DRUG CORES FOR SUSTAINED RELEASE OF THERAPEUTIC AGENTS

• US 20120187594A1
• Filed: 02/07/2012
• Published: 07/26/2012
• Est. Priority Date: 09/07/2007
• Status: Active Grant

• Current Assignee: Mati Therapeutics, Inc
• Original Assignee: QT Incorporated
• Inventors: Utkhede, Deepank, Shimizu, Robert W., Jain, Rachna, Boyd, Stephen, Gifford, Hanson S., de Juan, Eugene, Reich, Cary J.
• Granted Patent: US 8,628,792 B2
• Time in Patent Office: Days
• US Class Current: 264/157
• CPC Class Codes: A61F 2230/0069 cylindrical
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61F 9/00772 Apparatus for restoration of tear ducts
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• 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 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/802 Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A solid drug core insert can be manufactured by injecting a liquid mixture comprising a therapeutic agent and a matrix precursor into a sheath body. The injection can be conducted at subambient temperatures. The mixture is cured to form a solid drug-matrix core. The therapeutic agent can be a liquid at about room temperature that forms a dispersion of droplets in the matrix material. A surface of the solid drug core is exposed, for example by cutting the tube, and the exposed surface of the solid drug core releases therapeutic quantities of the therapeutic agent when implanted into the patient. In some embodiments, the insert body inhibits release of the therapeutic agent, for example with a material substantially impermeable to the therapeutic agent, such that the therapeutic quantities are released through the exposed surface, thereby avoiding release of the therapeutic agent to non-target tissues.

Claims

1-29. -29. (canceled)

30. A method of manufacturing a drug insert for an implant body adapted for disposition within or adjacent to a body cavity, tissue, duct or fluid of a patient,

the method comprising injecting into a precursor sheath body, at an extrusion temperature of less than about 25°

C., a mixture comprising a therapeutic agent and a silicone matrix such that the precursor sheath body is substantially filled therewith, the precursor sheath body being substantially impermeable to the agent,

curing the mixture, at a curing temperature greater than about 25°

C., in the precursor sheath body to provide a cured, filled precursor sheath body containing a precursor drug core; and

dividing the cured filled precursor sheath body to form a plurality of drug inserts.

31. The method of claim 30, wherein each of the plurality of drug inserts is of substantially the same length, and wherein an amount of the agent in a first insert of the plurality is similar to the amount of agent in any other insert of the plurality.

33. The method of claim 30, wherein the implant is adapted for disposition in or adjacent to an eye of a patient.

42. The method of claim 30, wherein:

a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix;

or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

43. The method of claim 30, wherein the amount of the therapeutic agent in a volumetric portion of the cured mixture varies from the amount of the therapeutic agent in any other equal volumetric portion of the cured mixture by no greater than about 10%.

44. The method of claim 30, wherein the amount of the therapeutic agent in a volumetric portion of the cured mixture varies from the amount of the therapeutic agent in any other equal volumetric portion of the cured mixture by no greater than about 5%.

45. The method of claim 30, wherein the amount of the agent in each of the plurality of drug inserts varies by no greater than about 10% therebetween.

46. The method of claim 30, wherein the amount of the agent in each of the plurality of drug inserts varies by no greater than about 5% therebetween.

47. The method of claim 30, wherein said dividing the cured filled precursor sheath body comprises cutting the cured filled precursor sheath body with a blade or with a laser.

48. The method of claim 30, wherein the implant body comprises a punctual plug adapted to be disposed within the punctum of the patient.

49. The method of any of claim 30, wherein the mixture further comprises a solvent in which the silicone matrix and the agent are soluble, and wherein curing comprises at least partial removal of the solvent following injection into the sheath body or precursor sheath body respectively.

50. The method of claim 49, wherein the solvent comprises a hydrocarbon, an ester, a halocarbon, an alcohol, an amide, or a combination thereof.

51. The method of claim 30, wherein said curing comprises placing the precursor sheath body in a humidity chamber, heating, or vacuum treatment.

52. The method of claim 30, wherein said curing the mixture comprises heating the mixture to the curing temperature, at a relative humidity, for a period of time.

53. The method of claim 52, wherein the curing temperature is in a range from about 25°

C. to about 100°

C., the relative humidity is in a range from about 30% to about 100%, and the period of time is in a range from about 1 minute to about 48 hours.

54. The method of claim 53, wherein the curing temperature is at least about 40°

C., or the relative humidity is at least about 80%, or both.

55. The method of claim 30, wherein said injecting comprises injecting under a pressure of at least about 40 psi.

56. The method of claim 30, wherein the extrusion temperature is in a range of about −

50°

C. to about 25°

C.

57. The method of claim 56, wherein the extrusion temperature is in a range of about −

10°

C. to about 10°

C.

58. The method of claim 30, wherein the mixture is injected such that the precursor sheath body is filled at a rate of no greater than about 0.5 cm/sec.

59. The method of claim 30, further comprising sealing each drug insert at one end thereof, a second end providing the exposed surface.

60. The method of claim 59, wherein each drug insert is sealed at one end thereof with a UV-curable adhesive, a cyanoacrylate, an epoxy, by pinching, with a heat weld, or with a cap.

61. The method of claim 60, further comprising irradiating the drug insert with a UV-curable adhesive with UV light.

62. The method of claim 60, further comprising, after sealing one end thereof, inserting each drug insert into a channel of an implant body adapted to receive the insert therein.

63. The method of claim 30, wherein the insert comprises about 0.1 wt % to about 50 wt % of the agent.

64. The method of claim 30, wherein the precursor sheath body comprises at least one of polyimide, PMMA, PET, stainless steel, or titanium.

65. The method of claim 30, wherein the agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, or a prostaglandin or prostaglandin analog;

an anti-inflammatory agent;

an anti-infective agent;

a dry eye medication;

or any combination thereof.

66. The method of claim 65, wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or any other compound with analgesic properties.

67. The method of claim 30, wherein the agent comprises latanoprost.

68. The method of claim 67, wherein the latanoprost is dispersed within the silicone as droplets thereof.

69. The method of claim 30, wherein the agent is dissolved in the matrix.

70. The method of claim 30, wherein the agent is bimatoprost, olopatadine, or cyclosporine.

71. The method of claim 30, wherein each drug insert comprises two or more therapeutic agents.

72. The method of claim 30, wherein the extrusion temperature comprises a temperature of less than about 20°

C.

73. The method of claim 30, wherein the extrusion temperature comprises a temperature of less than about 15°

C.

74. The method of claim 30, wherein the extrusion temperature comprises a temperature of less than about 10°

C.

75. The method of claim 30, wherein the extrusion temperature comprises a temperature of less than about 5°

C.

32. (canceled)

34-41. -41. (canceled)

76. A method for manufacturing a punctual plug, the method comprising;

injecting into a precursor sheath body, at an extrusion temperature of less than about 25°

C., a mixture comprising a therapeutic agent and a silicone matrix such that the precursor sheath body is substantially filled therewith, the precursor sheath body being substantially impermeable to the agent,

curing the mixture, at a curing temperature greater than about 25°

C., in the precursor sheath body to provide a cured, filled precursor sheath body containing a precursor drug core;

dividing the cured filled precursor sheath to form a plurality of drug inserts;

sealing each drug insert at one end of the drug insert; and

inserting each drug insert into a channel of an implant body adapted to receive the insert therein.