Stabilized injectable suspension of a steroidal drug

Abstract

A parenterally deliverable composition is provided, comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount. The aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation. The composition further comprises, as a component thereof or as an adjunct thereto, means for protecting the oxidative degradation susceptible agent from oxidative degradation.

What is claimed is:  
     
         1 . A parenterally deliverable composition comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount, wherein: 
 (a) the aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation; and    (b) the composition further comprises, as a component thereof or as an adjunct there to, means for protecting the oxidative degradation susceptible agent from oxidative degradation.    
     
     
         2 . The composition of  claim 1  wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.  
     
     
         3 . The composition of  claim 1  wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.  
     
     
         4 . The composition of  claim 3  wherein the polyoxyethylene surfactant is a polysorbate.  
     
     
         5 . The composition of  claim 3  wherein the polyoxyethylene surfactant is polysorbate 80.  
     
     
         6 . The composition of  claim 5  wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.  
     
     
         7 . The composition of  claim 5  wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.  
     
     
         8 . The composition of  claim 1  wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.  
     
     
         9 . The composition of  claim 1  wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.  
     
     
         10 . The composition of  claim 1  wherein the steroidal drug is medroxyprogesterone acetate.  
     
     
         11 . The composition of  claim 10  wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.  
     
     
         12 . The composition of  claim 10  wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.  
     
     
         13 . The composition of  claim 10  wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.  
     
     
         14 . The composition of  claim 1  wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises an antioxidant present as a component of the composition.  
     
     
         15 . The composition of  claim 1  wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises a chelating agent present as a component of the composition.  
     
     
         16 . The composition of  claim 1  wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises an oxygen-depleted atmosphere in headspace overlying the composition.  
     
     
         17 . The composition of  claim 16  wherein said atmosphere comprises less than about 5% oxygen.  
     
     
         18 . The composition of  claim 17  wherein said atmosphere consists essentially of nitrogen.  
     
     
         19 . A parenterally deliverable aqueous suspension composition comprising: 
 (a) medroxyprogesterone acetate, 100-200 mg/ml;    (b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;    (c) polysorbate 80, 2-4 mg/ml;    (d) sodium chloride, 6-12 mg/ml; and    (e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total; said composition having an oxygen-depleted atmosphere in headspace overlying the composition.    
     
     
         20 . The composition of  claim 19  comprising: 
 (a) medroxyprogesterone acetate, about 150 mg/ml;  
 (b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;  
 (c) polysorbate 80, about 2.5 mg/ml;  
 (d) sodium chloride, about 9 mg/ml;  
 (e) methylparaben, about 1.5 mg/ml;  
 (f) propylparaben, about 0.15 mg/ml; and  
 (g) water for injection, q.s.  
 
     
     
         21 . The composition of  claim 19  comprising, in a volume of about 0.65 ml: 
 (a) medroxyprogesterone acetate, about 104 mg;  
 (b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;  
 (c) polysorbate 80, about 1.95 mg;  
 (d) sodium chloride, about 5.2 mg;  
 (e) methylparaben, about 1.04 mg;  
 (f) propylparaben, about 0.10 mg;  
 (g) monobasic sodium phosphate monohydrate, about 0.45 mg;  
 (h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;  
 (i) L-methionine, about 0.98 mg;  
 (j) polyvinylpyrrolidone K17, about 3.25 mg; and  
 (k) water for injection, q.s.  
 
     
     
         22 . An article of manufacture comprising a sealed vessel having substantially oxygen-impermeable walls and a substantially oxygen-impermeable seal, and having contained therewithin: 
 (a) a parenterally deliverable aqueous suspension that comprises (i) a steroidal drug in a therapeutically effective amount and (ii) one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation; and    (b) an oxygen-depleted atmosphere in headspace overlying the composition.    
     
     
         23 . The article of  claim 22  wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.  
     
     
         24 . The article of  claim 22  wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.  
     
     
         25 . The article of  claim 24  wherein the polyoxyethylene surfactant is a polysorbate.  
     
     
         26 . The article of  claim 24  wherein the polyoxyethylene surfactant is polysorbate 80.  
     
     
         27 . The article of  claim 26  wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.  
     
     
         28 . The article of  claim 26  wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.  
     
     
         29 . The article of  claim 22  wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.  
     
     
         30 . The article of  claim 22  wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.  
     
     
         31 . The article of  claim 22  wherein the steroidal drug is medroxyprogesterone acetate.  
     
     
         32 . The article of  claim 31  wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.  
     
     
         33 . The article of  claim 31  wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.  
     
     
         34 . The article of  claim 31  wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.  
     
     
         35 . The article of  claim 22  wherein said atmosphere comprises less than about 5% oxygen.  
     
     
         36 . The article of  claim 22  wherein said atmosphere consists essentially of nitrogen.  
     
     
         37 . The article of  claim 22  wherein the parenterally deliverable aqueous suspension comprises: 
 (a) medroxyprogesterone acetate, 100-200 mg/ml;  
 (b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;  
 (c) polysorbate 80, 2-4 mg/ml;  
 (d) sodium chloride, 6-12 mg/ml; and  
 (e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total.  
 
     
     
         38 . The article of  claim 22  wherein the parenterally deliverable aqueous suspension comprises: 
 (a) medroxyprogesterone acetate, about 150 mg/ml;  
 (b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;  
 (c) polysorbate 80, about 2.5 mg/ml;  
 (d) sodium chloride, about 9 mg/ml;  
 (e) methylparaben, about 1.5 mg/ml;  
 (f) propylparaben, about 0.15 mg/ml; and  
 (f) water for injection, q.s.  
 
     
     
         39 . The article of  claim 22  wherein the parenterally deliverable aqueous suspension comprises, in a volume of about 0.65 ml: 
 (a) medroxyprogesterone acetate, about 104 mg;  
 (b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;  
 (c) polysorbate 80, about 1.95 mg;  
 (d) sodium chloride, about 5.2 mg;  
 (e) methylparaben, about 1.04 mg;  
 (f) propylparaben, about 0.10 mg;  
 (g) monobasic sodium phosphate monohydrate, about 0.45 mg;  
 (h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;  
 (i) L-methionine, about 0.98 mg;  
 (j) polyvinylpyrrolidone K17, about 3.25 mg; and  
 (k) water for injection, q.s.  
 
     
     
         40 . An article of manufacture comprising a vial having 
 (a) a first chamber that is substantially filled with a parenterally deliverable aqueous suspension that comprises (i) a steroidal drug in a therapeutically effective amount and (ii) one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation,    (b) a second chamber that is substantially empty but for a gaseous medium;    (c) a septum separating the first and second chambers and impermeable to contents thereof; and    (d) actuating means effective to bring the aqueous suspension and the gaseous medium in to contact by breach of the septum such that the gaseous medium acts as an effective headspace for agitation of the aqueous suspension.    
     
     
         41 . The article of  claim 40  wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.  
     
     
         42 . The article of  claim 40  wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.  
     
     
         43 . The article of  claim 42  wherein the polyoxyethylene surfactant is a polysorbate.  
     
     
         44 . The article of  claim 42  wherein the polyoxyethylene surfactant is polysorbate 80.  
     
     
         45 . The article of  claim 44  wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.  
     
     
         46 . The article of  claim 44  wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.  
     
     
         47 . The article of  claim 40  wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.  
     
     
         48 . The article of  claim 40  wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.  
     
     
         49 . The article of  claim 40  wherein the steroidal drug is medroxyprogesterone acetate.  
     
     
         50 . The article of  claim 49  wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.  
     
     
         51 . The article of  claim 49  wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.  
     
     
         52 . The article of  claim 49  wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.  
     
     
         53 . The article of  claim 40  wherein the parenterally deliverable aqueous suspension comprises: 
 (a) medroxyprogesterone acetate, 100-200 mg/ml;  
 (b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;  
 (c) polysorbate 80, 2-4 mg/ml;  
 (d) sodium chloride, 6-12 mg/ml; and  
 (e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total.  
 
     
     
         54 . The article of  claim 40  wherein the parenterally deliverable aqueous suspension comprises: 
 (a) medroxyprogesterone acetate, about 150 mg/ml;  
 (b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;  
 (c) polysorbate 80, about 2.5 mg/ml;  
 (d) sodium chloride, about 9 mg/ml;  
 (e) methylparaben, about 1.5 mg/ml;  
 (f) propylparaben, about 0.15 mg/ml; and  
 (g) water for injection, q.s.  
 
     
     
         55 . The article of  claim 40  wherein the parenterally deliverable aqueous suspension comprises, in a volume of about 0.65 ml: 
 (a) medroxyprogesterone acetate, about 104 mg;  
 (b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;  
 (c) polysorbate 80, about 1.95 mg;  
 (d) sodium chloride, about 5.2 mg;  
 (e) methylparaben, about 1.04 mg;  
 (f) propylparaben, about 0.10 mg;  
 (g) monobasic sodium phosphate monohydrate, about 0.45 mg;  
 (h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;  
 (i) L-methionine, about 0.98 mg;  
 (j) polyvinylpyrrolidone K17, about 3.25 mg; and  
 (k) water for injection, q.s.