Skin Penetration Enhancing Systems for Polar Drugs

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.