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, a tri-oxy active agent, 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 from about 4×10 4 moles to about 2.0×10 −3 moles. The tablet is a matrix tablet and 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 is equivalent to the respective amount of each active agent in the pharmaceutical tablet.

1 . A pharmaceutical matrix tablet for oral administration once every 12 hours:
 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 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 14 , 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 - 100 . (canceled)