Oral pharmaceutical film formulation for bitter tasting drugs

Abstract

The invention relates to a pharmaceutical film formulation comprising one or more bitter-tasting drug(s) or pharmaceutically acceptable salts thereof, one or more film formers, a bitterness masker containing one or more inorganic and/or organic salt(s) and at least two monocyclic monoterpenes, and one or more sweetening agent(s).

1 ) A pharmaceutical film formulation comprising
 one or more bitter tasting drug(s) or pharmaceutically acceptable salts thereof,   one or more film formers,   one bitterness masker containing
 a) one or more inorganic and/or organic salt(s) and 
 b) at least two monocyclic monoterpenes as well as 
   one or more sweetener(s).   
     
     
         2 ) The pharmaceutical film formulation according to  claim 1 , further comprising one or more humectants and/or one or more flavoring agent(s). 
     
     
         3 ) The pharmaceutical film formulation according to  claim 1 , wherein the bitter tasting drug is selected from cetirizine, sildenafil and sumatriptan. 
     
     
         4 ) The pharmaceutical film formulation according to  claim 1 , wherein the at least two monocyclic monoterpenes of the bitterness masker are selected from the group consisting of a compound of formula (A) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are identical or different from each other and each represent an OH group or a linear or branched C 1-4  alkyl group, and 
         R 3  represents a linear or branched C 1-4  alkyl or C 1-4  alkoxy group, which may optionally be substituted with an OH group, and/or 
         a compound of formula (B) 
       
       
         
           
           
               
               
           
         
         wherein 
         X represents O, NH or CH 2 , 
         R 1  and R 2  are identical or different from each other and each represents an OH group or a linear or branched C 1-4  alkyl group, and 
         R 3  represents a linear or branched C 1-4  alkyl group, which may optionally be substituted with an OH group, and 
         a compound of formula (C) 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are identical and each represents a linear or branched C 1-4  alkyl group, 
         R 3  represents an OH group or a linear or branched C 1-4  alkyl group, and 
         R 4  represents a saturated or unsaturated, linear or branched C 1-4  alkyl group and may optionally be substituted with an OH group. 
       
     
     
         5 ) The pharmaceutical film formulation according to  claim 1 , wherein the monocyclic monoterpenes of the bitterness masker are a mixture comprising
 (i) 1-(2,6,6-trimethylcyclohexenyl)-2-buten-1-one;   (ii) N-Ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide;   (iii) menthyl lactate;   (iv) menthol ethylene glycol carbonate and   (v) menthol propylene glycol carbonate.   
     
     
         6 ) The pharmaceutical film formulation according to  claim 1 , wherein said one or said more inorganic and/or organic salt(s) is/are selected from the group consisting of sodium chloride, magnesium chloride, ammonium chloride, sodium ascorbate, calcium ascorbate and sodium citrate. 
     
     
         7 ) The pharmaceutical film formulation according to  claim 1 , wherein the bitterness masker contains
 a) one or more salt(s), selected from the group consisting of sodium chloride, magnesium chloride, ammonium chloride, sodium ascorbate, calcium ascorbate and sodium citrate, and   b) a mixture comprising
 (i) (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one; 
 (ii) N-ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide; 
 (iii) menthyl lactate; 
 (iv) menthol ethylene glycol carbonate, and 
 (v) menthol propylene glycol carbonate. 
   
     
     
         8 ) The pharmaceutical film formulation according to  claim 1 , wherein the bitterness masker contains sodium chloride and a mixture comprising
 (i) (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one;   (ii) N-ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide;   (iii) menthyl lactate;   (iv) menthol ethylene glycol carbonate, and   (v) menthol propylene glycol carbonate.   
     
     
         9 ) The pharmaceutical film formulation according to  claim 2 , wherein the humectant comprises sorbitol and/or xylitol. 
     
     
         10 ) The pharmaceutical film formulation according to  claim 2 , wherein the humectant comprises a mixture of sorbitol and xylitol in a ratio of 1:1.5. 
     
     
         11 ) The pharmaceutical film formulation according to  claim 1 , wherein the sweetener(s) is/are selected from the group consisting of sucrose, sucralose, aspartame and acesulfame potassium. 
     
     
         12 ) The pharmaceutical film formulation according to  claim 2 , wherein the flavoring agent(s) is/are selected from the group consisting of grapefruit flavor, peppermint oil, peppermint flavor, levomenthol, menthol and low molecular weight organic acids. 
     
     
         13 ) The pharmaceutical film formulation according to  claim 1 , wherein the content of the bitter-tasting drug(s) is between 0.1 and 75% w/w, related to the dry weight of the film formulation. 
     
     
         14 ) The pharmaceutical film formulation according to  claim 1 , comprising
 one or more bitter tasting drug(s) or pharmaceutically acceptable salts thereof in an amount of at least 0.1-75% w/w,   one or more film formers in an amount of 1-90% w/w,   one bitterness masker containing
 a) one or more inorganic and/or organic salt(s) in an amount of 1-10% w/w and 
 b) at least two monocyclic monoterpenes in a total amount of 0.01-10% w/w and 
   one or more sweetener(s) in an amount of 1-15% w/w, in which the respective amounts are related to the dry weight of the film formulation.   
     
     
         15 ) The pharmaceutical film formulation according to  claim 14 , further comprising one or more humectants in an amount of 1-10% w/w and/or one or more flavoring agent(s) in an amount of 0.01-15% w/w, in which the respective amounts are related to the dry weight of the film formulation. 
     
     
         16 ) The pharmaceutical film formulation according to  claim 2 , comprising
 one or more bitter tasting drug(s) selected from the group consisting of cetirizine, sildenafil and sumatriptan, or pharmaceutically acceptable salts thereof in an amount of up to 75% w/w,   one or more film formers selected from the group consisting of methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose in an amount of 9-20% w/w,   a mixture of sorbitol and xylitol in a ratio of 1:1.5 in an amount of 2.5-5% w/w,   one bitterness masker containing
 a) NaCl in an amount of 1-2% w/w and 
 b) (i) (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one;
 (ii) N-Ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide; 
 (iii) menthyl lactate; 
 (iv) menthol ethylene glycol carbonate and 
 (v) menthol propylene glycol carbonate 
 in a total amount of 0.01-2% w/w, 
 
   sucralose in an amount of 2-6% w/w and   peppermint flavor and menthol in a total amount of 0.5-7% w/w,   
       in which the respective amounts are related to the dry weight of the film formulation. 
     
     
         17 ) The pharmaceutical film formulation according to  claim 1 , wherein the film formulation is a non-mucoadhesive film and wherein the non-mucoadhesive film is a monolayer. 
     
     
         18 ) The pharmaceutical film formulation according  claim 1 , which contains 50-75% w/w sildenafil citrate as an active ingredient related to the dry weight of the film formulation. 
     
     
         19 ) A method of making a pharmaceutical film formulation comprising at least one bitter tasting drug or a pharmaceutically acceptable salt thereof, having acceptable taste, the method comprising combining pharmaceutically acceptable excipients, with a mixture of
 (i) (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one;   (ii) N-Ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide;   (iii) menthyl lactate;   (iv) menthol ethylene glycol carbonate and   (v) menthol propylene glycol carbonate,   wherein the pharmaceutically acceptable excipients comprise NaCl, sucralose, and menthol.