Compositions for preserving photoreceptor cells, retinal pigment epithelial cells, or visual function

• US 10,639,345 B2
• Filed: 10/26/2018
• Issued: 05/05/2020
• Est. Priority Date: 04/23/2010
• Status: Active Grant

• Current Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Original Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Inventors: Vavvas, Demetrios G., Trichonas, Georgios, Miller, Joan W., Murakami, Yusuke
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): Lockard, Jon M
• Application Number:
  US16/171,837
• Publication Number:
  US 20190216881A1
• Time in Patent Office: 557 Days
• Field of Search: None
• CPC Class Codes: A61B 3/028 for testing visual acuity; for determination of refraction, e.g. phoropters
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61F 9/0008 Introducing ophthalmic products into the ocular cavity or retaining products therein putting in contact lenses A61F9/0061; introducing or retaining media in cavities of the body in general A61M31/00
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Provided are methods and compositions for maintaining the viability of photoreceptor cells and/or retinal pigment epithelial cells in a subject with an ocular disorder including, for example, age-related macular degeneration (AMD) (e.g., dry or neovascular AMD), retinitis pigmentosa (RP), or a retinal detachment. The viability of the photoreceptor cells and/or the retinal pigment epithelial cells can be preserved by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject having an eye with the ocular condition. The compositions, when administered, maintain the viability of the cells, thereby minimizing the loss of vision or visual function associated with the ocular disorder.

Claims

1. A composition for preserving the viability of photoreceptor cells, preserving the viability of retinal pigment epithelial cells, or preserving or improving visual function in an eye of a subject with retinal detachment, the composition comprising:

a pharmaceutically acceptable carrier, a necrostatin and an apoptosis inhibitor,

wherein the apoptosis inhibitor is selected from the group consisting of a pan-caspase inhibitor, a caspase-1 inhibitor, a caspase-3 inhibitor, a caspase-8 inhibitor, and a caspase-9 inhibitor, and

wherein the necrostatin is selected from the group consisting of;

(i) a Nec-1 related compound of Formula I;

2. The composition of claim 1, wherein the is a necrostatin is selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necrostatin-5, and necrostatin 7.

3. The composition of claim 2, wherein the necrostatin is an (R)-enantiomer of necrostatin-1.

4. The composition of claim 1, wherein the apoptosis inhibitor is a pan-caspase inhibitor.

5. The composition of claim 4, wherein the pan-caspase inhibitor is selected from the group consisting of Z-VAD, IDN-6556, and a combination of Z-VAD and IDN-6556.

6. The composition of claim 1, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are formulated for intravitreal or intraocular administration.

7. The composition of claim 1, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are formulated for sequential or simultaneous administration.

8. A pharmaceutical composition formulated for intraocular administration to an eye of a subject with an ocular condition, the composition comprising a pharmaceutically acceptable carrier, a necrostatin, and an apoptosis inhibitor,

wherein the composition is formulated to provide a final concentration of the necrostatin in the eye in the range from about 150 μ

M to about 1000 μ

M,

wherein the composition is formulated to provide a final concentration of the apoptosis inhibitor in the range from about 150 μ

M to about 500 μ

M,

wherein the apoptosis inhibitor is selected from the group consisting of a pan-caspase inhibitor, a caspase-1 inhibitor, a caspase-3 inhibitor, a caspase-8 inhibitor, and a caspase-9 inhibitor, and

wherein the necrostatin is selected from the group consisting of;

(i) a Nec-1 related compound of Formula I;

9. The composition of claim 8, wherein the necrostatin is selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necrostatin-5, and necrostatin-7.

10. The composition of claim 9, wherein the necrostatin is an (R)-enantiomer of necrostatin-1.

11. The composition of claim 8, wherein the apoptosis inhibitor is a pan-caspase inhibitor.

12. The composition of claim 11, wherein the pan-caspase inhibitor is selected from the group consisting of Z-VAD, IDN-6556, and a combination of Z-VAD and IDN-6556.