COMPOSITIONS AND METHODS FOR TREATING PRECOCIOUS PUBERTY
The present invention is directed to the controlled delivery of gonadotropin-releasing hormone (GnRH) agonists, preferably from a polymeric material that is implanted in the body. More specifically, the present invention relates to compositions comprised of a GnRH agonist, preferably histrelin, in a polymeric material that results in a desired and controlled delivery of a therapeutically effective amount of GnRH agonist over an extended period of time in order to treat central precocious puberty (CPP).
1 . A controlled release reservoir implant containing a formulation comprising (i) histrelin or its pharmaceutically acceptable salt and (ii) stearic acid, the reservoir implant comprising a hydrophilic copolymer obtained from a copolymerization of a mixture comprising about 45% hydroxyethyl methacrylate (HEMA) and about 55% hydroxypropyl methacrylate (HPMA), and which implant provides a therapeutically effective amount of the histrelin or its pharmaceutically acceptable salt in vivo to improve one or more symptoms of central precocious puberty in a patient, wherein the implant provides an average in vivo release rate between 65 micrograms and 70 micrograms of the histrelin or its salt daily in the patient over one year.
2 . The implant of claim 1 in which the mixture comprises about 45% of HEMA, about 54.5% HPMA and about 0.5% trimethylolpropane trimethacrylate (TMPTMA).
3 . The implant of claim 1 which provides an average in vitro release rate of 65 micrograms of the histrelin or its salt per day.
4 . The implant of claim 1 which releases histrelin or its salt at a rate to maintain a mean plasma concentration of histrelin of about 0.2 ng/ml to about 2 ng/ml over one year.
5 . The implant of claim 1 which releases histrelin or its salt at a rate to maintain a mean plasma concentration of histrelin of about 0.4 ng/ml to about 0.6 ng/ml over one year.
6 . A controlled release reservoir implant containing a formulation comprising (i) histrelin or its pharmaceutically acceptable salt and (ii) stearic acid, the reservoir implant comprising a hydrophilic copolymer obtained from a copolymerization of a mixture comprising about 45% hydroxyethyl methacrylate (HEMA), about 54.5% hydroxypropyl methacrylate (HPMA), and about 0.5% trimethylolpropane trimethacrylate (TMPTMA), and which implant provides a therapeutically effective amount of the histrelin or its pharmaceutically acceptable salt in vivo to improve one or more symptoms of central precocious puberty in a patient, wherein the implant provides an average in vivo release rate between 65 micrograms and 70 micrograms of the histrelin or its salt daily in the patient to maintain a mean plasma concentration of histrelin of about 0.2 ng/ml to about 2 ng/ml over one year.
7 . The implant of claim 6 in which the histrelin or its salt is released at a rate to maintain a mean plasma concentration of histrelin of about 0.4 ng/ml to about 0.6 ng/ml over one year.
8 . A controlled release reservoir implant containing a formulation comprising (i) 50 mg histrelin acetate and (ii) stearic acid, the reservoir implant comprising a hydrophilic copolymer obtained from a copolymerization of a mixture comprising about 45% HEMA, about 54.5% HPMA and about 0.5% TMPTMA, and which implant provides a therapeutically effective amount of the histrelin acetate in vivo to improve one or more symptoms of central precocious puberty in a patient, wherein the implant provides an average in vitro release rate of between 65 micrograms and 70 micrograms of the histrelin acetate daily over one year.
9 . The implant of claim 8 which upon implantation in a patient suffering from central precocious puberty releases histrelin acetate daily in the patient at a rate to maintain a mean plasma concentration of histrelin of about 0.2 ng/m to about 2 ng/ml over one year.
10 . The implant of claim 6 , wherein the implant provides an average in vivo release rate of 65 micrograms of the histrelin or its salt daily in the patient.
11 . The implant of claim 8 , wherein the implant provides an average in vivo release rate of 65 micrograms of the histrelin acetate daily in the patient.
12 . The implant of claim 8 , in which the histrelin acetate is released at a rate to maintain a mean plasma concentration of histrelin of about 0.4 ng/ml to about 0.6 ng/ml over one year.