Solid carriers for improved delivery of active ingredients in pharmaceutical compositions

• US 20030180352A1
• Filed: 05/30/2002
• Published: 09/25/2003
• Est. Priority Date: 11/23/1999
• Status: Abandoned Application

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Chen, Feng-Jing, Patel, Mahesh V.
• Application Number:
  US10/159,601
• Publication Number:
  US 20030180352A1
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of active ingredients contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides, and solubilizers. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides, and solubilizers. The compositions of the present invention can be used for improved delivery of active ingredients.

Claims

1. A pharmaceutical composition in the form of a solid carrier comprising an admixture of:

a) a therapeutically effective amount of lansoprazole; and

b) at least one excipient selected from the group consisting of;

i) a hydrophilic surfactant;

ii) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof; and

iii) a solubilizer.

2. The pharmaceutical composition of claim 1 wherein the lansoprazole is processed by a treatment with an interfacial modifying agent selected from the group consisting of surfactants, polymers, lipids, gelatins, saccharides, and combinations thereof.

3. The pharmaceutical composition of claim 2 wherein the treatment comprises coating the lansoprazole with the interfacial modifying agent.

4. The pharmaceutical composition of claim 1 wherein the admixture comprises a hydrophilic surfactant.

5. The pharmaceutical composition of claim 4 wherein the hydrophilic surfactant is a non-ionic hydrophilic surfactant having an HLB value of at least about 10 and is selected from the group consisting of alkylglucosides;

alkylmaltosides;

alkylthioglucosides;

lauryl macrogolglycerides;

polyoxyethylene alkyl ethers;

polyoxyethylene alkylphenols;

polyethylene glycol fatty acids esters;

polyethylene glycol glycerol fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

polyglycerol fatty acid esters;

polyoxyethylene glycerides;

polyoxyethylene sterols, derivatives, and analogues thereof;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;

tocopherol polyethylene glycol succinates;

sugar esters;

sugar ethers;

sucroglycerides; and

combinations thereof.

6. The pharmaceutical composition of claim 4 wherein the hydrophilic surfactant is an ionic surfactant selected from the group consisting of alkyl ammonium salts;

bile acids and salts, analogues, and derivatives thereof;

fatty acid derivatives of amino acids, carnitines, oligopeptides, and polypeptides;

glyceride derivatives of amino acids, oligopeptides, and polypeptides;

acyl lactylates;

mono- and diacetylated tartaric acid esters of mono- and diglycerides;

succinylated monoglycerides;

citric acid esters of mono- and diglycerides;

alginate salts;

propylene glycol alginate;

lecithins and hydrogenated lecithins;

lysolecithin and hydrogenated lysolecithins;

lysophospholipids and derivatives thereof;

phospholipids and derivatives thereof;

salts of alkylsulfates;

salts of fatty acids;

sodium docusate; and

combinations thereof.

7. The pharmaceutical composition of claim 1 wherein the admixture comprises a lipophilic additive.

8. The pharmaceutical composition of claim 7 wherein the lipophilic additive is a lipophilic surfactant selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

bile acids;

glycerol fatty acid esters;

acetylated glycerol fatty acid esters;

lower alcohol fatty acids esters;

polyethylene glycol fatty acids esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of mono/diglycerides;

propylene glycol diglycerides;

sorbitan fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

transesterified vegetable oils;

sterols;

sterol derivatives;

sugar esters;

sugar ethers;

sucroglycerides;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

combinations thereof.

9. The pharmaceutical composition of claim 7 wherein the lipophilic additive is a triglyceride selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and combinations thereof.

10. The pharmaceutical composition of claim 1 wherein the admixture comprises a solubilizer.

11. The pharmaceutical composition of claim 10 wherein the solubilizer is selected from the group consisting of alcohols and polyols;

ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000;

amides;

esters, and combinations thereof.

12. The pharmaceutical composition of claim 10 wherein the solubilizer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, polyethylene glycol, and combinations thereof.

13. The pharmaceutical composition of claim 1 wherein the admixture further comprises a bufferant selected from the group consisting of pharmaceutically acceptable bases, salts of pharmaceutically acceptable cations, and combinations thereof.

14. The pharmaceutical composition of claim 1 further comprising an anti-microbial agent.

15. The pharmaceutical composition of claim 14 wherein the anti-microbial agent is selected from the group consisting of amoxicillin, clarithromycin, erythromycin, metronidazole, tetracycline, and combinations thereof.

16. The pharmaceutical composition of claim 1 further comprising an antacid agent.

17. The pharmaceutical composition of claim 16 wherein the antacid agent is selected from the group consisting of aluminum hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, and combinations thereof.

18. The pharmaceutical composition of claim 1 wherein the solid carrier further comprises a substrate and the admixture is coated on the substrate as an encapsulation coat.

19. The pharmaceutical composition of claim 1 wherein the solid carrier is a bead, beadlet, granule, spherule, pellet, microcapsule, microsphere, or nanosphere.

20. The pharmaceutical composition of claim 1 wherein the solid carrier is enteric coated.

21. The pharmaceutical composition of claim 1 wherein the solid carrier is seal coated with a material selected from the group consisting of lipophilic surfactants, triglycerides, waxes, polymers, and combinations thereof.

22. The pharmaceutical composition of claim 21 wherein the seal coat further comprises a bufferant selected from the group consisting of pharmaceutically acceptable bases, salts of pharmaceutically acceptable cations, and combinations thereof.

23. The pharmaceutical composition of claim 21 wherein the seal coat material is digestible.

24. The pharmaceutical composition of claim 1 which is in the form of a capsule, sachet, sprinkle, dry syrup, or strip.

25. The pharmaceutical composition of claim 24 wherein the capsule is a gelatin capsule, a hydroxypropylmethylcellulose capsule, or a starch capsule.

26. The pharmaceutical composition of claim 1 wherein the solid carrier is prepared by spray congealing process.

27. The pharmaceutical composition of claim 1 wherein the solid carrier is prepared by a process without the need of introducing water or organic solvents.

28. A method of administering lansoprazole or a pharmaceutically acceptable salt, isomer or derivative thereof, to an individual comprising orally administering to the individual a dosage form of the pharmaceutical composition of claim 1.

29. The method of claim 28 wherein the individual is being treated for at least one condition selected from the group consisting of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease, erosive esophagitis, and pathological hypersecretory conditions.

30. A method of improving the oral bioavailability of lansoprazole, or a pharmaceutically acceptable salt, isomer or derivative thereof, in mammals under fed condition, comprising orally administering to the mammal a dosage form of the pharmaceutical composition of claim 1.

31. The method of claim 30 wherein the mammal is a human.

32. A method of improving the in vivo or ex vivo stability of an active ingredient at a pH within the range of about 1-6.8, wherein the active agent is selected from the group consisting of lansoprazole and pharmaceutically acceptable salts, isomers and derivatives thereof, in an acidic pH within thee range of about 1-6.8, comprising formulating the active ingredient in a pharmaceutical composition comprising at least one excipient selected from the group consisting of:

a) a hydrophilic surfactant;

b) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof, and

c) a solubilizer; and

optionally providing the pharmaceutical composition with a seal coat or an enteric coat.

33. A method of improving the stability of an active ingredient during storage, wherein in the active ingredient is selected from the group consisting of lansoprazole and pharmaceutically acceptable salts, isomers and derivatives thereof, comprising formulating the active ingredient in a pharmaceutical composition comprising at least one excipient selected from the group consisting of:

a) a hydrophilic surfactant;

b) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof; and

c) a solubilizer; and

optionally providing the pharmaceutical composition with a seal coat.

34. A pharmaceutical composition in the form of a solid carrier prepared by spray congealing comprising an admixture of:

a) a therapeutically effective amount of lansoprazole;

b) at least one hydrophilic surfactant;

c) a solubilizer;

wherein the solid carrier is seal coated with a material selected from the group consisting of lipophilic surfactants, triglycerides, waxes, polymers, and combinations thereof.

35. The pharmaceutical composition of claim 34 wherein the solid carrier is substantially free of bufferants selected from the group consisting of pharmaceutically acceptable bases, salts of pharmaceutically acceptable cations, and combinations thereof.

36. The pharmaceutical composition of claim 34 wherein the solid carrier is substantially free of hard fat.

37. A pharmaceutical composition in the form of a solid carrier comprising an admixture of:

a) a therapeutically effective amount of an active ingredient selected from the group consisting of esomeprazole, pantoprazole, rabeprazole, and pharmaceutically acceptable salts, isomers and derivatives thereof; and

b) at least one excipient selected from the group consisting of;

i) a hydrophilic surfactant;

ii) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof; and

iii) a solubilizer.

38. The pharmaceutical composition of claim 37 wherein the active ingredient is processed by a treatment with an interfacial modifying agent selected from the group consisting of surfactants, polymers, lipids, gelatins, saccharides, and combinations thereof.

39. The pharmaceutical composition of claim 38 wherein the treatment comprises coating the active ingredient with the interfacial modifying agent.

40. The pharmaceutical composition of claim 37 further comprising a bufferant selected from the group consisting of pharmaceutically acceptable bases, salts of pharmaceutically acceptable cations, and combinations thereof.

41. The pharmaceutical composition of claim 37 farther comprising an anti-microbial agent, an antacid agent, or combination thereof.

42. The pharmaceutical composition of claim 37 wherein the solid carrier further comprises a substrate, and the admixture is coated on the substrate as an encapsulation coat.

43. The pharmaceutical composition of claim 37 wherein the solid carrier is a bead, beadlet, granule, spherule, pellet, microcapsule, microsphere, or nanosphere.

44. The pharmaceutical composition of claim 37 wherein the solid carrier is enteric coated.

45. The pharmaceutical composition of claim 37 wherein the solid carrier is seal coated with a material selected from the group consisting of lipophilic surfactants, triglycerides, waxes, polymers, and combinations thereof.

46. The pharmaceutical composition of claim 45 wherein the seal coat further comprises a bufferant selected from the group consisting of pharmaceutically acceptable bases, salts of pharmaceutically acceptable cations, and combinations thereof.

47. The pharmaceutical composition of claim 37 is in the form of a capsule, tablet, effervescent tablet, sachet, sprinkle, dry syrup, or reconstitutable solid.

48. The pharmaceutical composition of claim 47 wherein the capsule is a gelatin capsule, a hydroxypropylmethylcellulose capsule or a starch capsule.

49. A method of administering an active ingredient selected from the group consisting of esomeprazole, pantoprazole, rabeprazole, and pharmaceutically acceptable salts, isomers and derivatives thereof, to an individual comprising orally administering to the individual a dosage form of the pharmaceutical composition of claim 37.

50. The method of claim 49 wherein the individual is being treated for at least one condition selected from the group consisting of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease, erosive esophagitis, and pathological hypersecretory conditions.

51. A method of improving the oral bioavailability of an active ingredient selected from the group consisting of esomeprazole, pantoprazole, rabeprazole, and pharmaceutically acceptable salts, isomers and derivatives thereof, in mammals under fed condition, comprising orally administering to the mammal a dosage form of the pharmaceutical composition of claim 37.

52. The method of claim 51 wherein the mammal is a human.

53. A method of improving the in vivo or ex vivo stability of an active ingredient at a pH within the range of about 1-6.8, wherein the active agent is selected from the group consisting of esomeprazole, pantoprazole, rabeprazole, and pharmaceutically acceptable salts, isomers and derivatives thereof, comprising formulating the active ingredient in a pharmaceutical composition comprising at least one excipient selected from the group consisting of:

a) a hydrophilic surfactant;

b) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof; and

c) a solubilizer; and

optionally providing the pharmaceutical composition with a seal coat or an enteric coat.

54. A method of improving the stability of an active ingredient during storage, wherein the active ingredient selected from the group consisting of esomeprazole, pantoprazole, rabeprazole, and pharmaceutically acceptable salts, isomers and derivatives thereof, comprising formulating the active ingredient in pharmaceutical composition comprising at least one excipient selected from the group consisting of:

a) a hydrophilic surfactant;

b) at least one lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof; and

c) a solubilizer; and

optionally providing the pharmaceutical composition with a seal coat, wherein at least one of the lipophilic additive or seal coat reduces the permeation of moisture to the active ingredient.

55. The method of claim 54 wherein the pharmaceutical composition is further provided with an enteric coat.