Kinase inhibitors

• US 20090286773A1
• Filed: 02/26/2009
• Published: 11/19/2009
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Gerald W. Devries, Jane Guo Shiah, Jeffrey L. Edelman, Julie A. Wurster, Lon T. Spada, Patrick Hughes, Sougato Boral, Thomas C. Malone, Xialing Guo
• Original Assignee: Allergan Incorporated (Abbvie Incorporated)
• Inventors: Guo, Xialing, Edelman, Jeffrey L., Spada, Lon T., Malone, Thomas C., Boral, Sougato, Wurster, Julie A., Hughes, Patrick, DeVries, Gerald W., Shiah, Jane Guo
• Granted Patent: US 8,455,656 B2
• Time in Patent Office: Days
• US Class Current: 514/228.200
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• 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: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to drug delivery systems comprising ocular implant, which include organic molecules, capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation, in combination with a polymer, which polymer serves to control, modify, modulate and/or slow the release of the therapeutic component into the environment of the eye in which said composite is placed.

Claims

1. An ocular implant comprising:

a tyrosine kinase inhibitor and a polymer matrix that releases drug at a rate effective to sustain release of an amount of the tyrosine kinase inhibitor from the implant for at least about one week after the implant is placed in an eye, wherein said tyrosine kinase inhibitor is a compound represented by the following general formula;

2. The implant of claim 1 wherein said polymer is a biodegradable polymer.

3. The implant of claim 1 wherein R¹ is selected from the group consisting of H, CH₃, F and Cl.

4. The implant of claim 1 wherein R¹ is H, F or Cl.

5. The implant of claim 1 wherein a is 0 or R is selected from the group consisting of NHCOR⁷ and N(R⁷)₂ wherein R⁷ is selected from the group consisting of hydrogen, C₁ to C₄ alkyl and phenyl, wherein said alkyl or phenyl may be substituted with hydroxy, methylol or amino substituents.

6. The implant of claim 5 wherein R⁷ is selected from the group consisting of hydrogen, methyl, ethyl, hydroxypropyl, and aminomethylol phenyl.

7. The implant of claim 1 wherein R⁶ is H.

8. The implant of claim 1 wherein c is 1.

9. The implant of claim 1 wherein R¹ is selected from the group consisting of H, i.e. b is 0, F and Cl.

10. The implant of claim 1 wherein a is 1 and R is selected from the group consisting of (C³R⁴)_dN(R²)₂, NR²(CR³R⁴)_dN(R²)₂, O(CR³R⁴)_dN(R²)₂, (CRR⁴)_dCC(CRR⁴)_dN(R²)₂, NR²C(O)(CR³R⁴)_dN(R²)₂.

11. The implant of claim 1, further comprising an additional ophthalmically acceptable therapeutic agent.

12. The implant of claim 1 wherein the tyrosine kinase inhibitor is dispersed within the biodegradable polymer matrix.

13. The implant of claim 1, wherein the matrix comprises at least one polymer selected from the group consisting of polylactides, poly (lactide-co-glycolides), polycaprolactones, derivatives thereof, and mixtures thereof.

14. The implant of claim 1, wherein the polymeric carrier is a poly-lactide-co-glycolide (PLGA) polymer.

15. The implant of claim 2, wherein the biodegradable polymer matrix is a PLGA.

16. The implant of claim 1 wherein the polymer matrix is a viscous aqueous carrier.

17. The implant of claim 11, wherein the polymer matrix is a hyaluronic acid.

18. The implant of claim 1, wherein the polymer matrix comprises a polymer selected from the group consisting of poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), polyesters, poly (ortho ester), poly(phosphazine), poly (phosphate ester), polycaprolactones, gelatin, collagen, derivatives thereof, and combinations thereof.

19. The implant of claim 1, wherein the implant comprises a first portion comprising a mixture of the tyrosine kinase inhibitor and a biodegradable polymer, and a different second portion comprising a biodegradable polymer substantially free of the tyrosine kinase inhibitor.

20. The implant of claim 1, wherein the matrix comprises a single type of polymer, and the implant releases the tyrosine kinase inhibitor for about 70 days at a substantially linear rate.

21. The implant of claim 1, wherein the matrix releases drug at a rate effective to sustain release of an amount of the tyrosine kinase inhibitor from the implant for more than one month from the time the implant is placed in the vitreous of the eye.

22. The implant of claim 1, wherein the implant is structured to be placed in the vitreous of the eye.

23. The implant of claim 1, wherein the tyrosine kinase inhibitor is provided in an amount from about 40% by weight to about 70% by weight of the implant, and the biodegradable polymer matrix comprises a poly (lactide-co-glycolide) in an amount from about 30% by weight to about 60% by weight of the implant.

24. The implant of claim 1 formed as a rod, a wafer, or a particle.

25. The implant of claim 1 which is formed by an extrusion process.

26. The implant of claim 1 wherein said compound is selected from the group consisting of 3-[5-(3-Diethylamino-propyl)-3,3-dimethyl-3H-isobenzofuran-1-ylidene]-5-fluoro-1,3-dihydro-indol-2-one,

3-[5-(3-Diethylamino-propyl)-3-methyl-3H-isobenzofuran-1-ylidene]-5-fluoro-1,3-dihydro-indol-2-one,

1-(2-Oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-carboxylic acid (2-diethylamino-ethyl)-amide,

5-Fluoro-3-{5-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-3,3-dimethyl-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one and

3-[1-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propionic acid.

27. A method of treating an ocular condition of an eye of a patient, comprising the step of placing a biodegradable intraocular implant in an eye of the patient, the implant comprising a tyrosine kinase inhibitor and a biodegradable polymer matrix, wherein the implant degrades at a rate effective to sustain release of an amount of the tyrosine kinase inhibitor from the implant effective to treat the ocular condition and the tyrosine kinase inhibitor the compound of claim 1.

28. The method of claim 27, wherein the method is effective to treat a retinal ocular condition.

29. The method of claim 27, wherein the ocular condition is glaucoma.

30. The method of claim 27, wherein the ocular condition is proliferative vitreoretinopathy.

31. The method of claim 27, wherein the implant is placed in the posterior of the eye.

32. The method of claim 27, wherein the implant is placed in the eye with a trocar.

33. The method of claim 27, wherein the implant is placed in the eye with a syringe.

34. The method of claim 27, further comprising a step of administering a therapeutic agent in addition to the tyrosine kinase inhibitor to the patient.

35. The implant of claim 1 wherein said compound is a pharmaceutically acceptable salt.