Method of Treating a Child with Central Precocious Puberty using an Extended Release Composition

Abstract

An extended release formulation is provided for use in a method for the treatment of Central Precocious Puberty (CPP) in pediatric patients 2 years of age or older. The extended release formulation comprises leuprolide or a pharmaceutically acceptable salt thereof, a biodegradable polymer, and a biocompatible organic solvent. The biodegradable polymer is comprised of poly(lactide-co-glycolide) (PLG) copolymer segments, poly(lactic acid-co-glycolic acid) (PLGA) copolymer segments, poly(lactide) (PL) polymer segments, poly(lactic acid) (PLA) polymer segments, or a combination thereof. The extended release formulation is administered as a subcutaneous injection of a flowable composition that forms a solid in situ depot. The extended release formulation releases leuprolide for a period of about 6 months for the effective treatment of CPP within a pediatric patient.

1 . A method of treating pediatric patients 2 years of age and older with central precocious puberty (CPP), the method comprising administering to a pediatric patient who has CPP, once per about six months, a subcutaneous injection of an extended release composition comprising:
 a. an organic solvent;   b. leuprolide or a pharmaceutically acceptable salt thereof, wherein the amount of leuprolide or the pharmaceutically acceptable salt thereof in the composition is independent from the weight of the pediatric patient and is not modified in subsequent administrations of the composition;   c. a biodegradable polymer comprising polymer segments selected from 85:15 poly(lactide-co-glycolide) (PLG) copolymer segments, 85:15 poly(lactic acid-co-glycolic acid) (PLGA) copolymer segments, or a combination thereof, wherein one distal end group of the polymer is hydroxyl-terminated and the other distal end group of the polymer is either hydroxyl-terminated or ester-terminated; and   
       wherein upon contact of the extended release composition with a bodily fluid, the solvent dissipates and an in situ solid depot forms; and 
       wherein the extended release composition, when administered once per about six months, reduces the pediatric patient's peak stimulated blood serum LH concentration to a pre-pubertal concentration level of <4 IU/L. 
     
     
         2 . The method of  claim 1 , wherein the amount of leuprolide or the pharmaceutically acceptable salt thereof in the extended release composition is about 40 mg to about 50 mg. 
     
     
         3 . The method of  claim 2 , wherein the leuprolide or pharmaceutically acceptable salt thereof is leuprolide acetate and the amount of leuprolide acetate in the extended release composition is about 45 mg. 
     
     
         4 . The method of  claim 1 , wherein the amount of leuprolide or the pharmaceutically acceptable salt thereof in the extended release composition is about 40 mg to 45 mg leuprolide free base equivalent. 
     
     
         5 . The method of  claim 4 , wherein the amount of leuprolide or the pharmaceutically acceptable salt thereof in the extended release composition is about 42 mg leuprolide free base equivalent. 
     
     
         6 . The method of  claim 1 , wherein a stimulation composition comprising GnRH or a GnRH agonist, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the pediatric patient for measuring the peak stimulated blood serum LH concentration within the pediatric patient prior to administration of the extended release composition to confirm a baseline peak stimulated blood serum LH concentration. 
     
     
         7 . The method of  claim 6 , wherein the stimulation composition comprises at least one GnRH agonist or pharmaceutically salt thereof selected from a group consisting of leuprolide, gonadorelin, goserelin, histrelin, nafarelin, buserelin, and triptorelin. 
     
     
         8 . The method of  claim 7 , wherein the stimulation composition comprises a leuprolide acetate solution administered subcutaneously at a dose of about 10 μg to about 20 per kg of the pediatric patient's body weight or at a dose of about 500 μg to about 1000 μg total. 
     
     
         9 . The method of  claim 1 , wherein a stimulation composition comprising GnRH or a GnRH agonist, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the pediatric patient for measuring the peak stimulated blood serum LH concentration within the pediatric patient at about three to about six months after administering the extended release composition to confirm suppression of peak stimulated blood serum LH concentration to a pre-pubertal level of <4 IU/L. 
     
     
         10 . The method of  claim 9 , wherein the stimulation composition comprises at least one GnRH agonist or pharmaceutically salt thereof selected from a group consisting of leuprolide, gonadorelin, goserelin, histrelin, nafarelin, buserelin, and triptorelin. 
     
     
         11 . The method of  claim 10 , wherein the stimulation composition comprises a leuprolide acetate solution administered subcutaneously at a dose of about 10 μg to about 20 per kg of the pediatric patient's body weight or at a dose of about 500 μg to about 1000 μg total. 
     
     
         12 . The method of  claim 1 , wherein the organic solvent is N-methyl-2-pyrrolidone (NMP). 
     
     
         13 . The method of  claim 1 , further comprising measuring the peak stimulated blood serum concentration levels of one or more CPP-associated hormones selected from the group consisting of follicle stimulating hormone (FSH), testosterone, and estradiol. 
     
     
         14 . The method of  claim 13 , wherein administration of the extended release composition reduces a peak stimulated blood serum FSH to a concentration of <2.5 IU/L. 
     
     
         15 . The method of  claim 13 , wherein administration of the extended release composition reduces a peak stimulated blood serum estradiol in a female pediatric patient to a concentration of <73.4 pmol/L (<20 pg/mL). 
     
     
         16 . The method of  claim 13 , wherein administration of the extended release composition reduces a peak stimulated blood serum testosterone in a male pediatric patient to a concentration of <1 nmol/L (<28.8 ng/dL). 
     
     
         17 . The method of  claim 1 , wherein a dose of the extended release composition comprises:
 a. about 165 mg of N-methyl-2-pyrrolidone (NMP);   b. about 165 mg of about 85:15 poly(DL lactide-co-glycolide) (PLG) copolymer segment; and   c. about 45 mg of leuprolide acetate.   
     
     
         18 . The method of  claim 1 , wherein the biodegradable polymer has a weight average molecular weight of between 20-26 kDa. 
     
     
         19 . The method of  claim 1 , wherein the biodegradable polymer comprises a polymer of the Formula:
   HO—(P)—C(═O)O—Ra—O(O═)C—(P)—OH
   
       wherein, Ra is an alkane diradical comprising about 4 to about 8 carbons and is a residue of an alkane diol; and 
       wherein, P are copolymer segments selected from poly(lactide-co-glycolide) (PLG) copolymer segments, poly(lactic acid-co-glycolic acid) (PLGA) copolymer segments, or a combination thereof. 
     
     
         20 . The method of  claim 1 , wherein the extended release composition reduces the mean bone growth velocity in the pediatric patient with CPP by about 25% over about a twelve-month treatment period. 
     
     
         21 . The method of  claim 1 , wherein administration of the extended release composition reduces the pediatric patient's mean ratio of bone age to chronological age at the time of measurement by about 5% over about a twelve-month treatment period. 
     
     
         22 . The method of  claim 1 , wherein the extended release composition comprises an injection dose volume of about 0.5 mL or less. 
     
     
         23 . The method of  claim 22 , wherein the extended release composition comprises an injection dose volume of about 0.375 mL. 
     
     
         24 . The method of  claim 1 , wherein the pediatric patient with CPP is treated with the extended release composition for a time period of about 6 months, of about 12 months, of about 18 months, of about 24 months, or longer. 
     
     
         25 . The method of  claim 1 , wherein the extended release composition is provided in a two-syringe system comprising:
 a. a first syringe containing about 45 mg of lyophilized leuprolide acetate or an equivalent amount of a different pharmaceutically acceptable salt of leuprolide;   b. a second syringe containing a solution of about 165 mg of about 85:15 poly(lactide-co-glycolide) (PLG) copolymer segment dissolved in about 165 mg of N-methyl-2-pyrrolidone (NMP); and   
       wherein, the first syringe is connected to the second syringe such that a passageway is formed between the first syringe and the second syringe to allow the passage of a flowable composition from one syringe to the other syringe; and 
       wherein the extended release composition is prepared by continuously mixing the contents of the second syringe back and forth into the contents of the first syringe of the connected two-syringe system for at least about 45 seconds to about at least 60 seconds or longer to form a uniform suspension. 
     
     
         26 . A method of treating a pediatric patient 2 years of age and older with CPP, the method comprising the steps of:
 (a) administering an injection of a stimulation composition comprising GnRH or a GnRH agonist, or a pharmaceutically acceptable salt thereof, to a pediatric patient 2 years of age or older who has CPP, wherein a blood sample from the pediatric patient is obtained within about at least thirty minutes of administering the stimulation composition for measuring a peak stimulated blood serum LH concentration;   (b) administering a subcutaneous dose of an extended release composition effective to treat CPP for about six months, if the pediatric patient has a peak stimulated blood serum LH concentration of >5 IU/L, wherein the extended release composition comprises:
 i. N-methyl-2-pyrrolidone (NMP); 
 ii. leuprolide or a pharmaceutically acceptable salt thereof; and 
 iii. a biodegradable polymer comprising polymer segments selected from 85:15 poly(lactide-co-glycolide) (PLG) copolymer segments, 85:15 poly(lactic acid-co-glycolic acid) (PLGA) copolymer segments, or a combination thereof, wherein one distal end group of the polymer is hydroxyl-terminated and the other distal end group of the polymer is either hydroxyl-terminated or ester-terminated; 
   (c) administering an additional injection of the stimulation composition to the pediatric patient at about three to about six months after administering the extended release composition of step (b) to confirm suppression of blood serum LH concentration to pre-pubertal level of <4 IU/L, wherein a blood sample from the pediatric patient is obtained within about at least thirty minutes of administering the subsequent stimulation composition for measuring a peak stimulated blood serum LH concentration; and   (d) repeating steps (b) and (c) as necessary to treat CPP if the peak stimulated blood serum LH concentration of step (c) at about three to about six months after step (b) of administering is <4 IU/L;   
       wherein the dose of the extended release composition is not individualized for the pediatric patient; 
       wherein upon contact of the extended release composition with a bodily fluid, the solvent dissipates and an in situ solid depot forms; and
 wherein the extended release formulation reduces the peak stimulated blood serum LH concentration of the pediatric patient to a pre-pubertal concentration level of <4 IU/L. 
 
     
     
         27 . A kit comprising:
 (a) at least one dose of an injectable stimulation composition comprising a solution of GnRH or a GnRH agonist, or a pharmaceutically acceptable salt thereof, effective for measuring the peak stimulated blood serum LH concentration within a pediatric patient 2 years of age or older who has CPP;   (b) at least one dose of an injectable extended release composition effective for the treatment of CPP in the pediatric patient by reducing the peak stimulated blood serum LH concentration to a pre-pubertal concentration level of <4 IU/L when administered about once every six months and comprising:
 i. N-methyl-2-pyrrolidone (NMP); 
 ii. about 40 mg to about 50 mg of leuprolide acetate or an equivalent amount of a different pharmaceutically acceptable salt of leuprolide; 
 iii. a biodegradable polymer comprising polymer segments selected from 85/15 poly(lactide-co-glycolide) (PLG) copolymer segments, 85/15 poly(lactic acid-co-glycolic acid) (PLGA) copolymer segments, poly(lactide) (PL) polymer segments, poly(lactic acid) (PLA) polymer segments, or a combination thereof, wherein one distal end group of the polymer is hydroxyl-terminated and the other distal end group of the polymer is either hydroxyl-terminated or ester-terminated; wherein upon contact of the extended release composition with a bodily fluid, NMP dissipates and an in situ solid depot forms; and 
   (c) instructions for the use thereof for treating CPP in the pediatric patient.