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.

1 - 20 . (canceled) 
     
     
         21 . An oil-in-water nanoemulsion composition comprising:
 an oil phase comprising long chain triglyceride and/or other oils;   an ionizable surfactant and a co-surfactant;   an aqueous phase;   a pH adjusting agent, and   an active component,   wherein the composition contains no alcohol.   
     
     
         22 . The composition of  claim 21 , 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. 
     
     
         23 . The composition of  claim 21 , wherein a mean droplet size (intensity-average, nm) is below 100 nm. 
     
     
         24 . The composition of  claim 21 , wherein the mean droplet size (intensity-average, nm) is below 75 nm. 
     
     
         25 . The composition of  claim 21 , wherein the composition contains 0.5-50% w/v oil phase. 
     
     
         26 . The composition of  claim 21 , wherein the nanoemulsion is stable and optically clear with an oil phase concentration between 0.5-50% w/v. 
     
     
         27 . The composition of  claim 26 , wherein the oil phase contains at least 10% w/w long chain triglycerides. 
     
     
         28 . The composition of  claim 21 , wherein the oil phase is chosen from soy bean 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. 
     
     
         29 . The composition of  claim 21 , wherein the total weight of the surfactant and the co-surfactant is less than or equal to 40%, or 36%, 30%, 20%, or 15% (w/v) of the composition. 
     
     
         30 . The composition of  claim 21 , wherein the total weight of the surfactant and the co-surfactant is less than or equal to that of the oil phase. 
     
     
         31 . The composition of  claim 21 , 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. 
     
     
         32 . The composition of  claim 21 , wherein the surfactant is ionizable in the pH range of 0-10. 
     
     
         33 . The composition of  claim 21 , wherein the surfactant concentration is less than 35%, 30%, or 21% w/v of the nanoemulsion composition. 
     
     
         34 . The composition of  claim 21 , wherein the surfactant is chosen from pharmaceutically acceptable biocompatible surfactants comprising phospholipids extracted from egg yolk or soy bean, phospholipids derivatives, synthetic phosphatidyl cholines, purified phosphatidyl cholines from vegetable origin, or hydrogenated phospholipid derivatives. 
     
     
         35 . The composition of  claim 21 , 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 deriviatives or salts; oleic acid, sodium oleate, cholic acid, sodium cholate, deoxycholic acid, deoxysodium cholate or a mixture thereof. 
     
     
         36 . The composition of  claim 21 , wherein the composition comprises 0.5-50% (w/v) of oil phase that contains 0.05-50% (w/v) of long chain triglyceride; 0.1-30% (w/v) of egg lecithin, 0.01-30% (w/v) polysorbate 80, and water. 
     
     
         37 . A stable, optically clear, oil-in-water nanoemulsion composition comprising:
 an oil phase comprising long chain triglyceride and/or other oils,wherein the composition comprises 0.5% to 50% (w/v) of the oil phase,   the oil phase contains at least 10% (w/v) of the long chain triglyceride;   an ionizable surfactant and a co-surfactant,   wherein the ionizable surfactant comprises 0.01% to 30% (w/v) of the composition, and   wherein the co-surfactant comprises 0.01% to 30% (w/v) of the composition;   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.   
     
     
         38 . 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 either in the oil phase or in the aqueous 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. 
 
     
     
         39 . The method of  claim 38 , 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). 
     
     
         40 . 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.