Ocular therapeutic agent delivery devices and methods for making and using such devices

• US 20030175324A1
• Filed: 03/15/2001
• Published: 09/18/2003
• Est. Priority Date: 03/15/2001
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Yuan, Peng, Robinson, Michael R., Smith, Janine A., Sung, Cynthia, Nussenblatt, Robert B., Csaky, Karl G.
• Granted Patent: US 6,713,081 B2
• Time in Patent Office: Days
• 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: A61F 9/00781 Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment drainage implants in general A61M27/002
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: B29D 11/023 Implants for natural eyes
• CPC Class Codes: B29K 2083/00 Use of polymers having silicon, with or without sulfur, nitrogen, oxygen, or carbon only, in the main chain, as moulding material
• CPC Class Codes: B29K 2827/18 PTFE, i.e. polytetrafluorethene, e.g. ePTFE, i.e. expanded polytetrafluorethene
• CPC Class Codes: Y10S 425/808 Lens mold

Abstract

Ocular implant devices for the delivery of a therapeutic agent to an eye in a controlled and sustained manner. Dual mode and single mode drug delivery devices are illustrated and described. Implants suitable for subconjunctival placement are described. Implants suitable for intravitreal placement also are described. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices that are presented herein.

Claims

1. A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising attaching an implant containing a therapeutic agent to eye tissues wherein the implant releases the therapeutic agent continuously to the eye by initial delivery of a loading dose to the eye followed by a period of time in which delivery of the therapeutic agent to the eye occurs via a substantially constant release rate.

2. The method according to claim 1, wherein the period of time of substantially constant release rate is approximately three months or more.

3. The method according to claim 1, wherein the period of time of substantially constant release rate is approximately six months or more.

4. The method according to claim 1, wherein the eye tissues comprise subconjunctival tissues.

5. The method according to claim 1, wherein the eye tissues comprise intravitreal tissues.

6. The method according to claim 1, wherein the substantially constant release rate is a maintenance dosage for treating a disease or disorder for which the eye treatment is directed.

7. An ocular implant providing sustained-release of a first therapeutic agent to the eye for a prolonged period of time, comprising:

a composite material matrix layer including;

(i) a first therapeutic agent, and

(ii) a polymeric matrix material into which the first therapeutic agent is dispersed, including (1) a bioerodible polymer permeable to the therapeutic agent, and (2) a water-soluble polymer having greater water solubility than the permeable polymer.

8. The ocular implant according to claim 7, further comprising a discrete solid core containing the first or a second therapeutic agent, and where the solid core is embedded within the composite material matrix layer.

9. The implant according to claim 8, wherein the composite material matrix layer comprises about 5 to about 50 wt % of the permeable polymer, about 0.05 to about 90 wt % of the water-soluble polymer, and about 1.0 to about 50 wt % of the first therapeutic agent.

10. The ocular implant according to claim 8, wherein therapeutic agent is dispersed, wherein the permeable polymer is superhydrolyzed polyvinyl alcohol and the water-soluble polymer is a cellulose ether polymer.

11. The implant according to claim 10, wherein the composite material matrix layer comprises about 5 to about 50 wt % of the superhydrolyzed polyvinyl alcohol, about 0.05 to about 90 wt % of the cellulose ether polymer, and about 1.0 to about 50 wt % of the first therapeutic agent.

12. The implant according to claim 10, wherein the cellulose ether polymer comprises hydroxyalkyl cellulose.

13. The implant according to claim 10, wherein the cellulose ether polymer comprises hydroxypropyl methyl cellulose.

14. The implant according to claim 10, wherein a part of the exterior surface area of the composite material matrix layer is covered by polymethyl methacrylate sufficient to adjust the rate of delivery of the therapeutic agent from the implant to the eye.

15. The implant according to claim 10, wherein the composite material matrix layer comprises about 5 to about 50 wt % superhydrolyzed polyvinyl alcohol.

16. The implant according to claim 10, wherein the therapeutic agent is selected from the group consisting of antibiotic agents, antibacterial agents, antiviral agents, anti-glaucoma agents, antiallergenic agents, anti-inflammatory agents, anti-angiogenesis compounds, antiproliferative agents, immune system modifying agents, anti-cancer agents, antisense agents, antimycotic agents, myotic agents, anticholinesterase agents, mydriatic agents, differentiation modulator agents, sympathomimetic agents, anaesthetic agents, vasoconstrictive agents, vasodillatory agents, decongestants, cell transport/mobility impending agents, polypeptides and protein agents, steroidal agents, carbonic anhydrase inhibitor agents, polycations, polyanions, lubricating agents, and mixtures thereof.

17. An ocular implant providing sustained-release of a therapeutic agent to the eye for a prolonged period of time, comprising:

(a) a composite material matrix layer including;

(i) a first therapeutic agent, and

(ii) a polymeric matrix material into which the first therapeutic agent is dispersed, including poly(ethylene vinyl) acetate and a cellulose ether polymer, and

(b) optionally, a discrete solid core containing an additional amount of the first therapeutic agent or a second different therapeutic agent, wherein said solid core being embedded within the composite material matrix layer.

18. A method of making an implant useful for providing sustained-release of a therapeutic agent to the eye for a prolonged period of time, comprising the steps of:

(a) forming a premixture by mixing and dispersing a therapeutic agent with a cellulose ether polymer in an aqueous medium effective to provide a suspension of the therapeutic agent;

(b) combining the premixture of step (a) with superhydrolyzed polyvinyl alcohol with mixing effective to form a substantially uniform mixture;

(c) applying the substantially uniform mixture upon a flat surface as a coating layer;

(d) optionally embedding a pellet of therapeutic agent within the coating layer;

(e) drying the coating layer to provide a composite material matrix layer including a polymer matrix;

(f) cutting out a section of the dried coating layer to provide an ocular implant.

19. The method according to claim 18, wherein the pellet embedding step (d) is practiced in the method.

20. The method according to claim 18, wherein the cellulose ether polymer comprises hydroxyalkyl cellulose.

21. The method according to claim 18, wherein the cellulose ether polymer comprises hydroxypropyl methyl cellulose.

22. The method according to claim 18, wherein combining step (b) comprising combining about 6 to about 50 wt % of the superhydrolyzed polyvinyl alcohol, about 0.05 to about 90 wt % of the cellulose ether polymer, and about 1.0 to about 50 wt % of the therapeutic agent, and the balance being water.

23. A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising attaching an implant containing a therapeutic agent to the eye, wherein the implant comprises a composite material matrix layer including a therapeutic agent, and a polymeric matrix material into which the therapeutic agent is dispersed including a superhydrolyzed polyvinyl alcohol permeable to the therapeutic agent and a cellulose ether polymer, and, optionally, a discrete solid core containing additional therapeutic agent and embedded within the composite material matrix layer, effective to deliver the therapeutic agent to the eye.

24. The method of claim 23, wherein the implant is attached to a subconjunctival region of the eye.

25. The method of claim 23, wherein the implant is attached to an intravitreal region of the eye.

26. The method of claim 23, wherein the discrete solid core is included, and delivery of the therapeutic agent proceeds as an initial loading dose delivery followed by sustained release of a lower, relatively constant rate of infusion.

27. The method of claim 23, wherein the therapeutic agent in the composite material matrix layer and the pellet comprises cyclosporine.

28. The method of claim 25, wherein the implant is attached to a subconjunctival region of the eye, and wherein therapeutic agent is delivered in an amount effective for corneal allograft therapy.

29. The method of claim 23, wherein the therapeutic agent in the composite material matrix layer and the pellet comprises 2-methoxyestradiol.

30. The method of claim 25, wherein the implant is attached to an intravitreal region of the eye, and wherein therapeutic agent is delivered in an amount effective for treatment of CNVM.

31. The method of claim 23, wherein treatment is performed on the eye of a mammalian organism.

32. An intraocular reservoir implant, comprising a therapeutic agent reservoir subassembly including an inner core comprising a therapeutic agent for the eye covered by and substantially radially centered within a polymeric layer comprising silicone material permeable to the therapeutic agent, and an ocular attachment means affixed to the polymeric layer of the subassembly.

33. The intraocular implant according to claim 32, wherein the polymeric layer additionally contains a dispersion of therapeutic agent therein.

34. The intraocular implant according to claim 32, wherein the attachment means comprises a suture stub.

35. The intraocular implant according to claim 32, wherein the attachment means comprises a crosslinked polyvinyl alcohol member.

36. The intraocular implant according to claim 32, wherein the attachment means is attached to the polymeric layer by an adhesive.

37. The intraocular implant according to claim 36, wherein the adhesive being permeable to an included therapeutic agent dispersed therein.

38. The intraocular implant according to claim 36, wherein the adhesive being permeable to a therapeutic agent that is attached to the adhesive in the form of a discrete inlay member.

39. The intraocular implant according to claim 32, further including a second therapeutic agent reservoir subassembly implant attached to the attachment means.

40. The intraocular implant according to claim 32, wherein the second therapeutic agent reservoir subassembly implant reservoir contains a different therapeutic agent than the therapeutic agent in the other therapeutic agent reservoir subassembly implant reservoir commonly attached to the same attachment means.

41. The intraocular implant according to claim 32, further including a silk mesh fabric embedded in the silicone at one end of the implant.

42. The intraocular implant according to claim 32, wherein the therapeutic agent is selected from the group consisting of antibiotic agents, antibacterial agents, antiviral agents, anti-glaucoma agents, antiallergenic agents, anti-inflammatory agents, anti-angiogenesis compounds, antiproliferative agents, immune system modifying agents, anti-cancer agents, antisense agents, antimycotic agents, myotic agents, anticholinesterase agents, mydriatic agents, differentiation modulator agents, sympathomimetic agents, anaesthetic agents, vasoconstrictive agents, vasodillatory agents, decongestants, cell transport/mobility impending agents, polypeptides and protein agents, steroidal agents, carbonic anhydride inhibitor agents, polycations, polyanions, and lubricating agents, singly or in combinations thereof.

43. A method of making an implant for intraocular delivery of therapeutic substances to the eye, comprising the steps of:

introducing flowable silicone into a microcentrifuge tube;

inserting a discrete thin walled tube comprising a low adhesion plastic inside the microcentrifuge tube;

centrifuging the microcentrifuge tube containing the silicone and low adhesion plastic, wherein a lower section of the plastic tube extends below the surface of the silicone fluid and a portion of the silicone fluid fills the lower section of the plastic tube;

curing the silicone wherein the silicon cures in contact with the plastic tube to form a hardened silicone base member therein;

introducing a therapeutic agent pellet and additional silicone fluid into the plastic tube;

centrifuging the microcentrifuge tube containing the plastic tube, silicone base member, pellet and additional silicone fluid, wherein the pellet is surrounded at all exposed peripheral sides and top surface by the additional silicone fluid;

optionally manually or mechanically centering the pellet as needed on the silicone base member;

hardening the additional silicone fluid to form an integral silicone/pellet subassembly within the plastic tube in which the pellet is surrounded on all sides by hardened silicone;

separating the plastic tube from the microcentrifuge tube;

separating the integral silicone/pellet subassembly from the plastic tube;

optionally trimming off end portions of the silicone; and

attaching the subassembly to a means for attachment to eye tissues.

44. A method of making an implant for intraocular delivery of therapeutic substances to the eye, comprising the steps of:

providing a circular wafer shaped tablet containing therapeutic agent, said tablet comprising a larger radial diameter than thickness;

fixing the tablet to a suture stub with silicone adhesive;

applying a bead of uncured silicone adhesive around the entire periphery of the tablet;

permitting the tablet coated with the bead of uncured silicone around the periphery thereof to stand at a temperature at which the silicone in the bead does not fully cure for a period of time effective to permit therapeutic agent in the tablet to diffuse into the silicone bead; and

after the step of permitting the nonfully cured silicone bead to stand long enough for the therapeutic agent to diffuse therein, fully curing the silicone in the bead by permitting the bead to stand until fully cured or via heating.

45. A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising attaching an implant containing a therapeutic agent in the vitreous tissues of the eye, wherein the implant comprises a therapeutic agent reservoir subassembly including an inner core comprising a therapeutic agent for the eye covered by and substantially radially centered within a polymeric layer comprising silicone material permeable to the therapeutic agent, and an ocular attachment means affixed to the polymeric layer, effective to deliver the therapeutic agent intravitreally.

46. The method of claim 45, wherein the eye treatment comprises treating uveitis, age-related macular degeneration, CNVM, and glaucoma with an effective amount of the therapeutic agent.

47. The method of claim 45, wherein the therapeutic agent comprises 2-methoxyestradiol.

48. The method of claim 45, wherein the therapeutic agent comprises 2-methyloxyestradiol, and the delivery of the therapeutic agent is in an amount effective to treat CNVM.

49. The method of claim 45, wherein the therapeutic agent comprises leflunomide, and the delivery of the therapeutic agent is in an amount effective to treat uveitis.

50. The method of claim 45, wherein treatment is performed on the eye of a mammalian organism.