Transdermal delivery formulations

Abstract

A transdermal formulation for the delivery of a nitric oxide booster or nitric oxide precursor to a subject is provided. The formulation can be applied to the treatment of various diseases or conditions by enhancing systemic level of nitric oxide.

1 . A transdermal formulation for enhancing systemic nitric oxide (NO), comprising:
 (a) an effective amount of an NO booster and optionally an NO precursor, wherein the NO booster comprises one or more agents selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin, quercetin, berberine, resveratrol and vitamin D, and wherein the NO precursor comprises a S-nitrosothiol-containing molecule, or a thiol-containing molecule and a nitrite source;   (b) a polyol in an amount sufficient to dissolve the effective amount of the NO booster, wherein the polyol and the NO booster are in a ratio ranging from about 8:1 to about 12:1; and optionally   (c) fatty acid, wherein the polyol and the fatty acid are in a ratio ranging from about 10:1 to about 50:1 by weight,   wherein the amounts of the polyol and the fatty acid are selected so that upon administration the effective amount of the NO booster is delivered transdermally.   
     
     
         2 . The transdermal formulation of  claim 1 , comprising the S-nitrosothiol-containing molecule as NO releasing agent. 
     
     
         3 . The transdermal formulation of  claim 1 , wherein the fatty acid is myristic acid. 
     
     
         4 . The transdermal formulation of  claim 1 , wherein the polyol is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, and glycerol. 
     
     
         5 . The transdermal formulation of  claim 1 , wherein the polyol is polyethylene glycol having a molecular weight ranging from 200 to about 600. 
     
     
         6 . The transdermal formulation of  claim 1 , which comprises curcumin. 
     
     
         7 . The transdermal formulation of  claim 1 , which comprises curcuminoids ranging from about 3% to about 10% by weight. 
     
     
         8 . The transdermal formulation of  claim 8 , wherein the amounts of the curcuminoids and the polyol are selected to provide a continued release of the curcuminoids over a period of about 15 hours. 
     
     
         9 . A method of treating a disease or condition associated with endothelial dysfunction in a subject, comprising administering to the subject the transdermal formulation of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein the disease or condition is selected from aging, chronic and acute inflammatory condition, chemically induced vascular inflammation, viral infection, bacterial infection, fungal infection, hypertension, coronary artery disease, heart failure, stroke, peripheral artery disease, myocardial infarction, diabetes, chronic renal failure, abnormal vascular smooth muscle cell proliferation, type 2 diabetes, insulin resistance, Lupus, HIV, inflammation resulting from radiation and drug treatment, hemoglobinopathies, cytokine storm associated condition induced by viral disease, erectile dysfunction, leg ulcer, inflammation associated with increased populations of senescent cells occurring with age, sleep apnea, sepsis, and chronic obstructive pulmonary disease. 
     
     
         11 . The method of  claim 9 , wherein the disease or condition is selected from the group consisting of cardiovascular disease, renal failure; hypertension, stroke and microemboli, open wound, sexual dysfunction, bladder dysfunction, neuropathic pain and cognitive decline. 
     
     
         12 . The method of  claim 9 , wherein the NO booster and its amount are selected to reduce one or more inflamatory makers by at least about 10%, wherein the one or more inflamatory makers are selected from the group consisting of TNF-α, TGFβ, MCP-1, IL-1α, IL-1β, IL-6, IL-10, MIF, TNF-β, MMP9, HIF-1, GLUT1, Hemox, PDK1, VEGF, CD11, and EMR1. 
     
     
         13 . The method of  claim 9 , wherein the subject has been diagnosed to have hypertension or is at risk of developing hypertension. 
     
     
         14 . The method of  claim 13 , wherein the NO booster and its amount are selected so that systolic pressure and/or diastolic pressure of the subject is reduced by at least 10 mm. 
     
     
         15 . The method of  claim 9 , wherein the subject has a higher than normal level of blood glucose or is at risk of developing a higher than normal level of blood glucose. 
     
     
         16 . The method of  claim 15 , wherein prior to the treatment the subject has an abnormal level of blood glucose, wherein the abnormal level is higher than a normal level or the level of a healthy subject by at least about 10%. 
     
     
         17 . The method of  claim 15 , wherein the NO booster and its amount are selected so that the blood glucose is reduced by at least about 10%. 
     
     
         18 . The method of  claim 9 , wherein the subject has been diagnosed to have type 2 diabetes. 
     
     
         19 . The method of  claim 18 , wherein the transdermal formulation comprises
 (a) an effective amount of one or more agents selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin, and quercetin;   (b) PEG having a molecular weight ranging from about 200 to about 600 in an amount sufficient to dissolve the effective amount of the one or more agents, wherein the PEG and the one or more agents are in a ratio ranging from about 8:1 to about 12:1; and   (c) myristic acid, wherein the PEG and the myristic acid are in a ratio ranging from about 10:1 to about 50:1 by weight.   
     
     
         20 . The method of  claim 19 , wherein the one or more agents comprise curcumin. 
     
     
         21 . The method of  claim 19 , wherein the one or more agents and their amount are selected so that it increases a subject's systemic NO level or plasma nitrite level by at least 10%. 
     
     
         22 . The method of  claim 19 , wherein the transdermal formulation is administered prophylactically.