Soft gelatin capsules containing a mixture of analgesics and decongestants, expectorants, antitussives and/or antihistamines

Abstract

Clear bioavailable liquid softgel fill compositions comprising a) at least one analgesic and one or more of decongestants, expectorants, antitussives and/or antihistamines; b) a matrix comprising a pharmaceutically acceptable poly(alkylene glycol) and a pharmaceutically acceptable alkylene glycol; c) a solubilizing agent comprising a pharmaceutically acceptable polymeric solubilizing agent and water are disclosed. Also disclosed are methods for the preparation of such clear fill compositions, and softgel capsules containing the clear bioavailable liquid fill composition.

1 . A clear bioavailable liquid softgel fill composition comprising:
 (a1) acetaminophen as active ingredient;   (a2) one or more additional active ingredients selected from the group consisting of dextromethorphan and pharmaceutically acceptable salts thereof; doxylamine and pharmaceutically acceptable salts thereof; guaifenesin; chlorpheniramine and pharmaceutically acceptable salts thereof; and phenylephrine and pharmaceutically acceptable salts thereof;   (b) a matrix comprising:
 20-70 wt % of a pharmaceutically acceptable poly(alkylene glycol), and 
 0.5-8 wt % of a pharmaceutically acceptable alkylene glycol; and 
   (c) a solubilizing agent comprising:
 1-30 wt % of a pharmaceutically acceptable polymeric solubilizing agent, and 
 1-10 wt % by weight water; 
   
       wherein said wt % values are based on the total weight of the composition, and wherein said fill composition is clear. 
     
     
         2 . The clear bioavailable liquid softgel fill composition of  claim 1 , comprising about 10 to about 60 wt % acetaminophen, about 0.3 to about 3 wt % dextromethorphan HBr, 0 to about 2 wt % doxylamine succinate, 0 to about 30 wt % guaifenesin, 0 to about 0.5 wt % chlorpheniramine maleate, and about 0.1 to about 2 wt % phenylephrine HCl. 
     
     
         3 . The clear bioavailable liquid softgel fill composition of  claim 1 , comprising about 20 to about 31 wt % acetaminophen, about 0.5 to about 1.2 wt % dextromethorphan HBr, 0 to about 1 wt % doxylamine succinate, about 10 to about 20 wt % guaifenesin, 0 to about 0.5 wt % chlorpheniramine maleate, and about 0.1 to about 0.8 wt % phenylephrine HCl. 
     
     
         4 . The clear bioavailable liquid softgel fill composition of  claim 1 , comprising about 22 to about 28 wt % acetaminophen, about 0.7 to about 0.9 wt % dextromethorphan HBr, 0 to about 0.6 wt % doxylamine succinate, about 14 to about 15 wt % guaifenesin, 0 to about 0.3 wt % chlorpheniramine maleate, and about 0.3 to about 0.5 wt % phenylephrine HCl. 
     
     
         5 . The clear bioavailable liquid softgel fill composition of  claim 1 , wherein said active ingredients are limited to acetaminophen, dextromethorphan HBr, guaifenesin, and phenylephrine HCl. 
     
     
         6 . A clear bioavailable liquid softgel fill composition consisting essentially of:
 (a1) about 22 to about 25 wt % acetaminophen;   (a2) about 0.7 to about 0.8 wt % dextromethorphan HBr;   (a3) about 14 to about 15 wt % guaifenesin;   (a4) about 0.3 to about 0.4 wt % phenylephrine HCl;   (b) a matrix consisting essentially of:
 about 47 to about 48 wt % of a pharmaceutically acceptable poly(alkylene glycol) or mixture of poly(alkylene glycol)s; and 
 about 2 to about 4 wt % of a pharmaceutically acceptable alkylene glycol; and 
   (c) a solubilizing agent consisting essentially of:
 about 3 to about 7 wt % of a pharmaceutically acceptable polymeric solubilizing agent; and 
 about 5 to about 6 wt % water, 
   
       wherein said wt % values are based on the total weight of the composition, and wherein said fill composition is clear. 
     
     
         7 . The clear fill composition of  claim 6 , wherein said pharmaceutically acceptable poly(alkylene glycol) is selected from the group consisting of PEG 400, PEG 600 and mixtures thereof; said pharmaceutically acceptable alkylene glycol is propylene glycol; and said pharmaceutically acceptable polymeric solubilizing agent is polyvinylpyrrolidone. 
     
     
         8 . The clear fill composition of  claim 7 , consisting essentially of about 48 wt % PEG 400, about 3.5 wt % propylene glycol, about 4.6 wt % polyvinylpyrrolidone K30, about 6 wt % water, about 22.8 wt % acetaminophen, about 0.7 wt % dextromethorphan HBr, about 14 wt % guaifenesin and about 0.4 wt % phenylephrine HCl. 
     
     
         9 . The clear bioavailable liquid softgel fill composition of  claim 1 , further containing an anti-oxidant. 
     
     
         10 . The clear bioavailable liquid softgel fill composition of  claim 9 , wherein said anti-oxidant is selected from the group consisting of BHA, BHT and mixtures thereof. 
     
     
         11 . A softgel capsule comprising a soft gelatin shell filled with the clear bioavailable liquid softgel fill composition of  claim 1 . 
     
     
         12 . A softgel capsule which comprises:
 a soft gelatin shell, and   a clear liquid softgel fill composition within the shell, said liquid softgel fill composition including:   (a1) about 22 to about 25 wt % acetaminophen;   (a2) about 0.7 to about 0.8 wt % dextromethorphan HBr;   (a3) about 14 to about 15 wt % guaifenesin;   (a4) about 0.3 to about 0.4 wt % phenylephrine HCl;   (b) a matrix consisting essentially of:
 about 47 to about 48 wt % of a pharmaceutically acceptable poly(alkylene glycol) or mixture of poly(alkylene glycol)s; and 
 about 2 to about 4 wt % of a pharmaceutically acceptable alkylene glycol; and 
   (c) a solubilizing agent consisting essentially of:
 about 3 to about 7 wt % of a pharmaceutically acceptable polymeric solubilizing agent; and 
 about 5 to about 6 wt % water, 
   
       wherein said wt % values are based on the total weight of the composition, and wherein said fill composition is clear. 
     
     
         13 . The softgel capsule of  claim 12 , wherein for said fill composition the pharmaceutically acceptable poly(alkylene glycol) is selected from the group consisting of PEG 400, PEG 600 and mixtures thereof; the pharmaceutically acceptable alkylene glycol is propylene glycol; and the pharmaceutically acceptable polymeric solubilizing agent is polyvinylpyrrolidone. 
     
     
         14 . The softgel capsule of  claim 13 , wherein said fill composition consists essentially of about 48 wt % PEG 400, about 3.5 wt % propylene glycol, about 4.6 wt % polyvinylpyrrolidone K30, about 6 wt % water, about 22.8 wt % acetaminophen, about 0.7 wt % dextromethorphan HBr, about 14 wt % guaifenesin and about 0.4 wt % phenylephrine HCl. 
     
     
         15 . The softgel capsule of  claim 12 , wherein the total amount of acetaminophen is 325 mg. 
     
     
         16 . The softgel capsule of  claim 12 , wherein the total amount of guaifenesin is 200 mg. 
     
     
         17 . A method of preparing a clear liquid softgel fill composition of  claim 1 , which method comprises:
 a) stirring polyethylene glycol or a mixture of polyethylene glycols, and propylene glycol with heating to 70° C.±10° C. until a clear solution is obtained;   b) slowly adding polyvinylpyrrolidone in small quantities with continuous mixing and heating to 70° C.±10° C., until a clear solution is obtained;   c) adding purified water with continuous mixing and heating to 70° C.±10° C., until a clear solution is obtained;   d) adding acetaminophen with continuous mixing and heating to 70° C.±10° C., until a clear solution is obtained;   e) adding guaifenesin with continuous mixing and heating to 70° C.±10° C., until a clear solution is obtained;   f) successively adding i) dextromethorphan HBr and ii) phenylephrine HCl with continuous mixing and optionally heating up to 80° C., until a clear solution is obtained; and   g) cooling to ambient temperature and deaerating the clear liquid softgel fill solution.   
     
     
         18 . The method of  claim 17 , wherein the polyethylene glycol is selected from the group consisting of PEG 400, PEG 600 and mixtures thereof. 
     
     
         19 . The method of  claim 17 , wherein the temperature of the solution during the addition of dextromethorphan HBr is up to 55° C., and the temperature of the solution during the addition of phenylephrine HCl is below 35° C.