Oral formulation for delivery of poorly absorbed drugs

Abstract

A composition for oral delivery of a poorly absorbed drug is disclosed. The composition includes the drug, an enhancer for increasing absorption of the drug through the intestinal mucosa, a promoter, which further increases the absorption of the drug in the presence of the enhancer, and optionally a protector for protecting the drug from physical or chemical decomposition or inactivation in the gastrointestinal tract. Illustrative enhancers include sucrose fatty acid esters, and illustrative promoters include aminosugars and amino acid derivatives, such as poly(amino acids). Illustrative protectors include methylcellulose, poly(vinyl alcohol), and poly(vinyl pyrrolidone).

The subject matter claimed is: 
     
         1 . A composition for oral delivery of a pharmaceutical agent that is poorly absorbed through the intestinal mucosa, the composition comprising a mixture of an effective amount of the pharmaceutical agent; an enhancer for increasing absorption of the pharmaceutical agent through the intestinal mucosa; a promoter that functions synergistically with the enhancer for further increasing absorption of the pharmaceutical agent through the intestinal mucosa; and optionally a protector for inhibiting decomposition or inactivation of the pharmaceutical agent;
 wherein the enhancer comprises fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycols, glycerides, or mixtures thereof;   wherein the promoter comprises amino acid derivatives, aminosugars, or mixtures thereof; and   wherein the protector comprises carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, poly(vinyl alcohol), poly(vinyl propylene), poly(vinylpyrrolidone), xanthan gums, sodium alginate, methacrylic acid copolymers, colloidal silica, synthetic silica, water-soluble cellulose ethers, hydroxypropylmethacrylates, tragacanth, water-soluble chitosan, polycarbophil, or mixtures thereof.   
     
     
         2 . The composition of  claim 1  wherein the protector is present and comprises methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, or mixtures thereof. 
     
     
         3 . The composition of  claim 1  wherein the enhancer comprises a fatty acid ester selected from sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, glycerol esters of a fatty acid, and mixtures thereof. 
     
     
         4 . The composition of  claim 1  wherein the enhancer comprises a nonionic surfactant selected from polyoxyethylene-polyoxypropylene glycol block copolymers, sorbitan fatty acid esters, fluorine-containing surfactants, octoxynols, polyoxyethylene sorbitans, polyoxyethylene ethers, polyethylene-polypropylene block copolymers, and mixtures thereof. 
     
     
         5 . The composition of  claim 1  wherein the promoter comprises glucosamine, galactosamine, N-acetylglucosamine, muramic acid, N-acetylmuramic acid, N-acetylgalactosamine, sialic acid, poly(allylamine), poly(L-lysine), poly(L-arginine), poly(L-histidine), poly(ethylenimine), poly(L/D-histidine), poly(L-arginine), poly(allylamine), poly(ethylamine), glucagon, glycyrrizhin, glutamic acid derivatives, bile salts, poly(ethylene glycol) derivatives, acylcarnitines, citric acids, or mixtures thereof. 
     
     
         6 . The composition of  claim 1  wherein the pharmaceutical agent comprises a peptide or protein, aminoglycoside antibiotic, or hydrophilic or amphipathic drug. 
     
     
         7 . The composition of  claim 1  wherein the pharmaceutical agent is selected from insulin, human growth hormone, calcitonin, isepamicin, netilmicin, teicoplanin, catechin, aztreonam, and paclitaxel. 
     
     
         8 . The composition of  claim 1  wherein the enhancer comprises a sucrose fatty acid ester, the promoter comprises glucosamine or poly(L-lysine), and the optional protector comprises methylcellulose or polyvinyl alcohol). 
     
     
         9 . The composition of  claim 8  wherein the sucrose fatty acid ester comprises sucrose stearate or sucrose palmitate. 
     
     
         10 . The composition of  claim 1  wherein the mixture comprises a tablet. 
     
     
         11 . The composition of  claim 10  further comprising an enteric coating. 
     
     
         12 . The composition of  claim 1  wherein the mixture further comprises at least one of diluents, binders, lubricants, disintegrators, colors, flavors, sweetening agents, and mixtures thereof. 
     
     
         13 . The composition of  claim 1  wherein the mixture is encapsulated. 
     
     
         14 . A composition for oral delivery of a hydrophilic or amphipathic drug, the composition comprising a mixture of the drug and
 an enhancer for increasing absorption of the drug through the intestinal mucosa, wherein the enhancer comprises fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycols, glycerides, or mixtures thereof; and   a promoter for functioning synergistically with the enhancer for further increasing absorption of the drug through the intestinal mucosa, wherein the promoter comprises poly(amino acids), aminosugars, or mixtures thereof.   
     
     
         15 . The composition of  claim 14  further comprising a protector for protecting the drug from decomposition or inactivation, wherein the protector comprises carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, poly(vinyl alcohol), poly(vinyl propylene), poly(vinylpyrrolidone), xanthan gums, sodium alginate, methacrylic acid copolymers, colloidal silica, synthetic silica, water-soluble cellulose ethers, hydroxypropyl methacrylates, tragacanth, water-soluble chitosan, polycarbophil, derivatives thereof, or mixtures thereof. 
     
     
         16 . The composition of  claim 15  wherein the enhancer comprises a sucrose fatty acid ester and the protector comprises methylcellulose, poly(vinyl alcohol), or polyvinyl pyrrolidone. 
     
     
         17 . The composition of  claim 14  wherein the promoter comprises glucosamine or poly(L-lysine). 
     
     
         18 . A method for increasing intestinal absorption of a poorly absorbable pharmaceutical agent, the method comprising orally administering a composition comprising a mixture of an effective amount of the pharmaceutical agent; an enhancer for increasing absorption of the pharmaceutical agent through the intestinal mucosa; a promoter that functions synergistically with the enhancer for further increasing absorption of the pharmaceutical agent through the intestinal mucosa; and optionally a protector for inhibiting decomposition or inactivation of the pharmaceutical agent;
 wherein the enhancer comprises fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycols, glycerides, or mixtures thereof;   wherein the promoter comprises amino acid derivatives, aminosugars, or mixtures thereof; and   wherein the protector comprises carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, poly(vinyl alcohol), poly(vinyl propylene), poly(vinylpyrrolidone), xanthan gums, sodium alginate, methacrylic acid copolymers, colloidal silica, synthetic silica, water-soluble cellulose ethers, hydroxypropylmethacrylates, tragacanth, water-soluble chitosan, polycarbophil, derivatives thereof, or mixtures thereof.   
     
     
         19 . The method of  claim 18  wherein the enhancer comprises a sucrose fatty acid ester and the promoter comprises glucosamine or poly(L-lysine). 
     
     
         20 . The method of  claim 19  wherein the protector comprises methylcellulose, polyvinyl alcohol), or polyvinyl pyrrolidone.