Abstract:
Alkanol flee glycol based oral analgesic compositions are provided, protected against microbiological degradation by a preservative agent which is a combination of methylparaben and phenylcarbiniol.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to oral alkanol free glycol based analgesic compositions containing high concentrations of benzocaine. More particularly, this invention relates to oral analgesic compositions in liquid and gel form having high potency and protected from microbiological degradation by a preservative agent which is a combination of methylparaben and phenylcarbinol. 
     2. Description of Related Art 
     An anesthetic composition comprising high concentrations of benzocaine is described in U.S. Pat. No. 5,446,063. The benzocaine is dispersed or suspended in an admixture of water and emollient vehicle and is not completely dissolved. Another benzocainie composition comprising high concentrations of benzocaine is described in U.S. Pat. No. 4,241,048. That patent discloses a composition containing benzocaine suspended in an essentially anhydrous carrier also containing a crystal growth suppressing agent. These prior art patents disclose the use of preservatives including methylparaben and propylparaben. 
     SUMMARY OF THE INVENTION 
     According to this invention, an oral analgesic glycol based composition which is anhydrous and alkanol free, containing high concentrations of benzocaine, is provided in liquid or gel form and which is protected from bacterial degradation by a preservative agent which is a combination of methylparaben and phenylcarbinol. The benzocaine compositions of the invention contain about 5 to about 20% by weight of benzocaine, based on the weight of the total composition. The amount of glycol based solvent system is about 40% to about 80% by weight based on the weight of the total composition when in liquid form, and about 40% to about 60% when in gel form. The glycol based solvent system contains about 80% to about 100% by weight of polyethylene glycol when in liquid form and in gel form, based on the weight of the glycol based solvent system, and advantageously up to about 20% by weight of a co-solvent for the benzocaine compatible with polyethylene glycol, based on the weight of the glycol based solvent system. The methylparaben component of the preservative agent can be about 0.05 to about 0.2% by weight of the total composition and the phenylcarbinol component of the preservative agent can be about 0.25 to about 0.5% by weight of the total composition. Co-solvents for the benzocaine compatible with polyethylene glycol are propylene glycol and glycerine. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention includes analgesic compositions in liquid form and in gel form and in regular strength and maximum strength. The regular strength forms contain about 7.5% to about 10% by weight of benzocaine and the maximum strength forms contain about 10% to about 20% by weight of benzocaine. 
     The liquid form of the invention can contain in addition to the benzocaine, the glycol based solvent system, and the preservative agent, sweeteners such as saccharin, flavoring agents such as spearmint and coloring agents. 
     The gel form of the invention contains in addition to the benzocaine, the glycol based solvent system, and the preservative agent, a thickening agent such as Carbomer 934 P brand of carboxy-vinyl polymer, and a co-solvent for the thickening agent such as gylcerin. The thickening agent can range from about 2% to about 2.5% by weight and the co-solvent for the thickening agent can range from about 16% to about 24% by weight of the total composition. Other suitable thickening agents include hydroxyethyl cellulose NF, hydroxypropyl cellulose NF, hydroxypropyl methyl cellulose USP, and polyethylene oxides MW 200,000 to 7 million. 
     The benzocaine, preservative agents and glycol solvent agents are commercially available in NF or USP grades. The glycerin is commercially available in NF grades containing up to 4% water and the taste of the final gel product is better using the 96% glycerin. 
     The polyethylene glycol component of the glycol solvent system can range from PEG 400 to PEG 600. Below about PEG 400, the polyethylene glycol does not dissolve the benzocaine with ease, and above about PEG 600, the polyethylene glycol is a waxy solid and difficult to work with. 
     The preparation of the formulation of the invention is illustrated in the following examples. In the examples, the polyethylene glycol PEG 400 was the commercial NF grade and Carbomer 934 P brand of carboxy-vinyl polymer was that of BF Goodrich. 
    
    
     EXAMPLE 1 
     The following ingredients were incorporated into the analgesic maximum strength liquid composition of this invention. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Weight % 
                 Grams Per 500 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 PEG 400 
                 10.0 
                 50.0 
               
               
                   
                 Propylene Glycl 
                 10.0 
                 50.0 
               
               
                   
                 Saccharin 
                 0.177 
                 0.885 
               
               
                   
                 PEG 400 
                 50.8 
                 254 
               
               
                   
                 Benzocaine 
                 17.7 
                 88.5 
               
               
                   
                 Methylparaben 
                 0.177 
                 0.885 
               
               
                   
                 Phenylcarbinol 
                 0.442 
                 2.21 
               
               
                   
                 N &amp; A Spearmint Flavor 
                 0.708 
                 3.54 
               
               
                   
                 PEG 400 
                 10.0 
                 50.0 
               
               
                   
                 Yellow #10 
                 0.0106 
                 0.0530 
               
               
                   
                 Red #40 
                 0.0106 
                 0.0530 
               
               
                   
                 Blue #1 
                 0.000221 
                 0.0011 
               
               
                   
                 Total 
                 100 
                 500 
               
               
                   
                   
               
             
          
         
       
     
     The ingredients were mixed in accordance with the following procedure: 
     Into a 150 ml. beaker were placed 50 grams each of PEG 400 and propylene glycol and the mixture was stirred and heated to 70-75° C. The saccharin was added to the heated solution which was then cooled to 25-30° C. Into a second container were placed 254 grams of PEG 400 and the benzocaine was added with stirring until the benzocaine had dissolved. Into a third container were placed 100 grams of PEG 400 and the dyes were added with stirring until dissolved. 
     To the benzocaine solution in the second container was added the saccharin solution from the first container and mixed well. The methyl paraben was then added to the second container with stirring until dissolved. The phenylcarbinol was then added to the second container and stirred until dissolved. Next, the flavors were added and then the dye solution from the third container. 
     The product was a uniform liquid at room temperature with no crystallization and no precipitation. The product is bitter but does not have a bitter after taste. 
     EXAMPLE 2 
     The following ingredients were incorporated into the analgesic regular strength liquid composition of this invention. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Weight % 
                 Grams Per 10 K 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 PFG 400 NF 
                 70.6 
                 7060. 
               
               
                   
                 Propylene Glycol USP 
                 8.93 
                 893.0 
               
               
                   
                 Saccharin NF 
                 0.223 
                 22.3 
               
               
                   
                 Benzocaine USP 
                 8.93 
                 893. 
               
               
                   
                 Methylparaben NF 
                 0.179 
                 17.9 
               
               
                   
                 Phenylcarbinol NF 
                 0.446 
                 44.6 
               
               
                   
                 N &amp; A Spearmint Flavor 
                 0.714 
                 71.4 
               
               
                   
                 PFG 400 NF 
                 10.0 
                 1000.0 
               
               
                   
                 D &amp; C Red #33 
                 0.000446 
                 0.0446 
               
               
                   
                 FD &amp; C Blue #1 
                 0.0000621 
                 0.00621 
               
               
                   
                 FD &amp; C Yellow #6 
                 0.00104 
                 0.104 
               
               
                   
                 D &amp; C Yellow 10 
                 0.00402 
                 0.402 
               
               
                   
                 Total 
                 100 
                 1003 
               
               
                   
                   
               
             
          
         
       
     
     The ingredients were mixed in accordance with the following procedure. 
     Into a 15 kilogram stainless steel kettle fitted with a Lightnin&#39; mixer were added 7060 g of PEG 400 and 893 g of propylene glycol. The mixer was turned on to form a vortex. The saccharin was added and mixed for 25 minutes. The benzocaine was slowly sprinkled into the vortex and stirred for 50 minutes until completely dissolved. Concurrently, 1000 g of PEG 400 were placed into a 1200 ml stainless steel beaker fitted with a Lightnin&#39; mixer which was turned on to form a vortex. The dyes were sequentially added and mixed until dissolved. 
     When benzocaine is completely dissolved in first container, add the methylparaben and when dissolved add to the phenylcarbinol and then the flavorings. The dye solution is then added to the first container with mixing. 
     The product was a clear amber, slightly viscous liquid with a flavor and odor characteristic of spearmint. 
     EXAMPLE 3 
     The following ingredients were incorporated into the analgesic maximum strength gel formulation of the invention. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredients 
                 Weight % 
                 Grams Per 2 Kg 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Part 1 
                   
                   
               
               
                   
                 PEG 400, USP 
                 42.8 
                 400.0 
               
               
                   
                 Glycerin 96% USP 
                 8.62 
                 400.0 
               
               
                   
                 Propylene Glycol 
                 17.2 
                 200.0 
               
               
                   
                 Saccharin 
                 9.216 
                 5.0 
               
               
                   
                 Carbomer 934P 
                 1.94 
                 45.0 
               
               
                   
                 Benzocaine, USP 
                 17.2 
                 400.0 
               
               
                   
                 Part II 
               
               
                   
                 Methylparaben, USP 
                 0.172 
                 4.0 
               
               
                   
                 Phenylcarbinol 
                 0.431 
                 10.0 
               
               
                   
                 Spearmint Flavor 
                 1.72 
                 40.0 
               
               
                   
                 Part III 
               
               
                   
                 PBG 400, USP 
                 10.0 
                 200.0 
               
               
                   
                 FD &amp; C Blue #1 
                 0.000086 
                 0.0020 
               
               
                   
                 D &amp; C Yellow #10 
                 0.00414 
                 0.0960 
               
               
                   
                 FD &amp; C Red #40 
                 0.00414 
                 0.0960 
               
               
                   
                 Part IV 
               
               
                   
                 PEG 400, USP 
                 QS to 2000 ml 
               
               
                   
                   
               
             
          
         
       
     
     The ingredients were mixed in accordance with the following procedure in a 2 kilogram jacketed Hobart bowl with a T-line mixer with a 2 inch blade and a stir bar plate. 
     Into the bowl were placed 400 grams of PEG 400, the glycerin (96%) and the propylene glycol and mixed at low speed until uniform. The mixture was heated to 75°-80° C. with steam, the saccharin was added as dissolved, and the mixture cooled to 55° C. The benzocaine and the carbomer were dry blended in a plastic bag and then added to the bowl with mixer at high speed to pull powders into the vortex. The sides were scraped regularly and a temperature of 60-65° C. was maintained. After 3.5 hours, the carbomer was completely dissolved and the methylparaben and phenylcarbinol was added and dissolved. 
     Into 400 ml beaker equipped with a bar/plate were added the coloring dyes and the resulting solution was added to the main batch with mixing until uniform then PEG 400 was added QS to 2000 ml in the main batch. 
     The product was a clear reddish-brown gel with an odor and taste characteristic of spearmint. EXAMPLE 4 
     The following ingredients were incorporated into the analgesic regular strength gel formulation of the invention. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredients 
                 Weight % 
                 Grams Per 2 kg. 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Part 1 
                   
                   
               
               
                   
                 PEG 400 NF 
                 50.6 
                 1012. 
               
               
                   
                 Propylene Glycol 
                 8.62 
                 172.4 
               
               
                   
                 Glycerin 
                 17.2 
                 344. 
               
               
                   
                 Saccharin NF Powder 
                 0.216 
                 4.32 
               
               
                   
                 Carbomer 934P 
                 1.94 
                 38.8 
               
               
                   
                 Benzocaine 
                 9.08 
                 181.6 
               
               
                   
                 Part II 
               
               
                   
                 Methylparaben 
                 0.172 
                 3.44 
               
               
                   
                 Phenylcarbinol 
                 0.431 
                 8.62 
               
               
                   
                 Spearmint Flavor 
                 1.72 
                 34.4 
               
               
                   
                 Part III 
               
               
                   
                 PEG 400 NF 
                 10.0 
                 200.0 
               
               
                   
                 D &amp; C Red #33 
                 0.000950 
                 0.0190 
               
               
                   
                 FD &amp; C Yellow #6 
                 0.00100 
                 0.0200 
               
               
                   
                 FD &amp; C Blue #1 
                 0.0000600 
                 0.0012 
               
               
                   
                 D &amp; C Yellow #10 
                 0.00250 
                 0.0500 
               
               
                   
                   
                 100% 
                 2000 
               
               
                   
                   
               
             
          
         
       
     
     The ingredients were mixed essentially in accordance with the procedure of Example 3. The product was a clear orangish brown soft gel with a mint odor and taste. 
     The alkanol free glycol based oral analgesic compositions of the invention are surprisingly resistant to microbiological degradation due to the unique preservative agent combination of methylparaben and phenylcarbinol. For example, the preservative agent was efficacious in testing in accordance with an adaptation of the USP methods for inoculating test organisms showing no growth for 28 days. 
     The five organisms used as test organisms were those listed in the USP as follows: 
     
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 
                   Escherichia coli 
                 
                 ATCC #8739 
               
               
                   
                 
                   Staphylococcus aurens 
                 
                 ATCC #6538 
               
               
                   
                 
                   Pseudomonas aeruginosa 
                 
                 ATCC #9027 
               
               
                   
                 
                   Candida albicans 
                 
                 ATCC #10231 
               
               
                   
                 
                   Aspergillus niger 
                 
                 ATCC #16404 
               
               
                   
                   
               
             
          
         
       
     
     In order to determine the efficacy of the preservation agents at lower concentrations additional samples were prepared corresponding to Examples 1 and 3 in which the preservation agent concentrations were 50% and 75% of the corresponding examples. 
     Accordingly three samples corresponding to Example 1 were prepared with the same proportions of ingredients as Example 1 except that the proportions of methylparaben and phenylcarbinol were each reduced by 25% in one sample, by 50% in the second sample, and by 75% in the third sample, the reduction in weight being replaced with PEG-400 in each instance. 
     Similarly three samples corresponding to Example 3 were prepared with the same proportions of ingredients as in Example 3 except that the proportions of methylparaben and phenylcarbinol were each reduced by 25% in one sample, by 50% in the second sample, and by 75% in the third sample, the reduction in weight being replaced with PEG-400 in each instance. 
     The samples corresponding to Examples 1 and 3 with reduced preservation agent concentrations were tested in accordance with the same procedure as the compositions of Examples 1 and 3 and again the analgesic compositions of the invention were surprisingly resistant to microbiological degradation showing no growth for 28 days. 
     The compositions of the invention must be anhydrous due to the poor water solubility of the methylparaben and the benzocaine and to provide an environment impervious to microbiological growth.