Compositions for Nanoemulsion Delivery Systems

Abstract

The present disclosure provides a pharmaceutically acceptable, stable, and optically clear oil-in-water nanoemulsions (intensity-averaged diameter<100 nm) with an oil phase comprising >10% w/v of long chain triglyceride, total surfactant and cosurfactant concentration less than that of oil phase and without the use of alcohol as cosolvent in the aqueous phase. The nanoemulsions of this disclosure have extremely favorable particle size distribution, optical clarity, and product stability against Ostwald ripening with high levels of oil concentrations. Poorly water soluble, therapeutically active agents and others can be incorporated in the nanoemulsion systems to improve their solubility/stability in aqueous medium or to enhance their delivery for use in pharmaceutical, food, cosmetic, and other applications by oral, intravenous, subcutaneous, intra muscular, inhalation, nasal, topical, ocular, and transdermal routes.

What is claimed is: 
     
         1 . An oil-in-water nanoemulsion composition comprising:
 an oil phase comprising at least 10% (w/v) long chain triglycerides,   an ionizable surfactant, and a co-surfactant,
 wherein a total amount of the ionizable surfactant and the co-surfactant is about 10% (w/v) to about 15% (w/v) of the composition; 
   an aqueous phase;   a pH adjusting agent, and   an active component,   wherein the composition contains no alcohol;   wherein the composition demonstrates stability for at least two months at 40° C./75% RH; and   wherein the mean droplet size (intensity-average, nm) of the composition is below 100 nm.   
     
     
         2 . The composition of  claim 1 , wherein the composition further comprises one or more agents chosen from a chelate agent, an antioxidant, an osmotic agent, a preservative, a suspending agent, or a buffering agent. 
     
     
         3 . The composition of  claim 1 , wherein the mean droplet size (intensity-average, nm) is below 75 nm. 
     
     
         4 . The composition of  claim 1 , wherein the composition contains 10-50% w/v oil phase. 
     
     
         5 . The composition of  claim 1 , wherein the nanoemulsion is stable and optically clear with an oil phase concentration between 10-50% w/v. 
     
     
         6 . The composition of  claim 1 , wherein an oil of the oil phase is chosen from soybean oil, safflower seed oil, olive oil, cottonseed oil, sunflower oil, fish oil, castor oil, sesame oil, peanut oil, corn oil, medium chain triglycerides, or mixtures thereof. 
     
     
         7 . The composition of  claim 1 , wherein the total weight of the surfactant and the co-surfactant is less than or equal to that of the oil of the oil phase. 
     
     
         8 . The composition of  claim 1 , wherein the ratio of the surfactant and the co-surfactant is in the range of 10:0.1 to 0.1:10, 10:1 to 1:10, 10:1 to 1:5, or 5:1 to 1:5. 
     
     
         9 . The composition of  claim 1 , wherein the ionizable surfactant is ionizable in the pH range of 0-10. 
     
     
         10 . The composition of  claim 1 , wherein the ionizable surfactant is chosen from pharmaceutically acceptable biocompatible surfactants comprising phospholipids extracted from egg yolk or soybean, phospholipids derivatives, synthetic phosphatidyl cholines, purified phosphatidyl cholines from vegetable origin, or hydrogenated phospholipid derivatives. 
     
     
         11 . The composition of  claim 1 , wherein the co-surfactant is chosen from pharmaceutically acceptable surfactants, comprising poloxamers, poloxamines; polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters or sorbitan fatty acid esters; ionic surfactants including cholic acid and deoxycholic acid; surface active derivatives or salts; oleic acid, sodium oleate, cholic acid, sodium cholate, deoxycholic acid, deoxysodium cholate or a mixture thereof. 
     
     
         12 . The composition of  claim 1 , wherein the composition comprises 0.01-15% (w/v) of egg lecithin and 0.01-15% (w/v) polysorbate 80. 
     
     
         13 . A stable, optically clear, oil-in-water nanoemulsion composition comprising:
 an oil phase comprising long chain triglyceride and/or other oils, an ionizable surfactant, and a co-surfactant,   wherein the composition comprises 10% to 50% (w/v) of the oil phase,   wherein the oil phase contains at least 10% (w/v) of the long chain triglyceride,   wherein the ionizable surfactant comprises 0.01% to 15% (w/v) of the composition, and   wherein the co-surfactant comprises 0.01% to 15% (w/v) of the composition,   wherein a total amount of the ionizable surfactant and the co-surfactant is about 10% (w/v) to about 15% (w/v) of the composition, and   wherein the ionizable surfactant and the co-surfactant are incorporated into the oil phase before the oil phase is added to the aqueous phase;   an aqueous phase containing no alcohol as the cosolvent;   a pH adjusting agent; and   an active component other than cyclosporine;   wherein the mean droplet size (intensity-average, nm) of the composition is below 100 nm,   wherein said droplets demonstrate stability for at least two months at 40° C./75% RH; and   wherein the composition contains no alcohol.   
     
     
         14 . A method for making a stable, optically clear, oil-in-water nanoemulsion composition of  claim 1  comprising the steps of:
 a) preparing an oil phase comprising a long chain triglyceride; 
 b) preparing an aqueous phase; 
 c) incorporating an active component other than cyclosporine either in the oil phase or in the aqueous phase; 
 d) incorporating a biocompatible surfactant and co-surfactant in the oil phase; 
 e) dispersing the oil phase in the aqueous phase to form a coarse emulsion; 
 f) forming a final emulsion by sonicating, high pressure homogenizing, or high shear processing the emulsion of step e); and adjusting the pH, 
 wherein the composition contains no alcohol. 
 
     
     
         15 . The method of  claim 14 , wherein the aqueous phase of step b) includes a pH adjustment agent, and the active component is added into the final emulsion formed in step f). 
     
     
         16 . A method for treating a subject in need therefore comprising administering a formulation comprising the nanoemulsion composition of  claim 1  to a subject, wherein the active component is less than 50% w/v of the formulation.