# US 9,433,679 B2 · Use of TRMP8 for treating opthalmic diseases or conditions involving tearing

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- Number: US 9,433,679 B2
- Document ID: US9433679B2
- Status: Granted
- Kind: B2
- Application number: 14/699,873
- Filed: 2015-04-29
- Published: 2015-11-05
- Granted: 2016-09-06
- Earliest claimed: 2010-09-08
- Assignees: Universidad Miguel Hernandez De Elche; Consejo Superior De Investigaciones Cientificas (Csic)
- Applicants: Universidad Miguel HernáNdez De Elche; Consejo Superior De Investigaciones CientíFicas C.S.I.C.
- Inventors: Carlos Belmonte Martínez; Juana Gallar Martínez; Antonio Ferrer Montiel; Asia Fernández Carvajal; Félix Viana de la Iglesia
- Web page: https://patentgrep.com/patent/US9433679B2

## CPC

- A61K 31/045: Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/047: having two or more hydroxy groups, e.g. sorbitol
- A61K 31/07: Retinol compounds, e.g. vitamin A (retinoic acids A61K31/203)
- A61K 31/075: Ethers or acetals
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/164: of a carboxylic acid with an aminoalcohol, e.g. ceramides
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/215: of carboxylic acids
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/221: with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
- A61K 31/245: Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60)
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/381: having five-membered rings
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- 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)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/662: Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/13: Cyclosporins
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 15/02: for disorders of the vagina
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to therapeutic compositions for the treatment of dry eye, more specifically to compositions comprising a TRPM8 receptor agonist ligand. Furthermore, the invention relates to therapeutic compositions for the treatment of epiphora, more specifically to compositions comprising a TRPM8 receptor antagonist.

## Claims

### Claim 1

A method for treating an ophthalmic disease or condition, said disease or condition involving tearing and/or relieving symptoms thereof comprising administering a therapeutically effective amount of a composition comprising a molecule binding specifically to the TRPM8(Transient receptor potential cation channel subfamily M member 8) receptor to a subject in need thereof,
(i) wherein the binding of the molecule to the TRPM8 receptor modulates the activity of the TRPM8 channel;
(ii) wherein the binding of the molecule to the TRPM8 receptor increases or decreases tear secretion caused by the ophthalmic disease or condition; and
(iii) wherein the amount of the molecule binding specifically to the TRPM8 receptor is not cytotoxic to the subject in need thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the molecule binding specifically to the TRPM8 receptor is a TRPM8 receptor agonist.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the molecule binding specifically to the TRPM8 receptor is a TRPM8 receptor antagonist.

### Claim 4 (depends on 2)

The method according to claim 2, wherein the ophthalmic disease or condition is xerophthalmia.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the ophthalmic disease or condition is epiphora.

### Claim 6 (depends on 4)

The method according to claim 4, wherein the xerophthalmia is associated with a disease or condition selected from the group consisting of vitamin A deficit, Sjogren syndrome, rheumatologic diseases, and burns.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the burns are chemical burns or thermal burns.

### Claim 8 (depends on 6)

The method according to claim 6, wherein the rheumatologic disease is rheumatoid arthritis.

### Claim 9 (depends on 5)

The method according claim 5, wherein the epiphora is associated with a disease or condition selected from the group consisting of Graves-Basedow disease, corneal ulcers, Ackerman syndrome, allergies, bacterial conjunctivitis, blepharitis, facial nerve palsy, ectropion, obstruction of the nasolacrimal duct, and obstruction of the lacrimal sac.

### Claim 10 (depends on 2)

The method according to claim 2, wherein the TRPM8 receptor agonist comprises a 5-methyl-2-isopropyl cyclohexane core structure.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the TRPM8 receptor agonist is selected from the group consisting of WS-5, CPS-369, CPS-368, CPS-125, menthyl lactate, menthone glycerin acetal Coolant Agent 10, (−)-Isopulegol, Cubelol, Hasegawa's cooling compound, WS-11, WS-12, WS-30, WS-3, WS-14, menthol, IFF' s New GRASS cooling material, and combinations thereof.

### Claim 12 (depends on 10)

The method according to claim 10, wherein the TRPM8 receptor agonist is WS12.

### Claim 13 (depends on 3)

The method to claim 3, wherein the TRPM8 receptor antagonist comprises a 5-methyl-2-isopropyl cyclohexane core structure.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the TRPM8 receptor antagonist is selected from the group consisting of MAD1d, MAD2e, and combinations thereof.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the molecule binding specifically to the TRPM8 receptor can be administered a variable number of times a day.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the molecule binding specifically to the TRPM8 receptor can be administered from 1 to 4 times a day.

### Claim 17 (depends on 2)

The method according to claim 2, wherein the composition comprises at least two TRPM8 agonists.

### Claim 18 (depends on 3)

The method according to claim 3, wherein the composition comprises at least two TRPM8 antagonists.

### Claim 19 (depends on 4)

The method according to claim 4, wherein the composition comprises a molecule binding specifically to the TRPM8 receptor and comprises at least one additional drug useful for the treatment of xerophthalmia.

### Claim 20 (depends on 19)

The method according to claim 19, wherein at least one additional drug useful for the treatment of xerophthalmia is selected from the group consisting of a corticoid, a vitamin, a muscarinic acetylcholine receptor agonist, an immunosuppressant, and a combination thereof.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the vitamin is vitamin A.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the muscarinic acetylcholine receptor agonist is pylocarpine.

### Claim 23 (depends on 21)

The method according to claim 21, wherein the immunosuppressant is cyclosporine.

### Claim 24 (depends on 5)

The method according to claim 5, wherein the composition comprises a molecule binding specifically to the TRPM8 receptor and comprises at least one additional drug useful for the treatment of epiphora.

### Claim 25 (depends on 24)

The method according to claim 24, wherein at least one additional drug useful for the treatment of epiphora is an antibiotic.

### Claim 26 (depends on 1)

The method according to claim 1, wherein the composition further comprises a lubricant.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the lubricant is selected from the group consisting of glycerol, hydroxypropyl methylcellulose, hydroxymethyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, hyaluronic acid, castor oil, mineral oil, hypromellose, carbomer, and combinations thereof.

### Claim 28 (depends on 1)

The method according to claim 1, wherein the subject is an animal subject.

### Claim 29 (depends on 1)

The method according to claim 1, wherein the molecule binding specifically to the TRPM8 receptor is not menthol.

### Claim 30 (depends on 4)

The method according to claim 4, wherein the symptoms of xerophthalmia are dryness sensation, ocular discomfort, or a combination thereof.