THERAPEUTIC COMPOSITIONS
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 .