Methods and formulations for enhancing the absorption and gastro-intestinal bioavailability of hydrophobic drugs

Abstract

A hydrophobic drug delivery system that includes a plant derived sterol (stanol) or a sterol (stanol) derived ester, an emulsifier and an active, hydrophobic drug, all dissolved and then dried to form a liposome delivery system.

1 . A solid, anhydrous drug delivery composition for normally difficultly soluble hydrophobic drug actives, which when added to water creates suspended liposomes, comprising 
 an amphiphile or emulsifier;    a sterol;    a drug active effective amount of a hydrophobic drug with the weight ratio of said amphiphile or emulsifier to the sterol and drug active combination being less than 3.0 and greater than 0.05.    
   
   
       2 . The composition of  claim 1  wherein the emulsifier is selected from, but not limited to, the following group: phospholipids and derivatives, mono and diglycerides, diacetyltartaric acid esters of mono and diglycerides, monoglyceride phosphate, acetylated monoglycerides, ethoxylated mono and diglycerides, lactylated monoglycerides, propylene glycol esters, polyglycerol esters, polysorbates, sorbitan esters, sodium and calcium stearoyl lactylate, succinylated monoglycerides, sucrose esters of fatty acids, fatty alcohols, sodium salts of fatty acids and combinations thereof.  
   
   
       3 . The composition of  claim 1  wherein the sterol is selected from, but not limited to, cholesterol and its derivatives, a plant derived sterol (stanol) or ester derived from the sterol (stanol) and combinations thereof.  
   
   
       4 . The composition of  claim 1  wherein a drug active effective amount is selected from any therapeutic class, but not limited to the following: anesthetics, anti-asthma agents, antibiotics, antidepressants, anti-diabetics, anti-epileptics, anti-fungals, anti-gout, anti-neoplastics, anti-obesity agents, anti-protozoals, anti-phyretics, anti-virals, anti-psychotics, calcium regulating agents, cardiovascular agents, corticosteroids, diuretics, dopaminergic agents, gastrointestinal agents, hormones (peptide and non-peptide), immunosuppressants, lipid regulating agents, phytoestrogens, prostaglandins, relaxants and stimulants, vitamins/nutritionals and xanthines.  
   
   
       5 . The drug delivery composition of  claim 1  wherein the emulsifier is lecithin or an active derivative of lecithin derived from food materials selected from the group consisting of soy, egg, or other recognized food or pharmaceutical grade commercial sources of lecithin material.  
   
   
       6 . The drug delivery composition of  claim 1  wherein the plant derived sterol (stanol) is a plant derived sterol (stanol) ester, derived from a plant or vegetable oil source.  
   
   
       7 . The composition of  claim 1  wherein the weight ratio of emulsifer to the weight ratio of the sterol (stanol) active drug combination is from 3.0 to 0.05.  
   
   
       8 . The composition of  claim 1  wherein the weight ratio of lecithin or an active derivative of lecithin to plant sterol (stanol) drug combination is 1.0.  
   
   
       9 . The composition of  claim 1  wherein the drug delivery composition includes as an additional hydrophobic compound vitamin E.  
   
   
       10 . The method of preparing a drug delivery system for normally difficultly soluble hydrophobic drug actives, comprising: 
 mixing an emulsifier with a plant derived sterol (stanol) or esters derived from plant sterol (stanol) in which the fatty acid ester moiety is derived from a vegetable oil, and a drug active, with a non-polar organic solvent;    removing the solvent to leave a solid residue of the mixed components;    adding water to the solid residue of the mixed components at a temperature less than the decomposition temperature of any one of the mixed components;    homogenizing the aqueous mixture;    drying the homogenized mixture; and    providing the dried solid residue of the mixed components in a solid pharmaceutical carrier format.    
   
   
       11 . The method of  claim 10  wherein the emulsifier is the phospholipid lecithin.  
   
   
       12 . The method of  claim 10  wherein the emulsifier is the phospholipid lysolecithin.  
   
   
       13 . The method of  claim 10  wherein the non-polar organic solvent is selected from the group consisting of ethyl acetate and heptane.  
   
   
       14 . The method of  claim 10  wherein the non-polar organic solvent is at its boiling point.  
   
   
       15 . The method of  claim 10  wherein the non-polar organic solvent is selected from the group consisting of heptane, chloroform, dichloromethane, isopropanol and supercritical carbon dioxide.  
   
   
       16 . The method of  claim 10  wherein the non-polar organic solvent is removed from the mix by elevating the temperature at or above the solvent's boiling point.  
   
   
       17 . The method of  claim 10  wherein the solvent removal continues until a solid residue that contains less than 0.5% solvent is provided.  
   
   
       18 . The method of  claim 17  wherein the solid formed after solvent removal is pulverized to produce a dispersible powder.  
   
   
       19 . The method of  claim 10  wherein the dried solid residue of the mixed components from  claim 17  is dispersed in water with vigorous stirring at a temperature less than the decomposition temperature of any of the mixed components.  
   
   
       20 . The method of  claim 10  wherein the pulverized powder from  claim 18  is added with vigorous stirring to water at a temperature that is less than the decomposition temperature of one of the components or the boiling point of water, whichever is lower.  
   
   
       21 . The method of  claim 10  wherein the aqueous mixture is homogenized in a homogenizer selected from the group consisting of a Gaulin homogenizer, a French press, a sonicator, and a microfluidizer.  
   
   
       22 . The method of  claim 10  wherein the homogenized aqueous mixture is dried in a drier selected from the group consisting of spray driers and lyophilizers.  
   
   
       23 . The composition of  claim 22  wherein a drying aid selected from the group consisting of starch, silicon dioxide and calcium silicate is added.  
   
   
       24 . The composition of  claim 23  wherein the solid is converted into a tablet or capsule, or added to a food product.  
   
   
       25 . A solid product that is formed from the composition in  claim 17  by subjecting the material to compression or extrusion for at least 15 seconds at a pressure of at least 100 psig.  
   
   
       26 . A solid product that is formed from the composition in  claim 18  by subjecting the material to compression or extrusion for at least 15 seconds at a pressure of at least 100 psig.  
   
   
       27 . A solid product that is formed from the composition in  claim 23  by subjecting the material to compression or extrusion for at least 15 seconds at a pressure of at least 100 psig.