DELAYED TOTAL RELEASE TWO PULSE GASTROINTESTINAL DRUG DELIVERY SYSTEM

• US 20020110593A1
• Filed: 06/04/1999
• Published: 08/15/2002
• Est. Priority Date: 06/04/1999
• Status: Active Grant

• Current Assignee: Dexcel Pharma Technologies (Dexcel Limited)
• Original Assignee: Dexcel Pharma Technologies (Dexcel Limited)
• Inventors: PENHASI, ADEL, LERNER, E. ITZHAK, FLASHNER, MOSHE
• Granted Patent: US 6,632,451 B2
• Time in Patent Office: Days
• US Class Current: 424/480
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/286 Polysaccharides, e.g. gums; Cyclodextrin
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

A two pulse gastrointestinal delivery system is provided. The system comprises a desired agent in combination with a swellable core material, the core being surrounded by an inner coat of a water-insoluble or relatively water-insoluble coating material in which particulate water-insoluble material is embedded. The inner coat is additionally surrounded by an outer coat that contains additional amounts of the desired agent. When the delivery device enters the gastrointestinal tract, the outer coat releases the desired agent contained therein and disintegrates, exposing the inner coat. The particulate matter in the inner coat takes up liquid, thus forming channels interconnecting the drug-containing core with the outside of the delivery device. Through these channels liquid enters the core which then swells to the point at which the inner coat is broken. When the integrity of the inner coat is destroyed, the core then disintegrates, immediately releasing all or most of the drug at a specific site. By controlling parameters in the device, such as the core material, carrier material in the coating, and particulate matter, the location of release of both pulses of the drug can be carefully controlled. The invention is also directed to a method of using the device for the treatment of disease by the release of drugs in the gastrointestinal tract in a location- and time-dependent manner.

Claims

1. A two pulse delivery device for delivering one or more desired agents to the gastrointestinal tract of an animal in need of the same, wherein said device comprises:

a. a core comprising said one or more desired agents and a core material that swells in the presence of an aqueous liquid;

b. an inner coat that surrounds said core, wherein said inner coat has an outer surface and comprises water-insoluble hydrophilic particulate matter embedded in a water-insoluble carrier such that in the presence of an aqueous liquid, said particulate matter forms channels in said inner coat that interconnect said core with said outer surface of said inner coat and wherein said inner coat bursts when said core is swollen; and

c. an outer coat that surrounds said outer surface of said inner coat, wherein said outer coat comprises one or more desired agents which may be identical to or different from the one or more desired agents that are present in said core.

2. The device of claim 1, wherein said outer coating releases said one or more agents in the stomach.

3. The device of claim 1, wherein said outer coating releases said one or more agents in the small intestine.

4. The device of claim 1, wherein said outer coating provides an immediate delivery of said one or more agents.

5. The device of claim 1, wherein said outer coating provides a short sustained delivery of said one or more agents.

6. The device of claim 1, wherein said outer coating is a press coat.

7. The device of claim 6, wherein said press coat is formed from a powder or mixture of powders.

8. The device of claim 6, wherein said press coat is formed from a granulate.

9. The device of claim 6, wherein said press coat comprises low methoxy pectin.

10. The device of claim 1, wherein said outer coating is a spray coat.

11. The device of claim 10, wherein said spray coat is a drug containing film.

12. The device of claim 1, wherein said outer coat and said core contain different agents.

13. The device of claim 1, wherein said water-insoluble carrier is selected from the group consisting of:

a dimethylaminoethylacrylate/ethylmethacrylate copolymer, a copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is about 1;

20;

an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, a copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1;

40;

ethylcellulose;

shellac; and

zein.

14. The device of claim 1, wherein said outer coat is further coated with an enteric coating.

15. The device of claim 1, wherein said swellable core material is selected from the group consisting of polysaccharide, cross-linked polyacrylic acid, and modified cellulose.

16. The device of claim 15, wherein said polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xantham gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, starch, microcrystalline starch, microcrystalline cellulose, metal salts thereof, and covalently crosslinked derivatives thereof.

17. The device of claim 15, wherein said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose and metal salts of carboxymethylcellulose.

18. The device of claim 1, wherein said particulate matter comprises a polymer selected from the group consisting of a water-insoluble polysaccharide, a water-insoluble cross-linked polysaccharide, a water-insoluble polysaccharide metal salt, a water-insoluble cross-linked protein, a water-insoluble cross-linked peptide, water insoluble protein:

polysaccharide complex, a water insoluble peptide;

polysaccharide complex, a polysaccharide or a protein or peptide rendered insoluble by interaction with a poly-cation or poly-anion and a water-insoluble cross-linked hydrophilic polymer in dried powder form.

19. The device of claim 18, wherein said polysaccharide is selected from the group consisting of an insoluble metal salt of pectin, xantham gum, carrageenan, tragacanth gum, locust bean gum, and alginic acid;

an insoluble crosslinked derivative of xantham gum, guar gum, dextran, carrageenan, tragacanth gum, locust bean gum, pectin, starch, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethyl-cellulose and alginic acid, cellulose, microcrystalline cellulose, insoluble starch and microcrystalline starch.

20. The device of claim 19, wherein said insoluble metal salt of alginic acid is selected from the group consisting of calcium alginate, zinc alginate, aluminum alginate, ferric alginate, and ferrous alginate.

21. The device of claim 19, wherein said insoluble metal salt of pectin is selected from the group consisting of calcium pectinate, zinc pectinate, aluminum pectinate, ferric pectinate, and ferrous pectinate.

22. The device of claim 18, wherein said cross-linking is by a cross-linking agent selected from the group consisting of formaldehyde, glutaraldehyde, epichlorhydrin, diacid chloride, diacid anhydride, diisocyanates, diamines and borax.

23. The device of claim 18, wherein said water insoluble cross-linked protein is selected from the group consisting of glutaraldehyde-cross-linked hydrolyzed gelatin, formaldehyde-cross-linked hydrolyzed gelatin, glutaraldehyde-cross-linked gelatin, formaldehyde-cross-linked gelatin, glutaraldehyde-cross-linked collagen and formaldehyde-cross-linked collagen.

24. The device of claim 18, wherein said water-insoluble cross-linked hydrophilic polymer is a carbomer.

25. The device of claim 18, wherein said water-insoluble cross-linked hydrophilic polymer is Crospovidone.

26. The device of claim 14, wherein said water-insoluble carrier is ethylcellulose, said water-insoluble hydrophilic particulate is calcium pectinate, and said enteric coating is a methacrylic acid/methylmethacrylate or ethylacrylate anionic copolymer based on i) methacrylic acid and methylmethacrylate or ii) on methacrylic acid and ethylacrylate, wherein the ratio of free carboxyl groups to the ester groups is approximately 1:

1.

27. The device of claim 1, wherein said desired agent is a diagnostic or therapeutic agent.

28. The device of claim 27, wherein said therapeutic agent is selected from the group consisting of a non-steroidal anti-inflammatory agent (NSAID), a steroid, a contraceptive, a steroidal hormone, an immunosuppressant, a bronchodilator, an anti-anginal, an anti-hypertensive, an anti-spasmodic agent, an anti-colitis agent, an anti-arrhythmia agent, an anti-neoplastic agent, a protein, a peptide, a hormone, a vaccine, an anticoagulant, an anti-migrane agent, glibenclamide, a 5-hydroxytryptamine type_1A receptor agonist, a 5HT₃ antagonist, metkepyhamid, menthol, an antibiotic, a prostaglandin E₁ analogue, a prokinetic drug, a cholinergic agonist, a dopamine antagonist, and a reversible inhibitor of acetylcholinesterase.

29. The device of claim 28, wherein said therapeutic agent is selected from the group consisting of a prokinetic drug, a cholinergic agonist, and a reversible inhibitor of acetylcholinesterase.

30. The device of claim 29, wherein said therapeutic agent is said reversible inhibitor of acetylcholinesterase.

31. The device of claim 30, wherein said reversible inhibitor of acetylcholinesterase is selected from the group consisting of pyridostigmine bromide, neostigmine, neostigmine bromide, neostigmine methylsulfate, physostigmine, physostigmine salicylate, rivastigmine and physostigmine sulfate.

32. The device of claim 28, wherein said therapeutic agent is a non-steroidal anti-inflammatory agent.

33. The device of claim 32, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, flurbiprofen and sulindac.

34. The device of claim 27, wherein said therapeutic active agent is useful for the treatment of colitis, Crohn'"'"'s disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrhythmia, local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinoma, cysts, an infectious disorder, Alzheimer'"'"'s disease or a parasitic disorder.

36. The method of claim 35, wherein said outer coat and said core contain different agents.

37. The method of claim 35, wherein said water-insoluble carrier is selected from the group consisting of:

a dimethylaminoethlyacrylate/ethylmethacrylate copolymer, a copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is about 1;

20;

an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, a copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1;

40;

ethylcellulose;

shellac; and

zein.

38. The method of claim 35, wherein said outer coat is further coated with an enteric coating.

39. The method of claim 35, wherein said swellable core material is selected from the group consisting of polysaccharide, cross-linked polyacrylic acid, and modified cellulose.

40. The method of claim 39, wherein said polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xantham gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, starch, microcrystalline starch, microcrystalline cellulose, metal salts thereof, and covalently crosslinked derivatives thereof.

41. The method of claim 39, wherein said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose and metal salts of carboxymethylcellulose.

42. The method of claim 35, wherein said particulate matter comprises a polymer selected from the group consisting of a water-insoluble polysaccharide, a water-insoluble cross-linked polysaccharide, a water-insoluble polysaccharide metal salt, a water-insoluble cross-linked protein, a water-insoluble cross-linked peptide, water insoluble protein:

polysaccharide complex, a water insoluble peptide;

polysaccharide complex, a polysaccharide or a protein or peptide rendered insoluble by interaction with a poly-cation or poly-anion and a water-insoluble cross-linked hydrophilic polymer in dried powder form.

43. The method of claim 42, wherein said polysaccharide is selected from the group consisting of an insoluble metal salt of pectin, xantham gum, carrageenan, tragacanth gum, locust bean gum, and alginic acid;

an insoluble crosslinked derivative of xantham gum, guar gum, dextran, carrageenan, tragacanth gum, locust bean gum, pectin, starch, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethyl-cellulose and alginic acid, cellulose, microcrystalline cellulose, insoluble starch and microcrystalline starch.

44. The method of claim 43, wherein said insoluble metal salt of alginic acid is selected from the group consisting of calcium alginate, zinc alginate, aluminum alginate, ferric alginate, and ferrous alginate.

45. The method of claim 43, wherein said insoluble metal salt of pectin is selected from the group consisting of calcium pectinate, zinc pectinate, aluminum pectinate, ferric pectinate, and ferrous pectinate.

46. The method of claim 42, wherein said cross-linking is by a cross-linking agent selected from the group consisting of formaldehyde, glutaraldehyde, epichlorhydrin, diacid chloride, diacid anhydride, diisocyanates, diamines and borax.

47. The method of claim 42, wherein said water insoluble cross-linked protein is selected from the group consisting of glutaraldehyde-cross-linked hydrolyzed gelatin, formaldehyde-cross-linked hydrolyzed gelatin, glutaraldehyde-cross-linked gelatin, formaldehyde-cross-linked gelatin, glutaraldehyde-cross-linked collagen and formaldehyde-cross-linked collagen.

48. The method of claim 42, wherein said water-insoluble cross-linked hydrophilic polymer is a carbomer.

49. The method of claim 42, wherein said water-insoluble cross-linked hydrophilic polymer is Crospovidone.

50. The method of claim 38, wherein said water-insoluble carrier is ethylcellulose, said water-insoluble hydrophilic particulate is calcium pectinate, and said enteric coating is a methacrylic acid/methylmethacrylate or ethylacrylate anionic copolymer based on i) methacrylic acid and methylmethacrylate or ii) on methacrylic acid and ethylacrylate, wherein the ratio of free carboxyl groups to the ester groups is approximately 1:

1.

51. The method of claim 35, wherein said desired agent is a diagnostic or therapeutic agent.

52. The method of claim 51, wherein said agent is said diagnostic agent.

53. The method of claim 51, wherein said agent is said therapeutic agent.

54. The method of claim 53, wherein said therapeutic agent is selected from the group consisting of a non-steroidal anti-inflammatory agent (NSAID), a steroid, a contraceptive, a steroidal hormone, an immunosuppressant, a bronchodialator, an anti-anginal, an anti-hypertensive, an anti-spasmodic agent, an anti-colitis agent, an anti-arrhythmia agent, an anti-neoplastic agent, a protein, a peptide, a hormone, a vaccine, an anticoagulant, an anti-migrane agent, glibenclamide, a 5-hydroxytryptamine type_1A receptor agonist, a 5HT₃ antagonist, metkepyhamid, menthol, an antibiotic, a prostaglandin E₁ analogue, a prokinetic drug, a cholinergic agonist, a dopamine antagonist, and a reversible inhibitor of acetylcholinesterase.

55. The method of claim 54, wherein said therapeutic agent is selected from the group consisting of a prokinetic drug, a cholinergic agonist, and a reversible inhibitor of acetylcholinesterase.

56. The method of claim 55, wherein said therapeutic agent is said reversible inhibitor of acetylcholinesterase.

57. The method of claim 56, wherein said reversible inhibitor of acetylcholinesterase is selected from the group consisting of pyridostigmine bromide, neostigmine, neostigmine bromide, neostigmine methylsulfate, physostigmine, physostigmine salicylate, rivastigmine and physostigmine sulfate.

58. The method of claim 53, wherein said therapeutic agent is a non-steroidal anti-inflammatory agent.

59. The method of claim 58, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, flurbiprofen and sulindac.

60. The method of claim 53, wherein said therapeutic active agent is useful for the treatment of colitis, Crohn'"'"'s disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrhythmia, local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinoma, cysts, an infectious disorder, Alzheimer'"'"'s disease or a parasitic disorder.

61. The method of claim 35, wherein the portion of the gastrointestinal tract in which said agent in said outer coat is released is selected from the group consisting of the stomach, the duodenum, the small intestine and the colon.

62. The method of claim 35, wherein the portion of the gastrointestinal tract wherein said agent in said inner coat is released is selected from the group consisting of the stomach, the duodenum, the small intestine, the colon, and the rectum.

63. The method of claim 35, wherein the portion of the gastrointestinal tract in which said agent in said outer coat is released is different than the portion of the gastrointestinal tract in which said agent in said core is released.

64. The method of claim 35, wherein the portion of the gastrointestinal tract in which said agent in said outer coat is released is the duodenum and wherein the portion of the gastrointestinal tract in which said agent in said core is released is the colon.

65. The method of claim 35, wherein said animal has been diagnosed as having a condition selected from the group consisting of colitis, Crohn'"'"'s disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrhythmia, local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinoma, cysts, infectious disorders, Alzheimer'"'"'s disease and parasitic disorders.

66. The method of claim 65, wherein said condition is constipation.

35. A method of delivering a desired agent to the gastrointestinal tract of an animal, wherein said method comprises oral administration of a two pulse delivery device for delivery of one or more desired agents to said gastrointestinal tract of said animal, said device comprising:

a. A core comprising said one or more desired agents and a core material that swells in the presence of an aqueous liquid;

b. an inner coat that surrounds said core, wherein said inner coat has an outer surface and comprises a water-insoluble hydrophilic particulate matter embedded in a water-insoluble carrier, wherein, in the presence of an aqueous liquid, said particulate matter forms channels in said inner coat that interconnect said core with said outer surface of said inner coat and wherein said inner coat bursts when said core is swollen; and

c. an outer coat that surrounds said outer surface of said first coat, wherein said outer coat comprises one or more desired agents which may be identical to or different from the one or more desired agents that are present in said core.