Therapeutic compositions

Abstract

The present invention provides oral formulations of poorly bioavailable and/or poorly absorbable, and/or poorly water soluble therapeutic agents. The invention features harmaceutical composition including a biopolymer, a therapeutic agent, for example an antimicrobial agent such as ceftriaxone, and an absorption enhancer, for example a polyoxyethylene alkyl ether absorption enhancer. Methods of making and using the pharmaceutical compositions is also described.

1 . A pharmaceutical composition comprising;
 a biopolymer;   a therapeutic agent; and   an enhancer.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent is an antimicrobial agent. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the antimicrobial agent is poorly bioavailable. 
     
     
         4 . The pharmaceutical composition of  claim 2 , wherein the antimicrobial agent is poorly water soluble. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the antimicrobial agent is a cephalosporin, a glycopeptide, a penicillin, a monobactam, an oxazolidinone, a lipopeptide, a carbapenem, an aminoglycoside, a β-lactamase inhibitor or combinations thereof. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is a cephalosporin. 
     
     
         7 . The pharmaceutical composition of  claim 6 , comprising a cephalosporin selected from ceftiofur, cefipime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, cefpirome, cefclidin, cefinenoxime, cefozoprane, or combinations thereof. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the cephalosporin is ceftriaxone. 
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is an aminoglycoside selected from amikacin, gentamicin, tobramycin, polymixin-B, streptomycin, kanamycin or combinations thereof. 
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is a glycopeptide selected from vancomycin, dalbavancin, oritavancin or combinations thereof. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the glycopeptide is vancomycin. 
     
     
         12 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is a carbapenem selected from meropenem, imipenem, MK0826, R-115,685, J-114,870 or CP5068. 
     
     
         13 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is a monobactam selected from aztreonam or carumonam. 
     
     
         14 . The pharmaceutical composition of  claim 5 , wherein the antimicrobial agent is a penicillin selected from piperacillin or amoxicillin. 
     
     
         15 . The pharmaceutical composition of  claim 5 , wherein the lipopeptide is daptomycin. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the biopolymer is a neutral or an anionic polymer. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the biopolymer is a cellulosic polymer. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the biopolymer is a hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or hydroxyethyl cellulose. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the biopolymer is a carbopol, or a polycarbophil. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein the biopolymer is a cationic polymer. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the biopolymer is a carageenan. 
     
     
         22 . The pharmaceutical composition of  claim 1 , wherein the enhancer is a polyoxyethylene alkyl ether, a monoglyceride of a fatty acid, a diglyceride of a fatty acid, a triglyceride of a fatty acid, a fatty acid, a fatty alcohol, or a salt of a fatty acid. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the enhancer is a monoglyceride of a C 12 -C 18  fatty acid, a diglyceride of a C 6 -C 18  fatty acid, or a triglyceride of a C 12 -C 18  fatty acid. 
     
     
         24 . The pharmaceutical composition of  claim 1 , wherein the enhancer is a mixture of one or more of a monoglyceride of a C 12 -C 18  fatty acid, a diglyceride of a C 6 -C 18  fatty acid, or a triglyceride of a C 12 -C 18  fatty acid. 
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the enhancer is gelicire. 
     
     
         26 . The pharmaceutical composition of  claim 1 , wherein the enhancer is a mixture of one or more of a polyoxyethylene alkyl ether, a monoglyceride of a fatty acid, a diglyceride of a fatty acid, a triglyceride of a fatty acid, or a salt of a fatty acid. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein the enhancer is a polyoxyethylene alkyl ether. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the polyoxyethylene alkyl ether has a plurality of alkyl chain lengths between 4 and 23. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the polyoxyethylene alkyl ether has a plurality of alkyl chain lengths from 10 to 15. 
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein the polyoxyethylene alkyl ether is laureth 12, ceteth 12, ceteth 15, oleth 10. 
     
     
         31 . The pharmaceutical composition of  claim 22 , wherein the fatty acid or fatty alcohol has from 10 to 18 carbons. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the fatty acid or fatty alcohol has from 12 to 16 carbons. 
     
     
         33 . The pharmaceutical composition of  claim 1 , wherein the enhancer comprises a fatty acid or fatty alcohol comprising from 10 to 18 carbons linked to a polyoxyethylene group of 8-18 units. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the enhancer comprises a fatty acid or fatty alcohol comprising from 12 to 16 carbons linked to a polyoxyethylene group of 10-15 units. 
     
     
         35 . The pharmaceutical composition of  claim 1 , wherein the ratio of enhancer to antimicrobial is between about 10:1 to about 1:2. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the ratio of enhancer to antimicrobial is between about 10:1 to about 1:1. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the ratio of enhancer to antimicrobial is between about 6:1 to about 1:1. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the ratio of enhancer to antimicrobial is about 2:1. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the enhancer is laureth 12. 
     
     
         40 . The pharmaceutical composition of  claim 37 , wherein the ratio of enhancer to antimicrobial is about 4:1. 
     
     
         41 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is substantially free of a cationic binding agent. 
     
     
         42 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is substantially free of a cationic biopolymer. 
     
     
         43 . The pharmaceutical composition of  claim 1 , wherein the enhancer is ceteth 12 and the biopolymer is polycarbophil. 
     
     
         44 . The pharmaceutical composition of  claim 1 , wherein the enhancer is ceteth 12 and the biopolymer is hydroxyethyl cellulose. 
     
     
         45 . The pharmaceutical composition of  claim 1 , wherein the enhancer is a ceteth and the biopolymer is a carbopol. 
     
     
         46 . The pharmaceutical composition of  claim 1 , wherein the bioavailability of the therapeutic agent is at least about ten times greater in the pharmaceutical formulation of  claim 1  than a formulation substantially free of an enhancer. 
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein the bioavailability of the therapeutic agent is at least about 20 times greater. 
     
     
         48 . An enterically coated tablet or capsule comprising the pharmaceutical composition of  claim 1 . 
     
     
         49 . The enterically coated tablet or capsule of  claim 48 , wherein the coating comprises a cellulosic polymer. 
     
     
         50 . The enterically coated tablet or capsule of  claim 49 , wherein the cellulosic polymer is hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or hydroxyethyl cellulose. 
     
     
         51 . An enterically coated bead or particle comprising the pharmaceutical composition of  claim 1 . 
     
     
         52 . The enterically coated bead or particle of  claim 51 , wherein the coating comprises a cellulosic polymer. 
     
     
         53 . The enterically coated bead or particle of  claim 52 , wherein the cellulosic polymer is hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or hydroxyethyl cellulose. 
     
     
         54 . A tablet or capsule comprising an enterically coated bead or particle of  claim 51 . 
     
     
         55 . A preparation for an oral suspension comprising an enterically coated bead or particle of  claim 51 . 
     
     
         56 . An enterically coated tablet, capsule, bead or particle comprising the pharmaceutical composition of  claim 1  where the components of the pharmaceutical composition are physically separated within the dosage form. 
     
     
         57 . An enterically coated tablet, capsule, bead or particle comprising the pharmaceutical composition of  claim 1  where the components of the pharmaceutical composition are intimately mixed within the dosage form. 
     
     
         58 . The pharmaceutical composition of  claim 1  in the form of a solid, semi-solid, or liquid. 
     
     
         59 . A method of making the pharmaceutical composition of  claim 1 , the method comprising:
 hydrating the biopolymer;   combining the therapeutic agent with the hydrated biopolymer to form a complex; and   combining the complex with the enhancer to provide the pharmaceutical composition of  claim 1 .   
     
     
         60 . A method of making the pharmaceutical composition of  claim 1 , the method comprising emulsifying one or more components of the pharmaceutical composition. 
     
     
         61 . A method of making the pharmaceutical composition of  claim 1 , the method comprising spray drying or spray congealing one or more components of the pharmaceutical composition. 
     
     
         62 . A method of treating an animal comprising administering to the animal the pharmaceutical composition of  claim 1 .