EXTENDING THE DURATION OF DRUG RELEASE WITHIN THE STOMACH DURING THE FED MODE
First Claim
1. A controlled-release oral drug dosage form for releasing a drug whose solubility in water is greater than one part by weight of said drug in ten parts by weight of water, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 15:
- 85 to about 80;
20, said polymeric matrix being one that swells upon imbibition of water thereby attaining a size large enough to promote retention in the stomach during said fed mode, that releases said drug into gastric fluid by the dissolution and diffusion of said drug out of said matrix by said gastric fluid, that upon immersion in gastric fluid retains at least about 40% of said drug one hour after such immersion and releases substantially all of said drug within about eight hours after such immersion, and that remains substantially intact until all of said drug is released.
5 Assignments
0 Petitions
Accused Products
Abstract
Drugs are formulated as unit oral dosage forms by incorporating them into polymeric matrices comprised of hydrophilic polymers that swell upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode. The oral formulation is designed for gastric retention and controlled delivery of an incorporated drug into the gastric cavity, and thus administered, the drug is released from the matrix into the gastric fluid by solution diffusion. The swollen polymeric matrix, having achieved sufficient size, remains in the gastric cavity for several hours if administered while the patient is in the fed mode, and remains intact long enough for substantially all of the drug to be released before substantial dissolution of the matrix occurs. The swelling matrix lowers the accessibility of the gastric fluid to the drug and thereby reduces the drug release rate. This process, together with diffusion retardation by selection of specific polymers, polymer molecular weights, and other variables, results in a sustained and controlled delivery rate of the drug to the gastric cavity.
51 Citations
44 Claims
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1. A controlled-release oral drug dosage form for releasing a drug whose solubility in water is greater than one part by weight of said drug in ten parts by weight of water, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 15:
- 85 to about 80;
20, said polymeric matrix being one that swells upon imbibition of water thereby attaining a size large enough to promote retention in the stomach during said fed mode, that releases said drug into gastric fluid by the dissolution and diffusion of said drug out of said matrix by said gastric fluid, that upon immersion in gastric fluid retains at least about 40% of said drug one hour after such immersion and releases substantially all of said drug within about eight hours after such immersion, and that remains substantially intact until all of said drug is released. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
- 85 to about 80;
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19. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach but also capable of altering intestinal flora in a manner detrimental to the health of said subject, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach and substantially avoiding contact of said drug with said intestinal flora. - View Dependent Claims (20, 21)
- 99.99 to about 80;
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22. A method of treating a subject suffering from infections selected from the group consisting of pneumonia, sinus bacterial infections, topical bacterial infections and staphylococcus infections, by administering to said subject a drug which is a member selected from the group consisting of amoxicillin, cefuroxime axetil, cefaclor, clindamycin, clarithromycin, azithromycin, and ceftazidine, without substantially causing side effects resulting from the alteration of the intestinal flora of said subject, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach and substantially avoiding contact of said drug with said intestinal flora. - View Dependent Claims (23)
- 99.99 to about 80;
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24. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach but also degradable by colonic bacterial enzymes residing in lower gastrointestinal tract enterocytes, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach and substantially avoiding contact of said drug with said intestinal enzymes and said drug transporters. - View Dependent Claims (25, 26)
- 99.99 to about 80;
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27. A method of treating a subject undergoing an organ transplant to suppress an immune response to said transplant, by administering cyclosporine to said subject without substantial degradation of said cyclosporine by colonic bacterial enzymes residing in enterocytes of the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said cyclosporine while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said cyclosporine dispersed therein at a weight ratio of cyclosporine to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said cyclosporine one hour after such immersion in gastric fluid, (d) releases substantially all of said cyclosporine within about ten hours after such immersion, and (e) remains substantially intact until all of said cyclosporine is released, thereby extending the release rate of said cyclosporine with time during said fed mode while releasing substantially all of said cyclosporine within said stomach and substantially avoiding contact of said cyclosporine with said colonic bacterial enzymes.
- 99.99 to about 80;
-
28. A method of treating a subject for heart disease by administering digoxin to said subject without substantial degradation of said digoxin by colonic bacterial enzymes residing in enterocytes of the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said digoxin while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said digoxin dispersed therein at a weight ratio of digoxin to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said digoxin one hour after such immersion in gastric fluid, (d) releases substantially all of said digoxin within about ten hours after such immersion, and (e) remains substantially intact until all of said digoxin is released, thereby extending the release rate of said digoxin with time during said fed mode while releasing substantially all of said digoxin within said stomach and substantially avoiding contact of said digoxin with said colonic bacterial enzymes.
- 99.99 to about 80;
-
29. A method of treating a subject suffering from a condition selected from the group consisting of ovarian cancer, colorectal cancer, gastric cancer, renal cancer, and breast cancer, by administering doxifluridine to said subject without substantial degradation of said doxifluridine by intestinal enzymes or substantial inactivation of said doxifluridine by drug transporters residing in enterocytes of the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said doxifluridine while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said doxifluridine dispersed therein at a weight ratio of doxifluridine to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said doxifluridine one hour after such immersion in gastric fluid, (d) releases substantially all of said doxifluridine within about ten hours after such immersion, and (e) remains substantially intact until all of said doxifluridine is released, thereby extending the release rate of said doxifluridine with time during said fed mode while releasing substantially all of said doxifluridine within said stomach and substantially avoiding contact of said doxifluridine with said enzymes.
- 99.99 to about 80;
-
30. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach but also susceptible to inactivation by drug transporters residing in lower gastrointestinal tract enterocytes, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach and substantially avoiding contact of said drug with said drug transporters. - View Dependent Claims (31)
- 99.99 to about 80;
-
32. A method of treating a subject undergoing an organ transplant to suppress an immune response to said transplant, by administering cyclosporine to said subject without substantial inactivation of said cyclosporine by p-glycoprotein in the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said cyclosporine while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said cyclosporine dispersed therein at a weight ratio of cyclosporine to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said cyclosporine one hour after such immersion in gastric fluid, (d) releases substantially all of said cyclosporine within about ten hours after such immersion, and (e) remains substantially intact until all of said cyclosporine is released, thereby extending the release rate of said cyclosporine with time during said fed mode while releasing substantially all of said cyclosporine within said stomach and substantially avoiding inactivation of said cyclosporine by p-glycoprotein in said lower gastrointestinal tract.
- 99.99 to about 80;
-
33. A method of treating a subject suffering from cancer by administering paclitaxel to said subject without substantial inactivation of said paclitaxel by p-glycoprotein in the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said paclitaxel while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said paclitaxel dispersed therein at a weight ratio of paclitaxel to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said paclitaxel one hour after such immersion in gastric fluid, (d) releases substantially all of said paclitaxel within about ten hours after such immersion, and (e) remains substantially intact until all of said paclitaxel is released, thereby extending the release rate of said paclitaxel with time during said fed mode while releasing substantially all of said paclitaxel within said stomach and substantially avoiding inactivation of said paclitaxel by p-glycoprotein in said lower gastrointestinal tract.
- 99.99 to about 80;
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34. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach and whose bioavailability is substantially greater in an acidic environment than an alkaline environment, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach where said drug is maintained in an acidic environment. - View Dependent Claims (35, 36)
- 99.99 to about 80;
-
37. A method of treating a subject suffering from a bacterial infection by administering an ester of ampicillin to said subject while maintaining maximum bioavailability of said ester of ampicillin, said method comprising orally administering to said subject a dosage form of said ester of ampicillin while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said ester of ampicillin dispersed therein at a weight ratio of said ester of ampicillin to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said ester of ampicillin one hour after such immersion in gastric fluid, (d) releases substantially all of said ester of ampicillin within about ten hours after such immersion, and (e) remains substantially intact until all of said ester of ampicillin is released, thereby extending the release rate of said ester of ampicillin with time during said fed mode while releasing substantially all of said ester of ampicillin within said stomach and maintaining said ester of ampicillin in the acidic environment of said stomach during said release.
- 99.99 to about 80;
-
38. A method of treating a subject suffering from anemia by administering iron salts to said subject while maintaining maximum bioavailability of said iron salts, said method comprising orally administering to said subject a dosage form of said iron salts while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said iron salts dispersed therein at a weight ratio of iron salts to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said iron salts one hour after such immersion in gastric fluid, (d) releases substantially all of said iron salts within about ten hours after such immersion, and (e) remains substantially intact until all of said iron salts is released, thereby extending the release rate of said iron salts with time during said fed mode while releasing substantially all of said iron salts within said stomach where said iron salts are maintained in an acidic environment.
- 99.99 to about 80;
-
39. A method of treating a subject suffering from a systemic fungal infection by administering ketoconazole to said subject while maintaining maximum bioavailability of said ketoconazole, said method comprising orally administering to said subject a dosage form of said ketoconazole while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said ketoconazole dispersed therein at a weight ratio of ketoconazole to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said ketoconazole one hour after such immersion in gastric fluid, (d) releases substantially all of said ketoconazole within about ten hours after such immersion, and (e) remains substantially intact until all of said ketoconazole is released, thereby extending the release rate of said ketoconazole with time during said fed mode while releasing substantially all of said ketoconazole within said stomach where said ketoconazole is maintained in an acidic environment.
- 99.99 to about 80;
-
40. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach but also degradable in an alkaline environment, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix in which said drug is dispersed at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach where said drug is maintained in an acidic environment. - View Dependent Claims (41)
- 99.99 to about 80;
-
42. A method of treating a subject infected with human immunodeficiency virus by administering nelfinar mesylate to said subject without substantial degradation of said nelfinar mesylate by intestinal flora or substantial inactivation of said nelfinar mesylate by drug transporters residing in enterocytes of the lower gastrointestinal tract, said method comprising orally administering to said subject a dosage form of said nelfinar mesylate while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said nelfinar mesylate dispersed therein at a weight ratio of nelfinar mesylate to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said nelfinar mesylate into gastric fluid by the dissolving of said nelfinar mesylate by said gastric fluid and either erosion of said matrix or diffusion of said dissolved nelfinar mesylate out of said matrix, (c) retains at least about 40% of said nelfinar mesylate one hour after such immersion in gastric fluid, (d) releases substantially all of said nelfinar mesylate within about ten hours after such immersion, and (e) remains substantially intact until all of said nelfinar mesylate is released, thereby extending the release rate of said nelfinar mesylate with time during said fed mode while releasing substantially all of said nelfinar mesylate within said stomach where said nelfinar mesylate is maintained in an acidic environment.
- 99.99 to about 80;
-
43. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach where said drug has at least one ionized group in the pH range 5 through 8, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (d) releases substantially all of said drug within about ten hours after such immersion, and (e) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach where said drug is maintained in an acidic environment.
- 99.99 to about 80;
-
44. A method of administering to a subject a drug that is therapeutic to said subject when absorbed in the stomach but also degradable in an acidic environment, said method comprising orally administering to said subject a dosage form of said drug while said subject is in a fed mode, said dosage form comprising a solid polymeric matrix with said drug dispersed therein at a weight ratio of drug to polymer of from about 0.01:
- 99.99 to about 80;
20, said polymeric matrix being one that;
(a) swells upon imbibition of gastric fluid to a size large enough to promote retention in the stomach during said fed mode, (b) releases said drug into gastric fluid by the dissolving of said drug by said gastric fluid and either erosion of said matrix or diffusion of said dissolved drug out of said matrix, (c) protects any unreleased drug in said matrix from said gastric fluid, (d) retains at least about 40% of said drug one hour after such immersion in gastric fluid, (e) releases substantially all of said drug within about ten hours after such immersion, and (f) remains substantially intact until all of said drug is released, thereby extending the release rate of said drug with time during said fed mode while releasing substantially all of said drug within said stomach where said drug is maintained in an acidic environment.
- 99.99 to about 80;
Specification