Combined diffusion/osmotic pumping drug delivery system

• US 6,352,721 B1
• Filed: 01/14/2000
• Issued: 03/05/2002
• Est. Priority Date: 01/14/2000
• Status: Expired due to Term

• Current Assignee: Osmotica Kereskedelmi Es Szolgaltato Kft (Osmotica Pharmaceuticals Plc)
• Original Assignee: Osmotica Corp.
• Inventors: Faour, Joaquina
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/483,282
• Time in Patent Office: 781 Days
• Field of Search: 424/464, 424/465, 424/468, 424/471, 424/472, 424/473, 424/474, 424/475, 424/479, 424/480, 424/467, 424/422, 424/423, 424/424, 424/427, 424/435, 424/436, 424/437
• US Class Current: 424/473
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

Delivery devices capable of delivering one or more active substances by diffusion through plural micropores in the membrane or by osmotic pumping through one or more preformed passageways in the membrane are provided. The device has an about centrally located expandable core completely surrounded by an active substance-containing layer, which is completely surrounded by the membrane. The device is capable of delivering insoluble, slightly soluble, sparingly soluble and very soluble active substances to an environment of use. The preferred delivery rate is zero order. The device can deliver an active substance for a period of about 12-24 hours.

Claims

1. A device for the controlled delivery of active agents to an environment of use, wherein the device comprises:

a) a core located approximately at the center of the device and comprising at least one expandable hydrophilic polymer and, optionally, an osmagent, said core being able to absorb fluids from the environment of use;

b) a composition immediately surrounding the core comprising at least one active substance and, optionally, one or more of an osmagent and an osmopolymer;

c) a membrane immediately surrounding the composition and comprising a mixture of a cellulose acylate, a poly(methacrylate) copolymer salt and a plasticizer, wherein the membrane permits delivery of the at least one active substance through a combination of diffusion and osmotic pumping; and

d) one or more preformed passageways and plural micropores in the membrane that communicate the composition with the outside of the device.

2. A device according to claim 1, wherein the expandable hydrophilic polymer is one or more of hydroxypropyl methylcellulose, alkylcelullose, hydroxyalkylcellulose, poly(alkylene oxide), and combinations thereof.

3. A device according to claim 1, wherein the membrane comprises about 1 to 99 weight percent of one or more cellulose esters, about 84 to 0.5 weight percent of one or more poly(methacrylate) copolymer salt and about 15 to 0.5 weight percent of one or more plasticizers.

4. A device according to claim 3, wherein the cellulose ester is selected form the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.

5. A device according to claim 3, wherein the poly(methacrylate) copolymer salt is poly(ammonium methacrylate) copolymer.

6. A device according to claim 3, wherein the plasticizer is selected from the group consisting of acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, acetylated monoglycerids, glycerol, poly(ethylene glycol), triacetin, propylene glycol, dibutyl phthalate, diethyl phthalate, dipropyl phthalate, dimethyl phthalate, dioctyl phthalate, dibutyl sebacate, dimethyl sebacate, castor oil, glycerol monostearate, and coconut oil.

7. A device according to claim 1, wherein the active agent is one of a biologically active agent, pharmacologically active agent, medicine, nutrient, food product, vitamin, insecticide, pesticide, herbicide, microbicide, algaecide, fungicide, grow regulating substance, parasiticide, sterilant, fertility promoter, biocide, rodenticide, disinfectant, plant growth promoter, preservative, fertility inhibitor, deodorant, catalysts, food supplement and cosmetic.

8. A device according to claim 1, wherein a slightly soluble or insoluble active substance is delivered predominantly through the at least one passageway and a soluble or sparingly soluble active substance is delivered predominantly through the plural micropores.

9. A device according to claim 1 further comprising an external coat comprising a second active substance for the immediate, rapid, controlled or delayed release of the second active substance, wherein the external coat surrounds at least a portion of the membrane.

10. A device according to claim 1, wherein the active substance is slightly soluble or insoluble in a fluid from the environment of use, and the active substance is delivered predominantly through the one or more preformed passageways.

11. A device according to claim 9, wherein the active substance is delivered at an approximately zero order rate.

12. A device according to claim 1, wherein the active substance is at least sparingly soluble in a fluid from the environment of use, and a significant portion of the active substance is delivered through the micropores of the membrane.

13. A device according to claim 12, wherein the active substance is delivered at an approximately zero order rate.

14. A device for the controlled delivery of an active substance to an environment of use wherein the active substance is one of very soluble, sparingly soluble, slightly soluble or insoluble in a fluid imbibed by the device from the environment of use, the device comprising:

a core expandable in a fluid from the environment of use, the core being approximately centrally located in the device;

a layer comprising the active substance in contact with and surrounding the core; and

a membrane in contact with and surrounding the layer and comprising at least one passageway made by mechanical means for delivery of the active substance by osmotic pumping and plural micropores for delivery of the active substance by diffusion, wherein the membrane comprises about 1 to 99 weight percent of one or more cellulose esters, about 84 to 0.5 weight percent of one or more poly(methacrylate) copolymer salt and about 15 to 0.5 weight percent of one or more plasticizers.

15. The device of claim 14, wherein a slightly soluble or insoluble active substance is delivered predominantly through the at least one passageway.

16. The device of claim 14, wherein a significant portion of a very soluble or sparingly soluble active substance is delivered through the plural micropores.

17. The device of claim 14, wherein the mechanical means is at least one of a laser and a drill.

18. The device of claim 14, wherein the fluid is an aqueous fluid.

19. The device of claim 14, wherein the core comprises an expandable polymer.

20. The device of claim 19, wherein the expandable polymer is selected from the group consisting of hydroxypropyl methylcellulose, alkylcelullose, hydroxyalkylcellulose, poly(alkylene oxide), and combinations thereof.

21. The device of claim 14, wherein the layer further comprises at least one of an osmagent and an osmopolymer.

22. The device of claim 21, wherein the osmagent is selected from the group consisting of sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-monohydrate lactose, glucose and combinations thereof.

23. The device of claim 21, wherein the osmopolymer is selected from the group consisting of hydroxypropyl methylcellulose, alkylcellulose, hydroxyalkylcellulose, poly(alkylene oxide), or a combination thereof.

24. A device according to claim 14, wherein the active substance is nifedipine.

25. The device of claim 14, wherein the at least one cellulose ester is independently selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.

26. The device of claim 14, wherein the at least one poly(methacrylate) copolymer salt is a poly(ammonium methacrylate) copolymer.

27. The device of claim 14, wherein the at least one plasticizer is selected from the group consisting of acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, acetylated monoglycerids, glycerol, poly(ethylene glycol), triacetin, propylene glycol, dibutyl phthalate, diethyl phthalate, dipropyl phthalate, dimethyl phthalate, dioctyl phthalate, dibutyl sebacate, dimethyl sebacate, castor oil, glycerol monostearate, and coconut oil.

28. A device according to claim 14, wherein the active substance is venlafaxine.

29. The device of claim 14 further comprising an external coat comprising a second active substance for the immediate, rapid, controlled or delayed release of the second active substance, wherein the external coat surrounds at least a portion of the membrane.

30. The device of claim 29, wherein the first and second active substances are the same.

31. The device of claim 29, wherein the first and second active substances are different.

32. A device according to claim 19, wherein the expandable core further comprises an osmagent.

33. A device according to claim 32, wherein the osmagent is selected from the group consisting of sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-monohydrate lactose, glucose and combinations thereof.

34. A device according to any one of claims 14-23, 25-27 or 29-33, wherein the active substance is a therapeutic agent.

35. A device according to claim 14, wherein the device is adapted for one of oral, buccal, sublingual, rectal, anal, dermal, subdermal, cutaneous, subcutaneous, intraperitoneal, ophthalmic, otic and implant administration.

36. A device according to claim 14 further comprising one or more of an adsorbent, antioxidant, buffering agent, colorant, flavorant, sweetening agent, anti-adherent, binder, diluent, direct compression excipient, disintegrant, tablet glidant, tablet opaquant and tablet polishing agent.

37. A device according to claim 14, wherein the active substance is cisapride.