Compositions and methods for treatment of eye disorders

• US 8,168,655 B2
• Filed: 05/17/2006
• Issued: 05/01/2012
• Est. Priority Date: 05/17/2005
• Status: Active Grant

• Current Assignee: Bausch + Lomb Ireland Ltd. (Bausch Health Cos., Inc.)
• Original Assignee: Sarcode Bioscience Inc. (Shire plc)
• Inventors: Gadek, Thomas, Burnier, John
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): HUANG, GIGI GEORGIANA
• Application Number:
  US11/436,906
• Publication Number:
  US 20060281739A1
• Time in Patent Office: 2,176 Days
• Field of Search: 514/307, 514/912
• US Class Current: 514/307
• CPC Class Codes: A61B 3/101 for examining the tear film
• CPC Class Codes: A61B 3/145 by video means
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/381 having five-membered rings
• 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 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4162 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 : Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 : ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/5377 : not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/54 : having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/541 : Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 33/00 : Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/06 : Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 38/07 : Tetrapeptides
• CPC Class Codes: A61K 38/08 : Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 : Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/1703 : from vertebrates
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 : Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 : Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 : Nose
• CPC Class Codes: A61K 9/0048 : Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 : Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/0053 : Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/04 : Artificial tears; Irrigation solutions
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 279/28 : having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
• CPC Class Codes: C07C 317/50 : at least one of the nitrogen atoms being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07D 207/06 : with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 217/00 : Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/06 : with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/20 : with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
• CPC Class Codes: C07D 217/26 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• 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 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: G01N 2333/705 : Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2333/70525 : ICAM molecules, e.g. CD50, CD54, CD102
• CPC Class Codes: G01N 2333/70546 : Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
• CPC Class Codes: G01N 2500/02 : Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 2500/20 : cell-free systems
• CPC Class Codes: G01N 2800/16 : Ophthalmology
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/5032 : on intercellular interactions
• CPC Class Codes: G01N 33/5047 : Cells of the immune system
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/6872 : Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.

Claims

1. A method of treating dry eye disease in a subject in need thereof comprising administering to said subject an effective amount of an LFA-1 antagonist or its pharmaceutically acceptable salts or esters, wherein said LFA-1 antagonist is

2. The method according to claim 1, wherein said administration comprises topical administration of said compound via a carrier vehicle selected from a group consisting of liquid drops, liquid wash, gel, ointment, spray, and liposome.

3. The method according to claim 2, wherein said topical administration comprises infusion of said compound to an eye of said subject via a device selected from the group consisting of a pump-catheter system, a continuous or selective release device, and a contact lens.

4. The method according to claim 1, wherein said administration involves systemically administering a liquid or liquid suspension of said compound via nose drops or nasal spray or nebulized liquid to oral or nasopharyngeal airways of said subject, such that an effective amount of said compound contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of said subject.

5. The method according to claim 1, wherein said administration involves administering an oral form of said compound, such that an effective amount of said compound contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of said subject via systemic absorption and circulation.

6. The method according to claim 1, wherein said administration is accomplished by administering an injectable form of said compound, such that an effective amount of said compound contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of said subject via systemic absorption and circulation.

7. The method according to claim 1, wherein said administration is accomplished by administering a suppository form of said compound, such that an effective amount of said compound contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of said subject via systemic absorption and circulation.

8. The method according to claim 1, wherein said administration is accomplished by administering an intraocular instillation of a gel, cream, powder, foam, crystals, liposomes, spray or liquid suspension form of said compound.

9. The method according to claim 1, wherein said compound is administered to the ocular surfaces of said subject in an amount sufficient to achieve concentrations thereof of from about 1×

10<sup>−

7</sup> to about 1×

10<sup>−

1</sup> moles/liter.

13. The method according to claim 1 wherein said administration is via a sustained release insert or implant, subconjunctival injection, intraocular injection, periocular injection, retrobulbar injection, or intracameral injection.

14. The method according to claim 1, wherein said administration involves delivery of a liquid or liquid suspension of said compound via nose drops or nasal spray or nebulized liquid to oral or nasopharyngeal airways of said subject, such that an effective amount of said compound contacts one or more of the lacrimal gland, conjunctival tissue, or ocular surface of the eye of said subject via nasolacrimal ducts.

15. The method according to claim 1, wherein said administration is accomplished by administering an injectable form of said compound, such that a therapeutically effective amount of said compound contacts one or more of the lacrimal tissues, conjunctival tissue or ocular surface of the eye of said subject via local delivery.

16. The method according to claim 3 wherein said continuous or selective release device is an ocular insert or implant.

17. The method according to claim 3 wherein an effective amount of said compound is distributed regionally to one or more of the nose, nasal passages, and nasal cavity.

18. The method according to claim 16 wherein said continuous or selective release device comprises a biocompatible polymer.

19. The method according to claim 8 wherein said administration comprises controlled release of said compound from a biocompatible polymer.

10. A method of treating dry eye disorder in a subject in need thereof comprising administering to an eye of said subject an effective amount of a pharmaceutical composition comprising an LFA-1 antagonist and/or its pharmaceutically acceptable salts or esters, wherein said LFA-1 antagonist is

11. A method of treating dry eye disease in a subject comprising performing a dry eye diagnostic test on said subject;

determining whether said subject suffers from a dry eye disease based on the results of said diagnostic step; and

upon diagnosis of said dry eye disease, administering to said subject an effective amount of a lymphocyte function associated antigen-1 (LFA-1) antagonist or a pharmaceutically acceptable salt or ester thereof, wherein said LFA-1 antagonist is

12. The method of claim 11 wherein said diagnostic step is performed by imaging an eye of said subject or analysis of a biological sample of an eye of said subject.