Non-steroidal anti-inflammatory drug formulations for topical applications to the skin

Abstract

Topical alcoholic or aqueous alcoholic gels containing ibuprofen or other NSAIDs, such as, naproxen, in substantially neutral salt form, have enhanced penetration through skin and may provide rapid pain/inflammation relief by including in the formulation 2-n-nonyl-1,3-dioxolane or other hydrocarbyl derivative of 1,3-dioxolane or 1,3-dioxane or acetal, as skin penetration enhancing compound. The amount of propylene glycol may be varied to adjust the initial flux of the NSAID through the skin, especially for ibuprofen, naproxen, and ketorolac.

1 . A substantially neutral ibuprofen containing alcoholic or aqueous alcoholic composition which comprises, on a weight basis, of the total composition: 
 a therapeutically effective amount of ibuprofen in the form of a pharmacologically acceptable salt of;    a skin penetration enhancing effective amount of C 7  to C 14 -hydrocarbyl substituted 1,3-dioxolane, 1,3-dioxane or acetal;    0 to about 18% of glycol having from 3 to 6 carbon atoms;    at least about 40% of volatile alcohol selected from the group consisting of ethanol, propanol and mixture thereof;    0 to about 40% of water;    base to provide a pH in the range of from about 6 to about 8, and,    optionally, a gelling agent effective to thicken the composition to avoid or minimize run-off when applied to the skin.    
   
   
       2 . The composition according to  claim 1  which comprises 
 from about 2 to 10% ibuprofen;    from about 4 to 15% of the enhancer wherein the hydrocarbyl group substituent has from about 7 to 10 carbon atoms;    from about 0 to 15% propylene glycol;    from about 55 to 70% ethanol;    from about 4 to 35% water;    base in amount to adjust the pH of the composition in the range of from about 6.5 to about 7.5, and,    0 to about 2% of cellulosic thickener.    
   
   
       3 . A substantially neutral alcoholic or aqueous alcoholic topical composition effective for the transdermal delivery of non-steroidal anti-inflammatory drug which comprises, based on the weight of the total composition, 
 a therapeutically effective amount of a pharmacologically acceptable salt of a non-steroidal anti-inflammatory drug selected from the group consisting of heteroaryl acetic acids, arylpropionic acids (other than ibuprofen), anthranilic acids, enolic acids, alkanones, sulindac and etodolac;    from about 0.5 to 25% of C 7  to C 14 -hydrocarbyl derivative of 1,3-dioxolane, 1,3-dioxane or acetal as skin penetration enhancer;    0 to about 40% of glycol having from 3 to 6 carbon atoms;    at least about 40% of volatile alcohol selected from the group consisting of ethanol, propanol and mixtures thereof;    up to about 40% water;    base in an amount to provide a pH of from about 6 to about 8, and    up to about 5% gelling agent.    
   
   
       4 . The composition according to  claim 3  which comprises: 
 from about 0.1 to 10% diclofenac, ketorolac, naproxen, flurbiprofen, ketoprofen or piroxicam;    from about 2 to 15% of the skin penetration enhancer;    0 to about 30% propylene glycol;    from about 35 to 70% ethanol, isopropanol or mixture thereof;    0 to about 20% water;    from about 0.1 to 3% gelling agent, and    base to provide a pH in the range of from about 6.5 to about 7.5.    
   
   
       5 . A glycol-free topical composition effective for the transdermal administration of naproxen, which comprise, on a weight basis of the total composition: 
 a pharmaceutically effective amount of naproxen,    from about 2 to 20% of 2-C 7 -C 14  hydrocarbyl substituted 1,3-dioxolane, 1,3-dioxane, or acetal skin penetration enhancer;    from about 35 to 85% ethanol, iso-propanol, or mixture thereof;    0 to about 40% water;    base in an amount to provide a pH in the range of from about 6 to about 8, and    up to about 5% gelling agent.    
   
   
       6 . A method for the transdermal administration of ibuprofen to a patient in need thereof which comprises 
 topically applying to the skin of the patient a substantially neutral composition comprising from about 5 to 15 weight percent of ibuprofen in a vehicle comprising a lower alcohol selected from the group consisting of ethanol, isopropanol and mixture thereof, alkyl glycol having from 3 to 6 carbon atoms, and water in a mixing ratio of alcohol:glycol:water of 40-80:0-20:0-40, said vehicle comprising from about 70 to 90 weight percent of the composition, and from about 5 to 15 weight percent of a skin penetration enhancing compound selected from the group consisting of 2-hydrocarbyl-1,3-dioxolane, 2-hydrocarbyl-1,3-dioxane and hydrocarbyl substituted-acetal, wherein the hydrocarbyl group has from 7 to 14 carbon atoms.    
   
   
       7 . A method for the transdermal administration of a non-steroidal antiinflammatory drug selected from the group consisting of heteroaryl acetic acids, arylpropionic acids (other than ibuprofen), anthranilic acids, enolic acids, alkanones, sulindac and etodolac to a patient in need thereof which comprises 
 topically applying to the skin of the patient a substantially neutral composition comprising from about 0.1 to 10 weight percent of the non-steroidal antiinflammatory drug in a vehicle comprising a lower alcohol selected from the group consisting of ethanol, isopropanol and mixture thereof, alkyl glycol having from 3 to 6 carbon atoms, and water in a mixing ratio of alcohol:glycol:water of 40-80:0-40:0-40, said vehicle comprising form about 70 to 90 weight percent of the composition, and from about 0.5 to 25 weight percent of a skin penetration enhancing compound selected from the group consisting of 2-hydrocarbyl-1,3-dioxolane, 2-hydrocarbyl-1,3-dioxane and hydrocarbyl substituted-acetal, wherein the hydrocarbyl group has from 7 to 14 carbon atoms.    
   
   
       8 . A method for the transdermal administration of naproxen to a patient in need thereof which comprises 
 topically applying to the skin of the patient a substantially neutral composition comprising a therapeutically effective amount of naproxen in a glycol-free vehicle comprising a lower alcohol selected from the group consisting of ethanol, isopropanol and mixture thereof, and water in a mixing ratio of alcohol:water of 35-85:10-40, said vehicle comprising from about 70 to 90 weight percent of the composition, and from about 2 to 20 weight percent of a skin penetration enhancing compound selected from the group consisting of 2-hydrocarbyl-1,3-dioxolane, 2-hydrocarbyl-1,3-dioxane and hydrocarbyl substituted-acetal, wherein the hydrocarbyl has from 7 to 14 carbon atoms.    
   
   
       9 . The composition of  claim 3 , wherein the non-steroidal antiinflammatory comprises a salt of diclofenac or ketoprofen.  
   
   
       10 . The composition of  claim 3 , wherein the non-steroidal antiinflammatory comprises a salt of diclofenac.  
   
   
       11 . The composition of  claim 4 , wherein the non-steroidal antiinflammatory comprises a salt of diclofenac.  
   
   
       12 . The composition of  claim 4 , wherein the non-steroidal antiinflammatory comprises a salt ketoprofen.  
   
   
       13 . The composition of  claim 3  wherein the amount of skin penetration enhancer is from about 5 to about 10%.  
   
   
       14 . The composition of  claim 3  which comprises 2-n-nonyl-1,3-dioxolane as skin penetration enhancing compound.  
   
   
       15 . The composition according to  claim 3  wherein the non-steroidal antiinflammatory drug comprises a salt of naproxen.