Drug Delivery Methods, Structures, and Compositions for Nasolacrimal System

• US 20070269487A1
• Filed: 04/02/2007
• Published: 11/22/2007
• Est. Priority Date: 03/31/2006
• Status: Active Grant

• Current Assignee: Mati Therapeutics, Inc
• Original Assignee: Forsight Labs, LLC
• Inventors: Gifford, Hanson, Boyd, Stephen, de Juan, Eugene, Reich, Cary, Deem, Mark
• Granted Patent: US 8,795,711 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61F 2220/0008 Fixation appliances for connecting prostheses to the body
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 2250/0087 colour-coded
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61F 9/0026 Ophthalmic product dispenser attachments to facilitate positioning near the eye
• CPC Class Codes: A61F 9/00772 Apparatus for restoration of tear ducts
• 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 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/0017 Non-human animal skin, e.g. pour-on, spot-on
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

An implant for insertion into a punctum of a patient comprises a body. The body has a distal end, a proximal end, and an axis therebetween. The distal end of the body is insertable distally through the punctum into the canalicular lumen. The body comprises a therapeutic agent included within an agent matrix drug core. Exposure of the agent matrix to the tear fluid effects an effective therapeutic agent release into the tear fluid over a sustained period. The body has a sheath disposed over the agent matrix to inhibit release of the agent away from the proximal end. The body also has an outer surface configured to engage luminal wall tissues so as to inhibit expulsion when disposed therein. In specific embodiments, the agent matrix comprises a non-bioabsorbable polymer, for example silicone in a non-homogenous mixture with the agent.

Claims

1. An implant for insertion into a punctum of a patient, the punctum providing a flow path for a tear fluid from an eye to a canalicular lumen, the implant comprising:

a body having a distal end, a proximal end, and an axis therebetween, the distal end of the body insertable through the punctum into the canalicular lumen, the body comprising a therapeutic agent included within an agent matrix drug core, exposure of the agent matrix to the tear fluid effecting an effective therapeutic agent release into the tear fluid over a sustained period, the body also having a sheath disposed over the agent matrix to inhibit release of the agent away from the proximal end and an outer surface configured to engage luminal wall tissues so as to inhibit expulsion when disposed therein.

2. The implant of claim 1, wherein the agent matrix comprises a non-bioabsorbable polymer.

3. The implant of claim 2, wherein the agent matrix comprises silicone in a non-homogenous mixture with the agent.

4. The implant of claim 3, wherein the non-homogenous mixture comprises a silicone matrix portion that is saturated with the therapeutic agent and an inclusions portion comprising inclusions of the therapeutic agent.

5. The implant of claim 1, wherein the outer surface is disposed on the sheath, and wherein the outer surface defines a body shape that inhibits expulsion of the body from the punctum.

6. The implant of claim 1, wherein the body further comprises a support structure over the agent matrix, the support structure defining the outer surface and configured to inhibit expulsion of the body from the punctum.

7. The implant of claim 6, wherein the support structure receives the sheath and agent matrix drug core therein and inhibits inadvertent expulsion of the agent matrix in use.

8. The implant of claim 6, wherein the support structure comprises a helical coil.

9. The implant of claim 6, wherein the support structure has a receptacle therein, and wherein the receptacle fittingly receives the sheath and agent matrix therein so as to allow unrestricted fluid communication between the proximal end and the tear film in use.

10. The implant of claim 1, wherein the outer surface expands radially when released within the punctum, and wherein the radial expansion inhibits the expulsion from the punctum.

11. The implant of claim 1, wherein the agent comprises a prostaglandin analogue, and wherein the extended period comprises at least 3 months.

12. An implant for insertion into a patient, the patient having a path for tear fluid associated with an eye, the implant comprising:

a body comprising a therapeutic agent and a support structure, the body configured to, when implanted at a target location along the tear fluid path, release a quantity of the therapeutic agent into the tear fluid each day for a sustained release period of days, the quantity being significantly less than 10% of a recommended daily drop-administered quantity of the therapeutic agent.

13. The implant of claim 12, wherein the quantity is less than 5% of the recommended drop-administered quantity.

14. The implant of claim 12, wherein the period comprises at least three weeks.

15. The implant of claim 12, wherein the period comprises at least three months.

16. The implant of claim 12, wherein the therapeutic agent comprises Timolol maleate.

17. The implant of claim 12, wherein the therapeutic agent comprises Latanoprost or another prostaglandin analogue.

18. The implant of claim 12, wherein the body comprises in a range from about 270 μ

g to about 1350 μ

g of the therapeutic agent.

19. The implant of claim 12, wherein the quantity is in a range from about 20 μ

g to about 135 μ

g.

20. The implant of claim 12, wherein the body comprises therapeutic agent in a range from about 3 μ

g to about 135 μ

g.

21. The implant of claim 20, wherein the therapeutic agent comprises a prostaglandin analog.

22. The implant of claim 20, wherein the therapeutic agent comprises latanoprost.

23. The implant of claim 20, wherein therapeutic agent comprises bimatoprost.

24. The implant of claim 12, wherein the quantity is in a range from about 5 ng to about 500 ng.

25. The implant of claim 12, wherein the body comprises therapeutic agent in a range from about 5 μ

g to about 30 μ

g.

26. The implant of claim 12, wherein the quantity is in a range from about 10 ng to about 150 ng.

27. A method of delivering a therapeutic agent to an eye having associated tear fluid, the method comprising:

placing a drug core in a canaliculus of the eye, the drug core comprising a matrix and inclusions of the therapeutic agent within the matrix, wherein a portion of the drug core is exposed to the tear;

releasing the therapeutic agent to the tear of the eye, wherein the therapeutic agent dissolves into the matrix such that the matrix remains substantially saturated with the therapeutic agent while the therapeutic agent is released through the exposed portion at therapeutic levels over a sustained period.

28. The method of claim 27, wherein a rate of release is substantially determined by solubility of the agent in the core, solubility of the agent in the tear and an area of the exposed portion.

29. The method of claim 27 wherein the drug is released through the exposed portion at therapeutic levels for about 90 days.

30. The method of claim 27, wherein the therapeutic agent comprises a prostaglandin analogue.

31. The method of claim 27, wherein the inclusions of the therapeutic agent comprise an oil.

32. The method of claim 27, wherein the therapeutic agent is encapsulated within the matrix and the matrix comprises a non-bioabsorbable polymer.

33. The method of claim 27, wherein the therapeutic agent has a solubility in water of less than about 0.03% percent by weight

34. The method of claim 27, wherein the therapeutic agent is released at therapeutic levels in response to a surfactant of the tear.

35. The method of claim 27, wherein a sheath is disposed over the core to define the exposed portion, and the exposed portion is oriented toward the eye on a proximal end of the core.

36. A punctal plug to treat glaucoma, the plug comprising:

a body no more than about 2.0 mm across, when inserted in the punctum for 35 days delivers at least a therapeutic quantity of therapeutic agent each day of the 35 days.

37. The punctal plug of claim 36, wherein the body no more than about 2.0 mm across comprises a cross sectional size no more than about 1.0 mm across while inserted into the patient.

38. The punctal plug of claim 36, wherein the body comprises a drug core and the therapeutic agent is delivered from the drug core, and the drug core is no more than about 1 mm across.

39. The punctal plug of claim 36, wherein the body is no more than about 2 mm in length.

40. A method of treating glaucoma with a punctal plug, the method comprising:

eluting at least 10 ng per day of a therapeutic agent from the punctal plug for at least 90 days.

41. The method of claim 40, wherein the therapeutic agent comprises at least one of Bimatoprost or Latanoprost.

42. The method of claim 40, wherein the therapeutic agent has a solubility in water no more than about 0.03% by weight.

43. A punctal plug to treat glaucoma, the plug comprising:

a plug body, the body comprising a therapeutic agent, wherein the body is adapted to release the therapeutic agent at therapeutic levels in response to a surfactant of the eye.

44. The plug of claim 43 wherein the therapeutic agent has a solubility in water no more than about 0.03% by weight.

45. The plug of claim 43 wherein the therapeutic agent comprises cyclosporin.

46. A punctal plug to treat glaucoma, the plug comprising:

a plug body, the body comprising a therapeutic agent, wherein the body is adapted to release from about 80 to 120 ng of the therapeutic agent into a tear of the eye for at least about 20 days.

47. The punctal plug of claim 46 wherein the therapeutic agent comprises at least one of Bimatoprost or Latanoprost.

48. A punctal plug to treat glaucoma, the punctal plug comprising:

a body comprising therapeutic agent stored within a volume no more than about 0.02 cm³, wherein the body is adapted to deliver therapeutic levels of the therapeutic agent for at least about 1 month.

49. The punctal plug of claim 48 wherein the body is adapted to deliver the therapeutic agent at therapeutic levels for at least about 3 months.

50. The punctal plug of claim 48 wherein the body is adapted to deliver the therapeutic agent with a substantially zero order release rate for the at least one month.

51. A composition of matter to treat glaucoma of an eye having an associated tear, the composition comprising:

inclusions comprising a concentrated form of a therapeutic agent, wherein the therapeutic agent comprises a solubility in water no more than about 0.03% by weight; and

a silicon matrix encapsulating the inclusions, wherein the therapeutic agent is soluble in the silicone matrix to release the therapeutic agent from the silicone matrix into the tear at therapeutic levels.

52. The composition of claim 51 wherein the therapeutic agent inclusions encapsulated within the silicon matrix comprise an inhomogeneous mixture of the inclusions encapsulated within the silicon matrix.

53. The composition of claim 51 wherein the inclusions comprise Latanoprost oil.