Lipid vesicle compositions with penetration enhancing agents

Abstract

The present application is related to a pharmaceutical composition a biphasic lipid vesicle comprising a lipid bilayer comprising vesicle forming lipids; an oil-in-water emulsion stabilized by one or more surfactants; one or more compounds; and one or more penetration enhancing agents. The one or more penetration enhancing agents include one or more non-ionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 10 or less, alone or combination with one or more penetration enhancing agents selected from one or more of terpenes, alkaloids, salicylate derivatives, and polycationic surfactants and combinations thereof. The present application is also related to a pharmaceutical composition comprising a biphasic lipid vesicle comprising a lipid bilayer comprising vesicle forming lipids; an oil-in-water emulsion stabilized by one or more polycationic surfactants; and one or more compounds.

1 . A method of generating biphasic lipid vesicles, comprising:
 a. preparing an oil-in-water emulsion by mixing one or more oil components of the oil-in-water emulsion with one or more aqueous components of the oil-in-water emulsion;   b. solubilizing one or more vesicle forming lipids in a solvent other than water;   c. adding one or more penetration enhancing agents to the oil components, the aqueous components, or the solubilized vesicle forming lipids, wherein the one or more penetration enhancing agents comprise one or more non-ionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 10 or less;   d. adding the oil-in-water emulsion to the solubilized vesicle forming lipids; and   e. mixing the oil-in-water emulsion and the solubilized vesicle forming lipids under mixing conditions effective to form the biphasic lipid vesicles comprising a lipid bilayer, the oil-in-water emulsion entrapped in the biphasic lipid vesicles, and the one or more penetration enhancing agents entrapped in the oil-in-water emulsion or the lipid bilayer.   
     
     
         2 . The method of  claim 1 , wherein the one or more penetration enhancing agents are entrapped in the oil-in-water emulsion. 
     
     
         3 . The method of  claim 1 , wherein the one or more penetration enhancing agents are entrapped in the lipid bilayer and the oil-in-water emulsion. 
     
     
         4 . The method of  claim 1 , wherein the lipid bilayer comprises about 10 wt %, about 9 wt %, about 8 wt %, about7 wt %, about 6 wt %, about 5 wt %, about 4 wt %, about3 wt %, about 2 wt %, about 1 wt %, about 0.5 wt % or about0.1 wt % of the one or more penetration enhancing agents. 
     
     
         5 . The method of  claim 1 , wherein the one or more non-ionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 10 or less comprises polyethylene glycol ethers of fatty alcohols, sorbitan esters, polysorbates, sorbitan esters, polyethylene glycol fatty acid esters, or any combination thereof. 
     
     
         6 . The method of  claim 5 , wherein the polyethylene glycol ethers of fatty alcohols having the HLB of about 10 or less comprise diethylene glycol hexadecyl ether, 2-(2-octadecoxyethoxy)ethanol, diethylene glycol monooleyl ether, polyoxyethylene (3) oleyl ether, polyoxyethylene (5) oleyl ether, or any combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the polyethylene glycol fatty acid esters having the HLB of about 10 or less comprise PEG-8 dilaurate, PEG-4 dilaurate, PEG-4 laurate, PEG-8 dioleate, PEG-8 distearate, PEG-8 distearate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, or any combination thereof. 
     
     
         8 . The method of  claim 1 , wherein the one or more non-ionic surfactants having the H LB of about 10 or less comprise an oleyl ether having the HLB of about 10 or less. 
     
     
         9 . The method of  claim 1 , wherein the one or more penetration enhancing agents further comprise one or more terpenes, one or more alkaloids, one or more salicylate derivatives, one or more polycationic surfactants, or any combination thereof. 
     
     
         10 . The method of  claim 9 , wherein the terpenes comprise eugenol, d-limonene, menthol, menthone, farnesol, neridol, camphor, nerol, thymol, or any combination thereof. 
     
     
         11 . The method of  claim 9 , wherein the salicylate derivatives comprise ethyl salicylate, salicylic acid, acetylsalicylic acid, trolamine salicylate, or any combination thereof. 
     
     
         12 . The method of  claim 9 , wherein the alkaloids comprise piperine, lobeline, caffeine, theobromine theophylline, nicotine, colchicine, N-methyl pyrrolidone, hygrine, capsaicin, berberine, sanguinarine, histamine, pilocarpine, or any combination thereof. 
     
     
         13 . The method of  claim 9 , wherein the polycationic surfactants comprise one or more gemini cationic surfactants and the one or more gemini cationic surfactants are of a quaternary ammonium type. 
     
     
         14 . The method of  claim 9 , wherein the polycationic surfactants comprise polycationic amino acids. 
     
     
         15 . The method of  claim 1 , wherein the one or more penetration enhancing agents having the HLB of about 10 or less comprise diethylene glycol monooleyl ether, PEG-4 dilaurate, sorbitan monopalmitate, or any combination thereof. 
     
     
         16 . The method of  claim 1 , wherein the oil-in-water emulsion of the biphasic lipid vesicles is stabilized by one or more surfactant comprising polyoxyethylene (10) cetyl ether and polysorbate 80. 
     
     
         17 . The method of  claim 1 , the solubilized vesicle forming lipids comprise one or more of phospholipids, glycolipids, lecithins, or ceramides. 
     
     
         18 . The method of  claim 1 , further comprising adding one or more compounds in (b). 
     
     
         19 . The method of  claim 18 , wherein the one or more compounds are entrapped in oil-in-water emulsion of the biphasic lipid vesicle, lipid bilayer of the biphasic lipid vesicle or both the oil-in-water emulsion and the lipid bilayer. 
     
     
         20 . The method of  claim 18 , wherein the one or more compounds comprise a small molecule, protein, peptide, carbohydrate, nucleic acid, vaccine antigen, plant extract, or any combination thereof.