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

• US 20040180075A1
• Filed: 05/03/2004
• Published: 09/16/2004
• Est. Priority Date: 03/15/2001
• Status: Active Grant

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Smith, Janine A, Yuan, Peng, Robinson, Michael R., Sung, Cynthia, Fronheiser, Matthew P., Nussenblatt, Robert B., Kim, Hyuncheol, Csaky, Karl G.
• Granted Patent: US 7,658,364 B2
• Time in Patent Office: Days
• US Class Current: 424/428
• 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 (10, 20, 121) for the delivery of a therapeutic agent to an eye (101, 301) in a controlled and sustained manner. Dual mode and single mode drug delivery devices (10, 20, 121) are illustrated and described. Implants (10, 20) suitable for subconjunctival placement are described. Implants (121, 10, 20) suitable for intravitreal placement also are described. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices (10, 20, 121) that are presented herein.

Claims

1. A method of delivering a therapeutic agent (12, 26) to an eye (101, 301) in need of treatment thereof, characterized by attaching an implant (10, 20, 121) containing a therapeutic agent (12, 26) to eye tissues (101, 301) in which the implant (10, 20, 121) releases the therapeutic agent (12, 26) continuously to the eye (101, 301) by initial delivery of a loading dose to the eye (101, 301) followed by a period of time in which delivery of the therapeutic agent (12, 26) to the eye (101, 301) occurs via a substantially constant release rate.

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

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

4. The method according to claim 1, characterized by the eye tissues (101, 301) being subconjunctival tissues.

5. The method according to claim 1, characterized by the eye tissues (101, 301) being intravitreal tissues.

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

7. An ocular implant (10, 20) providing sustained-release of a first therapeutic agent (12, 26) to the eye (301) for a prolonged period of time, characterized by:

a composite material matrix layer including;

(i) a first therapeutic agent (12), and

(ii) a polymeric matrix material (14) into which the first therapeutic agent (12) 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 (20) according to claim 7, characterized by a discrete solid core (26) containing the first or a second therapeutic agent (26), and where the solid core (26) is embedded within the composite material matrix layer.

9. The ocular implant (20) according to claim 8, characterized by the composite material matrix layer containing 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 (12).

10. The ocular implant (20) according to claim 9, characterized by the permeable polymer including superhydrolyzed polyvinyl alcohol and the water-soluble polymer including a cellulose ether polymer.

11. The ocular implant (20) according to claim 10, characterized by the composite material matrix layer containing 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 ocular implant (20) according to claim 10, characterized by the cellulose ether polymer including hydroxyalkyl cellulose.

13. The ocular implant (20) according to claim 10, characterized by the cellulose ether polymer including hydroxypropyl methyl cellulose.

14. The ocular implant (20) according to claim 10, characterized by a part of the exterior surface area of the composite material matrix layer being covered by polymethyl methacrylate sufficient to adjust the rate of delivery of the therapeutic agent (12, 26) from the implant (20) to the eye (301).

15. The ocular implant (20) according to claim 10, characterized by the composite material matrix layer containing about 5 to about 50 wt % superhydrolyzed polyvinyl alcohol.

16. The ocular implant (20) according to claim 10, characterized by the therapeutic agent (12, 26) being selected from the group consisting of antibiotic agents, antibacterial agents, antiviral agents, anti-glaucoma agents, antiallergenic agents, anti-inflammatory agents, anti-angiogenesis compounds, aitiproliferative 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 (10, 20) providing sustained-release of a therapeutic agent (12, 26) to the eye (301) for a prolonged period of time, characterized by:

(a) a composite material matrix layer including;

(i) a first therapeutic agent (12), and

(ii) a polymeric matrix material (14) 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 (26) containing an additional amount of the first therapeutic agent or a second different therapeutic agent (26), characterized by said solid core (26) being embedded within the composite material matrix layer.

18. A method of making an implant (10, 20) useful for providing sustained-release of a therapeutic agent (12, 26) to the eye (301) for a prolonged period of time, characterized by the steps of:

(a) forming a premixture by mixing and dispersing a therapeutic agent (12) 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 (26) 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 (10, 20).

19. The method according to claim 18, characterized by the pellet embedding step (d) being included in the method.

20. The method according to claim 18, characterized by the cellulose ether polymer including hydroxyalkyl cellulose.

21. The method according to claim 18, characterized by the cellulose ether polymer including hydroxypropyl methyl cellulose.

22. The method according to claim 18, characterized by combining step (b) including 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 (12, 26) to an eye (301) in need of treatment thereof, characterized by attaching an implant (10, 20) containing a therapeutic agent (12, 26) to the eye (301), in which the implant (10, 20) includes a composite material matrix layer including a therapeutic agent (12), and a polymeric matrix material (14) into which the therapeutic agent (12) is dispersed including a superhydrolyzed polyvinyl alcohol permeable to the therapeutic agent and a cellulose ether polymer, and, optionally, a discrete solid core (26) containing additional therapeutic agent and embedded within the composite material matrix layer, effective to deliver the therapeutic agent (12, 26) to the eye (301).

24. The method of claim 23, characterized by the implant (10, 20) being attached to a subconjunctival region of the eye (301).

25. The method of claim 23, characterized by the implant (10, 20) being attached to an intravitreal region of the eye (301).

26. The method of claim 23, characterized by the discrete solid core (26) being included, and delivery of the therapeutic agent proceeds as an initial loading dose (31) delivery followed by sustained release of a lower, relatively constant rate of infusion (32).

27. The method of claim 23, characterized by the therapeutic agent (12, 26) in the composite material matrix layer and the pellet containing cyclosporine.

28. The method of claim 25, characterized by the implant (10, 20) being attached to a subconjunctival region of the eye, and in which the therapeutic agent being delivered in an amount effective for corneal allograft therapy.

29. The method of claim 23, characterized by the therapeutic agent (12, 26) in the composite material matrix layer and the pellet containing 2-methoxyestradiol.

30. The method of claim 25, characterized by the implant (10, 20) being attached to an intravitreal region of the eye (301), and characterized by therapeutic agent (12, 26) being delivered in an amount effective for treatment of CNVM.

31. The method of claim 23, characterized by treatment being performed on the eye (301) of a mammalian organism.

32. An intraocular reservoir implant (121, 123), characterized by a first therapeutic agent reservoir subassembly (121, 121A) including an inner core (121″

) including a therapeutic agent for the eye (101) covered by and substantially radially centered within a polymeric layer (121′

) including silicone material permeable to the therapeutic agent, and an ocular attachment means (123) affixed to the polymeric layer of the subassembly.

33. The intraocular implant (121, 123) according to claim 32, characterized by the polymeric layer (121′

) additionally containing a dispersion of therapeutic agent (127) therein.

34. The intraocular implant (121, 123) according to claim 32, characterized by the attachment means (123) being a suture stub.

35. The intraocular implant (121, 123) according to claim 32, characterized by the attachment means (123) including a crosslinked polyvinyl alcohol member.

36. The intraocular implant (121, 123) according to claim 32, characterized by the attachment means (123) being attached to the polymeric layer (121′

) by an adhesive (125).

37. The intraocular implant (121, 123) according to claim 36, characterized by the adhesive (125) being permeable to an included therapeutic agent dispersed therein.

38. The intraocular implant (121, 123) according to claim 36, characterized as including a discrete inlay member (129) including therapeutic agent which is attached to said adhesive (125).

39. The intraocular implant (121, 123) according to claim 32, characterized as including a second therapeutic agent reservoir subassembly implant (121B) attached to the attachment means (123).

40. The intraocular implant (121, 123) according to claim 39, characterized by the second therapeutic agent reservoir subassembly implant reservoir (121B) containing a different therapeutic agent than the therapeutic agent in the first therapeutic agent reservoir subassembly implant reservoir (121A) commonly attached to the same attachment means (123).

41. The intraocular implant (121, 123) according to claim 32, characterized as including a silk mesh fabric embedded in the silicone at one end of the implant.

42. The intraocular implant (121, 123) according to claim 32, characterized by the therapeutic agent being 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 (10, 20, 121) for intraocular delivery of therapeutic substances to the eye (101, 301), characterized by the steps of:

providing a mold (1900) comprising an upper surface region (1906) including at least one impression (1901) provided therein including lateral and depth dimensions sufficient to receive a drug pellet (1904) and an upright rigid post (1902) fixed in location at a side of the impression (1901), in which the upper surface region (1906) includes polytetrafluoroethylene;

introducing flowable silicone fluid into the impression (1901), in which the silicone optionally contains a dispersion of therapeutic drug;

submerging a drug pellet (1904) in the silicone fluid;

centering the drug pellet (1904), in which the pellet (1904) is surrounded at all exposed peripheral sides and top surface thereof by the silicone fluid;

optionally spinning the mold (1900) via centrifugation sufficient to degas the silicone fluid;

optionally passing a polyester mesh (1905) down the post (1902) until submerged in the flowable silicone fluid;

hardening the silicone fluid to form an integral silicone/pellet subassembly;

separating the silicone-pellet subassembly from the upper surface region (1906) of the mold (1900).

44. The method of claim 43, characterized as including the additional step of attaching the integral silicone/pellet subassembly to a means for attachment to eye tissues.

45. A method of making an implant (89) for intraocular delivery of therapeutic substances to the eye, characterized by the steps of:

introducing flowable silicone (86) into a microcentrifuge tube (84);

inserting a discrete thin walled tube (82) including a low adhesion plastic inside the microcentrfuge tube (84);

centrifuging the microcentrifuge tube (84) containing the silicone (86) and low adhesion plastic tube (82), in which a lower section (82a) of the plastic tube (82) extends below the surface of the silicone fluid (86) and a portion (86a) of the silicone fluid (86) fills the lower section (82a) of the plastic tube (82a);

curing the silicone (86) characterized by the silicone cures in contact with the plastic tube (82) to form a hardened silicone base member (86a, 86b) therein;

introducing a therapeutic agent pellet (88) and additional silicone fluid (86c) into the plastic tube (82);

centrifuging the microcentrifuge tube (84) containing the plastic tube (82), silicone base member (86a, 86b), pellet (88) and additional silicone fluid (86c), characterized by the pellet (88) is surrounded at all exposed peripheral sides and top surface by the additional silicone fluid (86c);

optionally manually or mechanically centering the pellet (88) as needed on the silicone base member (86a);

hardening the additional silicone fluid (86c) to form an integral silicone/pellet subassembly (89) within the plastic tube (82) in which the pellet is surrounded on all sides by hardened silicone;

separating the plastic tube (82) from the microcentrifuge tube (84);

separating the integral silicone/pellet subassembly (89) from the plastic tube (82);

optionally trimming off end portions of the silicone; and

attaching the subassembly (89) to a means for attachment to eye tissues.

46. A method of making an implant (107, 109) for intraocular delivery of therapeutic substances to the eye, characterized by the steps of:

providing a circular wafer shaped tablet (107) containing therapeutic agent, said tablet comprising a larger radial diameter than thickness;

fixing the tablet (107) to a suture stub (109) with silicone adhesive;

applying a bead of uncured silicone adhesive (111) around the entire periphery of the tablet (107);

permitting the tablet (107) coated with the bead of uncured silicone (111) around the periphery thereof to stand at a temperature at which the silicone in the bead (111) does not fully cure for a period of time effective to permit therapeutic agent in the tablet (107) to diffuse into the silicone bead (111); and

after the step of permitting the nonfully cured silicone bead (111) to stand long enough for the therapeutic agent to diffuse therein, fully curing the silicone in the bead by permitting the bead (111) to stand until fully cured or via heating.

47. A method of delivering a therapeutic agent to an eye (301) in need of treatment thereof, characterized by the steps of attaching an implant (121, 123) containing a therapeutic agent (121″

, 127) in the vitreous tissues (609) of the eye, in which the implant (121, 123) contains a therapeutic agent reservoir subassembly (121) including an inner core (121″

) comprising a therapeutic agent (121″

) for the eye (101) covered by and substantially radially centered within a polymeric layer (121′

) including silicone material permeable to the therapeutic agent, and an ocular attachment means (123) affixed to the polymeric layer (121′

), effective to deliver the therapeutic agent (121″

, 127) intravitreally.

48. The method of claim 47, characterized by the eye treatment involving treating at least one of uveitis, age-related macular degeneration, CNVM, and glaucoma, with an effective amount of the therapeutic agent.

49. The method of claim 47, characterized by the therapeutic agent containing 2-methoxyestradiol.

50. The method of claim 47, characterized by the therapeutic agent containing 2-methyloxyestradiol, and the delivery of the therapeutic agent is in an amount effective to treat CNVM.

51. The method of claim 47, characterized by the therapeutic agent containing leflunomide, and the delivery of the therapeutic agent is in an amount effective to treat uveitis.

52. The method of claim 47, characterized by treatment being performed on the eye of a mammalian organism.