Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester

Abstract

The present invention relates to injectable, extended-release, pharmaceutical formulations comprising a nalbuphine ester prodrug homogenously dissolved in a solution comprising a pharmaceutically acceptable oil and an oil-miscible retaining solvent, as well as manufacturing processes and medical uses of the formulations. The invention further provides methods for adjusting the duration of action of the formulations by varying the ratio of the pharmaceutically acceptable oil and the oil-miscible retaining solvent.

We claim: 
     
         1 . A pharmaceutical formulation comprising a nalbuphine ester prodrug dissolved in a pharmaceutically acceptable oil and an oil-miscible retaining solvent,
 wherein the concentration of the nalbuphine ester prodrug in the formulation is greater than the solubility of the nalbuphine ester prodrug when added to a mixture of the pharmaceutically acceptable oil and the oil-miscible retaining solvent, and/or   wherein the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is equal to or greater than about 1.1:1.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE). 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the solubility of SDE in the oil-miscible retaining solvent is equal to or greater than about 100 mg/mL. 
     
     
         4 . The pharmaceutical formulation of  claim 2 , wherein the concentration of SDE in the formulation is equal to or greater than 70 mg/mL. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein the pharmaceutically acceptable oil is soybean oil, peanut oil, sesame oil, or a mixture thereof; and the oil-miscible retaining solvent is benzyl benzoate, benzyl alcohol, or a mixture thereof. 
     
     
         6 . The pharmaceutical formulation of  claim 5 , wherein the pharmaceutically acceptable oil is sesame oil and the oil-miscible retaining solvent is benzyl benzoate. 
     
     
         7 . The pharmaceutical formulation of  claim 6 , wherein the weight ratio of benzyl benzoate to sesame oil is about 1-3:1. 
     
     
         8 . The pharmaceutical formulation of  claim 6 , wherein the weight ratio of benzyl benzoate to sesame oil is about 0.8-1.2:1. 
     
     
         9 . The pharmaceutical formulation of  claim 6 , wherein the weight ratio of benzyl benzoate to sesame oil is about 0.65-2:1. 
     
     
         10 . The pharmaceutical formulation of  claim 6 , wherein the concentration of SDE in the formulation is about 75 mg/mL, and the weight ratio of benzyl benzoate to sesame oil is about 1.12:1. 
     
     
         11 . The pharmaceutical formulation of  claim 6 , wherein the concentration of SDE in the formulation is about 80 mg/mL, and the weight ratio of benzyl benzoate to sesame oil is about 1.18:1. 
     
     
         12 . The pharmaceutical formulation of  claim 6 , wherein the duration of action of the pharmaceutical formulation is equal to or greater than about 5 days. 
     
     
         13 . The pharmaceutical formulation of  claim 6 , wherein the release period of the pharmaceutical formulation is equal to or greater than about 14 days. 
     
     
         14 . The pharmaceutical formulation of  claim 1 , wherein the formulation is suitable for administration by intramuscular or subcutaneous injection. 
     
     
         15 . The pharmaceutical formulation of  claim 1 , wherein the concentration of the nalbuphine ester prodrug is greater than the solubility of the nalbuphine ester prodrug when added to the mixture of the pharmaceutically acceptable oil and the oil-miscible retaining solvent. 
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein
 the nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE);   the pharmaceutically acceptable oil is sesame oil and the oil-miscible retaining solvent is benzyl benzoate;   the weight ratio of benzyl benzoate to sesame oil is about 0.8-1.2:1; and   the concentration of SDE in the formulation is greater than about 70 mg/mL.   
     
     
         17 . The pharmaceutical formulation of  claim 1 , wherein the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is equal to or greater than about 1.1:1. 
     
     
         18 . The pharmaceutical formulation of  claim 17 , wherein
 the nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE);   the pharmaceutically acceptable oil is sesame oil and the oil-miscible retaining solvent is benzyl benzoate;   the weight ratio of benzyl benzoate to sesame oil is about 1.1-3:1; and   the concentration of SDE in the formulation is greater than about 70 mg/mL.   
     
     
         19 . A method for preparing a pharmaceutical formulation, the method comprising the steps of:
 (1) dissolving a nalbuphine ester prodrug in an oil-miscible retaining solvent; and   (2) mixing the solution resulting from step (1) with a pharmaceutically acceptable oil to give a homogenous solution,   wherein the formulation is suitable for administration by injection.   
     
     
         20 . The method of  claim 19 , wherein the nalbuphine ester prodrug is dissolved in the solution resulting from step (2) at a concentration greater than the solubility of the nalbuphine ester prodrug when added to a mixture of the oil-miscible retaining solvent and the pharmaceutically acceptable oil. 
     
     
         21 . The method of  claim 19 , wherein the nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE). 
     
     
         22 . The method of  claim 21 , wherein the solubility of SDE in the oil-miscible retaining solvent is equal to or greater than about 100 mg/mL. 
     
     
         23 . The method of  claim 21 , wherein the concentration of SDE in the formulation is greater than about 70 mg/mL. 
     
     
         24 . The method of  claim 19 , wherein the pharmaceutically acceptable oil is soybean oil, peanut oil, sesame oil, or a mixture thereof; and the oil-miscible retaining solvent is benzyl benzoate, benzyl alcohol, or a mixture thereof. 
     
     
         25 . The method of  claim 24 , wherein the pharmaceutically acceptable oil is sesame oil and the oil-miscible retaining solvent is benzyl benzoate. 
     
     
         26 . The method of  claim 25 , wherein the weight ratio of benzyl benzoate to sesame oil is about 0.8-1.2:1. 
     
     
         27 . The method of  claim 19 , wherein the formulation is suitable for administration by intramuscular or subcutaneous injection. 
     
     
         28 . A method for treating pain, comprising administering a therapeutically effective amount of the pharmaceutical formulation of  claim 8  to a subject in need thereof,
 wherein the pharmaceutical formulation is administered by intramuscular injection 6-36 hours prior to the onset of pain symptoms. 
 
     
     
         29 . The method of  claim 28 , wherein the onset of pain symptoms is during or after a surgical operation on the subject. 
     
     
         30 . The method of  claim 28 , wherein the pharmaceutical formulation is administered to deliver a total dose of up to about 160 mg of SDE. 
     
     
         31 . A pharmaceutical formulation comprising a nalbuphine ester prodrug and a release-controlling solution, wherein the formulation is suitable for administration by injection and releases the nalbuphine ester prodrug in an extended manner. 
     
     
         32 . The pharmaceutical formulation of  claim 31 , wherein the release-controlling solution comprises a pharmaceutically acceptable oil and an oil-miscible retaining solvent. 
     
     
         33 . The pharmaceutical formulation of  claim 32 , wherein the pharmaceutically acceptable oil is soybean oil, peanut oil, sesame oil, or a mixture thereof; and the oil-miscible retaining solvent is benzyl benzoate, benzyl alcohol, or a mixture thereof. 
     
     
         34 . The pharmaceutical formulation of  claim 32 , wherein the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is greater than about 1, and the duration of action of the pharmaceutical formulation is equal to or greater than about 5 days and/or the release period of the pharmaceutical formulation is equal to or greater than about 14 days. 
     
     
         35 . The pharmaceutical formulation of  claim 32 , wherein the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is less than about 1, and the duration of action of the pharmaceutical formulation is less than about 6 days and/or the release period of the pharmaceutical formulation is less than about 14 days. 
     
     
         36 . A method for preparing an extended release formulation comprising a nalbuphine ester prodrug with a predetermined release period, comprising the steps of:
 (1) providing an oil-miscible retaining solvent and a pharmaceutically acceptable oil, wherein the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is adjusted based on the predetermined release period, and   (2) mixing the nalbuphine ester prodrug with the oil-miscible retaining solvent and the pharmaceutically acceptable oil, to give a homogeneously dissolved solution.   
     
     
         37 . The method of  claim 36 , wherein step (2) comprises first mixing the nalbuphine ester prodrug with the oil-miscible retaining solvent to give a clear solution, and then mixing the clear solution with the pharmaceutically acceptable oil. 
     
     
         38 . The method of  claim 36 , wherein step (2) comprises mixing the nalbuphine ester prodrug with a mixture of the oil-miscible retaining solvent and the pharmaceutically acceptable oil. 
     
     
         39 . The method of  claim 36 , wherein the predetermined release period is greater than about 14 days, and the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is greater than about 1. 
     
     
         40 . The method of  claim 36 , wherein the predetermined release period is less than about 14 days, and the weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is less than about 1.