Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer

Abstract

The disclosed invention is drawn to pharmaceutical tablets that provide delivery of active agents having at least three oxygen-containing groups, as well as a second active ingredient. Non-limiting examples of three oxygen-containing group active agents include guaifenesin, codeine, hydrocodone, and their pharmaceutically acceptable salts. In one embodiment, a pharmaceutical tablet for oral administration once every 12 hours is provided. The tablet includes a first active agent that is a tri-oxy active agent, a second active agent, and a release rate controlling non-ionic oxyl-containing hydrophilic polymer. The total oxyl content of the hydrophilic polymer in the tablet is about 4×10 −4 moles to about 2.0×10 −3 moles.

1 . A pharmaceutical matrix tablet for oral administration once every 12 hours, comprising:
 a first active agent that is a tri-oxy active agent,   a second active agent, and   a release rate controlling non-ionic oxyl-containing hydrophilic polymer   wherein the total oxyl content of the hydrophilic polymer in the tablet is from about 4×10 −4  moles to about 2.0×10 −3  moles, and
 wherein a single-dose administration of one or more tablets to a subject under fasted conditions provides a mean C max  for each of the first active agent and the second active agent that is 70% to 135% of a respective mean C max  provided by administering an immediate release oral dosage form to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, wherein cumulative dosage amounts administered over the 12 hour time period of each active agent in the immediate release oral dosage is equivalent to the respective amount of each active agent in the pharmaceutical tablet. 
   
     
     
         2 . The pharmaceutical tablet of  claim 1 , wherein the hydrophilic polymer is a cellulose polymer. 
     
     
         3 . The pharmaceutical tablet of  claim 2 , wherein the cellulose polymer is hydroxypropyl methyl cellulose (HPMC). 
     
     
         4 . The pharmaceutical tablet of  claim 3 , wherein the hydroxypropyl methyl cellulose has an average methoxy content of about 15 mole % to about 30 mole %. 
     
     
         5 . The pharmaceutical tablet of  claim 3 , wherein the hydroxypropyl methyl cellulose has an average methoxy content of about 18 mole % to about 25 mole %. 
     
     
         6 . The pharmaceutical tablet of  claim 3 , wherein the hydroxypropyl methyl cellulose is present in the tablet in an amount of 40 mg to about 175 mg. 
     
     
         7 . The pharmaceutical tablet of  claim 3 , wherein the hydroxypropyl methyl cellulose is present in the tablet in an amount of 60 mg to about 150 mg. 
     
     
         8 . The pharmaceutical tablet of  claim 1 , wherein the first active agent is selected from the group consisting of guaifenesin, codeine, hydrocodone, and their pharmaceutically acceptable salts. 
     
     
         9 . The pharmaceutical tablet of  claim 8 , wherein the mean C max  of the first active agent does not vary by more than 40% when administered with food as compared to administration under fasted condition. 
     
     
         10 . The pharmaceutical tablet of  claim 1 , wherein the second active agent is a tri-oxy active agent. 
     
     
         11 . The pharmaceutical tablet of  claim 1 , wherein the second active agent is a non-tri-oxy active agent. 
     
     
         12 . The pharmaceutical tablet of  claim 11 , wherein the second active agent is selected from the group consisting of chlorpheniramine, cyclopentamine, dexchlorpheniramine, diphenhydramine, brompheniramine, dexbrompheniramine, dextromethorphan tripolidine, desloratadine, cyproheptadine, phenylephrine, pyrallamine, pseudoephedrine, azalastin, loratidine, theophyline and their salts or esters thereof and combinations thereof. 
     
     
         13 . The pharmaceutical tablet of  claim 11 , wherein the second active agent is chlorpheniramine or its acceptable salt. 
     
     
         14 . The pharmaceutical tablet of  claim 1 , wherein the tablet further includes a third active agent. 
     
     
         15 . The pharmaceutical tablet of  claim 1 , wherein the third active agent is a decongestant. 
     
     
         16 . The pharmaceutical tablet of  claim 1 , wherein the first active agent is codeine. 
     
     
         17 . The pharmaceutical tablet of  claim 16 , wherein the ratio of total molar content of the oxyl groups in the hydrophilic polymer to the total molar content of the oxygen-containing groups in the codeine is about 2.5 to about 9. 
     
     
         18 . The pharmaceutical tablet of  claim 16 , wherein the codeine comprises about 25 wt % to about 30 wt % of the tablet. 
     
     
         19 . The pharmaceutical tablet of  claim 16 , wherein the second active agent is chlorpheniramine or pharmaceutically acceptable salts thereof. 
     
     
         20 . The pharmaceutical tablet of  claim 19 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., about 30% to about 40% of the amount of codeine is released in the first 0.5 to 1 hour and the amount of chlorpheniramine released in the same time is between 80% and 120% of the amount of codeine released. 
     
     
         21 . The pharmaceutical tablet of  claim 19 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50% of the amount of codeine and chlorpheniramine is about 1.5 to 3 hours. 
     
     
         22 . The pharmaceutical tablet of  claim 19 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 70% of the amount of chlorpheniramine is released in about 3 hours to 4 hours, and the amount of codeine released in the same time period is between 80% and 120% of the amount of chlorpheniramine released. 
     
     
         23 . The pharmaceutical tablet of  claim 19 , wherein the tablet further includes a third active agent that is a decongestant. 
     
     
         24 . The pharmaceutical tablet of  claim 23 , wherein the decongestant is pseudoephedrine or phenylephrine or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The pharmaceutical tablet of  claim 16 , wherein the second active agent is guaifenesin. 
     
     
         26 . The pharmaceutical tablet of  claim 25 , wherein the codeine comprises about 3.5 wt % to about 4 wt % of the tablet. 
     
     
         27 . The pharmaceutical tablet of  claim 25 , wherein the codeine is present in an amount of about 30 mg, the guaifenesin is present in an amount of about 600 mg, and the hydrophilic polymer is hydroxypropyl methyl cellulose and comprises about 8 wt % to about 20 wt % of the tablet. 
     
     
         28 . The pharmaceutical tablet of  claim 27 , wherein upon administration to a subject the tablet provides a guaifenesin C min  of about 3 ng/mL or more, at steady state. 
     
     
         29 . The pharmaceutical tablet of  claim 25 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., an amount of about 25 wt % to about 35 wt % of the guaifenesin is released after 0.5 hour to about 1 hour and an amount of codeine released in the same time is between 70% and 130% of the amount of guaifenesin released. 
     
     
         30 . The pharmaceutical tablet of  claim 25 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., time for 50% of the amount of guaifenesin and codeine is about 1.5 to 3 hours. 
     
     
         31 . The pharmaceutical tablet of  claim 25 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 80% of the amount of codeine is released in about 8 hours, and the amount of guaifenesin released in the same time period is between 80% and 120% of the amount of codeine released. 
     
     
         32 . The pharmaceutical tablet of  claim 25 , wherein, further comprising a third active agent that is a decongestant. 
     
     
         33 . The pharmaceutical tablet of  claim 32 , wherein the decongestant is selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutically acceptable salts thereof. 
     
     
         34 . The pharmaceutical tablet of  claim 1 , wherein the first active is guaifenesin. 
     
     
         35 . The pharmaceutical tablet of  claim 34 , wherein the guaifenesin is present in the tablet in an amount of about 600 mg. 
     
     
         36 . The pharmaceutical tablet of  claim 34 , wherein the second active agent is hydrocodone. 
     
     
         37 . The pharmaceutical tablet of  claim 36 , wherein the guaifenesin is present in an amount of about 600 mg, the hydrocodone is present in an amount of 5 mg, and the hydrophilic polymer is hydroxypropyl methyl cellulose and comprises about 8 wt % to about 20 wt % of the tablet. 
     
     
         38 . The pharmaceutical tablet of  claim 36 , wherein upon administration to a subject the tablet provides a guaifenesin C min  of about 3 ng/mL or more, at steady state. 
     
     
         39 . The pharmaceutical tablet of  claim 36 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., about 20 to about 40% the amount of guaifenesin is released after 0.5 hour to about 1 hour, and the amount of hydrocodone released in the same time is between 70% and 130% of the amount of guaifenesin released. 
     
     
         40 . The pharmaceutical tablet of  claim 36 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50% of the amount of guaifenesin and of hydrocodone is about 2 hours. 
     
     
         41 . The pharmaceutical tablet of  claim 36 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 80% of the amount of hydrocodone is released in about 8 hours, and the amount of guaifenesin released in the same time period is between 80% and 120% of the amount of hydrocodone released. 
     
     
         42 . The pharmaceutical tablet of  claim 36 , further comprising a third active agent that is a decongestant. 
     
     
         43 . The pharmaceutical tablet of  claim 42 , wherein the decongestant is selected from the group consisting of pseudoephedrine, phenylephrine, and their pharmaceutically acceptable salts. 
     
     
         44 . The pharmaceutical tablet of  claim 1 , wherein the tablet is a single layer tablet. 
     
     
         45 . A pharmaceutical matrix tablet for oral administration once every 12 hours, comprising:
 a first active agent that is a tri-oxy active agent,   a second active agent, and   a release rate controlling non-ionic oxyl-containing hydrophilic polymer,   wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., about 50 wt % of the first active agent is released in about 1.5 hours to about 3.2 hours,   wherein the ratio of the amount of first active released to the amount of second active agent released at 1 hour and at 4 hours is between about 0.7:1 and about 1.3:1, and wherein the total oxyl content of the hydrophilic polymer is 4×10 −4  to about 2×10 −3  moles per tablet.   
     
     
         46 . The pharmaceutical tablet of  claim 45 , wherein the first active agent is selected from the group consisting of codeine, hydrocodone, guaifenesin, and their pharmaceutically acceptable salts. 
     
     
         47 . The pharmaceutical tablet of  claim 46 , wherein the mean C max  of the first active agent does not vary more than 40% when administered with food as compared to administration under fasted condition. 
     
     
         48 . The pharmaceutical tablet of  claim 45 , wherein the hydrophilic polymer is a cellulose polymer. 
     
     
         49 . The pharmaceutical tablet of  claim 48 , wherein the cellulose polymer is a hydroxypropyl methyl cellulose (HPMC). 
     
     
         50 . The pharmaceutical tablet of  claim 49 , wherein the hydroxypropyl methyl cellulose has an average methoxy content of about 15 mole % to about 30 mole %. 
     
     
         51 . The pharmaceutical tablet of  claim 49 , wherein the hydroxypropyl methyl cellulose has an average methoxy content of about 18 mole % to about 25 mole %. 
     
     
         52 . The pharmaceutical tablet of  claim 49 , wherein the hydroxypropyl methyl cellulose is present in the tablet in an amount of 40 mg to about 175 mg. 
     
     
         53 . The pharmaceutical tablet of  claim 49 , wherein the hydroxypropyl methyl cellulose is present in the tablet in an amount of about 60 mg to about 150 mg. 
     
     
         54 . The pharmaceutical tablet of  claim 45 , wherein the second active agent is a tri-oxy active agent. 
     
     
         55 . The pharmaceutical tablet of  claim 45 , wherein the second active agent is a non-tri-oxy active agent. 
     
     
         56 . The pharmaceutical tablet of  claim 55 , wherein the second active agent is selected from the group consisting of chlorpheniramine, cyclopentamine, dexchlorpheniramine, diphenhydramine, brompheniramine, dexbrompheniramine, dextromethorphan, tripolidine, desloratadine, cyproheptadine, phenylephrine, pyrallamine, pseudoephedrine, azalastin, loratidine, theophyline and combinations thereof. 
     
     
         57 . The pharmaceutical tablet of  claim 56 , wherein the second active agent is chlorpheniramine or its pharmaceutically acceptable salt. 
     
     
         58 . The pharmaceutical tablet of  claim 45 , further comprising a third active agent that is a decongestant. 
     
     
         59 . The pharmaceutical tablet of  claim 45 , wherein the first active agent is codeine. 
     
     
         60 . The pharmaceutical tablet of  claim 59 , wherein the ratio of total content of the oxyl groups in the hydrophilic polymer to the total molar content of the oxygen-containing groups in the codeine is about 2.5 to about 9. 
     
     
         61 . The pharmaceutical tablet of  claim 59 , wherein the second active agent is chlorpheniramine or pharmaceutically acceptable salts thereof. 
     
     
         62 . The pharmaceutical tablet of  claim 61 , wherein the codeine comprises about 25 wt % to about 30 wt % of the tablet. 
     
     
         63 . The pharmaceutical tablet of  claim 61 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., about 30% to about 40% of the amount of codeine is released in the first 0.5 to 1 hour, and the amount of chlorpheniramine released in the same time is between 80% and 120% of the amount of codeine released. 
     
     
         64 . The pharmaceutical tablet of  claim 61 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50% of the amount of codeine and chlorpheniramine is about 1.5 to 3 hours. 
     
     
         65 . The pharmaceutical tablet of  claim 61 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 70% of the amount of chlorpheniramine is released in about 3 hours to 4 hours, and the amount of codeine released in the same time period is between 80% and 120% of the amount of chlorpheniramine released. 
     
     
         66 . The pharmaceutical tablet of  claim 61 , further comprising a third active agent that is a decongestant. 
     
     
         67 . The pharmaceutical tablet of  claim 66 , wherein the decongestant is selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutically acceptable salts thereof. 
     
     
         68 . The pharmaceutical tablet of  claim 61 , wherein the second active agent is guaifenesin. 
     
     
         69 . The pharmaceutical tablet of  claim 68 , wherein the codeine comprises about 3.5 wt % to about 4.0 wt % of the tablet. 
     
     
         70 . The pharmaceutical tablet of  claim 68 , wherein the codeine is present in an amount of about 30 mg, the guaifenesin is present in an amount of about 600 mg, and the hydrophilic polymer is hydroxypropyl methyl cellulose and comprises about 8 wt % to about 20 wt % of the tablet. 
     
     
         71 . The pharmaceutical tablet of  claim 68 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., an amount of about 25 wt % to about 35 wt % of guaifenesin is released after 0.5 hour to 1 hour, and an amount of codeine released in the same time is between 70% and 130% of the amount of guaifenesin released. 
     
     
         72 . The pharmaceutical tablet of  claim 68 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50 wt % of the amount of each of the guaifenesin and the codeine is about 1.5 hours to about 3 hours. 
     
     
         73 . The pharmaceutical tablet of  claim 68 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 80% of the amount of codeine is released in about 8 hours, and the amount of guaifenesin released in the same time period is between 80% and 120% of the amount of codeine released. 
     
     
         74 . The pharmaceutical tablet of  claim 68  wherein the tablet provides a C min  of guaifenesin is 3 ng/mL or more, at steady state. 
     
     
         75 . The pharmaceutical tablet of  claim 68 , wherein the tablet provides a guaifenesin C min  of about 850 ng/mL to about 1700 ng/mL. 
     
     
         76 . The pharmaceutical tablet of  claim 68 , wherein the ratio of the amount of first active released to the amount of second active agent released at a single time point between 1.5 hours and 4 hours is about 0.8:1 and about 1.2:1. 
     
     
         77 . The pharmaceutical tablet of  claim 68 , further comprising a third active agent that is a decongestant. 
     
     
         78 . The pharmaceutical tablet of  claim 77 , wherein the decongestant is selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutically acceptable salts. 
     
     
         79 . The pharmaceutical tablet of  claim 45 , wherein the first active is guaifenesin. 
     
     
         80 . The pharmaceutical tablet of  claim 79 , wherein the guaifenesin is present in the tablet in an amount of about 600 mg. 
     
     
         81 . The pharmaceutical tablet of  claim 79 , wherein the ratio of the total molar content of oxyl groups in the hydrophilic polymer to the total molar content of the oxygen containing groups in the guaifenesin is about 0.07 to 0.18. 
     
     
         82 . The pharmaceutical tablet of  claim 79 , wherein the second active agent is hydrocodone. 
     
     
         83 . The pharmaceutical tablet of  claim 82 , wherein the guaifenesin is present in an amount of about 600 mg, the hydrocodone is present in an amount of 5 mg, and the hydrophilic polymer is hydroxypropyl methyl cellulose and comprises about 8 wt % to about 20 wt % of the tablet. 
     
     
         84 . The pharmaceutical tablet of  claim 83 , wherein upon steady state administration to a subject the tablet provides a guaifenesin C min  of about 3 ng/mL or more. 
     
     
         85 . The pharmaceutical tablet of  claim 82 , wherein the tablet provides a mean guaifenesin C max  of about 850 ng/mL to about 1700 ng/mL. 
     
     
         86 . The pharmaceutical tablet of  claim 82 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., an amount of about 20 wt % to about 40 wt % of the guaifenesin is released after 0.5 hour to 1 hour and an amount of hydrocodone released in the same time is between 70% and 130% of the amount of guaifenesin released. 
     
     
         87 . The pharmaceutical tablet of  claim 82 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50% of the amount of guaifenesin and of hydrocodone is about 2 hours. 
     
     
         88 . The pharmaceutical tablet of  claim 82 , wherein when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., at least about 80% of the amount of hydrocodone is released in about 8 hours, and the amount of guaifenesin released in the same time period is between 80% and 120% of the hydrocodone released. 
     
     
         89 . The pharmaceutical tablet of  claim 82 , further comprising a third active agent that is a decongestant. 
     
     
         90 . The pharmaceutical tablet of  claim 89 , wherein, the decongestant is selected from the group consisting of pseudoephedrine, phenylephrine, and their pharmaceutically acceptable salts. 
     
     
         91 . The pharmaceutical tablet of  claim 45 , wherein the tablet is a single layer tablet. 
     
     
         92 . The pharmaceutical tablet of  claim 45 , wherein a single-dose administration of one or more tablets to a subject under fasted conditions provides a mean C max  of each of the first active agent and the second active agent that is 70% to 135% of a respective mean C max  provided after administering an immediate release oral dosage form to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, wherein cumulative dosage amounts administered over the 12 hour time period of each active agent is equivalent to the respective amount of each active agent in the pharmaceutical tablet. 
     
     
         93 . A method of treating cough and/or cold symptoms in a human subject, comprising administering to the human subject a tablet of  claim 1  or  claim 45 . 
     
     
         94 . The method of  claim 93 , wherein the administration can be done without regard to food. 
     
     
         95 . A pharmaceutical matrix tablet for oral administration once every 12 hours, comprising:
 a first active agent that is a tri-oxy active agent,   a second active agent, and   a release rate controlling non-ionic oxyl-containing hydrophilic polymer, wherein, the tablet is substantially free of ionic polymer; and
 wherein a single-dose administration of one or more tablets to a subject under fed conditions provides a mean C max  for each of the first active agent and the second active agent that is 70% to 135% of a respective mean C max  provided by administering the same dosage form to a subject under fasted conditions every 12 hour time period, wherein cumulative dosage amounts administered over the 12 hour time period of each active agent in the dosage form is equivalent to the respective amount of each active agent in the pharmaceutical tablet. 
   
     
     
         96 . The pharmaceutical tablet of  claim 95 , wherein the hydrophilic polymer is hydroxypropyl methyl cellulose (HPMC). 
     
     
         97 . The pharmaceutical tablet of  claim 95 , wherein the first active agent is selected from the group consisting of guaifenesin, codeine, hydrocodone, and their pharmaceutically acceptable salts. 
     
     
         98 . The pharmaceutical tablet of  claim 95 , wherein the mean C max  of the first active agent does not vary by more than 40% when administered with food as compared to administration under fasted condition. 
     
     
         99 . The pharmaceutical tablet of  claim 95 , wherein the second active agent is selected from the group consisting of chlorpheniramine, cyclopentamine, dexchlorpheniramine, diphenhydramine, brompheniramine, dexbrompheniramine, dextromethorphan tripolidine, desloratadine, cyproheptadine, phenylephrine, pyrallamine, pseudoephedrine, azalastin, loratidine, theophyline and their salts or esters thereof and combinations thereof. 
     
     
         100 . The pharmaceutical tablet of  claim 95 , wherein the total oxyl content of the hydrophilic polymer in the tablet is from about 4×10 −4  moles to about 2.0×10 −3  moles.