Solid salt form of alpha-6-mpeg6-o-hydroxycodone as opioid agonists and uses thereof

Abstract

Solid forms of certain opioid agonists are provided herein. Methods of preparing the solid forms, methods of using the solid forms, and pharmaceutical compositions comprising the solid forms are also provided herein.

What is claimed is: 
     
         1 . A solid salt form of α-6-mPEG 6 -O-hydroxycodone. 
     
     
         2 . The solid salt form of α-6-mPEG 6 -O-hydroxycodone of  claim 1 , wherein the salt form is a disordered crystalline form. 
     
     
         3 . The solid salt form of α-6-mPEG 6 -O-hydroxycodone of  claim 1 , wherein the salt form is a crystalline form. 
     
     
         4 . The solid salt form of any one of the preceding claims, wherein the solid salt form is α-6-mPEG 6 -O-hydroxycodone phosphate salt. 
     
     
         5 . The solid salt form of any one of the preceding claims, wherein the α-6-mPEG 6 -O-hydroxycodone phosphate salt is a monophosphate salt. 
     
     
         6 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction peak values comprising: 2.0±0.2, 15.0±0.2, and 17.0±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         7 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction peak values comprising: 2.0±0.2, 5.5±0.2, 15.0±0.2, 17.0±0.2, and 20.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         8 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction peak values comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         9 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction peak values comprising: 2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         10 . The solid form of any one of the preceding claims, wherein the solid salt form has at least one X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         11 . The solid form of any one of the preceding claims, wherein the solid salt form has at least two X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         12 . The solid form of any one of the preceding claims, wherein the solid salt form has at least three X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         13 . The solid form of any one of the preceding claims, wherein the solid salt form has at least four X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         14 . The solid form of any one of the preceding claims, wherein the solid salt form has at least five X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         15 . The solid form of any one of the preceding claims, wherein the solid salt form has at least six X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         16 . The solid form of any one of the preceding claims, wherein the solid salt form has at least seven X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         17 . The solid form of any one of the preceding claims, wherein the solid salt form has at least eight X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         18 . The solid form of any one of the preceding claims, wherein the solid salt form has at least nine X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         19 . The solid form of any one of the preceding claims, wherein the solid salt form has at least ten X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         20 . The solid form of any one of the preceding claims, wherein the solid salt form has at least eleven X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         21 . The solid form of any one of the preceding claims, wherein the solid salt form has at least twelve X-ray powder diffraction peak values selected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         22 . The solid form of any one of the preceding claims, wherein the solid salt form has at least thirteen X-ray powder diffraction peak value selected from the group comprising: 2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         23 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction two theta peak values substantially similar to those of  FIG. 1 . 
     
     
         24 . The solid salt form of any one of the preceding claims, wherein the solid salt form has X-ray powder diffraction two theta peak values substantially similar to any one of those of  FIG. 16 . 
     
     
         25 . The solid salt form of any one of the preceding claims, wherein the α-6-mPEG 6 -O-hydroxycodone phosphate salt exhibits a first broad endothermic peak over a range of about 10° C. to about 140° C.; a second endothermic peak at about 160° C. to about 164° C. and a third endothermic peak at about 170° C. to about 173° C. on a differential scanning calorimeter. 
     
     
         26 . The solid salt form of any one of the preceding claims, wherein the solid salt form exhibits an endothermic peak as measured by a differential scanning calorimeter with an onset of about 174° C. to about 179° C. and a peak from about 177° C. to about 181° C. 
     
     
         27 . The solid salt form of any one of the preceding claims, wherein the solid salt form exhibits an endothermic peak as measured by a differential scanning calorimeter with an onset of about 175° C. to about 178° C. and a peak from about 178° C. to about 180° C. 
     
     
         28 . The solid salt form of any one of the preceding claims, wherein the solid salt form has a particle size distribution wherein DV[10] is about 3 μm to about 15 μm; DV[50] is about 40 μm to about 60 μm; and DV[90] is about 90 μm to about 120 μm. 
     
     
         29 . The solid salt form of any one of the preceding claims, wherein the solid salt form has a particle size distribution wherein DV[10] is about 5 μm to about 13 μm; DV[50] is about 45 μm to about 55 μm; and DV[90] is about 90 μm to about 115 μm. 
     
     
         30 . The solid salt form of any one of the preceding claims, wherein the solid salt form has a particle size distribution wherein DV[10] is about 6 μm to about 11 μm; DV[50] is about 45 μm to about 55 μm; and DV[90] is about 90 μm to about 112 μm. 
     
     
         31 . The solid salt form of any one of the preceding claims, wherein the solid salt form has a particle size distribution wherein DV[10] is about 7 μm to about 9 μm; DV[50] is about 47 μm to about 53 μm; and DV[90] is about 92 μm to about 109 μm. 
     
     
         32 . A method of preparing the solid form of α-6-mPEG 6 -O-hydroxycodone phosphate of any one of the preceding claims, comprising:
 dissolving α-6-mPEG 6 -O-hydroxycodone free base in a mixture of a first solvent and a second solvent; combining the α-6-mPEG 6 -O-hydroxycodone solution with a solution of phosphoric acid in a third solvent and fourth solvent; combining the α-6-mPEG 6 -O-hydroxycodone phosphoric acid solution with a mixture fifth solvent and a sixth solvent to form a slurry; filtering the slurry to yield the α-6-mPEG 6 -O-hydroxycodone phosphate salt in solid form. 
 
     
     
         33 . A method of preparing the solid form of α-6-mPEG 6 -O-hydroxycodone phosphate of any one of the preceding claims, comprising:
 dissolving α-6-mPEG 6 -O-hydroxycodone free base in about 2 relative volumes of a mixture methanol and tert-butyl methyl ether (2:1 ratio of methanol to tert-butyl methyl ether); 
 combining the α-6-mPEG 6 -O-hydroxycodone solution with a solution of phosphoric acid in about 1.2 relative volumes of a mixture methanol and tert-butyl methyl ether (2:1 ratio of methanol to tert-butyl methyl ether); 
 combining the α-6-mPEG 6 -O-hydroxycodone phosphoric acid solution with about 14 relative volumes of a mixture of heptanes and tert-butyl methyl ether (4:1 ratio of heptanes to tert-butyl methyl ether) to form a slurry; 
 filtering the slurry to yield the α-6-mPEG 6 -O-hydroxycodone phosphate salt in solid form. 
 
     
     
         34 . The method of  claim 33 , wherein the α-6-mPEG 6 -O-hydroxycodone phosphoric acid solution is combined with the mixture of heptanes and tert-butyl methyl ether over about 1 to about 3 hours. 
     
     
         35 . A method of preparing the solid form of α-6-mPEG 6 -O-hydroxycodone phosphate of any one of the preceding claims, comprising dissolving α-6-mPEG 6 -O-hydroxycodone free base in a mixture of tert-butyl methyl ether and heptanes; adding phosphoric acid to form a slurry; stirring the slurry, and filtering to recover the solid α-6-mPEG 6 -O-hydroxycodone phosphate salt. 
     
     
         36 . The method of  claim 35 , wherein the phosphoric acid is added over a time of about 30 minutes to about 3 hours. 
     
     
         37 . The method of  claim 35  or  36 , wherein the phosphoric acid is added over about 1 hour. 
     
     
         38 . The method of any one of  claims 35  to  37 , wherein the phosphoric acid is added at about ten minute intervals over the course of about 30 minutes to about 3 hours. 
     
     
         39 . The method of any one of  claims 35  to  38 , wherein the phosphoric acid is added at about ten minute intervals over the course of about 1 hour. 
     
     
         40 . The method of any one of  claims 35  to  39 , wherein the solid α-6-mPEG 6 -O-hydroxycodone phosphate salt is washed with tert-butyl methyl ether. 
     
     
         41 . The method of any one of  claims 35  to  40 , wherein the amount of α-6-mPEG 6 -O-hydroxycodone free base is “X” kilograms; the volume of tert-butyl methyl ether is 5*“X” liters; and the volume of heptanes is “X” liters. 
     
     
         42 . The method of any one of  claims 35  to  41 , wherein after the phosphoric acid has been added, the solution is allowed to stir for about 1 to about 4 hours. 
     
     
         43 . The method of any one of  claims 35  to  42 , wherein after the phosphoric acid has been added, the solution is allowed to stir for about 2 hours. 
     
     
         44 . The method of any one of  claims 35  to  43 , wherein the solution of α-6-mPEG 6 -O-hydroxycodone free base is maintained at a temperature of about 15° C. 
     
     
         45 . The method of any one of  claims 35  to  44 , wherein the solution of α-6-mPEG 6 -O-hydroxycodone is maintained at a temperature of about 15° C. while the phosphoric acid is being added. 
     
     
         46 . The method of any one of  claims 35  to  45 , wherein the solution of α-6-mPEG 6 -O-hydroxycodone is maintained at a temperature of about 15° C. throughout the addition of phosphoric acid. 
     
     
         47 . The method of any one of  claims 35  to  46 , wherein the reaction mixture contains water. 
     
     
         48 . The method of any one of  claims 35  to  47 , wherein the amount of water is about 0.4-0.8 wt %. 
     
     
         49 . The method of any one of  claims 35  to  48 , wherein the amount of phosphoric acid is about 0.8 molar equivalents to about 1.2 molar equivalents. 
     
     
         50 . The method of any one of  claims 35  to  49 , wherein the amount of phosphoric acid is about 0.9 molar equivalents to about 1.1 molar equivalents. 
     
     
         51 . The method of any one of  claims 35  to  50 , wherein the amount of phosphoric acid is about 1.0 molar equivalents. 
     
     
         52 . The method of any one of  claims 35  to  51 , wherein the phosphoric acid is an aqueous solution of phosphoric acid. 
     
     
         53 . A solid α-6-mPEG 6 -O-hydroxycodone phosphate salt, prepared according to the method of any one of  claims 32  to  52 . 
     
     
         54 . A crystalline solid α-6-mPEG 6 -O-hydroxycodone phosphate salt, prepared according to the method of any one of  claims 32  to  52 . 
     
     
         55 . A disordered crystalline solid α-6-mPEG 6 -O-hydroxycodone phosphate salt, prepared according to the method of any one of  claims 32  to  52 . 
     
     
         56 . The solid salt form of  claim 1  or  claim 2 , wherein the solid salt form is α-6-mPEG 6 -O-hydroxycodone D-tartrate salt. 
     
     
         57 . The solid salt form of  claim 56 , wherein the α-6-mPEG 6 -O-hydroxycodone D-tartrate salt is a monotartrate salt. 
     
     
         58 . The solid salt form of  claim 56  or  claim 57 , wherein the solid form of α-6-mPEG 6 -O-hydroxycodone D-tartrate salt has X-ray powder diffraction peak values comprising: 2.5±0.2 and 15.0±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         59 . The solid salt form of any one of  claims 56  to  58 , wherein the solid form of α-6-mPEG 6 -O-hydroxycodone D-tartrate salt has X-ray powder diffraction peak values comprising: 2.5±0.2, 15.0±0.2, 20.0±0.2, and 23.5±0.2 degrees two theta, when measured with Cu Kα radiation. 
     
     
         60 . The solid salt form of any one of  claims 56  to  59 , wherein the solid salt form has X-ray powder diffraction two theta peak values substantially similar to those of  FIG. 7  and/or  FIG. 12 . 
     
     
         61 . A method of preparing the solid form of α-6-mPEG 6 -O-hydroxycodone D-tartrate of any one of  claims 1 ,  2 , and  56  to  60 , comprising:
 dissolving α-6-mPEG 6 -O-hydroxycodone free base in a first solvent; combining the α-6-mPEG 6 -O-hydroxycodone solution with a solution of D-tartaric acid in a second solvent; adding a third solvent to the α-6-mPEG 6 -O-hydroxycodone D-tartaric acid solution to form a slurry; and filtering the slurry to yield the α-6-mPEG 6 -O-hydroxycodone D-tartrate salt in solid form. 
 
     
     
         62 . A method of preparing the solid form of α-6-mPEG 6 -O-hydroxycodone D-tartrate of any one of  claims 1 ,  2 , and  56  to  60 , comprising:
 dissolving α-6-mPEG 6 -O-hydroxycodone free base in about 2 relative volumes of tetrahydrofuran; combining the α-6-mPEG 6 -O-hydroxycodone solution with a solution of D-tartaric acid in a 2 relative volumes of tetrahydrofuran; adding about 6 equivalents of heptanes to the α-6-mPEG 6 -O-hydroxycodone D-tartaric acid solution to form a slurry; and filtering the slurry to yield the α-6-mPEG 6 -O-hydroxycodone D-tartrate salt in solid form. 
 
     
     
         63 . The method of  claim 62 , wherein the heptanes are added to the α-6-mPEG 6 -O-hydroxycodone and D-tartaric acid solution over about 30 minutes. 
     
     
         64 . A solid α-6-mPEG 6 -O-hydroxycodone D-tartrate salt, prepared according to the method of any one of  claims 61  to  63 . 
     
     
         65 . The solid salt form of any one of  claims 56 - 60  and  64 , wherein the solid salt form exhibits a first broad endothermic peak over a range of about 40° C. to about 110° C. and a second endothermic peak at about 126° C. on a differential scanning calorimeter. 
     
     
         66 . A method of treating pain in a patient comprising administering a solid salt form of α-6-mPEG 6 -O-hydroxycodone of any one of the preceding claims. 
     
     
         67 . The method of  claim 66 , wherein the pain is moderate to severe pain. 
     
     
         68 . The method of  claim 66  or  67 , wherein the solid salt form of α-6-mPEG 6 -O-hydroxycodone is administered as necessary over a 24 hour period to manage moderate to severe pain. 
     
     
         69 . A pharmaceutical composition comprising the solid salt form of α-6-mPEG 6 -O-hydroxycodone of any one of the preceding claims and at least one pharmaceutically acceptable excipient. 
     
     
         70 . The pharmaceutical composition of  claim 69 , wherein the pharmaceutical composition is a tablet. 
     
     
         71 . The pharmaceutical composition of  claim 69  or  claim 70 , wherein the tablet is a film coated tablet. 
     
     
         72 . The pharmaceutical composition of  claim 70  or  claim 71 , wherein the tablet has a loading of the solid salt form of α-6-mPEG 6 -O-hydroxycodone of about 10 percent to about 50 percent. 
     
     
         73 . The pharmaceutical composition of any one of  claims 70  to  72 , wherein the tablet has a loading of the solid salt form of α-6-mPEG 6 -O-hydroxycodone of about 20 percent to about 50 percent. 
     
     
         74 . The pharmaceutical composition of any one of  claims 70  to  73 , wherein the tablet has a loading of the solid salt form of α-6-mPEG 6 -O-hydroxycodone of about 30 percent to about 40 percent. 
     
     
         75 . The pharmaceutical composition of any one of  claims 70  to  74 , wherein the tablet has a loading of the solid salt form of α-6-mPEG 6 -O-hydroxycodone of about 35 percent. 
     
     
         76 . The pharmaceutical composition of any one of  claims 70  to  74 , wherein the tablet has a loading of the solid salt form of α-6-mPEG 6 -O-hydroxycodone of about 30 percent. 
     
     
         77 . The pharmaceutical composition of any one of  claims 70  to  76  wherein the tablet has a friability of less than about 1.0 percent. 
     
     
         78 . The pharmaceutical composition of any one of  claims 70  to  77 , wherein the tablet has a friability of less than about 0.10 percent. 
     
     
         79 . The pharmaceutical composition of any one of  claims 70  to  78 , wherein the tablet has a friability of less than about 0.05 percent. 
     
     
         80 . The pharmaceutical composition of any one of  claims 69  to  79 , wherein the solid salt form of α-6-mPEG 6 -O-hydroxycodone is α-6-mPEG 6 -O-hydroxycodone phosphate. 
     
     
         81 . The pharmaceutical composition of any one of  claims 69  to  79 , wherein the solid salt form of α-6-mPEG 6 -O-hydroxycodone is α-6-mPEG 6 -O-hydroxycodone tartrate. 
     
     
         82 . The pharmaceutical composition of any one of  claims 69  to  81 , wherein the composition comprises about 5 mg to about 1000 mg of the solid salt form of α-6-mPEG 6 -O-hydroxycodone. 
     
     
         83 . The pharmaceutical composition of any one of  claims 69  to  82 , wherein the composition comprises about 50 mg to about 500 mg of the solid salt form of α-6-mPEG 6 -O-hydroxycodone. 
     
     
         84 . The pharmaceutical composition of any one of  claims 69  to  83 , wherein the composition comprises one of more excipients selected from the group comprising dibasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. 
     
     
         85 . The pharmaceutical composition of any one of  claims 69  to  84 , the excipients comprise dibasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. 
     
     
         86 . The pharmaceutical composition of any one of  claims 70  to  85 , wherein the tablet comprises intragranular and extragranular components. 
     
     
         87 . The pharmaceutical composition of any one of  claims 70  to  85 , wherein the tablet comprises intragranular components. 
     
     
         88 . A method of treating pain in a patient, comprising administering the pharmaceutical composition of any one of  claims 69  to  87 . 
     
     
         89 . The method of  claim 88 , wherein the pain is moderate to severe pain. 
     
     
         90 . The method of  claim 90  or  89 , wherein the composition is administered as necessary over a 24 hour period to manage moderate to severe pain. 
     
     
         91 . A method of preparing free flowing solid granules comprising α-6-mPEG 6 -O-hydroxycodone or a solid α-6-mPEG 6 -O-hydroxycodone phosphate salt form. 
     
     
         92 . The solid salt form of any one of the preceding claims, having a purity of at least about 90%. 
     
     
         93 . The solid salt form of any one of the preceding claims, having a purity of at least about 95%.