Delivery of TRPM8 agonists to the ocular margins for relief of ocular disorders

Abstract

The present invention provides a method for treating an ocular disorder in a subject in need thereof, comprising topically administering a therapeutically effective amount of a TRPM8 agonist to surfaces of ocular margin of the subject, wherein the ocular margin is the primary target site for delivery of the TRPM8 agonist. The method may use a wiping, brushing, or spraying approach, and is more effective and efficient than the conventional method using eye drops.

Description

[0001] DELIVERY OF TRPM8 AGONISTS TO THE OCULAR MARGINS FOR RELIEF OF OCULAR DISORDERS

[0002] Cross-Reference to Related Application

[0003]

[0001] This application claims priority to United States Application No. 63 / 707 ,749, filed on October 15, 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] Field of the Invention

[0005]

[0002] The present invention pertains generally to the field of ocular drug delivery', and more specifically to the rationale and benefits of a novel drug-delivery method, which uses a wiping, or brushing, or spraying method to deliver drugs (e.g.. for delivery of a TRPM8 agonist) to targets on the ocular surfaces. Compared to the traditional method of drug application (e.g., use of eye drops), the wiping, or brushing, or spraying method for such drug delivery' according to the present invention is much more effective and efficient.

[0006] Background of the Invention

[0007]

[0003] The front one-third of the eyeball (i.e., anterior segment) and its surfaces are constantly exposed to the external environment. The anatomical structures in this anterior segment, including the eyelids, eyeball, conjunctiva, lachrymal system, precorneal film, and cornea, are subject to injury by physical, chemical, and biological agents, and / or by inflammation. The ty pical symptoms of such injury include blurring of vision, itching, irritation, fatigue in vision, a sense of drymess, burning sensations, and pain. The signs of injury' are redness, swelling, and increased blood flow. Ophthalmic products such as solutions, ointments, and inserts are used to manage the symptoms and signs of eye injury.

[0008]

[0004] The most common form of drug delivery to treat eye disorders has been eye drops. This method has lower costs than ointments or inserts and is familiar to the patient. Eye drops, however, have limitations. The precorneal space in normal subjects is about 7 pL per eye. As such, individual eye drops ranging from 20 to 45 pL may be absorbed into the nasolacrimal duct or roll down the cheek. Also, eye drops require manual dexterity’ to self-administer. The patient is taught to recline their head at a 45 to 55° angle and to administer the drops while keeping their eyes open. Frequent dosing, e.g., four times daily, can be challenging if the patient is young or old. Nevertheless, conventional eye drops represent -90% of formulations for eye disorders. This standardized procedure of ocular delivery’ is conspicuous at the pharmacy where eye drops are on display.

[0005] The primary objectives of any ocular drug-delivery' system are to maintain optimal therapeutic drug concentrations at the target site and to reduce dosage frequency. See. e.g., Gote et al., J Pharmacol Exp Ther. 2019 Sep; 370(3):602-604. The delivery must contend with the fluid dynamics of the ocular system and its static penetration barriers. The ocular surface and its margins are densely innervated with sensory nerve fibers. After the injury, these fibers incite dysesthesia, accounting for many symptoms and signs of blepharitis, conjunctivitis, and other anterior segment diseases. Coohng agents, acting on an integral membrane protein called TRPM8 to generate sensations of coolness, may be helpful for the relief of anterior segment disorders. However, the exact methods of drug delivery' to target and maintain optimal therapeutic drug concentration are uncertain. TRPM8 green fluorescent nen e fibers of mice are present in the eyelids' margins and cornea but not on the conjunctiva. These TRPM8 receptors are the putative target sites. Both eye drops and cotton swabs have been proposed as drug delivery' systems for the TRPM8 treatment of dry disease, but little information using modem pharmacokinetic techniques has appeared on the drug concentrations at the target sites.

[0006] In the past 25 years, there have been significant advances in understanding ocular target sites for perceiving rtch, pain, and pressure. For example, ion channel proteins that selectively code for thermosensation (coolness and heat) and pain have been identified and mapped on the cornea. See e.g., Schecterson et al., Mol. Vis. 2020; 26:576-581. Fig. 1 shows the schematic of TRP channel and neuropeptide vesicle expression in the cornea. Fig. 1 illustrates a schematic distribution of TRP channels in the cornea. The nerve fibers form simple, ramifying, and complex terminals on tissues. On the cornea, TRPM8 form all three patterns, but TRPV1 and TRPA1 fibers are found mainly in simple and ramifying patterns. As show n in Fig. 1, neurons expressing TRPM8 not only extend to the periphery with complex terminals, but are also found in ramifying terminals in the pericentral region and simple terminals in the center of the cornea. Neurons expressing TRPV 1 colocalize with CGRP and ScgII and extend to the comeal surface as ramifying and simple termini. Neurons expressing TRPA1 colocalize with SCG3 and NG200 and terminate in the stroma and sub-basal regions. The TRPM8 fiber, coding for coohng sensations, appears to have its distinct cable line to the brain. This TRPM8 receptor on nerve fibers is the target site for drug delivery on the ocular surfaces. However, the optimal choice of the active pharmaceutical ingredient (API) and the precise methods of optimal drug delivery' remain unexplored. In particular, while use of eye drops may be a primary and conventional choice for applying the API, there are limitations. For instance, when an eye drop is applied to the eyeball, the momentum of the drop will cause a lateral splash. The splash event occurs in milliseconds, giving little contact and residence time for the active ingredient on the eye surface.

[0009]

[0007] The present invention offers a novel and effective approach (e.g., an optimal delivery method, a topical medication and a usage of TRPM8 agonists) for treating ocular disorders, with improved existing efficacy, safety, and patient compliance as compared with the traditional eye drop delivery route.

[0010] Brief Summary of the Invention

[0011]

[0008] The present invention provides a novel delivery' method, a topical medication and a usage of TRPM8 agonists for treating ocular disorders in a subject in need, by using a wiping (e.g., with wipes), or brushing, or spraying method to deliver drugs to targets on the ocular surfaces. Compared to traditional eye drop delivery route, the present invention was surprisingly found to exhibit at least the following advantages for delivery' of TRPM8 agonists to ocular margins: (1) instant cooling sensation and longer retention time; (2) quick relief of ocular pain caused by dry eye disorders (DED); (3) instant and long-lasting refreshing feeling from fatigue: and (4) reduced risks of eye irritation caused by eye drops and chronic use of preservatives in eye drops. The present invention provides a chronic-use drug product or kit to use a wiping, or brushing, or spraying method (e.g., with wipes) to treat ocular disorders. Examples of the ocular disorder to be treated include but are not limited to DED, eye fatigue, and ocular pain caused by DED.

[0012]

[0009] The delivery method of this invention enables treating ocular disorders in a subject in need thereof, and includes a step of topically applying a therapeutically effective amount of a TRPM8 agonist in a formulation onto ocular margin of the subject. The formulation according to the present invention can be liquid, solid or semi-solid (like a gel). The formulation according to the present invention can be delivered with finger, a cotton swab, a wipe, a pad, a brush, or a spray nozzle. The ocular margin surface region may include supraorbital (eyelid) region, infraorbital (cheekbone) region, nasal region (nasociliary7nerve), zygomatic region, or any combination thereof. More specifically, the supraorbital region according to the present invention includes but is not limited to upper eyelid (preferably eyelid margin near eyelashes), lower eyelid (preferably eyelid margin near eyelashes), medial canthus, lateral canthus, and superior orbital rim.

[0013]

[0010] The present invention also provides a topical medication for treating ocular disorders in a subject in need thereof, comprising topically applying a therapeutically effective amount of a TRPM8 agonist in a formulation onto ocular margin surfaces of the subject. The formulation according to the present invention can be an aqueous formulation. The formulation may include a pharmaceutically acceptable amount of surfactants / solubilizers, and / or gelling agents, and / or gel adjusting agents, and / or pH adjusting agents, and / or osmolarity adjusting agents, and / or preservatives.

[0014] [OH] The present invention further provides a novel usage of a TRPM8 agonist for manufacturing a medication for treating ocular disorders in a subject in need thereof, wherein the medication includes a therapeutically effective amount of the TRPM8 agonist in a formulation. The formulation is adapted for topical delivery of the TRMP8 agonist to an ocular margin surface of the subject. Examples of the TRPM8 agonists suitable for the present invention include but are not limited to menthol, 1-di-isopropyl-phosphinoyl-alkane (DIP A) compounds (e.g.. Cryosim-1, Cryosim-2, Cryosim-3). Icilin, p-methane carboxamides such as WS-3 ( / V-ethyl-p-menthane-3-carboxamide), WS-5 ( V-[[(17?,25,57?)-5-methyl-2-(l- methylethyl)cyclohexyl]carbonyl]-glycine, ethyl ester), WS-12 (lR,2S,5R)-N-(4-

[0015] Methoxy phenyl)-p-menthanecarboxamide), WS-14 (A-tert-But l-p-menthane-3- carboxamide), p-hydroxymenthane carboxamides, WS-23 (2-Isopropyl-A,2,3- trimethylbutyramide), WS-27 ( / V-Ethyl-2.2-diisopropylbutanamide). menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, exocyclic olefin analogues of menthol, or other derivatives of these compounds.

[0016]

[0012] Examples of the DIP A compounds include the following:

[0013] Particularly, according to the present invention, the sensory’ qualities of a cooling agent (C3, cryosim-3, DIPA-1-9, 1 -diisopropylphosphorylnonane) were tested on volunteers using wipes or eye drops. Surprisingly, wipes were observed to be more comfortable and better tolerated by subjects than conventional eye drops. Next, the elution of C3 from different wipe matrices was examined. Several matrices with suitable properties for incorporating C3 were identified and discovered. Finally, the pharmacokinetic (PK) properties of C3 after wiping or drops were examined in an animal (rabbit) model. The PK results were surprising and conclusive in favor of wipes. Wiping, compared to conventional eye drops, substantially increased delivery of the active pharmaceutical ingredient (API) onto the lids, conjunctiva, and tears, emphasizing (stressing) the higher concentration at target sites and instilling confidence in the method's effectiveness. Moreover, delivery7of the API to the posterior segment of the eye was less, and plasma concentrations of API, indicative of systemic absorption, were also less. From these quantitative studies, we deduce that the primary target sites for API delivery’ are located on the ocular margins and not the cornea. These sites are best reached with wipes and give a higher concentration at target sites. The impact of drops delivered onto the cornea is less desirable. The lower systemic absorption of the API also favors using wipes.

[0017]

[0014] These quantitative studies are the first of its kind and the results are surprising in showing the superiority of the wipe method when compared to conventional eye drops. In human trials, the wipe method was twice as effective as drops. Inventors accordingly deduced that the primary target sites for API delivery are located on the ocular margins, not the cornea. Both sites can be reached with wipes, but wipes are able to yield a higher concentration at target sites than drops. The impact of drops delivered onto the cornea is avoided with wipes. The lower systemic absorption of the API also favors using wipes.

[0018]

[0015] According to the present invention, the wipe and / or a pad material may include not limited to cotton, rayon (known as viscose), lyocell, cellulose, chemically modified cellulose, polyester, polypropylene, polyethylene terephthalate (PET), nylon, velour / velvet, microfiber (blend of PET and Nylon), plant-based fibers like wood / bamboo pulp, or any blend of these materials.

[0019]

[0016] One aspect of the present invention provides a method for treating an ocular disorder in a subject in need thereof, including at least a step of topically administering a therapeutically effective amount of a TRPM8 agonist to surface(s) of ocular margin of the subj ect, wherein the ocular margin is the primary target site for delivery of the TRPM8 agonist.

[0017] In some embodiments, the TRPM8 agonist is delivered at a higher amount to the primary target site than to the cornea, which is still tolerable and non-irritating.

[0020]

[0018] In some embodiments, the surfaces of the ocular margin include receptive fields located on a supraorbital region, an infraorbital region, a nasal region, a zygomatic region, or any combination thereof.

[0021]

[0019] For instance, the supraorbital region may include upper eyelid, lower eyelid, medial canthus, lateral canthus, and / or supenor orbital rim.

[0022]

[0020] In some further embodiments, the upper eyelid may include eyelid margin near eye lashes; while the lower eyelid may include eyelid margin near eyelashes.

[0023]

[0021] In some embodiments, the TRPM8 agonist is topically applied onto the ocular margin with a finger, a cotton swab, a wipe, a pad, a brush, or a spray nozzle.

[0024]

[0022] Examples of the TRPM8 agonist include but are not limited to menthol, a DIPA compound, icilin, WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0025]

[0023] In some embodiments, the TRPM8 agonist include menthol, a DIPA compound. WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0026]

[0024] In some further embodiments, TRPM8 agonist include menthol, WS-12, or a DIPA compound, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0027]

[0025] Steill in some further embodiments, the TRPM8 agonist include a DIPA compound, and the DIPA compound comprises DIPA-6, DIPA-7, DIPA-8, or DIPA-9, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0028]

[0026] In some embodiments, the TRMP8 agonist is administered in the form of a pharmaceutical formulation comprising the TRMP8 agonist and a pharmaceutically acceptable carrier. The pharmaceutical formulation may be in the form of liquid, solid, semi-solid, gel, cream, or ointment. In some further embodiments, the pharmaceutical formulation is in the form of liquid.

[0029]

[0027] In some embodiments, the TRPM8 agonist is contained in the pharmaceutical formulation at a concentration ranging from about 0.01 mg / rnL to about 20 mg / mL, or ranging from about 0.5 mg / mL to about 10 mg / mL, or ranging from about 1.0 mg / mL to about 5.0 mg / rnL.

[0030]

[0028] In some embodiments, the pharmaceutical formulation has a viscosity ranging from about 250 cPs to about 100,000 cPs, from about 500 cPs to about 10,000 cPs, from about 1 cPs to about 5,000 cPs, from about 25 cPs to about 1,000 cPs, from about 1 cPs to about 100,000 cPs, from about 1 cPs to about 1,000 cPs, or from about 25 cPs to about 300 cPs.

[0031]

[0029] For instance, the pharmaceutical formulation may have a viscosity ranging from about 250 cPS to about 100,000 cPs, or from about 500 cPs to about 10,000 cPs, when applied with a finger; or a viscosity ranging from about 1 cPs to about 5,000 cPs or from about 25 cPs to about 1,000 cPs, when applied with a wipe and / or a pad; or a viscosity ranging from about 1 cPs to about 100.000 cPs, or from about 25 cPs to about 1.000 cPs, when applied with a cotton swab or a brush; or a viscosity ranging from about 1 cPs to about 1,000 cPs, or ranging from about 25 cPs to about 300 cPs, when applied with a spray nozzle.

[0032]

[0030] In some embodiments, the pharmaceutical formulation further includes one or more of a surfactant or solubilizer, a gelling agent, a gel adjusting agent, a pH adjusting agent, an osmolarity adjusting agent, and / or a preservative.

[0033]

[0031] A gel adjusting agent is a substance used to modify the properties of a gel formulation, including its viscosity, texture, stability, and release characteristics. For instance, cationic ions (such as calcium ions, sodium ions, or other positively charged ions) are gel adjusting agent for sodium alginate, since they increase viscosity of sodium alginate gel by forming ionic cross-linking bonds with the negatively charged carboxylate groups in sodium alginate chains.

[0032] Examples of the surfactant or solubilizer include but are not limited to an organic solvent selected from ethanol, isopropyl alcohol, or denatured alcohol; a non-ionic surfactant or solubilizer such as polysorbate 80. polysorbate 60. polysorbate 20, polyethylene glycol (PEG), ethoxylated fatty alcohol, PEG-40 hydrogenated castor oil, polyoxyl castor oil, and polyoxyl hydrogenated castor oil; and an ionic surfactant such as benzalkonium chloride and cetylpyridinium chloride.

[0034]

[0033] Examples of the gelling agent include but are not limited to sodium hyaluronate, deacetylated gellan gum, sodium alginate, xanthan gum, carrageenan, poloxamer, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose), hydroxyethyl cellulose, and any combination thereof;

[0035]

[0034] Examples of the preservative include but are not limited to sorbic acid, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, EDTA- 2Na or any combination thereof.

[0036]

[0035] In some embodiments, the pharmaceutical formulation includes a surfactant or solubilizer at a concentration ranging from about 0.01wt% to about 5.0 wt%.

[0036] In some embodiments, the pharmaceutical formulation includes a gelling agent at a concentration ranging from about 0.01 wt% to about 20 wt%. or from about 0.3 wt% to about 6 wt%.

[0037]

[0037] In some embodiments, the pharmaceutical formulation has a pH ranging from about 3.5 to about 8.0, or from about 4.0 to about 7.0.

[0038]

[0038] In some embodiments, the ocular disorder may be dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, and / or keratitis. For instance, the ocular disorder is dry eye syndrome.

[0039]

[0039] In some further embodiments, the dry eye syndrome comprises an aqueous-deficient disorder, a hyperevaporative disorder, or a combination thereof.

[0040]

[0040] In another aspect, the present invention provides a kit for treating an ocular disorder in a subject, comprising (i) a pharmaceutical formulation comprising an effective amount of a TRMP8 agonist and a pharmaceutically acceptable carrier, and (ii) an instruction for administrating the pharmaceutical formulation to ocular margin of the subject as the primary7target site for delivery of the TRPM8 agonist.

[0041]

[0041] In some embodiments, the pharmaceutical formulation is instructed to be administrated by a wiping, brushing, or spaying method. For instance, the pharmaceutical formulation may be instructed to be administrated by a wipe.

[0042]

[0042] In some embodiments, the TRPM8 agonist comprises menthol, a DIPA compound, icilin, WS-3, WS-5, WS-12, WS-14. WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0043]

[0043] In some embodiments, the ocular disorder is dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, and / or keratitis.

[0044]

[0044] A further aspect of the present invention provides an eyelid wipe for treating an ocular disorder in a subject, wherein the eyelid wipe comprises a therapeutically effective amount of a TRPM8 agonist to be topically administrated to the eyelid of the subject.

[0045]

[0045] In some embodiments, the TRPM8 agonist may include menthol, a DIPA compound, icilin, WS-3, WS-5, WS-12, WS-14. WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0046]

[0046] In some embodiments, the ocular disorder is the dysesthesia from the dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, and / or keratitis.

[0047] As used herein, the term “of’ may also imply “and,” unless such an interpretation results in a contradiction or infeasibility.

[0047]

[0048] As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and / or therapy.

[0048]

[0049] As used herein, the terms "individual." "patient." or "subject" are used interchangeably. None of the terms require or are limited to situation characterized by the supervision (e g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker).

[0049]

[0050] As used herein, a "therapeutically effective amount" refers to a sufficient amount of TRPM8 agonists, at a reasonable benefit / risk ratio applicable to treating ocular disorders in a subject in need thereof. It is understood, however, that the total daily usage of TRPM8 agonists may be decided by the attending physician or personal coach within the scope of sound medical judgment. The specific effective dose level for any particular subject will depend upon a variety of factors including the other disorder being treated and the severity of the disorder; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration and route of administration; the duration of the administration; drugs used in combination or coincidental with TRPM8 agonists; and like factors well known in the medical arts or sports science. In addition, a "therapeutically effective amount" is the amount that will elicit the biological or medical response of a tissue, system, or subject that is being sought by a researcher or clinician.

[0050]

[0051] One of skill in the art recognizes that an amount may be considered "effective" even if the condition is not totally eradicated or prevented, but it or its symptoms and / or effects are improved or alleviated partially in the subject. Various indicators for determining the effectiveness of a method are known to those skilled in the art of treating ocular disorders in a subject in need thereof.

[0051]

[0052] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology7, protocols, and reagents, etc., described herein and as such can vary. Other terms are defined herein within the description of the various aspects of the invention. Brief Descriptions of the Drawings

[0052]

[0053] Fig. 1 illustrates the schematic of TRP channel and neuropeptide vesicle expression in the cornea.

[0053]

[0054] Fig.2 illustrates the fluorescent images of TRPM8 GFP-label mouse.

[0054]

[0055] Fig. 3 illustrates the method of use of eyelid wipes.

[0055]

[0056] Figs. 4A-4D illustrate the pK data after eye drop or eyelid administration in Example 3.

[0057] Fig. 5 illustrates Schirmer’s test result before and after ocular eye drop or eyelid administration in Example 3.

[0056] Detailed Description of the Invention

[0057]

[0058] Reference will now be made in detail to the preferred embodiments of the invention, examples of which are further illustrated. While the invention will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the invention to these embodiments. To the contrary, the invention is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the claims. Furthermore, in the detailed description of the present invention, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be obvious to one of ordinary' skill in the art that the present invention may be practiced without these specific details. In other instances, well known methods, procedures, components, and other features have not been described in detail as not to unnecessarily obscure aspects of the present invention.

[0058]

[0059] Generally speaking, the present invention provides a novel drug-delivery method, which uses a wiping, or brushing, or spraying method to deliver a TRPM8 agonist to targets on the ocular surfaces, which is more effective and efficient as compared to the traditional method using eye drops.

[0059]

[0060] The cold-sensing actions of a neuronal membrane protein called TRPM8 was discovered by David Julius and Ardem Patapoutian in 2002. They shared the Nobel Prize in 2021. The TRPM8 receptor has a central pore containing the cold-sensing element. When activated by temperature of ~I8°C (64°F), entry of cations into the axon discharges nerve signals to the brain which are interpreted as coolness. Molecules designed for TRPM8 agonism act on an allosteric site to facilitate the opening of pores.

[0060]

[0061] The TRPM8 protein, placed inside a lipid sandwich with a co-factor, sense and transduce a drop in temperature with action potentials. In this cell-free system, mitochondria, nucleic acids or other cellular constituents are not needed. The firing rates of the action potentials are robust. When the signals are conveyed by dedicated nerve fibers into the brain, they are interpreted as coolness. The tonic activity of neuronal discharge can be heard from brain neurons. At room temperature, the discharges sound like a melodic, gentle pitter patter of raindrops on the rooftop, late at night. When an ice cube is brought near the receptive field, the signals sound like a downpour.

[0061]

[0062] Ocular discomfort can be relieved by cooling, but the following questions remained unexplored prior to the present invention: (i) What is the best method of delivering a TRPM8 agonist to treat conditions such as dry eye disease (DED)? (ii) Where are the target receptors located and how should the active ingredient, a TRPM8 agonist, be administered?

[0062]

[0063] After extensive experiments, inventors surprisingly found that the best method is by delivering a TRPM8 agonist to surfaces of ocular margin (e.g., wiping the agonist onto the eyelids), and not by using eye drops, which is the conventional method of ocular drug delivery. In some embodiments, a TRPM8 agonist, a 1 -diisopropylphosphorylalkane called Cryosim-3 (C3), is chosen. It is water soluble, so it could be administered in a one-phase aqueous system. The comparison of C3 levels in different parts of the eye after wiping or eye drops explained why wipes were better. The pharmacokinetic (PK) values of Area-Under-the Curve (AUC) and Cmax (maximal concentrations) by wiping gave higher AUC and Cmax at the eyelids, bulbar conjunctiva, and tears: critical regions for pharmacological activity.

[0063]

[0064] When wiped, the eyelash sen es as a wick to deliver the C3 onto the ocular rim. The eyelid blink then acts as a windshield wiper to smoothly distribute the C3 over the eyeball surface. Eye drops by contrast splash and overflow the limited precorneal space. The sensory benefits of wipes over eye drops were confirmed by clinical trials in human subjects. Thus, for the first time, the rationale and value for wipe delivery of a TRPM8 agonist to the ocular margins for therapy, were validated by experiment.

[0064]

[0065] One aspect of the present invention provides a method for treating an ocular disorder in a subject in need thereof, including topically applying a therapeutically effective amount of a TRPM8 agonist onto ocular margin surface of the subject (e.g., as the primary target site for drug delivery). The TRPM8 agonist may be in the form of a pharmaceutical formulation, e.g., in a liquid, solid or semi-solid (like a gel) form. The TRMP8 agonist or a pharmaceutical formulation containing it for the treatment of this invention can be delivered with a finger, a cotton swab, a wipe, a pad, a brush, or a spray nozzle. The ocular margin surface region may include supraorbital (eyelid) region, infraorbital (cheekbone) region, nasal region (nasociliary nerve), zygomatic region, or any combination thereof. For instance, the supraorbital (SO) region according to the present invention may include upper eyelid (preferably eyelid margin near eyelashes), lower eyelid (preferably eyelid margin near eyelashes), medial canthus, lateral canthus, and / or superior orbital rim.

[0065]

[0066] Fig.2 illustrates the fluorescent images of TRPM8 GFP-label mouse. This illustration was collected by Prof. Li FengXian and Prof. Liu Qin at Washington University, St. Louis, Missouri. As shown in Fig. 2, the white streaks are TRPM8 fibers in the tissue of transgenic mice wherein the TRPM8 was labelled with green fluorescent protein. Dense TRPM8 innervation was found on the mouse eyelid and cornea, but not on the conjunctiva. The TRPM8 receptor targets are in the receptive fields of the frontal nerve, nasociliary nerve, and lacrimal nerve. The frontal nerve brings sensory information from the upper eyelid and forehead along supratrochlear and supraorbital nerves. The lacrimal nerve innervates the lacrimal gland. Nasociliary nerve has several sensory branches in the orbit. The infratrochlear nerve is a branch of the nasociliary nerve, which itself is a branch of the ophthalmic nerve. The infratrochlear nerve provides sensory innervation to the skin on the medial aspect of the orbit, including the region near the inner comer of the eye. This area of the face includes the tear ducts and adj acent skin.

[0066]

[0067] Eyelid wipes activate frontal nerves and nasociliary nerves. Eye drops activate nasociliary' nerves. Thus, eye wipes deliver the active ingredient to a larger receptive field. The intended targets are shown in Fig. 2.

[0067]

[0068] In some embodiments, the formulation according to the present invention can be an aqueous formulation, wherein the aqueous formulation can be used to deliver both water- soluble, water-insoluble, and / or oil-soluble TRPM8 agonists.

[0068]

[0069] In some embodiments, the TRPM8 agonist-containing formulation can be applied 2-4 times a day to the ocular margin surface of the subject for at least one week, preferably 2 times a day.

[0069]

[0070] In another aspect, the present invention provides a topical medication for treating ocular disorders in subject in need thereof, comprising topically applying a therapeutically effective amount of TRPM8 agonists in a formulation onto an ocular margin surface of the subject, wherein the formulation according to the present invention can be an aqueous formulation, and may further include pharmaceutically acceptable amount of surfactants / solubilizers, and / or gelling agents, and / or gel adjusting agents, and / or pH adjusting agents, and / or osmolarity7adjusting agents, and / or preservatives.

[0070]

[0071] In some embodiments, the formulation according to the present invention can be an aqueous formulation. For instance, the aqueous formulation like a micellular solution may be be used to deliver both water-soluble, water-ins olubale, and / or oil-soluble TRPM8 agonists.

[0072] In some embodiments, the concentration of TRPM8 agonists in the formulation may be 0.01 mg / mL to 20 mg / mL, preferably ranging from 0.5 mg / mL to 10 mg / mL.

[0071]

[0073] In some embodiments, the pH range of the formulation is 3. -8.0, preferably ranging from 4.0-7.0.

[0072]

[0074] Examples of the surfactants / solubilizers can be organic solvents, non-ionic surfactants, ionic surfactants, or any combination thereof, at concentrations, e.g.. ranging from 0.01wt%- 5.0 wt%. The organic solvents may be ethanol, isopropyl alcohol, or denatured alcohol. The non-ionic surfactants / solubilizer may be polysorbate 80, polysorbate 60, polysorbate 20, polyethylene glycol (PEG), ethoxylated fatty alcohols, PEG-40 hydrogenated castor oil, polyoxyl castor oil. or polyoxyl hydrogenated castor oil. The ionic surfactants can be benzalkonium chloride or cetylpyridinium chloride.

[0073]

[0075] In a further aspect, the present invention provides a usage of a TRPM8 agonist for manufacturing a medication for treating ocular disorders in a subject in need thereof, where in the medication includes a therapeutically effective amount of the TRPM8 agonist, e.g., contained a formulation. The formulation is adapted for topical delivery of the TRMP8 agonists to ocular margin surface of the subject. Examples of the TRPM8 agonist according to the present invention include but are not limited to menthol; 1-diisopropylphosphinoylalkane (DIPA) compounds (like Cryosim-1. Cryosim-2, Cryosim-3); icilin; the p-menthane carboxamides such as WS-3 (A-ethyl-p-menthane-3-carboxamide). WS-5 (A-[[(lR,2S,5 )-5- methyl-2-(l-methylethyl)cyclohexyl]carbonyl]-glycine, ethyl ester), WS-12 \R,2S,5R)-N-(4- Methoxyphenyl)-p-menthanecarboxamide), WS- 14 (A-tert-But l-p-menthane-3- carboxamide); the acyclic amides such as WS-23 (2-lsopropyl-A.2.3-trimethylbutyramide). WS-27 (A-Ethyl-2,2-diisopropylbutanamide); menthyl lactate; rontundifolone; eucalyptol; borneol; cubebol; isopropyl-3-methyl-2-methylenecyclohexanol; exocyclic olefin analogues of menthol, or other derivatives of these compounds.

[0074]

[0076] The invention is further elucidated with specific examples. It is understood that these examples are only used to describe the invention but not intended to limit the scope of invention. The experimental methods with no specific conditions in the following examples, are usually prepared under conventional conditions in literature or according to the conditions suggested by the excipient manufacturer. Unless specifically stated, all percentages, ratios, proportions, or fractions in this invention are calculated by weight by weight. Unless specifically defined in this invention, all professional and scientific terms used herein have the same meaning as well-trained personnel may be familiar with. In addition, any methods and materials similar or equivalent to those recorded in this invention can be applied to this invention. The preferred embodiments and materials described herein are used only for exemplary purposes.

[0075] Mechanisms of Action

[0076]

[0077] When an aqueous solution is delivered onto the ocular surface, several scenarios can be described.

[0077]

[0078] When an eye drop is applied to the eyeball, the momentum of the drop will cause a lateral splash. Using Bernoulli’s equation, the height L of the eye dropper above the eye yields the speed of the drop and its accompanying splash, u = (2gL)0.5. Thus, even for modest dropper heights of 5 cm, drops fall at 100 cm / s causing substantial lateral splashes, wherein most of the liquid is splashed across the target. The splash event occurs in milliseconds, giving little contact and residence time for the active ingredient on the eye surface.

[0078]

[0079] When the liquid is delivered via an absorbent material and wiped over the eyelid and eyelashes, a much more controlled deposition process is achieved. The use of an applicator enables a thin 0.02 cm layer of fluid to be deposited on the eyelid and eyelashes. This layer is uniform in thickness across the eyelid, which ultimately enables it to be spread more uniformly on the eye than the eye drops.

[0079]

[0080] Fig. 3 illustrates the method of use of eyelid wipes, particularly as to how the method of use of eyelid wipes distributes the drug to receptors. As shown in Fig. 3, after wiping, fluid in the layer (the fluid layer) is drawn into the eye by a combination of gravitational forces and the wicking action of individual strands of eyelash. The subsequent blink pushes the liquid in a downward concentric direction and the precorneal film, now containing the active ingredients, is swept across the eye surface like a gentle wave over a calm lake. This method takes advantage of the larger surfaces of the eyelid and eyelashes and the natural lubrication processes of the blink to deposit the ingredients uniformly and in appropriate volumes onto the ocular surfaces.

[0080]

[0081] The result according to the present invention is a game-changer for concepts in ocular drug delivery, a paradigm shift. The quantitative data here showed that the optimal therapeutic dose could be doubled by wiping when compared to drops. Formulations for wipes also gave greater fl exi bi 1 ity than drops.

[0081] Example 1: Preparation of Water-soluble TRPM8 Agonist Formulation

[0082]

[0082] In this example, Cryosim-3 (DIPA-9) w as used as an example of w ater-soluble TRPM8 agonist. As shown in Table 1, sodium hyaluronate was used as the gelling agent in the formulation. First, sodium hyaluronate powder was weighed and dissolved in water for injection (Part I). Then mannitol was added to the sodium hyaluronate solution. Polysorbate 80 was subsequently added into the solution before the addition of Cryosim-3. Once mannitol was completely dissolved, Cryosim-3 was added into the above solution under continuous agitation. 0.1M HC1 solution and 10 wt% trometamol solution was prepared to adjust the pH of the formulation to 4.0-7.0, preferably ranging from 4.5 to 6.0. For instance, 100 g of 10 wt% trometamol solution was prepared by dissolving 10 g of trometamol in 90 g (or mL) of distilled water while stirring, for a total mass of 100 grams. Water for injection (Part II) was then added to the solution to make the final amount to 100wt%. The solution was stirred for approximately 10 minutes. The formulations thus obtained were sterile filtered by passing through a 0.45 pm sterilizing grade filter first and then followed by two-stage 0.22 pm filtration.

[0083] Table 1. Formulation compositions for water-soluble TRPM8 agonists

[0084]

[0083] The osmolarity of Fl and F2 was within the range of 270-320 mOsmol / kg. The viscosity result had shown that Fl gave a viscosity around 25-40 centipoise (cps) at 30 rpm and 50 rpm at 25 °C, F2 offered a larger viscosity around 170-300 cPs at 6 rpm, 15 rpm, 30 rpm and 50 rpm at 25 °C. The viscosity of sodium hyaluronate decreased with an increase of measurement temperature. Fl was suitable for applications through a wipe, a pad, cotton swab, and / or a spray nozzle, while F2 was suitable for applications w ith a finger, a w ipe, a pad, a cotton swab, and / or a spray nozzle. Example 2: Preparation of Oil-soluble TRPM8 Agonist Formulation

[0085]

[0084] In this example. WS-12 was used as an example of a hydrophobic, water-insoluble TRPM8 agonist. The oil-soluble TRPM8 agonists are substances that can dissolve in oils and organic solvents and activate TRPM8, such as icilin, eucalyptol, WS-3, WS-12, WS-14, WS- 27, etc. In order to increase their bioavailability and efficacy, the oil-soluble TRPM8 agonists were formulated in water-based systems with emulsifiers, solubilizers or co-solvents. As shown in Table 2, the corresponding amount of WS-12 was dissolved in polyoxyl 35 castor oil to prepare Solution 1 (WS-12 / polyoxyl 35 castor oil solution). Polyoxyl 35 castor oil was preheated and melted at 60 °C to facilitate the dissolving of WS-12.

[0086]

[0085] Hypromellose was used as the gelling agent in a formulation. Hypromellose is insoluble in hot water, and soluble in low temperatures. Hypromellose is often dissolved by theL‘hot / cold’ technique. More accurately, to prepare Solution 2 (Hypromellose solution), hypromellose was dispersed in hot water (90 °C) first and then dissolved at low temperature (in water bath of 5°C) under continuous stirring. Solution 3 (NaCl / NaH2PC>4 stock solution) was prepared in a beaker under continuous stirring at 1200 rpm until complete dissolution. Solution 1 (WS-12 / polyoxyl 35 castor oil solution) was added stepwise and under continuous stirring into Solution 3 (NaCl / NaH2PO4 stock solution). Then, pH was adjusted to 7.0 with 10 N NaOH or 5N HC1. The obtained Solutionl / Solution 3 mixture was added into Solution 2 (Hypromellose solution) under continuous stirring for 20 minutes. The pH of Solution 1 / Solution 3 / Solution 2 mixture was adjusted to 7.0 with 10 N NaOH or 5N HC1. Water was added for injection to the solution to make the amount to 100wt%. After continued stirring for approximately 10 minutes, formulations were sterile filtered. The final solution was passed through a 0.45 pm sterilizing grade filter first and then followed by two stage 0.22 pm filtration.

[0087] Table 2. Formulation compositions for oil-soluble TRPM8 agonist

[0088] Example 3: Ocular Pharmacokinetic Study in New Zealand White Rabbits

[0089]

[0086] An ocular pharmacokinetic (PK) study was conducted in New Zealand White (NZW) Rabbits by PharmOptima, Portage, Michigan. The study protocol was approved by the institutional animal care and use committee (“IACUC”).

[0090]

[0087] Background: Transient receptor potential melastatin 8 (TRPM8) is a receptor that mediates a cooling sensation upon activation and plays a role in basal tear secretion. TRPM8- expressing sensory neurons innervate both the cornea and eyelid margins. The tests suggested that delivering TRPM8 agonists to the eyelid margins using wipes, rather than via conventional eye drops, offered a viable and potentially superior method for treating ocular diseases.

[0091]

[0088] Methods: In preclinical pharmacokinetic (PK) studies, New Zealand White (NZW) rabbits were administered a 0.2% solution of Ciyosim-3. a novel TRPM8 agonist, either by eye drops or via an eyelid wipe applied to the upper lid margin. Ocular tissues and blood samples were collected and analyzed using LC-MS / MS. Pharmacokinetic parameters were derived using sparse sampling and noncompartmental analysis with Phoenix WinNonlin®.

[0092]

[0089] Results: The PK data demonstrated that eyelid wiping, compared to eye drops, enhanced delivery of Cryosim-3 to key target tissues, including the upper eyelid margin, conjunctiva, and tear film, resulting in higher local drug concentrations. Importantly, Cryosim-3 concentrations in the posterior segment and systemic circulation were significantly lower following wipe application, suggesting reduced systemic exposure.

[0093]

[0090] Human Sensory Evaluation: A blinded, single-use sensory test in human volunteers compared the perceptual cooling effects of Cryosim-3 (0.1%) and WS-12 (0.003%), another TRPM8 agonist in clinical development, delivered via both eyelid wipes and eye drops. Cryosim-3 applied via eyelid wipe produced a cooling sensation lasting approximately 40 minutes — substantially longer than the 15-minute effect observed with eye drops. In contrast, WS-12 failed to elicit any perceptible cooling in either format, likely due to its poor solubility in aqueous formulations.

[0094]

[0091] Conclusion: These findings supported the superior pharmacokinetic and sensory profile of Cryosim-3 when delivered via eyelid wipes. This method targeted the TRPM8-rich ocular margins more effectively than eye drops while minimizing systemic exposure. Furthermore, the robust cooling response confirmed the feasibility of this novel delivery7approach for the treatment of dry eye and other ocular surface diseases.

[0095]

[0092] More specifically, twenty-four rabbits were used in a PK study to test plasma, ocular fluids, and tissue concentrations after topical ocular administration of the test article as wipes or drops. The formulations used were Formulation 5 in Example 1, via eye drop (Group 1) and topical upper eyelid margin (Group 2) administration respectively. A calibrated positive displacement pipette was used to administer 35 pL onto the globe of each eye and on the lid margin of upper eyelid in a sweeping motion. Animals were observed before euthanasia. After blood collections at 15 and 30 minutes, and 1, 2, 4, and 8 hours post-dose on Day 1, tears were collected for 60 seconds using Schirmer tear strips from two animals / group / timepoint. Tear strip measurements were recorded. After tear collection, animals were euthanized with an intravenous barbiturate. Aqueous humor was collected via paracentesis of the anterior chamber of each eye. The bulbar conjunctiva was removed, rinsed, and collected from each eye. The eye lids were removed, and the upper and lower palpebral conjunctiva were removed, rinsed, and collected into one container per eye followed by the collection of the upper lid margin of each eye. The additional ocular tissues collected by dissection were vitreous humor, cornea, iris-ciliary body, choroid, retina, and sclera. Fluids and tissues were placed in tared tubes.

[0096]

[0093] Blood samples, tears, aqueous humor, conjunctiva bulbar, conjunctiva palpebral, cornea, iris ciliary7body, vitreous humor, retina, choroid, sclera, and upper lid margin were collected from all animals at approximately 15 and 30 minutes, and 1. 2, 4. and 8 hours post dose. Concentrations of Cryosim-3 in plasma, tears, aqueous humor, conjunctiva bulbar, conjunctiva palpebral, cornea, iris-ciliary body, choroid, retina, sclera, vitreous humor, and upper lid margin were determined by analysis with the LC-MS / MS method.

[0097]

[0094] Figs. 4A-4D illustrate the pK data after eye drop or eyelid administration. As shown in Fig. 4A, plasma concentrations of the test ingredient (Cryosim-3) were lower after wiping than after eye drops. It is likely that use of eye drops results in more systemic absorption of the drug via the nasolacrimal duct. Fig. 4B shows the comparison of concentrations of Cryosim-3 in eyelids, palpebral conjunctiva, tears and cornea after delivery with wipes or eye drops. Levels of the drug were determined by analysis with a LC-MS / MS method. Fig. 4C shows the concentrations of Cryosim-3 in bulbar conjunctiva (B.C.) after delivery with wipes or eye drops. Levels of the drug were determined by analysis with a LC-MS / MS method. The bulbar conjunctiva surface is analogous to the "w indshield’' of a car after wiping. The B.C. is in full contact with the eyelids and cornea nerve fibers. Fig. 4D shows the comparison of concentrations of Ciyosim-3 in sclera, aqueous humor, choroid plexus, vitreous humor and retina after delivery' with wipes or eye drops. Levels of the drug were determined by analysis with a LC-MS / MS method. Sensory TRPM8 nerve fibers are not expected to be functionally significant in these tissues.

[0098]

[0095] Table 3 summarizes the average Cryosim-3 concentrations in plasma and ocular matrices following ocular eye drop or eyelid administration.

[0099] Table 3. Average Cryosim-3 Concentrations in Plasma and Ocular Matrices following Ocular Eye Drop or Eyelid Administration

[0100]

[0096] The levels of Cryosim-3, measured by the Cmax and AUC, were higher after eyelid administration when compared to eye drop administration in tears, cornea, bulbar conjunctiva, palpebral conjunctiva, and upper lid margin. This PK data clearly showed how the API was distributed and dispersed after wiping or drops. Surprisingly, wiping on eyelid margins fulfilled the primary goals of ocular drug delivery, namely, “to maintain optimal therapeutic drug concentrations at the target site and to reduce dosage frequency.”

[0101]

[0097] The PK results were conclusive in favor of wipes. It was shown that the wipe method increased concentrations in the upper lid margin, bulbar Conjunctiva (BC), Palpebral Conjunctiva (PC) and in tears, more than those from delivery with drops, but plasma concentrations from wipes are lower. The drops gave higher concentrations in the cornea and anterior / posterior segments, and plasma. Wiping, compared to drops, increased delivery of C3 onto the upper lids, conjunctiva, and tears, emphasizing the higher concentration at target sites and instilling confidence in the method's effectiveness. Moreover, delivery of C3 to the posterior segment of the eye was less, and plasma concentrations of C3, indicative of systemic absorption, were also less. From these surprisingly quantitative studies, inventors deduced that the primary optimal target sites for C3 delivery are located on the ocular margins and not the cornea. These sites were best reached with wipes, yielding a higher concentration at target sites. The impact of drops delivered onto the cornea was less desirable. The lower systemic absorption of C3 also favored using wipes. Wipes achieved better delivery to the receptive fields of the supraorbital nerve and less to the cornea, and also with less systemic absorption.

[0102]

[0098] Fig. 5 illustrates Schirmer’s test result before and after ocular eye drop or eyelid administration. Schirmer’s test result obtained pre- and post-administration of the ophthalmic composition, either via eye drop or eyelid margin application. Peak tear secretion was observed at approximately 1 hour following eye drop administration. In contrast, eyelid margin application produced a more prolonged effect, with a peak tear secretion noted at 2 hours post-dose. As shown in Fig. 5, drug delivered via both eye drop, and upper eyelid routes increased the tear secretion up to 8 hours (baseline adjusted). Effect reached to maximum at 1-hour via eye drop administration while lasts longer at 2-hour post-dose via upper eyelid dosing route. It was a surprising result demonstrating that wiping on eyelid margin had achieved sustained efficacy on tear secretion compared to eye drop administration.

[0103]

[0099] The concentrations of Cryosim-3 were observed up to 8 hours in all ocular tissues and fluids. The systemic concentration of Cryosim-3 in plasma and whole blood was low in all groups at all timepoints and BLQ (LLOQ= 0.100 ng / mL) after 4 hours in Group 2 and at 8 hours for Group 1. [1001 The concentration differences between groups were indicative of the specific dose route for each group. For example, the concentrations of Cryosim-3 were higher in the cornea, AH and ICB where the formulation was administered directly to the cornea (Group 1); while the concentrations of Cryosim-3 were higher in the upper eyelid margin, tears, and conjunctiva when the formulation was administered to the eyelid. The concentrations of Cryosim-3 were consistent in both groups for retina, choroid and VH. Cryosim-3 was well tolerated with no abnormal observations noted post dose or prior to euthanasia.

[0104] Example 4: Sensory Test for TRPM8 Agonists Wipes Among Different Target Regions

[0105]

[0101] This study was a blinded single-use sensory test on four different target regions on face including the supraorbital, infraorbital, nasal, and zygomatic regions on human volunteer subjects. One active and one placebo were given to each participant each day to test on the left and right side of the face, respectively. One wipe was applied once to each region. Different regions were tested sequentially. The sensory test samples were listed in Table 4.

[0106] Table 4. Sensory test sample list on supraorbital, infraorbital, nasal, and zygomatic regions

[0107] ASHRAE 7-point Comfort Visual Analog Scale (-3 to +3, cold to hot) and Tolerability Visual Analog Scale (0 to 100, no discomfort to severe discomfort), respectively. Participants were asked to write a number within the range of the scales to determine the strength of the cooling sensation and tolerability at the following times: 0, 0.5, 2.5, 5, 15, 30, 45, 60 minutes. The sensory score at 0 minutes represented the baseline sensation that a subject feels before drug administration. This score was used to establish the sensory state prior to any influence from the drug. On the other hand, the sensory score at 0.5 minutes reflected the sensation immediately after drug administration. This allowed for the assessment of early sensory effects caused by the drug, indicating how quickly the drug starts to affect sensation. If the participant returned to baseline score of zero in both comfortability and tolerability for two timepoints in a row, they could proceed to the next region after 15-minute rest periods.

[0108]

[0103] Each participant’s active score was compared to its relevant vehicle score. A response score from 0 to 5 was assigned to each comparison based on the degree of change the raw active score had from the raw vehicle score, 0 meaning no difference and 5 representing a large difference between the active and vehicle. The adjusted response score for each participant was totaled and listed by their respective formulations and concentrations. The totaled cooling responses by formulation and concentration were then organized and totaled by testing regions for further comparison.

[0109]

[0104] The condensed sample sensory data was summarized in Table 5. Sensory test data for each formulation was compared against its respective vehicle. Each formulation was assigned a comfort and tolerability response score from zero to five based on the comfort and tolerability response difference when compared to the vehicle response. The sensory test data showed that C3 wipes provided a stronger comfort response than WS-12 wipes, especially on supraorbital and infraorbital regions. 0.2% C3 in vehicle formulation showed the highest response across all TRPM8 agonist regions out of all testing solutions. Similarly, 0.003% WS-12 in vehicle formulation showed the highest response compared to WS-12 dissolved in oil or organic solvent. Out of each testing region, the supraorbital (eyelid) region gave the highest cooling response for strength and duration, followed secondly by the infraorbital (cheekbone) region, and lastly the zygomatic and nasal regions showed similar response. It was interesting to discover that infraorbital region gave a relatively strong cooling sensation without an increase of tolerability response, as compared with supraorbital region. There was no difference for WS-12 in organic solvent at different concentrations. The comfortability and tolerability scores for WS-12 in EL-35 were zero in the four target regions.

[0110] Table 5. Sensory scores on supraorbital, infraorbital, nasal, and zygomatic regions

[0111]

[0112] Example 5: Sensory Test for TRPM8 Agonists Eyelid Wipes and Eye drops

[0113]

[0105] This study was a blinded single-use sensory test on one human volunteer subject to compare the sensory effect of eyelid wipes and eye drops using different TRPM8 agonists. In this study, C3 and WS-12 were used as an example of water-soluble and oil-soluble TRPM8 agonists, respectively. 0.1% C3 formulation and 0.003% WS-12 formulation were given to the participant to test on the left and right side of the face, respectively for eyelid wipes and eye drops. The sensory test samples were listed in Table 6.

[0114] Table 6. Sensory test sample list of TRPM8 Agonists eyelid wipes and eye drops

[0115]

[0106] The participant was asked to record the comfortability and tolerability based on the ASHRAE 7-point Comfort Visual Analog Scale (-3 to +3, cold to hot) and Tolerability Visual Analog Scale (0 to 100, no discomfort to severe discomfort), respectively. Participant was asked to write a number within the range of the scales to determine the strength of the cooling sensation and tolerability at the following times: 0, 0.5, 2.5, 5, 15, 30, 45, 60 minutes. The sensory score at 0 minutes represented the baseline sensation that a subject feels before drug administration. This score was used to establish the sensory state prior to any influence from the drug. On the other hand, the sensory score at 0.5 minutes reflected the sensation immediately after drug administration. This allowed for the assessment of early sensory effects caused by the drug, indicating how quickly the drug starts to affect sensation.

[0116] Table 7. Comfort VAS and Tolerability VAS sensory scores.

[0117]

[0107] The Comfort VAS and Tolerability VAS sensory scores through eye drops and eyelid wipes of TRPM8 agonists were summarized in Table 7. Negative Comfort VAS scores indicated varying degrees of cooling sensation. The more negative the score, the stronger the cooling sensation. 0.1% C3 had a longer lasting cooling response in eyelid wipes than eye drops. The cooling sensation of 0.1% C3 eyelid wipes lasted for 40 minutes, while that of 0.1% C3 eye drops disappeared after only 15 minutes. The cooling sensation by wiping delivery on ocular margins (such as eyelid wipes) lasted significantly longer than the sensation produced by eye drops. It was surprisingly discovered that the cooling effect from eyelid wipes lasts more than twice as long as that from eye drops. Drugs administered through eye drops are often quickly eliminated from the eye due to the drainage effect, eye blinking, dilution by tears, etc. It was also found that for 0.003% WS-12 product, either eye drops or eyelid wipes did not provide cooling sensation for participants in the study. This might be due to extremely low concentration of WS-12 in solutions.

[0118] [1081 The Tolerability Visual Analog Scale (VAS) was a tool used to measure the level of discomfort experienced by participants. In this scale, 0 indicated no discomfort at all, while 100 indicated the most severe discomfort possible. The eye drops had a high initial discomfort score from dropping into the eye, but dissipated within 5 minutes. Wiping on the eyelid had no discomfort or very mild discomfort to participants as compared to eye drop administrations.

[0119]

[0109] Although specific embodiments and examples of this invention have been illustrated herein, it will be appreciated by those skilled in the art that any modifications and variations can be made without departing from the spirit of the invention. The examples and illustrations above are not intended to limit the scope of this invention. Any combination of embodiments of this invention, along with any obvious extensions or analogs, are within the scope of this invention. Further, it is intended that this invention encompass any arrangement, which is calculated to achieve that same purpose, and all such variations and modifications fall within the scope of the appended claims.

[0120] [HO] All the features disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example of a generic series of equivalent or similar features.

Claims

WHAT IS CLAIMED IS:

1. A method for treating an ocular disorder in a subject in need thereof, comprising topically administering a therapeutically effective amount of a TRPM8 agonist to surface(s) of ocular margin of the subject, wherein the ocular margin is the primary target site for delivery of the TRPM8 agonist.

2. The method of claim 1, wherein the TRPM8 agonist is delivered at a higher amount to the primary target site than to the cornea.

3. The method of claim 1 or 2, wherein the method delivers more TRPM8 agonist to key target tissues, including the upper eyelid margin, conjunctiva, and tear film, and less TRPM8 agonist to posterior segment and systemic circulation of the subject, as compared to a method administrating the same amount of the TRPM8 agonist via eye drop administration.

4. The method of any one of claims 1 to 3, wherein the surface(s) of the ocular margin comprise receptive fields located on a supraorbital region, an infraorbital region, a nasal region, a zygomatic region, or any combination thereof.

5. The method of any one of claims 1 to 4, wherein the TRPM8 agonist comprises menthol, a DIPA compound, icilin, WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein the TRPM8 agonist comprises menthol, a DIPA compound, WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, or an analog, derivative, or pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the TRPM8 agonist comprises menthol, WS-12, or a DIPA compound, or an analog, derivative, or pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the TRPM8 agonist comprises a DIPA compound, and the DIPA compound comprises DIPA-6, DIPA-7, DIPA-8, or DIPA-9, or an analog, derivative, or pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1 to 8, wherein the TRMP8 agonist is administered in the form of a pharmaceutical formulation comprising the TRMP8 agonist and a pharmaceutically acceptable carrier.

10. The method of any one of claims 1 to 9, wherein the pharmaceutical formulation is in the form of liquid, solid, semi-solid, gel, cream, or ointment.11 . The method of claim 10, wherein the pharmaceutical formulation is in the form of liquid.

12. The method of any one of claims 9 to 11, wherein the TRPM8 agonist is contained in the pharmaceutical formulation at a concentration ranging from about 0.01 mg / mL to about 20 mg / mL, or ranging from about 0.5 mg / mL to about 10 mg / mL, or ranging from about 1.0 mg / mL to about 5.0 mg / mL.

13. The method of any of claims 9 to 12, wherein the pharmaceutical formulation further comprises a surfactant or solubilizer, a gelling agent, a gel adjusting agent, a pH adjusting agent, an osmolarity adjusting agent, or a preservative.

14. The method of claim 13, wherein the surfactant or solubilizer comprises an organic solvent selected from ethanol, isopropyl alcohol, or denatured alcohol; a non-ionic surfactant or solubilizer selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 20, polyethylene glycol (PEG), ethoxylated fatty alcohol, PEG-40 hydrogenated castor oil, polyoxyl castor oil, and polyoxyl hydrogenated castor oil; or an ionic surfactant selected from the group consisting of benzalkonium chloride and cetylpyridinium chloride; the gelling agent comprises sodium hyaluronate, deacetylated gellan gum, sodium alginate, xanthan gum, carrageenan, poloxamer, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose), hydroxyethyl cellulose, or any combination thereof; the gel adjusting agent comprises a univalent or divalent cationic agent selected from the group consisting of sodium chloride, potassium chloride, zirconium chloride, magnesium chloride, or any combination thereof; the pH adjusting agent comprises trometamol or tromethamine, sodium hydroxide, hydrochloric acid, boric acid, disodium phosphate, monosodium phosphate, sodium bicarbonate, sodium acetate, or any combination thereof; the osmolarity adjusting agent comprises mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, or any combination thereof; or the preservative comprises sorbic acid, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, EDTA-2Na or any combination thereof.

15. The method of any one of claims 9 to 14, wherein the pharmaceutical formulation comprises the surfactant or solubilizer at a concentration ranging from about 0.01wt% to about 5.0 wt%; or the pharmaceutical formulation comprises the gelling agent at a concentration ranging from about 0.01 wt% to about 20 wt%, or from about 0.3 wt% to about 6 wt%.

16. The method of any one of claims 9 to 15, wherein the pharmaceutical formulation has a pH ranging from about 3.5 to about 8.0, or from about 4.0 to about 7.0.

17. The method of any one of claims 1 to 16, wherein the ocular disorder is dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, uveitis, or keratitis.

18. The method of claim 17, wherein the ocular disorder is dry eye syndrome.

19. The method of claim 18, wherein the dry eye syndrome comprises an aqueous-deficient disorder, a hyperevaporative disorder, or a combination thereof.

20. A kit for treating an ocular disorder in a subject, comprising (i) a pharmaceutical formulation comprising an effective amount of a TRMP8 agonist and a pharmaceutically acceptable carrier, and (ii) an instruction for administrating the pharmaceutical formulation to ocular margin of the subject as the primary target site for delivery of the TRPM8 agonist.

21. The kit of claim 20, wherein the TRPM8 agonist comprises menthol, aDIPA compound, icilin, WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof.

22. The kit of claim 20 or 21, wherein the ocular disorder is dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, or keratitis.

23. An eyelid wipe for treating an ocular disorder in a subject, wherein the eyelid wipe comprises a therapeutically effective amount of a TRPM8 agonist to be topically administrated to the eyelid of the subject.

24. The eyelid wipe of claim 23, wherein the TRPM8 agonist comprises menthol, a DIPA compound, icilin, WS-3, WS-5, WS-12, WS-14, WS-23, WS-27, menthyl lactate, rontundifolone, eucalyptol, borneol, cubebol, isopropyl-3-methyl-2-methylenecyclohexanol, or an analog, derivative, or pharmaceutically acceptable salt thereof; or the ocular disorder is dry eye syndrome, neuropathic pain, eye fatigue, allergic conjunctivitis, blepharitis, conjunctivitis, or keratitis.

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