Microporous-semipermeable laminated osmotic system

• US 4,256,108 A
• Filed: 05/21/1979
• Issued: 03/17/1981
• Est. Priority Date: 04/07/1977
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Theeuwes, Felix
• Primary Examiner(s): Michell, Robert W.
• Assistant Examiner(s): ROSENBAUM, C FRED
• Application Number:
  US06/034,275
• Time in Patent Office: 666 Days
• Field of Search: 128/213 R, 128/260-261
• US Class Current: 424/424
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts

Abstract

An osmotic therapeutic system for delivering a drug is disclosed. The system comprises a drug delivery module which module comprises a rate controlling laminated wall surrounding a reservoir and has a portal for delivering drug from the system. The laminated wall comprises a semipermeable lamina in laminar arrangement with a microporous lamina to provide a wall that is permeable to an external fluid, impermeable to drug and maintains its integrity during the delivery of drug. The reservoir contains a drug, or a mixture of drug and a solute which drug or solute is soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid. In operation, drug is released from the system by fluid being imbibed through the wall into the reservoir at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall thereby producing a solution of drug, or a solution of solute containing drug which solution is released through the portal at a controlled rate over a prolonged period of time.

Claims

1. An osmotic therapeutic system for the controlled dispensing of a drug formulation to an animal, which system comprises:

(a) a shaped laminated wall comprising a lamina formed of a semipermeable material permeable to the passage of an external fluid and substantially impermeable to the passage of drug formulation, and a lamina formed of a microporous material, said laminated wall surrounding and forming;

(b) a compartment containing the drug formulation which exhibits an osmotic pressure gradient across the wall, and wherein the drug is a member selected from the group of drugs that act on the peripheral and central nervous systems, adrenergic and cholinergic receptors, skeletal system, skeletal and smooth muscles, circulatory and cardiovascular systems, synoptic and neuroeffector sites, alimentary and excretory systems, endocrine, hormone, autocoid, reproductive and immunological systems; and

,

(c) a passageway in the laminated wall communicating with the compartment and the exterior of the osmotic system for dispensing drug from the system over a prolonged period of time.

2. The osmotic therapeutic system for the controlled dispensing of drug formulation according to claim 1, wherein the animal is a human, and the system is sized and shaped for oral administration of the drug to the gastrointestinal tract of the human.

3. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is hydrazaline hydrochloride.

4. The osmotic therapeutic system for dispensing drug formulation according to claim 1, wherein in operation, when the system is in use in the animal, fluid is imbibed through the laminated wall into the compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby forming a solution containing drug that is dispensed through the passageway at a controlled rate over a prolonged period of time to the animal.

5. The osmotic therapeutic system for the controlled dispensing of drug formulation according to claim 1, wherein the formulation comprises an osmotically effective solute.

6. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is a β

-adrenoceptor blocking drug.

7. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is pindolol.

8. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is propranolol.

9. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is practolol.

10. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is metoprolol.

11. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is oxprenolol.

12. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is timolol.

13. The osmotic therepeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is atenolol.

14. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is alprenolol.

15. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is acebutolol.

16. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is bupranolol.

17. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is labetolol.

18. The osmotic therepeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 41.4% by weight of cellulose acetate having an acetyl content of 32%, 43.6% by weight of cellulose acetate having an acetyl content of 39.8%, 7.5% by weight of polyethylene glycol 4000 and 7.5% by weight of hydroxypropyl methylcellulose, the microporous lamina comprises 45% by weight of cellulose acetate having an acetyl content of 39.8%, 27.5% by weight of polyethylene glycol 4000, and the compartment houses 288 mg of oxprenolol azelate, 6 mg of polyvinyl pyrrolidone and 3 mg of magnesium stearate

19. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 41.4% by weight of cellulose acetate having an acetyl content of 32%, 43.6% by weight of cellulose acetate having an acetyl content of 39.8% and 15% by weight of hydroxypropyl methylcellulose, the microporous lamina comprises 45% by weight of cellulose acetate having an acetyl content of 39.8%, 27.5% by weight of hydroxypropyl methylcellulose and 27.5% by weight of polyethylene glycol, and the compartment houses 292 mg of oxprenolol sebacinate, 591 mg of mannitol, 34 mg of polyvinyl pyrrolidone and 9 mg of magnesium stearate.

20. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is an antihypertensive drug.

21. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is clonidine.

22. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is methyldopa.

23. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is an ester of α

-methyldopa.

24. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is pivaloyloxyethylester of α

-methyldopa.

25. The osmotic therpeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 60% by weight of cellulose acetate having an acetyl content of 38.3%, 25% by weight of hydroxypropyl methylcellulose and 15% by weight of polyethylene glycol 400, the microporous lamina comprises 40% by weight of cellulose acetate having an average acetyl content of 38.3%, 45% by weight of sorbitol and 15% by weight of polyethylene glycol 400, and the compartment houses 487 mg of pivaloyloxyethylester of α

-methyldopa hydrochloride dihydrate, 3 mg of disodium ethylenediamine tetraacetic acid, 32 mg of polyvinyl pyrrolidone and 2 mg of magnesium stearate.

26. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 60% by weight of cellulose acetate having an average acetyl content of 38.3%, 25% by weight of hydroxypropyl methylcellulose and 15% by weight of polyethylene glycol 400, a microporous lamina comprising 40% by weight cellulose acetate having an average acetyl content of 38.3%, 15% by weight of hydroxypropyl methylcellulose and 45% by weight of sorbitol, and the compartment houses 487 mg of pivaloyloxyethylester of α

-methyldopa hydrochloride dihydrate, 3 mg of disodium ethylenediamine tetraacetic acid, 31 mg of polyvinyl pyrrolidone and 2.1 mg of magnesium stearate.

27. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is hydralazine.

28. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 42.5% by weight of cellulose acetate having an acetyl content of 39.8%, 42.5% by weight of cellulose acetate having an acetyl content of 32% and 15% by weight of hydroxypropyl methylcellulose, the microporous lamina comprises 32.5% by weight of cellulose acetate having an acetyl content of 32%, 32.5% by weight of cellulose acetate having an acetyl content of 39.8% and 35% by weight of hydroxypropyl methylcellulose, and the compartment houses 50 mg of hydralazine hydrochloride, 214 mg of mannitol, 1 mg of hydroxypropyl methylcellulose and 1 mg of magnesium stearate.

29. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is a hormone and autocoid synthesis inhibitor.

30. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is an anti-inflammatory drug.

31. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is indomethacin.

32. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is diclofenac.

33. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is sulindac.

34. The osmotic therapuetic system for the controlled dispensing of drug according to claim 1, wherein the drug is naproxen.

35. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is fenoprofen.

36. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is aspirin.

37. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 50% by weight of cellulose acetate having an acetyl content of 39.8% and 50% by weight of cellulose acetate having an acetyl content of 32%, a microporous lamina comprising 45% by weight of cellulose acetate having an acetyl content of 39.8%, 27.5% by weight of polyethylene glycol 4000 and 27.5% by weight of hydroxypropyl methylcellulose, and the compartment houses 105 mg of sodium indomethacin trihydrate, 8.5 mg of polyvinyl pyrrolidone, and 8.5 mg of stearic acid.

38. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 50% by weight of cellulose acetate having an acetyl content of 32% and 50% by weight of cellulose acetate having an acetyl content of 38.3%, a microporous lamina comprising 45% by weight of cellulose acetate having an acetyl content of 38.3%, 45% by weight of sorbitol and 10% by weight of polyethylene glycol 4000, and the compartment houses 105 mg of sodium indomethacin trihydrate, 8.4 mg of polyvinyl pyrrolidone and 8.4 mg of stearic acid.

39. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is a histamine receptor antagonist.

40. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is cimetidine.

41. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises 41.4% by weight of cellulose acetate having an acetyl content of 32%, 43.6% by weight of cellulose acetate having an acetyl content of 39.8%, 7.5% by weight of hydroxypropyl methylcellulose and 7.5% by weight of polyethylene glycol, a microporous lamina comprising 45% by weight of cellulose acetate having an acetyl content of 39.8%, 27.5% by weight of polyethylene glycol 4000, and 27.5% by weight of hydroxypropyl methylcellulose, and the compartment houses 600 mg of theophylline sodium glycinate, 24 mg of polyvinyl pyrrolidone and 6 mg of magnesium stearate.

42. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is terbutaline.

43. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the drug is valporate.

44. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the semipermeable lamina comprises two different cellulose polymers.

45. The osmotic therapeutic system for the controlled dispensing of drug according to claim 1, wherein the microporous lamina contains a non-toxic pore-former.

46. An osmotic therapeutic system for the controlled dispensing of a beneficial formulation to an animal, wherein the system comprises:

(a) a shaped laminated wall comprising a semipermeable lamina permeable to the passage of an external fluid and substantially impermeable to the passage of drug formulation, and a lamina formed of a microporous material having a plurality of micropores with micropaths through the lamina, said micropores having a reflection coefficient of less than 1, from 5 to 95% micropores of from 10 angstroms to 100 micron size, and a flux through the micropores expressed by;

##EQU20## wherein J is the volume transported per unit of lamina area having N number of micropores of radius N, ζ

is the tortuosity, η

is the viscosity of the fluid in the micropores, and Δ

P is the pressure difference across the lamina with thickness Δ

x, said laminated wall surrounding and forming;

(b) a compartment housing the drug formulation, wherein the drug is a member selected from the group consisting of anticonvulsant, antiparkinson, analgesics, hormonal, diuretic, opthalmic, tranquilizer, hypoglycemic, anti-infective, antipyretic, and psychic energizer drugs,

(d) wherein in operation, when the system is in the animal and dispensing drug, fluid therefrom is imbibed through the laminated wall into the compartment, thereby forming a solution of drug formulation that is dispersed through the passageway at a controlled rate over a prolonged period of time.

47. The osmotic therapeutic system for the controlled dispensing of drug according to claim 46, wherein the system is sized and adapted for placement in the eye and the compartment houses timolol.

48. The osmotic therapeutic system for the controlled dispensing of drug according to claim 46, wherein the system is sized and adapted for placement in the eye, and the drug in the compartment is an opthalmic β

-adrenergic blocker.

49. The osmotic therapeutic system for the controlled dispensing of drug according to claim 46, wherein the system is sized and adapted for placement in the eye and the compartment houses the opthalmic drug metoprolol.

50. The osmotic therapeutic system for the controlled dispensing of drug according to claim 46, wherein microporous lamina has a surface area A with a plurality of pores according to the following relation:

##EQU21## wherein N is the number of pores and ε

is the porosity, A the area of the lamina, and r the pore radius.

51. A method for the controlled administration of a drug formulation to the gastrointestinal tract of a human, which method comprises:

A. admitting orally into the gastrointestinal tract an osmotic therapeutic system comprising;

(1) a shaped laminated wall comprising a lamina formed of a semipermeable material that is permeable to the passage of drug formulation, and a lamina made of a material that forms a microporous lamina in the gastrointestinal tract, which microporous lamina comprises a plurality of micropores having a reflection coefficient of less than 1, said laminated wall surrounding and forming;

(2) a compartment containing the drug formulation that exhibits an osmotic pressure gradient across the wall;

(3) a passageway in the wall communicating with the compartment and the exterior of the system for administering drug from the system; and

,

B. administering drug to the gastrointestinal tract by imbibing fluid through the wall into the compartment, thereby forming a solution containing drug that is dispensed through the passageway at a controlled rate in a therapeutically effective amount over a prolonged period of time.

52. The method for the controlled administration of the drug according to claim 51, wherein the microporous lamina formed in the gastrointestinal tract comprises a plurality of micropores with paths through the microporous lamina, said micropores exhibiting a reflection coefficient of less than 1, the microporous lamina having from 5 to 95% micropores of from 10 angstroms to 100 microns in size, and a fluid flux through the micropores of:

##EQU22## wherein J is the fluid volume transported per unit time, said microporous lamina having N number of micropores of radius r, η

is the viscosity of the fluid and Δ

P is the pressure difference across the semipermeable lamina with a thickness Δ

X.

53. The method for the controlled administration of drug formulation according to claim 51, wherein the material that forms a microporous lamina contains a pore-former that is leached from the material in the gastrointestinal tract.

54. The method for the controlled administration of drug according to claim 51, wherein the microporous lamina is formed during operation of the system be leaching a pore-former present in the material, and the formed microporous lamina has a surface area A and a plurality of pores according to the following relation:

##EQU23## wherein N is the number of pores and ε

is the porosity, and r the pore radius.

55. The method for the controlled administration of drug according to claim 51, wherein the microporous lamina is formed in the gastrointestinal tract by leaching from the microporous forming material a souble pore-former, and the micropores formed by leaching the pore-former have a radius of:

##EQU24## wherein J is the volume flux, η

is the viscosity of the liquid, ε

is the porosity, Δ

P is the pressure difference across the lamina, Δ

x is the thickness of the lamina and τ

is the tortuosity.

56. The method for the controlled administration of drug according to claim 51, wherein the drug formulation comprises a drug and an osmotically effective solute.

57. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is indomethacin.

58. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is pivaloyloxyethylester of α

-methyldopa hydrochloride dihydrate.

59. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is cimetidine.

60. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is oxprenolol.

61. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is metoprolol.

62. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is propranolol.

63. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is hydralazine.

64. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is clonidine.

65. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is sulindac.

66. The method for the controlled administration of drug according to claim 51, wherein the drug in the compartment is naproxen.