Complexes to improve oral absorption of poorly absorbable antibiotics

• US 6,248,360 B1
• Filed: 06/21/2000
• Issued: 06/19/2001
• Est. Priority Date: 06/21/2000
• Status: Expired due to Term

• Current Assignee: International Health Management Associates
• Original Assignee: International Health Management Associates
• Inventors: Choi, Seung-Ho, Lee, Jeoung-Soo
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/598,089
• Time in Patent Office: 363 Days
• Field of Search: 424/487, 424/423, 424/484, 424/488, 424/464, 424/485, 514/781
• US Class Current: 424/487
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/14 Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

The present invention provides compositions and methods for increasing absorption of poorly absorbable antibiotics, particularly third generation cephalosporin antibiotics, in oral dosage solid and/or suspension forms. Specifically, the composition is comprised of a biopolymer that is preferably swellable and/or mucoadhesive, a poorly absorbable antibiotic, and a cationic binding agent contained within the biopolymer such that the binding agent is tonically bound or complexed to at least one member selected from the group consisting of the biopolymer and the antibiotic.

Claims

1. A pharmaceutical composition for oral delivery comprising:

a) a biopolymer;

b) a poorly absorbable antibiotic contained within or ionically bound to the biopolymer; and

c) a metal cation ionically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic.

2. The pharmaceutical composition of claim 1 wherein the biopolymer, when hydrated, is mucoadhesive.

3. The pharmaceutical composition of claim 1 wherein the biopolymer, when hydrated, is swellable.

4. The pharmaceutical composition of claim 1 wherein the poorly absorbable antibiotic and metal cation are present at a molar ratio of from about 10:

1 to 1;

5.

5. The pharmaceutical composition of claim 4 wherein the poorly absorbable antibiotic to metal cation molar ratio is about 5:

1.

6. The pharmaceutical composition of claim 1 wherein the poorly absorbable antibiotic and biopolymer are present at a molar ratio from about 5:

1 to 1;

5.

7. The pharmaceutical composition of claim 6 wherein the poorly absorbable antibiotic to biopolymer molar ratio is about 2:

1.

8. The pharmaceutical composition of claim 1 wherein the biopolymer is selected from the group consisting of carrageenan, pectin, chondroitin sulfate, sodium alginate, poly(methacrylic acid), and combinations thereof.

9. The pharmaceutical composition of claim 1 wherein the poorly absorbable antibiotic is selected from the group consisting of charged cephalosporins, charged peptide and polypeptide antibiotics, charged aminoglycosides, and combinations thereof.

10. The pharmaceutical composition of claim 9 wherein the charged cephalosporin is a third generation cephalosporin.

11. The pharmaceutical composition of claim 10 wherein the third generation cephalosporin is selected from the group consisting of ceftiofur, cefepime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, moxalactam, and combinations thereof.

12. The pharmaceutical composition of claim 9 wherein the charged aminoglycoside is selected from the group consisting of amikacin, tobramycin, and combinations thereof.

13. The pharmaceutical composition of claim 9 wherein the charged peptide or polypeptide antibiotic is selected from the group consisting of vancomycin, daptomycin, polymixin-B, bacitracin, and combinations thereof.

14. The pharmaceutical composition of claim 1 wherein the metal cation is selected from the group consisting of calcium, potassium, magnesium, iron, copper, zinc, aluminum, manganese, chromium, cobalt, nickel, sodium, and combinations thereof.

15. The pharmaceutical composition of claim 14 wherein the metal cation is calcium.

16. The pharmaceutical composition of claim 14 wherein the metal cation is zinc.

17. The pharmaceutical composition of claim 1 wherein the metal cation is tonically bound to the biopolymer forming a metal cation-biopolymer combination and the antibiotic is entrained within the metal cation-biopolymer combination.

18. The pharmaceutical composition of claim 1 wherein the metal cation is complexed to the antibiotic forming a metal cation-antibiotic complex and the metal cation-antibiotic complex is entrained within the biopolymer.

19. The pharmaceutical composition of claim 1 wherein the metal cation is complexed to the antibiotic and the metal cation is further ionically bound to the biopolymer forming an antibiotic-metal cation-biopolymer bridge.

20. The pharmaceutical composition of claim 1 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the metal cation is calcium.

21. The pharmaceutical composition of claim 1 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the metal cation is zinc.

22. The pharmaceutical composition of claim 1 wherein the composition is a suspension for oral delivery.

23. The pharmaceutical composition of claim 1 wherein the composition is in a solid oral dosage form.

24. A pharmaceutical composition for oral delivery comprising:

a) a biopolymer;

b) a poorly absorbable antibiotic contained within or ionically bound to the biopolymer; and

c) a cationic molecule tonically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic.

25. The pharmaceutical composition of claim 24 wherein the biopolymer, when hydrated, is mucoadhesive.

26. The pharmaceutical composition of claim 24 wherein the biopolymer, when hydrated, is swellable.

27. The pharmaceutical composition of claim 24 wherein the poorly absorbable antibiotic and cationic molecule are present at a molar ratio of from about 1:

4 to 1;

1.

28. The pharmaceutical composition of claim 27 wherein the poorly absorbable antibiotic to cationic molecule molar ratio is from about 1:

2 to 1;

1.

29. The pharmaceutical composition of claim 24 wherein the poorly absorbable antibiotic and biopolymer are present at a molar ratio from about 5:

1 to 1;

5.

30. The pharmaceutical composition of claim 29 wherein the poorly absorbable antibiotice to biopolymer molar ratio is about 2:

1.

31. The pharmaceutical composition of claim 24 wherein the biopolymer is selected from the group consisting of carrageenan, pectin, chondroitin sulfate, sodium alginate, poly(methacrylic acid), and combinations thereof.

32. The pharmaceutical composition of claim 24 wherein the poorly absorbable antibiotic is selected from the group consisting of charged cephalosporins, charged peptide and polypeptide antibiotics, charged aminoglycosides, and combinations thereof.

33. The pharmaceutical composition of claim 32 wherein the charged cephalosporin is a third generation cephalosporin.

34. The pharmaceutical composition of claim 33 wherein the third generation cephalosporin is selected from the group consisting of ceftiofur, cefepime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, moxalactam, and combinations thereof.

35. The pharmaceutical composition of claim 32 wherein the charged aminoglycoside is selected from the group consisting of amikacin, tobramycin, and combinations thereof.

36. The pharmaceutical composition of claim 32 wherein the charged peptide or polypeptide antibiotic is selected from the group consisting of vancomycin, daptomycin, polymixin-B, bacitracin, and combinations thereof.

37. The pharmaceutical composition of claim 24 wherein the cationic molecule is selected from the group consisting of cationic polymers, basic amino acids, quaternary ammonium salts, and combinations thereof.

38. The pharmaceutical composition of claim 37 wherein the cationic molecule is a cationic polymer.

39. The pharmaceutical composition of claim 37 wherein the cationic molecule is a basic amino acid.

40. The pharmaceutical composition of claim 37 wherein the cationic molecule is a quaternary ammonium salt.

41. The pharmaceutical composition of claim 38 wherein the cationic polymer is selected from the group consisting of poly(allylamine), poly-(L-lysine), poly-(L-arginine), dodecyl trimethyl ammonium bromide, polyethylenimines (primary, secondary, and tertiary), and combinations thereof.

42. The pharmaceutical composition of claim 39 wherein the basic amino acid is selected from the group consisting of arginine, lysine, histidine, and combinations thereof.

43. The pharmaceutical composition of claim 40 wherein the quaternary ammonium salt is selected from the group consisting of benzalkonium derivatives, cetyl pyridinium derivatives, dodecyl-trimethyl ammonium salt derivatives, tetradecyl-trimethyl ammonium salt derivatives, cetyl-trimethyl ammonium salt derivatives, and combinations thereof.

44. The pharmaceutical composition of claim 24 wherein the cationic molecule is tonically bound to the biopolymer forming a cationic molecule-biopolymer combination and the antibiotic is entrained within the cationic molecule-biopolymer combination.

45. The pharmaceutical composition of claim 24 wherein the cationic molecule is tonically bound to the antibiotic forming a cationic molecule-antibiotic combination and the cationic molecule-antibiotic combination is entrained within the biopolymer.

46. The pharmaceutical composition of claim 24 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the cationic molecule is arginine.

47. The pharmaceutical composition of claim 24 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the cationic molecule is lysine.

48. The pharmaceutical composition of claim 24 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the cationic molecule is cetyl pyridinium chloride.

49. The pharmaceutical composition of claim 24 wherein the biopolymer is carrageenan, the antibiotic is ceftriaxone, and the cationic molecule is selected from the group consisting of poly(ethylenimine), dodecyl trimethyl ammonium bromide, and combinations thereof.

50. The pharmaceutical composition of claim 24 wherein the composition is a solid oral dosage form.

51. A method of delivering a poorly absorbable antibiotic to the blood stream of an animal comprising the steps of:

a) orally administering to said animal a composition comprising a biopolymer, an effective amount of a poorly absorbable antibiotic contained within or ionically bound to said biopolymer, and a cationic binding agent ionically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic;

b) causing the biopolymer to swell and adhere to a mucosal membrane lining of an intestinal wall of said animal; and

c) delivering the antibiotic from said composition to the mucosal membrane lining such that the antibiotic, and optionally the binding agent, cross the intestinal wall and enter the bloodstream.

52. The method of claim 51 wherein the cationic binding agent is selected from the group consisting of metal cations, cationic polymers, basic amino acids, quaternary ammonium salts, and combinations thereof.

53. The method of claim 51 wherein the biopolymer is selected from the group consisting of carrageenan, pectin, chondroitin sulfate, sodium alginate, poly(methacrylic acid), chitosan, and combinations thereof.

54. The method of claim 51 wherein the poorly absorbable antibiotic is selected from the group consisting of charged cephalosporins, charged peptide and polypeptide antibiotics, charged aminoglycosides, and combinations thereof.

55. The method of claim 54 wherein the charged cephalosporin is a third generation cephalosporin.

56. The method of claim 55 wherein the third generation cephalosporin is selected from the group consisting of ceftiofur, cefepime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, moxalactam, and combinations thereof.

57. The method of claim 54 wherein the charged aminoglycoside is selected from the group consisting of amikacin, tobramycin, and combinations thereof.

58. The method of claim 54 wherein the charged peptide or polypeptide antibiotic is selected from the group consisting of vancomycin, daptomycin, polymixin-B, bacitracin, and combinations thereof.

59. The method of claim 51 further comprising the preliminary step of preparing a suspension of the biopolymer having the poorly absorbable antibiotic and the cationic binding agent contained within the biopolymer for oral delivery.

60. The method of claim 51 further comprising the preliminary step of preparing a solid dose containing the biopolymer having the poorly absorbable antibiotic and the cationic binding agent contained within the biopolymer for oral delivery.