Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells

Patent metadata

Field	Value
Publication number	US-9849128-B2
Application number	US-201715455575-A
Country	US
Kind code	B2
Filing date	Mar 10, 2017
Priority date	Jan 28, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

First claim

The invention claimed is:

1. A unit dose of a pharmaceutical composition that contains an amount of the compound shown in Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein the composition contains a formulation of the compound suitable for administration into an osteoarthritic joint of a subject in need thereof; and
wherein the formulation of the composition and the amount of the compound in the unit dose configure the unit dose to be effective in treating the osteoarthritic joint by decreasing the severity of one or more signs or symptoms of osteoarthritis in the joint without causing adverse effects when administered to the joint as a single dose.

2. The unit dose according to claim 1 , wherein the pharmaceutical composition contains a hyaluronan.

3. The unit dose according to claim 1 , wherein the formulation is a sustained release formulation.

4. The unit dose according to claim 3 , wherein the sustained release formulation includes a gel, a polymeric matrix, or a microparticle.

5. The unit dose according to claim 1 , which is effective in decreasing the severity of the one or more symptoms when administered as a single dose into the osteoarthritic joint followed by a non-treatment interval of at least two weeks.

6. The unit dose according to claim 1 , which is effective for inhibiting erosion of a proteoglycan layer in the osteoarthritic joint when administered into the joint.

7. The unit dose according to claim 1 , which results in production of collagen Type II in the osteoarthritic joint when administered into the joint.

8. A product that comprises a unit dose of a pharmaceutical composition according to claim 1 and a package insert that describes the use and attendant benefits of the composition in treating osteoarthritis.

9. A medical appliance or device containing a unit dose of a pharmaceutical composition according to claim 1 , wherein the appliance or device is configured for injecting the pharmaceutical composition it contains into an osteoarthritic joint.

10. The unit dose according to claim 1 , packaged in a kit containing a plurality of such doses.

11. The unit dose according to claim 1 , wherein one of the signs that is decreased in severity as a result of being treated with the unit dose is production of the senescence-associated secretory phenotype (SASP) factor interleukin 6 (IL 6) or matrix metallopeptidase 3 (MMP3).

12. The unit dose according to claim 1 , wherein one of the signs that is decreased in severity as a result of being treated with the unit dose is expression of the senescence marker p16.

13. The unit dose according to claim 1 , wherein one of the signs that is decreased in severity as a result of being treated with the unit dose is a favoring of a contralateral unaffected joint in preference to the osteoarthritic joint.

14. The unit dose according to claim 1 , wherein one of the symptoms that is decreased in severity as a result of being treated with the unit dose is pain experienced by the subject in the osteoarthritic joint.

15. The unit dose according to claim 1 , which is effective in promoting production of collagen Type II in the osteoarthritic joint.

Assignees

• Buck Inst Res Aging
• Unity Biotechnology Inc
• Mayo Found Medical Education & Res
• Univ Johns Hopkins

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Davalos Albert
• Demaria Marco
• David Nathaniel
• Vasserot Alain Philippe
• Kirkland James L
• Tchkonia Tamar
• Zhu Yi
• Elisseeff Jennifer
• Kim Chaekyu
• Jeon Okhee

Classifications

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K9/0073

  Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M) · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title