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Claims for Patent: 6,635,280

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Claims for Patent: 6,635,280

Title: Extending the duration of drug release within the stomach during the fed mode
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.
Inventor(s): Shell; John W. (Hillsborough, CA), Louie-Helm; Jenny (Union City, CA), Markey; Micheline (Santa Cruz, CA)
Assignee: DepoMed, Inc. (Menlo Park, CA)
Application Number:10/045,823
Patent Claims: 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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 15:85 to 80:20, said dosage form being one that when swollen in a dimensionally unrestricted manner as a result of imbibition of water is of a size exceeding the pyloric diameter in the fed mode 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 after such immersion, and that remains substantially intact until substantially all of said drug is released.

2. A dosage form in accordance with claim 1 in which the solubility of said drug in water is greater than one part by weight of said drug in five parts by weight of water.

3. A dosage form in accordance with claim 1 in which said drug is a member selected from the group consisting of metformin hydrochloride, vancomycin hydrochloride, captopril, erythromycin lactobionate, ranitidine hydrochloride, sertraline hydrochloride, tramadol and ticlopidine hydrochloride.

4. A dosage form in accordance with claim 1 in which said drug is metformin hydrochloride.

5. A dosage form in accordance with claim 1 in which said drug is sertraline hydrochloride.

6. A dosage form in accordance with claim 1 in which said drug is captopril.

7. A dosage form in accordance with claim 1 in which said drug is vancomycin hydrochloride.

8. A dosage form in accordance with claim 1 in which said polymeric matrix is formed of a polymer selected from the group consisting of poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum.

9. A dosage form in accordance with claim 8 in which said alkyl-substituted celluloses are members selected from the group consisting of hydroxymethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropylmethyl-cellulose, and carboxymethyl-cellulose.

10. A dosage form in accordance with claim 1 in which said polymeric matrix is formed of poly(ethylene oxide) at a molecular weight of at least about 4,000,000.

11. A dosage form in accordance with claim 1 in which said polymeric matrix is formed of poly(ethylene oxide) at a molecular weight in the range of about 4,500,000 to about 10,000,000.

12. A dosage form in accordance with claim 1 in which said polymeric matrix is formed of poly(ethylene oxide) at a molecular weight in the range of about 5,000,000 to about 8,000,000.

13. A dosage form in accordance with claim 1 in which said polymeric matrix upon immersion in gastric fluid retains at least about 50% of said drug one hour after such immersion.

14. A dosage form in accordance with claim 1 in which said polymeric matrix upon immersion in gastric fluid retains at least about 60% of said drug one hour after such immersion.

15. A dosage form in accordance with claim 1 in which said polymeric matrix upon immersion in gastric fluid retains at least about 80% of said drug one hour after such immersion.

16. A dosage form in accordance with claim 1 further comprising a member selected from the group consisting of glyceryl monostearate and sodium myristate, formulated with said drug to further retard the release of said drug to said gastric fluid.

17. A dosage form in accordance with claim 1 in which said polymeric matrix consists of two cylindrical tablets, each measuring about 9 mm to about 12 mm in length and about 6.5 mm to about 7 mm in diameter.

18. A dosage form in accordance with claim 1 in which said polymeric matrix consists of a single elongated tablet measuring about 18 mm to about 22 mm in length, about 6.5 mm to about 7.8 mm in width, and about 6.2 to 7.5 mm in height.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

20. A method in accordance with claim 19 in which said drug is a member selected from the group consisting of amoxicillin, cefuroxime axetil, cefaclor, clindamycin, clarithromycin, azithromycin, ceftazidine, and ciprofloxacin.

21. A method in accordance with claim 19 in which said drug is a highly soluble drug selected from the group consisting of amoxicillin, cefuroxime axetil, cefaclor, and clindamycin.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

23. A method in accordance with claim 22 in which said drug is a highly soluble drug selected from the group consisting of amoxiillin, cefuroxime axetil, cefaclor, and clindamycin.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

25. A method in accordance with claim 24 in which said drug is a member selected from the group consisting of cyclosporine, digoxin, and doxifluridine.

26. A method in accordance with claim 24 in which said drug is doxifluridine.

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 one or more polymers forming a solid polymeric matrix with said cyclosporine incorporated therein at a weight ratio of cyclosporine to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said cyclosporine within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said digoxin incorporated therein at a weight ratio of digoxin to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said digoxin within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said doxifluridine incorporated therein at a weight ratio of doxifluridine to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said doxifluridine within about ten hours after such immersion,

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.

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 one or more polymers forming comprising a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

31. A method in accordance with claim 30 in which said drug is a member selected from the group consisting of cyclosporine and paclitaxel.

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 one or more polymers forming a solid polymeric matrix with said cyclosporine incorporated therein at a weight ratio of cyclosporine to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said cyclosporine within about ten hours after such immersion,

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.

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 one or more polymers forming solid polymeric matrix with said paclitaxel incorporated therein at a weight ratio of paclitaxel to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said paclitaxel within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

35. A method in accordance with claim 34 in which said drug is a member selected from the group consisting of esters of ampicillin, iron salts, digoxin, and ketoconazole.

36. A method in accordance with claim 34 in which said drug is a member selected from the group consisting of esters of ampicillin.

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 one or more polymers forming a solid polymeric matrix with said ester of ampicillin incorporated therein at a weight ratio of said ester of ampicillin to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said ester of ampicillin within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said iron salts incorporated 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) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said iron salts within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said ketoconazole incorporated therein at a weight ratio of ketoconazole to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said ketoconazole within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix in which said drug is incorporated at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

41. A method in accordance with claim 40 in which said drug is nelfinar mesylate.

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 one or more polymers forming a solid polymeric matrix with said nelfinar mesylate incorporated therein at a weight ratio of nelfinar mesylate to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said nelfinar mesylate within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (d) releases substantially all of said drug within about ten hours after such immersion,

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.

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 one or more polymers forming a solid polymeric matrix with said drug incorporated therein at a weight ratio of drug to polymer of from 0.01:99.99 to 80:20, said polymeric matrix being one that: (a) when swollen in a dimensionally unrestricted manner as a result of imbibition of gastric fluid is of a size exceeding the pyloric diameter in the fed mode 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, and (e) releases substantially all of said drug within about ten hours after such immersion,

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.

45. A dosage form in accordance with claim 1 in which said dosage form releases substantially all of said drug within about ten hours after immersion in gastric fluid.

46. A dosage form in accordance with claim 1 in which said dosage form releases substantially all of said drug within about eight hours after immersion in gastric fluid.

47. A dosage form in accordance with claim 4 in which said polymeric matrix comprises a polymer selected from the group consisting of poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum.

48. A dosage form in accordance with claim 4 in which said polymeric matrix comprises an alkyl-substituted cellulose.

49. A dosage form in accordance with claim 4 in which said polymeric matrix comprises an alkyl-substituted cellulose selected from the group consisting of hydroxymethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropylmethyl-cellulose, and carboxymethyl-cellulose.

50. A dosage form in accordance with claim 4 in which said polymeric matrix comprises hydroxypropylmethyl-cellulose.

51. A dosage form in accordance with claim 4 in which said polymeric matrix comprises hydroxypropylmethyl-cellulose having a viscosity ranging from 11,000 to 110,000 centipoise as measured in a 2% solution at 20.degree. C.

52. A dosage form in accordance with claim 4 in which said polymeric matrix upon immersion in gastric fluid retains at least about 50% of said metformin hydrochloride one hour after such immersion.

53. A dosage form in accordance with claim 4 in which said polymeric matrix upon immersion in gastric fluid retains at least about 60% of said metformin hydrochloride one hour after such immersion.

54. A dosage form in accordance with claim 4 in which said polymeric matrix comprises poly(ethylene oxide) having a molecular weight of at least about 4,000,000.

55. A dosage form in accordance with claim 4 in which said polymeric matrix comprises poly(ethylene oxide) having a molecular weight ranging from about 4,500,000 to about 10,000,000.

56. A dosage form in accordance with claim 4 in which said polymeric matrix comprises poly(ethylene oxide) having a molecular weight ranging from about 5,000,000 to about 8,000,000.

57. A dosage form in accordance with claim 1 in which said drug is ciprofloxacin.

58. A dosage form in accordance with claim 57 in which said polymeric matrix comprises a polymer selected from the group consisting of poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum.

59. A dosage form in accordance with claim 57 in which said polymeric matrix comprises an alkyl-substituted cellulose.

60. A dosage form in accordance with claim 57 in which said polymeric matrix comprises an alkyl-substituted cellulose selected from the group consisting of hydroxymethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropylmethyl-cellulose, and carboxymethyl-cellulose.

61. A dosage form in accordance with claim 57 in which said polymeric matrix comprises hydroxypropylmethyl-cellulose.

62. A dosage form in accordance with claim 57 in which said polymeric matrix upon immersion in gastric fluid retains at least about 60% of said metformin hydrochloride one hour after such immersion.

63. A dosage form in accordance with claim 57 in which said polymeric matrix comprises poly(ethylene oxide).

64. A dosage form in accordance with claim 1 in which said drug is an iron salt.

65. A dosage form in accordance with claim 64 in which said polymeric matrix comprises a polymer selected from the group consisting of poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum.

66. A dosage form in accordance with claim 64 in which said polymeric matrix comprises an alkyl-substituted cellulose.

67. A dosage form in accordance with claim 64 in which said polymeric matrix comprises an alkyl-substituted cellulose selected from the group consisting of hydroxymethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropylmethyl-cellulose, and carboxymethyl-cellulose.

68. A dosage form in accordance with claim 64 in which said polymeric matrix comprises hydroxypropylmethyl-cellulose.

69. A dosage form in accordance with claim 64 in which said polymeric matrix upon immersion in gastric fluid retains at least about 60% of said metformin hydrochloride one hour after such immersion.

70. A dosage form in accordance with claim 64 in which said polymeric matrix comprises poly(ethylene oxide).
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