Skin Penetration Enhancing Systems for Polar Drugs

Abstract

The invention relates to pharmaceutical compositions and related methods for the topical administration of polar drugs. In a particular embodiment, the invention relates to a pharmaceutical composition comprising an active pharmaceutical agent that is a polar drug, such as potassium 2,5-dihydroxybenzenesulfonate, at least one occlusive agent, and at least one stabilizer.

1 . A topical pharmaceutical skin penetration enhancing system, comprising:
 a. an active pharmaceutical agent;   b. an occlusive agent; and   c. a stabilizer,   
       wherein the active pharmaceutical agent is polar or ionic and wherein at least 0.1% of the applied dose of the active pharmaceutical agent is capable of penetrating skin over a period of 24 hours. 
     
     
         2 . The system of  claim 1 , wherein at least 0.5% of the applied dose of the active pharmaceutical agent is capable of penetrating skin over a period of 24 hours. 
     
     
         3 . The system of  claim 1 , wherein at least 1.0% of the applied dose of the active pharmaceutical agent is capable of penetrating skin over a period of 24 hours. 
     
     
         4 . The system of  claim 1 , wherein at least 3.0% of the applied dose of the active pharmaceutical agent is capable of penetrating skin over a period of 24 hours. 
     
     
         5 . The system of  claim 1 , wherein at least 5.0% of the applied dose of the active pharmaceutical agent is capable of penetrating skin over a period of 24 hours. 
     
     
         6 . The system of  claim 1 , wherein the active pharmaceutical agent is in a salt form. 
     
     
         7 . The system of  claim 1 , further comprising a surfactant. 
     
     
         8 . The system of  claim 1 , further comprising one or more of an agent selected from the group consisting of: a stiffening agent, a preservative, an antioxidant, a pH adjuster, and a solvent. 
     
     
         9 . The system of  claim 1 , wherein the active pharmaceutical agent is a 2,5-dihydroxybenzene derivative represented by Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —(CH 2 ) a Y or —CH═CH—(CH 2 ) p Y; 
         Y is —SO 3 H, —(SO 3 ) − .X + , —SO 3 R 3 , —PO 3 H, —(PO 3 ) − .X + , —PO 3 R 3 , —CO 2 H, —(CO 2 ) − .X +  or —CO 2 R 3 ; 
         X +  is an organic cation or an inorganic cation, such that the general charge of the compound of Formula (I) is neutral; 
         R 9  and R 9′  are independently selected from —OH and —OR 2 , wherein when R 9  and R 9′  are both —OR 2 , then said R 9  and R 9′  can be the same or different; 
         R 2  is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkylcarbonyl group or a substituted or unsubstituted arylcarbonyl group; 
         R 3  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; 
         a is a number selected from 0, 1, 2, 3, 4, 5 and 6; and 
         p is a number selected from 0, 1, 2, 3, 4, 5 and 6. 
       
     
     
         10 . The system of  claim 9 , wherein the active pharmaceutical agent is selected from the group consisting of:
 calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate);   potassium 2,5-dihydroxybenzenesulfonate (potassium dobesilate);   magnesium 2,5-dihydroxybenzenesulfonate (magnesium dobesilate); and   diethylamine 2,5-dihydroxybenzenesulfonate (ethamsylate).   
     
     
         11 . The system of  claim 10 , wherein the active pharmaceutical agent is potassium 2,5-dihydroxybenzenesulfonate (potassium dobesilate). 
     
     
         12 . A topical pharmaceutical composition comprising potassium 2,5-dihydroxybenzenesulfonate (potassium dobesilate), wherein when the pharmaceutical composition is applied to skin in a Bronaugh flow-through diffusion cell system
 (a) at a dose of about 5 mg/cm 2  of the composition;   (b) the cells are maintained at a constant temperature of about 32° C.;   (c) the receptor phase is phosphate buffered saline comprising 0.1% sodium azide and 4% bovine serum albumin; and   (d) the receptor phase flow-through is about 1 to 2 mL per hour, the in vitro tissue permeation of the potassium 2,5-dihydroxybenzenesulfonate ranges from about 1.0% to about 10% of the applied dose within 24 hours of application.   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the in vitro tissue permeation of the potassium 2,5-dihydroxybenzenesulfonate ranges from about 0.5% to about 5% within 12 hours of application. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the in vitro tissue permeation of the potassium 2,5-dihydroxybenzenesulfonate ranges from about 0.2% to about 2.0% within 6 hours of application. 
     
     
         15 . The system of  claim 1 , wherein the occlusive agent is selected from the group consisting of: hydrocarbon waxes and oils. 
     
     
         16 . The system of  claim 15 , comprising at least two occlusive agents wherein the at least two occlusive agents are white petrolatum and mineral oil. 
     
     
         17 . The system of  claim 1 , wherein the stabilizer is a surfactant selected from the group consisting of: emulsifying agents, cleansing agents, foam boosters, solubilizing agents, suspending agents, and hydrotropes. 
     
     
         18 . The system of  claim 17 , wherein the stabilizer is an emulsifying agent selected from the group consisting of: steareth, sorbitan, polysorbate, and polyethylene glycol derivatives. 
     
     
         19 . The system of  claim 18 , comprising at least two emulsifying agents wherein the at least two emulsifying agents are steareth-2 (Brij 72) and steareth-21 (Brij 721). 
     
     
         20 . A topical pharmaceutical skin penetration enhancing system, comprising:
 a. potassium 2,5-dihydroxybenzenesulfonate (potassium dobesilate);   b. about 0.1-99% of at least one occlusive agent; and   c. about 0.1-5% of at least one surfactant.   
     
     
         21 . The system of  claim 20 , further comprising a preservative, an antioxidant, a pH adjuster, and a solvent. 
     
     
         22 . The system of  claim 20 , comprising about 0.1-20.0% potassium 2,5-dihydroxybenzenesulfonate, about 0.1-90.0% white petrolatum, about 0.1-90.0% mineral oil, about 0.1-50% stearyl alcohol, about 0.05-50% cetyl alcohol, about 0.1-5% steareth-2 (Brij 72), and about 0.1-5% steareth-21 (Brij 721). 
     
     
         23 . The system of  claim 22 , further comprising about 0.1-5% benzyl alcohol, about 0.001-0.5% sodium thiosulfate pentahydrate, about 0.01-10% acetic acid, about 0.001-1.0% sodium acetate, and about 0-90.0% water. 
     
     
         24 . The system of  claim 23 , comprising about 10% potassium 2,5-dihydroxybenzenesulfonate, about 20% white petrolatum, about 20% mineral oil, about 2.5% stearyl alcohol, about 0.5% cetyl alcohol, about 1.0% steareth-2, about 4.0% steareth-21, about 0.5% benzyl alcohol, about 0.1% sodium thiosulfate pentahydrate, about 0.05% acetic acid, about 0.02% sodium acetate, and water to 100%. 
     
     
         25 . A method of treating a skin disorder, comprising topically administering the system of  claim 24  to the effected area of a patient.