Controlled release polymeric compositions of bone growth promoting compounds

Abstract

The present invention is directed to an improved system for controlled release of a bone growth promoting compound and to a flowable composition for its formation. The flowable composition is composed of a bone growth promoting compound, a thermoplastic polymer and an organic solvent. The flowable composition is capable of forming a biodegradable and/or bioerodible microporous, solid polymer matrix. The matrix is useful as an implant in patients (humans and animals) for delivery of a bone growth promoting compound to certain tissues.

1 . A pharmaceutical composition suitable for in situ formation of an implant in a patient comprising: 
 (a) a pharmaceutically acceptable, biodegradable thermoplastic polymer or copolymer that is insoluble in aqueous or body fluid;    (b) a biocompatible organic solvent which solubilizes the thermoplastic polymer, is dispersible in situ in body fluid, is highly soluble in water and is capable of dissipating from the polymer system into surrounding tissue fluid whereupon the thermoplastic polymer forms the implant; and    (c) a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 
 (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid;  
 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid; and  
 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid.  
   
     
     
         2 . The composition of  claim 1  wherein the composition forms a controlled release implant at or near the site of local administration.  
     
     
         3 . The composition of  claim 1  wherein the composition forms a controlled release implant at or near the site of the bone fracture, bone injury or bone defect.  
     
     
         4 . The composition of  claim 1  wherein the compound is the sodium salt of (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.  
     
     
         5 . The composition of  claim 1  wherein the compound is the free acid of (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.  
     
     
         6 . The composition of  claim 4  wherein the amount of the compound is between about 5 to about 50 mgA/ml of the composition.  
     
     
         7 . The composition of  claim 6  wherein the amount of the compound is about 5, 10 or 50 mgA/ml of the composition.  
     
     
         8 . The composition of  claim 1  wherein the polymer is selected from the group consisting of polylactides, polyglycolides and copolymers thereof.  
     
     
         9 . The composition of  claim 8  wherein the copolymer has an inherent viscosity of about 0.20 dl/g to about 0.40 dl/g.  
     
     
         10 . The composition of  claim 9  wherein the copolymer has an inherent viscosity of about 0.20 dl/g.  
     
     
         11 . The composition of  claim 8  wherein the copolymer is poly-lactic-co-glycolic acid (PLGH).  
     
     
         12 . The composition of  claim 11  wherein the ratio of lactic acid to glycolic acid is about 1 to about 1.  
     
     
         13 . The composition of  claim 8  wherein the copolymer is polyethylene glycol (PEG) end-capped poly-lactic-co-glycolic acid (PLGH).  
     
     
         14 . The composition of  claim 13  wherein the weight % of PEG to PLGH is between about 3 to about 5%.  
     
     
         15 . The composition of  claim 1  wherein the solvent is N-methyl-2-pyrrolidone (NMP).  
     
     
         16 . The composition of  claim 1  wherein the copolymer is poly-lactic-co-glycolic acid (PLGH) and wherein the solvent is N-methyl-2-pyrrolidone (NMP).  
     
     
         17 . The composition of  claim 16  wherein the weight percentage of PLGH to NMP in solution is between about 30% and about 60% of PLGH to between about 70% and about 40% of NMP.  
     
     
         18 . The composition of  claim 17  wherein the weight percentage of PLGH to NMP in solution is selected from the following: 
 about 37% PLGH to about 63% NMP; about 45% PLGH to about 55% NMP; about 50% PLGH to about 50% NMP; and about 55% PLGH to about 45% NMP.  
 
     
     
         19 . The composition of  claim 18  wherein the weight percentage of PLGH to NMP in solution is about 50% PLGH to about 50% NMP.  
     
     
         20 . A pharmaceutical kit suitable for in situ formation of a biodegradable implant in the body of a patient, which comprises: 
 A) a device containing a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 
 (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid;  
 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid; and  
 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid; and  
   B) a device containing a flowable composition of a biodegradable, biocompatible, pharmaceutically acceptable thermoplastic polymer that is insoluble in aqueous or body fluid and a pharmaceutically acceptable solvent that is dispersible in situ in body fluid and is highly water soluble, wherein the concentrations and formulas of the polymer and the solvent in the flowable composition are effective to form an implant in situ when the flowable composition contacts body fluid;    C) wherein the devices have an outlet for the compound or the flowable composition, an ejector for expelling the compound or the flowable composition through the outlet and a hollow tube fitted to the outlet; and wherein the contents of the two devices are mixed together immediately prior to delivering the contents of the device containing the mixture into the body of the patient.    
     
     
         21 . The pharmaceutical kit of  claim 20  wherein the concentrations and formulas of the polymer and the solvent are effective to form a space filling implant in the body of the patient.  
     
     
         22 . The pharmaceutical kit of  claim 20  wherein the polymer is selected from the group consisting of polylactides and copolymers thereof with glycolide.  
     
     
         23 . The pharmaceutical kit of  claim 22  wherein the copolymer is poly-lactic-co-glycolic acid (PLGH).  
     
     
         24 . The pharmaceutical kit of  claim 23  wherein the ratio of lactic acid to glycolic acid is about 1 to about 1.  
     
     
         25 . The pharmaceutical kit of  claim 20  wherein the solvent is N-methyl-2-pyrrolidone (NMP).  
     
     
         26 . The pharmaceutical kit of  claim 20  wherein the compound is in the lyophilized form.  
     
     
         27 . A method of forming an implant in-situ, in a living body, comprising the steps of: 
 (a) dissolving a non-reactive, water-insoluble biodegradable polymer in a biocompatible, highly water soluble organic solvent that is dispersible in body fluid in situ to form a flowable composition;    (b) adding an effective amount of a compound to the flowable composition to provide a pharmaceutical composition;    (c) placing the pharmaceutical composition within the body; and    (d) allowing the solvent to dissipate to produce a solid or gel implant which releases the compound by diffusion, erosion or a combination of diffusion and erosion as the implant biodegrades;    wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
 (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid;  
 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid; and  
 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid;  
   wherein the polymer is selected from the group consisting of polylactides and copolymers thereof with glycolide; and    wherein the solvent is N-methyl-2-pyrrolidone (NMP).    
     
     
         28 . A method of  claim 27  wherein the copolymer is poly-lactic-co-glycolic acid (PLGH).  
     
     
         29 . A method of  claim 27  further comprising delivering said liquid in-situ through a syringe.  
     
     
         30 . A method of  claim 27  wherein the implant is formed at or near a bone fracture, bone defect or bone injury in the body.  
     
     
         31 . A biodegradable drug delivery implant for a body produced according to the method of  claim 27 .  
     
     
         32 . A kit for achieving a therapeutic effect in a mammal which has been prescribed the joint administration of the ingredients designated as (1) and (2) below, each ingredient forming a portion of said kit, comprising in association 
 (1) a therapeutically effective amount of an active ingredient, said active ingredient being (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid; or 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;    (2) a flowable composition of a biodegradable, biocompatible, pharmaceutically acceptable thermoplastic polymer that is insoluble in aqueous or body fluid and a pharmaceutically acceptable, highly water soluble solvent that is dispersible in situ in body fluid, wherein the concentrations and formulas of the polymer and the solvent in the composition are effective to form an implant in situ when said composition contacts body fluid; in a second unit dosage form; and    (3) directions for the administration of the ingredients (1) and (2) in a manner to achieve the desired therapeutic effect.    
     
     
         33 . A kit of  claim 32  wherein the active ingredient is the sodium salt of (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.  
     
     
         34 . A kit of  claim 32  wherein the active ingredient is the free acid of (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.  
     
     
         35 . A kit of  claim 32  wherein the polymer is selected from the group consisting of polylactides, polyglycolides and copolymers thereof.  
     
     
         36 . A kit of  claim 35  wherein the polymer is selected from the group consisting of polylactides and copolymers thereof with glycolide.  
     
     
         37 . A kit of  claim 36  wherein the copolymer is poly-lactic-co-glycolic acid (PLGH).  
     
     
         38 . A kit of  claim 37  wherein the ratio of lactic acid to glycolic acid is about 1 to about 1.  
     
     
         39 . A kit of  claim 32  wherein the solvent is N-methyl-2-pyrrolidone (NMP).  
     
     
         40 . A kit of  claim 32  wherein the compound is in the lyophilized form.