Flavoring systems for pharmaceutical compositions and methods of making such compositions

Abstract

A flavoring system for a liquid pharmaceutical composition and pharmaceutical compositions containing such flavoring systems are disclosed. Flavoring systems of the invention include at least one sweetening agent, at least two flavored ingredients, and at least one flavor modifier selected from the group consisting of citric acid, sodium citrate, sodium chloride, and mixtures thereof. At least two of the flavored ingredients are selected from the group consisting of a vanilla flavored ingredient, a peppermint flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof. The one or more sweetening agents comprise glycerin, monoammonium glycyrrhizinate, saccharin sodium, acesulfame potassium, high fructose corn syrup, and/or mixtures thereof. Pharmaceutical compositions of the invention include a flavoring system of the invention, a solvent system, and at least one pharmaceutically active agent, such as lopinavir or derivatives thereof, ritonavir or derivatives thereof, or mixtures thereof. Methods for making such liquid pharmaceutical compositions are also disclosed.

1 . A flavoring system useful in a liquid pharmaceutical composition containing lopinavir or derivatives thereof, ritonavir or derivatives thereof, or mixtures thereof, said system comprising: 
 (a) one or more sweetening agents; and    (b) two or more flavored ingredients selected from the group consisting of a menthol flavored ingredient, a peppermint flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof; and    (c) one or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid and mixtures thereof.    
     
     
         2 . A flavoring system of  claim 1  wherein the one or more sweetening agents comprises high fructose corn syrup.  
     
     
         3 . A flavoring system of  claim 1  wherein the one or more flavor modifiers comprises two ingredients selected from the group consisting of sodium citrate, sodium chloride, citric acid and mixtures thereof.  
     
     
         4 . A flavoring system of  claim 1  wherein the one or more flavor modifiers are sodium citrate, citric acid, and sodium chloride.  
     
     
         5 . A flavoring system of  claim 1  wherein the two or more flavored ingredients comprise three flavored ingredients selected from the group consisting of a menthol flavored ingredient, a peppermint flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof.  
     
     
         6 . A flavoring system of  claim 1  wherein the two or more flavored ingredients comprise four flavored ingredients and said four flavored ingredients are menthol crystals, vanilla flavor, candy flavor, and peppermint oil.  
     
     
         7 . A flavoring system of  claim 1  further comprising one or more sweetening agents in an amount of at least about 20% by weight and not greater than about 67% by weight of the total weight of the pharmaceutical composition.  
     
     
         8 . A flavoring system of  claim 1  further comprising one or more sweetening agents in an amount of at least about 22% by weight and not greater than about 27.5% by weight of the total weight of the pharmaceutical composition.  
     
     
         9 . A flavoring system of  claim 1  further comprising the flavored ingredients in a total amount of at least about 1.4% by weight and not greater than about 3.5% by weight of the total weight of the pharmaceutical composition.  
     
     
         10 . A flavoring system of  claim 1  further comprising the flavored ingredients in 
 an amount of at least about 2.4% by weight and not greater than about 2.8% by weight of the total weight of the pharmaceutical composition.    
     
     
         11 . A flavoring system useful in a liquid pharmaceutical composition containing lopinavir or derivatives thereof, ritonavir or derivatives thereof, or mixtures thereof, said system comprising: 
 (a) one or more sweetening agents;    (b) three or more flavored ingredients selected from the group consisting of a menthol flavored ingredient, a peppermint flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof; and    (c) two or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid and mixtures thereof.    
     
     
         12 . A flavoring system of  claim 11  wherein the three or more flavored ingredients are a menthol flavored ingredient, a peppermint flavored ingredient, a vanilla flavored ingredient, and a cotton candy flavored ingredient.  
     
     
         13 . A flavoring system of  claim 12  wherein the menthol flavored ingredient is menthol crystals and the peppermint flavored ingredient is peppermint oil.  
     
     
         14 . A flavoring system useful in a liquid pharmaceutical composition containing lopinavir or derivatives thereof, ritonavir or derivatives thereof, or mixtures thereof, said system comprising: 
 (a) a menthol flavored ingredient in an amount of at least about 0.03% and not greater than about 0.25% by weight based upon the total weight of the pharmaceutical composition;    (b) a peppermint flavored ingredient in an amount of at least about 0.15% and not greater than about 0.60% by weight based upon the total weight of the pharmaceutical composition;    (c) a vanilla flavored ingredient in an amount of at least about 0.70% and not greater than about 1.5% by weight based upon the weight of the total pharmaceutical composition;    (d) a cotton candy flavored ingredient in an amount of at least about 0.55% and not greater than about 1.10% by weight based upon the total weight of the pharmaceutical composition;    (e) one or more sweetening agents in an amount of at least about 20% by weight and not greater than about 67% by weight based upon the total weight of the pharmaceutical composition; and    (f) two or more flavor modifiers in a total amount of at least about 0.10% by weight and not greater than about 1.0% by weight based upon the total weight of the pharmaceutical composition, said two or more flavor modifiers being selected from the group consisting of sodium citrate, citric acid, sodium chloride, and mixtures thereof.    
     
     
         15 . A flavoring system of  claim 14  wherein the menthol flavored ingredient is menthol crystals.  
     
     
         16 . A flavoring system of  claim 14  wherein the peppermint flavored ingredient is peppermint oil.  
     
     
         17 . A flavoring system of  claim 14  wherein the two or more flavor modifiers are sodium citrate, citric acid, and sodium chloride.  
     
     
         18 . (canceled)  
     
     
         19 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents and two or more flavored ingredients selected from the group consisting of a menthol flavored ingredient, a peppermint flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) one or more pharmaceutically active agents, said one or more pharmaceutically active agents being selected from the group consisting of ritonavir or derivatives thereof, lopinavir or derivatives thereof, and mixtures thereof; and    (c) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         20 . A pharmaceutical composition of  claim 19  further comprising the solvent system in an amount of at least about 32% by weight and not greater than about 69% by weight based upon the total weight of the pharmaceutical composition.  
     
     
         21 . A pharmaceutical composition of  claim 19  further comprising a flavoring system in an amount of at least about 20% by weight and not greater than about 70% by weight based upon the total weight of the pharmaceutical composition.  
     
     
         22 . A pharmaceutical composition of  claim 19  further comprising one or more pharmaceutically active agents in an amount of at least about 4% and not greater than about 10% by weight based upon the total weight of the pharmaceutical composition.  
     
     
         23 . A pharmaceutical composition of  claim 19  further comprising one or more pharmaceutically active agents in an amount of about 10% by weight based upon the total weight of the pharmaceutical composition.  
     
     
         24 . A pharmaceutical composition of  claim 19  wherein the one or more pharmaceutically active agents comprises ritonavir.  
     
     
         25 . A pharmaceutical composition of  claim 19  wherein the one or more pharmaceutically active agents comprises a mixture of lopinavir and ritonavir.  
     
     
         26 . A pharmaceutical composition of  claim 19  wherein the one or more pharmaceutically active agents comprises derivatives of lopinavir.  
     
     
         27 . A pharmaceutical composition of  claim 19  wherein the one or more pharmaceutically active agents comprises derivatives of ritonavir.  
     
     
         28 . A pharmaceutical composition of  claim 19  wherein the solvent system comprises one or more alkyl alcohols and one or more alkylene glycols.  
     
     
         29 . A pharmaceutical composition of  claim 28  wherein the one or more alkyl alcohols comprise ethanol and the one or more alkylene glycols comprise propylene glycol.  
     
     
         30 . A pharmaceutical composition of  claim 28  further comprising a thickening agent.  
     
     
         31 . A pharmaceutical composition of  claim 30  wherein the thickening agent is polyvinylpyrrolidone.  
     
     
         32 . A pharmaceutical composition of  claim 19  further comprising a bioavailability enhancer.  
     
     
         33 . A pharmaceutical composition of  claim 32  wherein the bioavailability enhancer is a castor oil derivative.  
     
     
         34 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents and three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) ritonavir;    (c) lopinavir;    (d) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         35 . A pharmaceutical composition of  claim 34  further comprising: 
 (a) ritonavir in an amount of about 2% by weight based upon the total weight of the pharmaceutical composition; and    (b) lopinavir in an amount of about 8% by weight based upon the total weight of the pharmaceutical composition.    
     
     
         36 . A pharmaceutical composition of  claim 34  wherein the three or more flavored ingredients are a peppermint flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and a vanilla flavored ingredient.  
     
     
         37 . A pharmaceutical composition of  claim 36  wherein the peppermint flavored ingredient is peppermint oil in an amount of about 0.30% by weight; wherein the menthol flavored ingredient is menthol crystals in an amount of about 0.05% by weight; wherein the vanilla flavored ingredient is vanilla flavor in an amount of about 1.25% by weight; and wherein the cotton candy flavored ingredient is cotton candy flavor in an amount of about 1.00% by weight; and wherein all amounts by weight are based upon the total weight of the pharmaceutical composition.  
     
     
         38 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents and three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) one or more derivatives of ritonavir;    (c) one or more derivatives of lopinavir; and    (d) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         39 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents, three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) ritonavir; and    (c) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         40 . A pharmaceutical composition of  claim 39  wherein the three or more flavored ingredients are a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, and a cotton candy flavored ingredient.  
     
     
         41 . A pharmaceutical composition of  claim 39  wherein the solvent system comprises three or more solubilizing agents selected from the group consisting of water, ethanol, propylene glycol, and mixtures thereof.  
     
     
         42 . A pharmaceutical composition of  claim 34  further comprising ritonavir in an amount of at least about 1.30% by weight and not greater than about 2.10% by weight based upon the weight of the pharmaceutical composition.  
     
     
         43 . A pharmaceutical composition of  claim 42  further comprising ritonavir in an amount of about 2% by weight based upon the weight of the pharmaceutical composition.  
     
     
         44 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents, three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) one or more derivatives of ritonavir; and    (c) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         45 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents and three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) lopinavir; and    (c) a solvent system, said solvent system comprising two or more solvents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof.    
     
     
         46 . A pharmaceutical composition of  claim 45  wherein the three or more flavored ingredients are a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, and a cotton candy flavored ingredient.  
     
     
         47 . A pharmaceutical composition of  claim 45  wherein the solvent system comprises three or more solubilizing agents selected from the group consisting of water, ethanol, propylene glycol, and mixtures thereof.  
     
     
         48 . A pharmaceutical composition of  claim 34  further comprising lopinavir in an amount of at least about 2.50% by weight and not greater than about 8% by weight based upon the total weight of the pharmaceutical composition.  
     
     
         49 . A liquid pharmaceutical composition comprising: 
 (a) a flavoring system, said flavoring system comprising one or more sweetening agents and three or more flavored ingredients selected from the group consisting of: a peppermint flavored ingredient, a menthol flavored ingredient, a vanilla flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof;    (b) one or more derivatives of lopinavir; and    (c) a solvent system, said solvent system comprising two or more solvents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof    
     
     
         50 . A method for making a liquid pharmaceutical composition, said composition comprising: (1) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents, (ii) two or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof (iii) two or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, said method comprising steps of: 
 (a) charging a vessel with at least a portion of the solvent system;    (c) dissolving the one or more pharmaceutically active agents in the at least a portion of the solvent system in the vessel;    (d) dissolving any non-liquid flavor modifiers and any non-liquid sweetening agents in water to form a side mixture; and    (e) combining in the vessel the at least a portion of the solvent system containing the one or more dissolved pharmaceutically active agents with any side mixture, any one or more liquid sweetening agents, any flavor modifiers in liquid form, the flavored ingredients and any remaining portion of the solvent system.    
     
     
         51 . A method according to  claim 50  wherein the composition further comprises a derivative of castor oil, and further comprising a step of heating the castor oil derivative prior to adding said derivative to the vessel.  
     
     
         52 . A method according to  claim 50  wherein the solvent system comprises three or more solubilizing agents selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol, and mixtures thereof; and wherein the step of charging the vessel comprises combining the three or more solubilizing agents.  
     
     
         53 . A method according to  claim 50  wherein one of the two or more flavored ingredients is menthol crystals; and further comprising a step of dissolving said menthol crystals in the portion of the solvent system in the vessel prior to dissolving the one or more pharmaceutically active agents.  
     
     
         54 . A method according to  claim 50  wherein the step of charging the vessel with at least a portion of the solvent system comprises adding water, ethanol, and propylene glycol to the vessel.  
     
     
         55 . A method for making a liquid pharmaceutical composition, said composition comprising: (1) a solvent system, said solvent system comprising three or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents selected from the group consisting of: glycerin, high fructose corn syrup, monoammonium glycyrrhizinate, saccharin sodium, acesulfame potassium, and mixtures thereof; (ii) three or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, and a cotton candy flavored ingredient, and (iii) three or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, said method comprising steps of: 
 (a) charging a vessel with a portion of the solvent system, said portion comprising water, ethanol, and propylene glycol;    (b) dissolving the one or more pharmaceutically active agents in the portion of the solvent system in the vessel;    (c) adding one or more sweetening agents to the vessel, wherein said step of adding the one or more sweetening agents comprises adding at least one liquid sweetening agent;    (d) dissolving any non-liquid flavor modifiers and any one or more non-liquid sweetening agents in water to form a side mixture; and    (e) adding the side mixture, any additional sweetening agents, any flavor modifiers in liquid form, and the flavored ingredients to the vessel.    
     
     
         56 . A method according to  claim 55  wherein the vessel is a mixing vessel and further comprising a step of mixing the contents in the vessel.  
     
     
         57 . A method according to  claim 55  wherein the composition further comprises a castor oil derivative, and further comprising steps of heating the castor oil derivative and adding said derivative to the vessel.  
     
     
         58 . A method according to  claim 55  further comprising a step of adding a thickening agent to the vessel.  
     
     
         59 . A method according to  claim 58  wherein the thickening agent is polyvinylpyrrolidone.  
     
     
         60 . A method according to  claim 55  wherein the step of adding the side mixture and the flavored ingredients comprises adding a peppermint flavored ingredient, a vanilla flavored ingredient, and a cotton candy flavored ingredient to the vessel.  
     
     
         61 . A method according to  claim 55  wherein the three or more flavored ingredients comprises menthol crystals and further comprising a step of dissolving the menthol crystals in the solvent system in the vessel prior to dissolving the one or more pharmaceutically active agents.  
     
     
         62 . A method for making a liquid pharmaceutical composition, said composition comprising: (1) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents, (ii) two or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof and (iii) two or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, said method comprising steps of: 
 (a) charging a vessel with at least a portion of the solvent system;    (b) dissolving the one or more pharmaceutically active agents in the at least a portion of the solvent system in the vessel; and    (c) combining in the vessel the at least a portion of the solvent system containing the one or more dissolved pharmaceutically active agents, the flavor modifiers, the sweetening agents, the flavored ingredients and any remaining portion of the solvent system.    
     
     
         63 . A liquid pharmaceutical composition comprising: (1) a solvent system, said solvent system comprising two or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents selected from the group consisting of: glycerin, high fructose corn syrup, monoammonium glycyrrhizinate, acesulfame potassium, saccharin sodium, and mixtures thereof; (ii) two or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof; and (iii) two or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, and made by a process comprising steps of: 
 (a) charging a vessel with at least a portion of the solvent system;    (b) dissolving the one or more pharmaceutically active agents in the at least a portion of the solvent system in the vessel;    (c) dissolving any non-liquid flavor modifiers and any one or more non-liquid sweetening agents in water to form a side mixture; and    (d) combining in the vessel the at least a portion of the solvent system containing the one or more dissolved pharmaceutically active agents with any side mixture, any one or more liquid sweetening agents, any one or more flavor modifiers in liquid form, the flavored ingredients and any remaining portion of the solvent system.    
     
     
         64 . A liquid pharmaceutical composition of  claim 63  wherein the one or more pharmaceutically active agents comprises ritonavir and lopinavir.  
     
     
         65 . A liquid pharmaceutical composition of  claim 63  wherein the one or more pharmaceutically active agents comprises any one or more derivatives of ritonavir and any one or more derivatives of lopinavir.  
     
     
         66 . A liquid pharmaceutical composition comprising: (1) a solvent system, said solvent system comprising three or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents selected from the group consisting of: glycerin, acesulfame potassium, monoammonium glycyrrhizinate, high fructose corn syrup, saccharin sodium and mixtures thereof; (ii) three or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof; and (iii) three or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, and made by a process comprising steps of: 
 (a) charging a vessel with a portion of the solvent system, said portion comprising water, ethanol, and propylene glycol;    (b) dissolving the one or more pharmaceutically active agents in the portion of the solvent system in the vessel;    (c) adding one or more sweetening agents to the vessel, wherein said step of adding one or more sweetening agents comprises adding any one or more liquid sweetening agents to the vessel;    (d) dissolving any non-liquid flavor modifiers and any non-liquid sweetening agents in water to form a side mixture; and    (e) adding the side mixture, any remaining solvent system, the flavored ingredients, and any flavor modifiers in liquid form to the vessel.    
     
     
         67 . A liquid pharmaceutical composition of  claim 66  wherein the pharmaceutically active agent is ritonavir.  
     
     
         68 . A liquid pharmaceutical composition of  claim 66  wherein the pharmaceutically active agent comprises one or more derivatives of ritonavir.  
     
     
         69 . A liquid pharmaceutical composition comprising: (1) a solvent system, said solvent system comprising three or more solubilizing agents selected from the group consisting of water, alkyl alcohols, alkylene glycols, and mixtures thereof; (2) a flavoring system, said flavoring system comprising (i) one or more sweetening agents selected from the group consisting of: glycerin, monoammonium glycyrrhizinate, acesulfame potassium, high fructose corn syrup, saccharin sodium and mixtures thereof; (ii) three or more flavored ingredients selected from the group consisting of a peppermint flavored ingredient, a vanilla flavored ingredient, a menthol flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof; and (iii) three or more flavor modifiers selected from the group consisting of sodium citrate, sodium chloride, citric acid, and mixtures thereof; and (3) one or more pharmaceutically active agents selected from the group consisting of lopinavir or derivatives thereof, ritonavir or derivatives thereof, and mixtures thereof, and made by a process comprising steps of: 
 (a) charging a vessel with at least a portion of the solvent system;    (b) dissolving the one or more pharmaceutically active agents in the at least a portion of the solvent system in the vessel; and    (c) combining in the vessel the at least a portion of the solvent system containing the one or more dissolved pharmaceutically active agents, the flavor modifiers, the sweetening agents, the flavored ingredients and any remaining portion of the solvent system.