Benzoic Acid, Benzoic Acid Derivatives and Heteroaryl Carboxylic Acid Conjugates of Hydrocodone, Prodrugs, Methods of Making and Uses Thereof

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

1 . A composition comprising 5 mg of benzoate-hydrocodone hydrochloride. 
     
     
         2 . The composition of  claim 1  wherein the composition is a conjugate. 
     
     
         3 . The composition of  claim 1  wherein the composition is a prodrug. 
     
     
         4 . The composition of  claim 1  wherein the 5 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 3.4 mg of hydrocodone. 
     
     
         5 . The composition of  claim 1  wherein the mean AUC 0-24h  of hydrocodone is about 70.69 hours×ng/mL±17.39 hours×ng/mL when administered orally to a human. 
     
     
         6 . The composition of  claim 1  wherein the mean AUC inf  of hydrocodone is about 79.37 hours×ng/mL±18.67 hours×ng/mL when administered orally to a human. 
     
     
         7 . The composition of  claim 1  wherein the mean C max  of hydrocodone is about 12.8 ng/mL±3.84 ng/mL when administered orally to a human. 
     
     
         8 . The composition of  claim 1  wherein the mean T max  of hydrocodone is about 1.866 hours±0.901 hours when administered orally to a human. 
     
     
         9 . The composition of  claim 1  wherein the median T max  of hydrocodone is about 1.5 hours when administered orally to a human. 
     
     
         10 . The composition of  claim 1  wherein the range of T max  of hydrocodone is from about 0.5 hours to 4 hours when administered orally to a human. 
     
     
         11 . The composition of  claim 1  wherein the mean t 1/2  of hydrocodone is about 3.79 hours±0.88 hours when administered orally to a human. 
     
     
         12 . A composition comprising 6.67 mg of benzoate-hydrocodone hydrochloride. 
     
     
         13 . The composition of  claim 12  wherein the composition is a conjugate. 
     
     
         14 . The composition of  claim 12  wherein the composition is a prodrug. 
     
     
         15 . The composition of  claim 12  wherein the 6.67 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 4.54 mg of hydrocodone 
     
     
         16 . The composition of  claim 12  wherein the mean AUC 0-24h  of hydrocodone is from about 112,088 hours×pg/mL±28,774 hours×pg/mL to about 132,618 hours×pg/mL±34,198 hours×pg/mL when administered orally to a human. 
     
     
         17 . The composition of  claim 12  wherein the mean AUC inf  of hydrocodone is from about 115,773 hours×pg/mL±29,099 hours×pg/mL to about 136,499 hours×pg/mL±34,899 hours×pg/mL when administered orally to a human. 
     
     
         18 . The composition of  claim 12  wherein the mean C max  of hydrocodone is from about 16,859 pg/mL±4,153 pg/mL to about 21,061 pg/mL±4,426 pg/mL when administered orally to a human. 
     
     
         19 . The composition of  claim 12  wherein the mean T max  of hydrocodone is from about 1.241 hours±0.394 hours to about 1.595 hours±0.922 hours when administered orally to a human. 
     
     
         20 . The composition of  claim 12  wherein the mean median T max  of hydrocodone is from about 1 hour to about 1.25 hours when administered orally to a human. 
     
     
         21 . The composition of  claim 12  wherein the mean range of T max  of hydrocodone is from about 0.5 hours to about 4 hours when administered orally to a human. 
     
     
         22 . The composition of  claim 12  wherein the mean t 1/2  of hydrocodone is from about 4.190 hours±0.638 hours to about 4.347 hours±0.681 hours when administered orally to a human. 
     
     
         23 . A composition comprising 10 mg of benzoate-hydrocodone hydrochloride. 
     
     
         24 . The composition of  claim 23  wherein the composition is a conjugate. 
     
     
         25 . The composition of  claim 23  wherein the composition is a prodrug. 
     
     
         26 . The composition of  claim 23  wherein the 10 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 6.8 mg of hydrocodone. 
     
     
         27 . The composition of  claim 23  wherein the mean AUC 0-24h  of hydrocodone is about 165.4 h×ng/mL±42.35 h×ng/mL when administered orally to a human. 
     
     
         28 . The composition of  claim 23  wherein the mean AUC inf  of hydrocodone is about 172.5 h×ng/mL±43.44 h×ng/mL hours×ng/mL when administered orally to a human. 
     
     
         29 . The composition of  claim 23  wherein the mean C max  of hydrocodone is about 24.7 ng/mL±6.43 ng/mL when administered orally to a human. 
     
     
         30 . The composition of  claim 23  wherein the mean T max  of hydrocodone is about 1.700 hours±0.880 hours when administered orally to a human. 
     
     
         31 . The composition of  claim 23  wherein the median T max  of hydrocodone is about 1.5 hours when administered orally to a human. 
     
     
         32 . The composition of  claim 23  wherein the range of T max  of hydrocodone is from about 0.5 hours to 4 hours when administered orally to a human. 
     
     
         33 . The composition of  claim 23  wherein the mean t 1/2  of hydrocodone is about 4.36 hours±0.81 hours when administered orally to a human. 
     
     
         34 . A composition comprising 13.34 mg of benzoate-hydrocodone hydrochloride. 
     
     
         35 . The composition of  claim 34  wherein the composition is a conjugate. 
     
     
         36 . The composition of  claim 34  wherein the composition is a prodrug. 
     
     
         37 . The composition of  claim 34  wherein the 13.34 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 9.08 mg of hydrocodone 
     
     
         38 . The composition of  claim 34  wherein the mean AUC 0-4h  of hydrocodone is about 92,940 hours×pg/mL±20,158 hours×pg/mL when administered orally to a human. 
     
     
         39 . The composition of  claim 34  wherein the mean AUC 0-24h  of hydrocodone is about 212,948 hours×pg/mL±52,803 hours×pg/mL when administered orally to a human. 
     
     
         40 . The composition of  claim 34  wherein the mean AUC inf  of hydrocodone is about 219,357 hours×pg/mL±57,283 hours×pg/mL when administered orally to a human. 
     
     
         41 . The composition of  claim 34  wherein the mean C max  of hydrocodone is about 33,946 pg/mL±8,407 pg/mL when administered orally to a human. 
     
     
         42 . The composition of  claim 34  wherein the mean T max  of hydrocodone is about 1.173 hours±0.709 hours when administered orally to a human. 
     
     
         43 . The composition of  claim 34  wherein the median T max  of hydrocodone is about 1.0 hour when administered orally to a human. 
     
     
         44 . The composition of  claim 34  wherein the range of T max  of hydrocodone is from about 0.5 hours to 4 hours when administered orally to a human. 
     
     
         45 . The composition of  claim 34  wherein the mean t 1/2  of hydrocodone is about 4.448 hours±0.590 hours when administered orally to a human. 
     
     
         46 . A composition comprising 6.67 mg of benzoate-hydrocodone hydrochloride and 325 mg acetaminophen. 
     
     
         47 . The composition of  claim 46  wherein the composition is a conjugate. 
     
     
         48 . The composition of  claim 46  wherein the composition is a prodrug. 
     
     
         49 . The composition of  claim 46  wherein the 6.67 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 4.54 mg of hydrocodone 
     
     
         50 . The composition of  claim 46  wherein the mean AUC 0-24h  of acetaminophen is from about 16.388 hours×μg/mL±3.987 hours×μg/mL to about 14.640 hours×μg/mL±4.424 hours×μg/mL when administered orally to a human. 
     
     
         51 . The composition of  claim 46  wherein the mean AUC inf  of acetaminophen is from about 17.220 hours×μg/mL±3.696 hours×μg/mL to about 14.683 hours×μg/mL±3.867 hours×μg/mL when administered orally to a human. 
     
     
         52 . The composition of  claim 46  wherein the mean C max  of acetaminophen is from about 3.810 μg/mL±1.301 μg/mL to about 4.067 μg/mL±1.319 μg/mL when administered orally to a human. 
     
     
         53 . The composition of  claim 46  wherein the mean T max  of acetaminophen is from about 0.717 h±0.394 hours to about 1.243 hours±1.064 hours when administered orally to a human. 
     
     
         54 . The composition of  claim 46  wherein the mean median T max  of acetaminophen is from about 0.5 hours to about 1 hour when administered orally to a human. 
     
     
         55 . The composition of  claim 46  wherein the mean range of T max  of acetaminophen is from about 0.5 hours to about 4 hours when administered orally to a human. 
     
     
         56 . The composition of  claim 46  wherein the mean t 1/2  of acetaminophen is from about 4.934 hours±0.977 hours to about 4.781 hours±1.303 hours to 5.269 hours±1.856 hours when administered orally to a human. 
     
     
         57 . A composition comprising 13.34 mg of benzoate-hydrocodone hydrochloride and 750 mg acetaminophen. 
     
     
         58 . The composition of  claim 57  wherein the composition is a conjugate. 
     
     
         59 . The composition of  claim 57  wherein the composition is a prodrug. 
     
     
         60 . The composition of  claim 57  wherein the 13.34 mg of benzoate-hydrocodone hydrochloride contains a molar equivalent of 9.08 mg of hydrocodone 
     
     
         61 . The composition of  claim 57  wherein the mean AUC 0-4h  of acetaminophen is about 17.622 hours×μg/mL±4.247 hours×μg/mL when administered orally to a human. 
     
     
         62 . The composition of  claim 57  wherein the mean AUC 0-24h  of acetaminophen is about 30.526 hours×μg/mL±12.736 hours×μg/mL when administered orally to a human. 
     
     
         63 . The composition of  claim 57  wherein the mean AUC inf  of acetaminophen is about 28.945 h×μg/mL±7.069 h×μg/mL when administered orally to a human. 
     
     
         64 . The composition of  claim 57  wherein the mean C max  of acetaminophen is about 7.951 μg/mL±2.157 μg/mL when administered orally to a human. 
     
     
         65 . The composition of  claim 57  wherein the mean T max  of acetaminophen is about 0.797 hours±0.567 hours when administered orally to a human. 
     
     
         66 . The composition of  claim 57  wherein the median T max  of acetaminophen is about 0.5 hours when administered orally to a human. 
     
     
         67 . The composition of  claim 57  wherein the range of T max  of acetaminophen is from about 0.5 hours to 3 hours when administered orally to a human. 
     
     
         68 . The composition of  claim 57  wherein the mean t 1/2  of acetaminophen is about 4.787 hours±1.210 hours when administered orally to a human.