Osmotic system having laminar arrangement for programming delivery of active agent

• US 4,008,719 A
• Filed: 02/02/1976
• Issued: 02/22/1977
• Est. Priority Date: 02/02/1976
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Ayer, Atul D., Theeuwes, Felix
• Primary Examiner(s): Medbery, Aldrich F.
• Application Number:
  US05/654,195
• Time in Patent Office: 386 Days
• Field of Search: 128/260, 128/261, 128/268, 128/272, 424/19, 424/20, 424/21, 424/22, 424/33, 424/15, 424/37, 424/28
• US Class Current: 424/427
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

An osmotic system for delivering an agent is disclosed. The system comprises a wall surrounding a compartment and has a passageway for delivering agent from the compartment. The wall is formed of a laminae comprising a lamina consisting of a multiplicity of materials in laminar arrangement with a lamina consisting of a material or of a multiplicity of materials to provide a laminated wall that is permeable to agents and maintains its integrity during the delivery of agent. The compartment contains an agent that is soluble in an external fluid and exhibits an osmotic pressure gradient across the wall against the fluid, or the agent has limited solubility in the fluid and is mixed with an osmotically effective compound soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid. In operation, agent is released from the system by fluid being imbibed through the wall into the compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall producing a solution containing agent, or a solution of compound containing agent which solution in either operation is released through the passageway at a controlled and continuous rate over a prolonged period of time.

Claims

1. An osmotic system for dispensing an active agent to an environment of use, said system comprising:

a. a shaped wall comprising a pair of laminae comprising an exterior lamina consisting of a multiplicity of materials blended to form a lamina that is permeable to the passage of an external fluid and maintains its physical and chemical integrity in the environment of use, and an interior lamina consisting of a multiplicity of materials blended to form a lamina that is permeable to the passage of an external fluid, substantially impermeable to the passage of agent and maintains its physical and chemical integrity in the presence of agent, said wall surrounding, with the interior lamina facing;

b. a compartment containing an active agent that is soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid;

c. a compartment in the wall communicating with the compartment and the exterior of the device for dispensing agent from the device; and

d. wherein in operation when the device is in the environment of use, fluid from the environment is continually inbibed through the 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 continuously dissolving agent which is dispensed at a controlled and continuous rate over a prolonged period of time.

2. The osmotic system for dispensing an agent according to claim 1 wherein the exterior lamina is substantially non-erodible and inert in the environment of use.

3. The osmotic system for dispensing an agent according to claim 1 wherein the interior lamina is substantially non-erodible and inert in the presence of agent and solutions thereof.

4. The osmotic system for dispensing an agent according to claim 1 wherein the laminae comprise at least one semipermeable lamina forming material.

5. The osmotic system for dispensing an agent according to claim 1 wherein the laminae comprise a cellulose ester having a degree of substitution on its anhydroglucose groups of greater than 0 and up to 3 inclusive.

6. The osmotic system for dispensing an agent according to claim 1 wherein the laminae contain a member selected from the group consisting of cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate and cellulose acetate butyrate.

7. The osmotic system for dispensing an agent according to claim 1 wherein the laminae contain at least one material that imparts stability to the laminae.

8. The osmotic system for dispensing an agent according to claim 1 wherein the system is sized, shaped and adapted as a dosage form for dispensing an agent in the gastrointestinal tract.

9. The osmotic system for dispensing an agent according to claim 1 wherein the passageway is formed in the environment of use.

10. The osmtoic system for dispensing an agent according to claim 1 wherein the agent is a member selected from the group consisting of locally and systemically acting drugs.

11. The osmotic system for dispensing an agent according to claim 1 wherein the agent is a member selected from the group consisting of acetazolamide, methazolamide, potassium chloride, niacin, aspirin, meprobamate, salicylamide, theophylline monoethanolamine, aminophylline, procainamide hydrochloride, colchicine and atropine.

12. The osmotic system for dispensing an agent according to claim 1 wherein the laminae contain a plasticizer.

13. The osmotic system for dispensing an agent according to claim 1 wherein the laminae containing a plasticizer selected from the group consisting of cyclic and acyclic plasticizers.

14. The osmotic system for dispensing an agent according to claim 1 wherein the laminae contain an amphipatic dispersant comprising hydrophilic and hydrophobic groups.

15. The osmotic system according to claim 1 wherein the laminae contain a dispersant selected from the group consisting of anionic, cationic, nonionic and amphoteric dispersants.

16. The osmotic system for dispersing an agent according to claim 1 wherein the laminae contain a flux regulator that decreases or increases the permeability of the laminae to the passage of fluid.

17. The osmotic system for dispensing an agent according to claim 1 wherein the laminae contain a cellulose ether.

18. The osmotic system for dispensing an agent according to claim 1 wherein the compartment contains an osmotically effective compound that exhibits an osmotic pressure gradient across the wall from greater than 0 up to 500 atmospheres.

19. The osmotic system for dispensing an agent according to claim 1 wherein the system is sized, shaped and adapted for placement in a vagina.

20. An osmotic system for the continuous dispensing of an active agent to an environment of use comprising:

a. a shaped wall comprising an interior lamina consisting of at least two materials that form a lamina permeable to the passage of an external fluid, substantially impermeable to the passage of agent and essentially mantains its physical and chemical integrity in the presence of agent, said lamina in laminar arrangement with an exterior lamina formed of a material permeable to the passage of fluid and essentially maintains is physical and chemical integrity in the environment of use, said wall surrounding, with the interior lamina facing;

b. a compartment containing the active agent that is soluble in the external fluid and exhibits an osmotic pressure gradient across the wall against the fluid;

c. a passageway in the wall communicating with the compartment and the exterior of the system for dispensing agent from the system; and

,

d. wherein in operation when the system is placed in the environment of use, fluid from the environment is imbibed through the 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 dissolving agent which is dispersed through the passageway at a controlled and continuous rate over a prolonged period of time.

21. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina is formed of a semipermeable material and a stabilizing material that imparts integrity to the lamina.

22. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina is formed of a semipermeable material, a stabilizing material and a dispersant that blends the materials.

23. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina is formed of a semipermeable material, a stabilizing material, a dispersant, and a plasticizer.

24. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina is formed of a semipermeable material, a stabilizing material, a dispersant, a plasticizer, and a flux regulator.

25. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a cellulose ester having a degree of substitution on its anhydroglucose groups of greater than 0 and up to 3 inclusive.

26. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a member selected from the group consisting of cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate, and cellulose acetate butyrate.

27. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a stabilizing material selected from the group consisting of cellulose esters having on its anhydroglucose groups a degree of substitution greater than 0 and up to 3 inclusive, cellulose ethers and mixtures thereof.

28. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a semipermeable material and a stabilizing material possessing different chemical and physical properties than the semipermeable material and selected from the group consisting of cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, and mixtures thereof.

29. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a plasticizer selected from the group consisting of cyclic and acyclic plasticizers and mixtures thereof.

30. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a plasticizer selected from the group consisting of phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, sulfonamides and halogenated phenyls.

31. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a dispersant selected from the group consisting of anionic, cationic, nonionic and amphoteric dispersants, and mixtures thereof.

32. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a dispersant selected from the group consisting of polyoxyalkylene glycol, esters of polyoxyalkylene glycols, esters of polyhydric alcohols, sulfated esters, sulfated amides, quaternary ammonium salts, alkanolamine fatty acids, tertiary alkylamonium salts, and mixtures thereof.

33. The osmotic system for dispensing an agent according to claim 20 wherein the system is sized, shaped and adapted for dispensing an agent in the gastrointestinal tract.

34. The osmotic system for dispensing an agent according to claim 20 wherein the agent is a member selected from the group consisting of locally and systemically acting drugs.

35. The osmotic system for dispensing an agent according to claim 20 wherein the soluble agent is mixed with an osmotically effective compound.

36. The osmotic system for dispensing an agent according to claim 20 wherein the passageway is formed in the environment of use.

37. The osmotic system for dispensing an agent according to claim 20 wherein the agent in the compartment is mixed with a member selected from the group consisting of a binder, a pharmaceutically acceptable dye, a lubricant, and mixtures thereof.

38. The osmotic system for dispensing an agent according to claim 20 wherein the agent is a member selected from the group consisting of tolbulamide, tolazamide, chloropropamide, mannitol hexanitrate, tranylcypromine, progestational steroids, and estrogenic steroids.

39. The osmotic system for dispensing an agent according to claim 20 wherein the interior lamina contains a flux regulator selected from the group consiting of aliphatic diols, polyalkylene glycols, poly(α

,ω

)-alkylenediols, esters of alkylene glycols and mixtures thereof.

40. The osmotic system for dispensing an agent according to claim 20 wherein the exterior lamina is a member selected from the group consisting of cellulose ethers, polyamides and polyurethanes.

41. An osmotic system for the continuous dispensing of an active agent to an environment of use comprising:

a. a shaped wall comprising an interior lamina formed of a semipermeable material that is permeable to the passage of an external fluid, substantially impermeable to the passage of agent and essentially maintains its physical and chemical integrity in the presence of agent, said lamina laminated to an exterior lamina formed of at least two materials with the lamina permeable to the passage of fluid and essentially maintains its physical and chemical integrity in the environment of use, said wall surrounding, with the interior lamina facing;

b. a compartment containing an active agent that is soluble in the external fluid and exhibits an osmtoic pressure gradient across the wall against the fluid;

c. a passageway in the wall communicating with the compartment and the exterior of the system for dispensing agent from the system; and

,

d. wherein in operation when the system is placed in the environment of use, fluid from the environment is imbibed through the wall into the compartment in a tendency towards osmotic equilibrium at a rate determined by the osmotic pressure gradient across the wall, thereby dissolving agent which is dispensed through the passageway at a controlled and continuous rate over a prolonged period of time.

42. The osmotic system for dispensing an agent according to claim 41 wherein the semipermeable material forming the interior lamina is a polymer.

43. The osmotic system for dispensing an agent according to claim 41 wherein the exterior lamina comprises a semipermeable polymeric lamina forming material blended with a hydrophobic stabilizing material and a hydrophilic flux regulating material.

44. The osmotic system for dispensing an agent according to claim 41 wherein the passageway is formed in the environment of use.

45. The osmotic system for dispensing an agent according to claim 41 wherein the exterior lamina comprises a semipermeable polymeric lamina forming material blended with a plasticizer.

46. The osmotic system for dispensing an agent according to claim 41 wherein the exterior lamina comprises a semipermeable polymer, a stabilizing material, a dispersant, a flux regulating material and a plasticizer that lowers the glass transition temperature of the polymer.

47. The osmotic system for dispensing an agent according to claim 41 wherein the agent is a drug and the system is sized, shaped and adapted for dispensing the drug to a receptor selected from the group consisting of eye, ear, nose, gastrointestinal ract, vagina, uterus, anus, skin, and systemic circulation drug receptor sites.

48. The osmotic system for dispensing an agent according to claim 41 wherein the agent is a member selected from the group consisting of idoxuridine, phenylephrine, pilocarpine, pilocarpine salts, eserine, carbachol, phospholine iodine, demecarium bromide, cyclopentolate, homatropine, scopolamine, epinephrine and mixtures thereof.

49. An osmotic system for the continuous dispensing of an active agent to an environment of use comprising:

a. a shaped laminated wall comprising at least two laminae comprising a multiplicity of materials, said laminae forming a laminated wall that is permeable to the passage of an external fluid and substantially impermeable to the passage of agent with the wall surrounding and forming;

b. a compartment containing an active agent;

c. a passageway in the wall communicating with the compartment and the exterior of the system for dispensing agent from the system; and

,

d. wherein the operation, when the system is placed in the environment of use, fluid from the environment is continuously imbibed through the laminated wall, having a total thickness h_t, into the compartment in a tendency towards osmotic equilibrium at a rate proportional to the fluid transmission rate (kπ

)_t of the laminated wall which rate is governed by the following equation;

##EQU5## wherein h₁, h₂ and h_n are the thickness of the individual lamina, and (kπ

)₁, (kπ

)₂ and (kπ

)_n are the fluid transmission rates for the respective laminae, said imbibed fluid continuously dissolving agent which is dispensed from the system at a controlled and continuous rate over a prolonged period of time.

50. An osmotic system for continuously dispensing an agent according to claim 49 wherein the laminated wall comprises a lamina that is substantially impermeable to agent in the compartment and to compounds in the environment of use.

51. The osmotic system for continuously dispensing an agent according to claim 49 wherein the laminated wall comprises a lamina next to the compartment that is essentially non-erodible and inert in the presence of agent.

52. The osmotic system for continuously dispensing an agent according to claim 49 wherein the laminated wall comprises a lamina distant from the compartment that is essentially non-erodible and inert in the environment of use.

53. The osmotic system for continuously dispensing an agent according to claim 49 wherein the laminated wall comprises three laminae.

54. The osmotic system for continuously dispensing an agent according to claim 49 wherein the agent has limited solubility in the fluid and is mixed with an osmotically effective compound that exhibits an osmotic pressure gradient across the laminated wall against the fluid.

55. The osmotic system for continuously dispensing an agent according to claim 49 wherein the inner lamina is a member selected from the group consisting of cellulose ethers, cellulose esters, polyurethanes and polyamides.

56. An osmotic system for the continuous dispensing of an active agent to an environment of use comprising:

a. a shaped laminated wall comprising at least two laminae comprising one lamina made of a multiplicity of materials and one lamina made of a semipermeable material, said laminae forming a laminated wall that is permeable to the passage of an external fluid and substantially impermeable to the passage of agent with the wall surrounding and forming;

b. a compartment containing an active agent;

c. a passageway through the wall communicating with the compartment and the exterior of the system for dispensing agent from the system; and

d. wherein in operation when the system is placed in the environment of use, fluid from the environment is continuously imbided through the laminated wall, having a total thickness h_t, into the compartment in a tendency towards osmotic equilibrium at a rate proportional to the fluid transmission rate (kπ

)_t of the laminated wall which rate is governed by the following equation;

##EQU6## wherein h₁, h₂ and h _n are the thickness of the individual lamina, and (kπ

)₁, (kπ

)₂ and (kπ

)_n are the fluid transmission rates for the respective laminae, said imbibed fluid continuously dissolving agent that is dispensed from the system at a controlled and continuous rate over a prolonged period of time.

57. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises a lamina that is substantially impermeable to agent in the compartment and to compounds in the environment of use.

58. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises a lamina formed of a multiplicity of materials and positioned next to the compartment, said lamina being essentially non-erodible and inert in the presence of agent.

59. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises a lamina formed of a semipermeable material and positioned next to the compartment, said lamina being essentially non-erodible and inert in the presence of agent.

60. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises a lamina formed of a multiplicity of materials and positioned distant from the compartment, said lamina being essentially non-erodible and inert in the environment of use.

61. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises a lamina formed of a semipermeable material and positioned distant from the compartment, said lamina being essentially non-erodible and inert in the environment of use.

62. An osmotic system for continuously dispensing an agent according to claim 56 wherein the laminated wall comprises three laminae.

63. An osmotic system for continuously dispensing an agent according to claim 56 wherein the agent has limited solubility in the fluid and is mixed with an osmotically effective compound that exhibits an osmotic pressure gradient across the laminated wall against the fluid.