein component d) is a constrained peptide of 6 to 12 alpha-amino acids. 
     
     
         48 . A pre-formulation as claimed in  claim 38  wherein component d) comprises Gly-NH 2 , N-Et-NH 2 , or AzaGly-NH 2  at the N-terminus. 
     
     
         49 . A pre-formulation as claimed in  claim 38  wherein component d) is at least one peptide selected from: GnRH-I, GnRH-II, GnRH-III, Fertirelin, Leuprorelin (Leuprolide), Buserelin, Histrelin, Deslorelin, Goserelin, Narafelin, and Triptorelin. 
     
     
         50 . A pre-formulation as claimed in  claim 38  wherein component d) is Leuprolide or Goserelin. 
     
     
         51 . A pre-formulation as claimed in  claim 38  wherein component d) is a GnRH agonist. 
     
     
         52 . A pre-formulation as claimed in  claim 38  wherein component d) is a GnRH antagonist. 
     
     
         53 . A pre-formulation as claimed in  claim 38  wherein:
 component a) is present in an amount of 40-70 wt %; 
 component b) is present in an amount of 30-60 wt %; 
 component c) is present in an amount of 0.1-10 wt %; and 
 component d) is present in an amount of 0.1-10 wt %. 
 
     
     
         54 . A method for the treatment of at least one condition in a human or non-human mammalian subject in need thereof, said condition being selected from neoplastic diseases, cancers, breast cancer, prostate cancer, benign prostatic hypertrophy, premature or delayed puberty in adolescents, hirsuitism, alzheimer's disease, hypogonadism, anovulation, amenorrhea, oligospermia, endometriosis, leiomyomata (uterine fibroids), premenstral syndrome, polycystic ovarian disease, or for use as part of IVF treatment;
 said method comprising administering to said subject a pre-formulation as claimed in  claim 38 .   
     
     
         55 . The method as claimed in  claim 54  comprising administration by i.m., s.c., or deep s.c. injection. 
     
     
         56 . The method as claimed in  claim 54  comprising administration by means of a pre-filled administration device. 
     
     
         57 . The method as claimed in  claim 54  comprising administration through a needle smaller than 20 gauge. 
     
     
         58 . The method as claimed in  claim 54  comprising a single administration every 20 to 360 days.