Treatment of neurogenic sensitization disorder

Abstract

In particular, the present invention provides a method for treating a neuropathic ocular pain disorder in a subject in need thereof, comprising topically applying a therapeutically effective amount of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound to the ocular surface of the subject for at least one week, wherein the DIPA compound is dissolved in a liquid vehicle adapted to deliver the DIPA compound to the ocular surface in a concentrated manner.

Description

Background Art

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 205,848, filed on January 11, 2021, the content of which is hereby incorporated by reference in its entirety.

[0002] Background of the Invention Sir Charles Sherrington defined pain around 1900 as "the psychic adjunct of the forced defensive reflex." The modern definition of "pain" by the International Association for the Study of Pain (IASP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.

[0003] The updated notes accompanying the new definition are as follows: pain is always a personal experience and is affected to varying degrees by biological, psychological, and social factors; pain and nociception are different phenomena; and pain cannot be inferred from the activity of sensory neurons alone.

[0004] Through life experiences, individuals learn the concept of pain. The reports of those who have experienced pain should be respected.

[0005] Pain usually serves an adaptive role but can have an adverse effect on function and social and psychological well - being.

[0006] Verbal description is just one of several behaviors for expressing pain; the inability to communicate does not negate the possibility that humans or non - human animals experience pain.

[0007] The definitions of Sherrington and IASP have a recognition and emphasis on the mental and experiential aspects of pain, namely, the recognition that pain is an event recognized by the mind.

[0008] Advances in neurophysiology and molecular biology have accelerated our understanding of the mechanisms of pain. It is now recognized that pain is activated by increased release of unmyelinated, small-diameter sensory fibers called polymodal C fibers. Pain is classified as nociceptive or neuropathic. Nociceptive pain is caused by cellular damage such as trauma, inflammation, and immune disorders. Neuropathic pain is caused by damage to nerve fibers that transmit pain signals. Sensations that can accompany pain include irritation, pruritus (itch), fatigue, and discomfort. In this application, psychological symptoms associated with nociception are also classified as “sensory discomfort” or paresthesia.

[0009] Chronic pain is defined as persistent or recurrent pain lasting for three months or more. There are optional designators for each patient's pain severity, and it can be graded based on intensity, pain-related distress, and functional impairment. Types of chronic pain include cancer pain, postoperative and post-traumatic pain, musculoskeletal pain, headaches and orofacial pain, visceral pain, and neuropathic pain.

[0010] Neuropathic pain can occur spontaneously or be induced, as an increased response to painful stimuli (hyperalgesia) or as a painful response to stimuli that are normally not painful (allodynia). The increased amplification of pain in hyperalgesia or allodynia is called "sensitization," and this can occur in the peripheral nervous system (peripheral sensitization) or the central nervous system (central sensitization). The IASP now standardizes these terms. The term "hypersensitivity" is not used to describe pain because it traditionally refers to undesirable reactions caused by the immune system, including allergies and autoimmunes.

[0011] As used herein, “sensitization” refers to an increased responsiveness of nociceptive neurons to their normal input and / or supplementation of their response to subthreshold input.

[0012] "Central sensitization" refers to an increase in the responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.

[0013] "Peripheral sensitization" refers to an increase in the responsiveness of peripheral nociceptive neurons to stimuli in their receptive fields and a decrease in their threshold.

[0014] Neuropathic ocular pain (NOP) refers to pain originating from the surface of the eye (defined as the epithelium of the cornea, corneal margin, conjunctiva, and eyelid margin). One mechanism of NOP results from repeated direct injury to the corneal nerves. Abnormal regeneration of nerve endings with upregulation of nociceptors may cause peripheral sensitization. The persistent pain can then lead to central hypersensitization and distress. NOP can occur after the eye injury has healed, even if there is no detectable anatomical damage—the so-called "clean pain" of the cornea. NOP is also called corneal neuropathy, corneal neuralgia, kertao neuralgia, and corneal allodynia. Currently, chronic pain is a more standardized term in the International Classification of Diseases, 11th Edition, and the classification of chronic pain is described in Chapter 21, Section MG30. NOP is classified as chronic neuropathic pain.

[0015] NOP has a significant negative impact on the patient's quality of life. The pain, photosensitivity, and sensation of irritation are intense, persistent, and permanent, impairing the ability to perform everyday activities such as watching television, reading, driving, and working. Physical and social functioning declines, and distress occurs. A large group of NOP patients suffer from chronic dry eye syndrome that does not respond to conventional treatments. However, NOP can occur even without signs of dry eye disease, such as changes in tear secretion rate or changes in tear quality or stability (due to meibomian gland dysfunction, for example). Particularly difficult to treat is NOP after refractive surgery or cataract surgery. Because the pain is persistent, difficult to treat, and mentally overwhelming, patients become desperate and suicidal. A recent well-known case is JS, a 35-year-old television meteorologist from Detroit and mother of two young children, who committed suicide after NOP following LASIK surgery. A thorough and up-to-date discussion of NOP is presented in a paper by Anat Galor of the University of Miami, Florida (Galor, A. et al., The Ocular Surface, 2018, 16, 31-44; Mehra D., Anat Galor, Ophthalmology and Therapy, 2020, 9(3): 427-47).

[0016] By definition, chronic neuropathic pain is a condition lasting more than three months. In patients with NOP, this usually means that everything has been tried within three months, but with limited success. For example, treatment of the ocular surface with artificial tears, ointments, and gels is recommended. These are followed by punctal plugs, topical and systemic antibiotics, anti-inflammatory steroids, and anti-inflammatory drugs such as cyclosporine and livitage. Nerve growth factors and autologous serum are speculative procedures for nerve regeneration therapy. Another course of action is to administer drugs that affect the central nervous system, such as antidepressants (e.g., amitriptyline, nortriptyline), anticonvulsants (e.g., carbamazepine), NSAIDs, tramadol, and gabapentin / pregabalin, but all have varying success rates. If NOP is associated with migraines, treating the migraines may help alleviate NOP. New and effective treatments for NOP are needed. [Overview of the Initiative]

[0017] The present invention provides a method and a topical agent for treating neurogenic eye pain disorders in subjects requiring treatment for neurogenic eye pain disorders.

[0018] In one embodiment, the present invention provides a method for treating neuropathic ophthalmic pain disorder in a subject requiring treatment of neuropathic ophthalmic pain disorder, comprising topically applying a therapeutically effective amount of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound to the ocular surface of the subject. The synthesis and receptor bioassay of DIPA are described in U.S. Patent No. 10,195,217, which is incorporated herein by reference. DIPA is applied to the ocular surface for at least one week, the DIPA compound is dissolved in a liquid vehicle, and the liquid vehicle is adapted for concentrated delivery of the DIPA compound to the ocular surface.

[0019] In some embodiments, the DIPA compound is dissolved in a liquid vehicle at a concentration of 0.5 to 5 mg / ml therein, and the liquid vehicle delivers the DIPA compound to the ocular surface.

[0020] In some embodiments, the liquid vehicle is an aqueous solution.

[0021] In some embodiments, the liquid vehicle is water or isotonic saline.

[0022] In some embodiments, the DIPA compound is dissolved in the liquid vehicle at a concentration of 0.5 - 5 mg / ml.

[0023] In some embodiments, the DIPA compound dissolved in the liquid vehicle is delivered to the ocular surface of the subject by wiping.

[0024] In some embodiments, DIPA dissolved in the liquid vehicle is applied to the ocular surface of the subject four times a day.

[0025] In some embodiments, the DIPA compound is

Chemical formula

[0026] In some embodiments, the neurogenic ocular pain disorder is caused by dry eye disease.

[0027] In some embodiments, the neurogenic ocular pain disorder is caused by eye surgery.

[0028] In some embodiments, the neurogenic ocular pain disorder is caused by eye trauma.

[0029] In a second aspect, the present invention provides a topical agent for treating neurogenic ocular pain disorder in a subject in need thereof, comprising an aqueous solution containing a therapeutically effective amount of a DIPA compound, which can be DIPA-1-7, DIPA-1-8, or DIPA-1-9 (i.e., 1-[diisopropyl-phosphinoyl]-nonane).

[0030] In some embodiments, the concentration of the DIPA compound in the aqueous solution is 0.5 - 5 mg / mL.

[0031] In some embodiments, neurogenic eye pain disorders are caused by dry eye conditions.

[0032] In some embodiments, neurogenic eye pain disorders are caused by eye surgery.

[0033] In some embodiments, neurogenic eye pain disorders are caused by eye trauma.

[0034] In a third aspect, the present invention provides the use of a DIPA compound (e.g., DIPA-1-7, DIPA-1-8, or DIPA-1-9) for manufacturing a pharmaceutical for treating neurogenic ophthalmic pain disorder in a subject requiring treatment of neurogenic ophthalmic pain disorder, wherein the pharmaceutical comprises a therapeutically effective amount of the DIPA compound (e.g., DIPA-1-7, DIPA-1-8, or DIPA-1-9) and a liquid vehicle, the liquid vehicle being adapted for concentrated delivery of the DIPA compound to the ocular surface of the subject.

[0035] These and other features, aspects, and advantages of the present invention will be better understood by referring to the following description and the appended claims. [Brief explanation of the drawing]

[0036] Next, embodiments of the present invention will be described in more detail with reference to the attached drawings:

[0037] [Figure 1] This describes a method for topical application of gauze containing cryosim-3, which targets TRPM8 in the eyelid margin.

[0038] [Figure 2] This is a schematic diagram illustrating the mechanism of action of TRPM8 agonists in reducing eye pain in patients with dry eye. [Modes for carrying out the invention]

[0039] (Detailed description of the invention) The above summary section, the detailed description section, and the following claims refer to specific features of the present invention. It should be understood that the disclosure of the present invention herein includes all possible combinations of such specific features. For example, if a specific feature is disclosed in the context of a particular aspect or embodiment of the present invention, or a particular claim, that feature may also be used, to the extent possible, in combination with and / or in connection with other particular aspects and embodiments of the present invention, and more broadly in the present invention.

[0040] In one embodiment, the present invention provides a method for treating neurogenic ophthalmic pain disorder in a subject requiring treatment for neurogenic ophthalmic pain disorder, comprising topically applying a therapeutically effective amount of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound to the ocular surface of the subject for at least one week, wherein the DIPA compound is dissolved in a liquid vehicle, and the liquid vehicle is adapted to concentrate the delivery of the DIPA compound to the ocular surface.

[0041] In a second aspect, the present invention provides a topical agent for treating neurogenic ophthalmic pain disorders in subjects requiring treatment of neurogenic ophthalmic pain disorders, comprising an aqueous solution containing a therapeutically effective amount of a DIPA compound (e.g., DIPA-1-7, DIPA-1-8, or DIPA-1-9).

[0042] In a third aspect, the present invention provides the use of a DIPA compound (e.g., DIPA-1-7, DIPA-1-8, or DIPA-1-9) for manufacturing a pharmaceutical for treating neurogenic ophthalmic pain disorder in a subject requiring treatment of neurogenic ophthalmic pain disorder, wherein the pharmaceutical comprises a therapeutically effective amount of the DIPA compound (e.g., DIPA-1-7, DIPA-1-8, or DIPA-1-9) and a liquid vehicle, the liquid vehicle being adapted for concentrated delivery of the DIPA compound to the ocular surface of the subject.

[0043] Patients with neurogenic ophthalmic pain disorder experience neurogenic ophthalmic pain (NOP). Neurogenic ophthalmic pain (NOP) refers to pain originating from the ocular surface (defined as the epithelium of the cornea, corneal margin, conjunctiva, and eyelid margin). In some embodiments, neurogenic ophthalmic pain disorder is caused by dry eye disease. In some embodiments, neurogenic ophthalmic pain disorder is caused by eye surgery. In some embodiments, neurogenic ophthalmic pain disorder is caused by eye trauma.

[0044] Neurobiology and Mechanisms of Action of the Ocular Surface: Around 200 million years ago, certain organisms acquired the ability to control metabolic heat production (endothermic) and maintain a constant internal body temperature (homeothermic) (McNab, BK The evolution of endothermy in the phylogeny of mammals. American Naturalist 112: 1-21, 1978). This evolutionary shift from "cold-blooded" to "warm-blooded" physiological functions allowed such species to adapt to and survive in changeable environments. In connection with this change, sensory systems developed and refined to monitor and control body temperature, particularly in the eyes and upper respiratory tract, and to regulate drinking, thirst, and tear secretion. Coolness is a nerve signal that radiates from the surface of an organism, such as the eyes, face, nose, ears, and neck. For example, about 92% of the thermoreceptive input from the facial skin of mammals comes from cryoreceptors. These neurons are active in a sustained state of tension at 15-18°C (Hutchison, WD et al., J. Neurophysiol. 77: 3252-3266, 1997; Takashima, Y. et al., J. Neurosci., 27, 14147-14157, 2007).

[0045] The primary detector of coolness and coldness is an intrinsic membrane protein known as TRPM8 (Bautista, DM et al., Nature 448: 204-208, 2007). Another receptor that responds to cold is TRPA1. The anatomical structure of neurons containing TRPM8 has been mapped in mice (Dhaka et al., J. Neurosci. 28: 566-575, 2008; Schecterson et al., Molecular Vision 26:576-587, 2020). Peripheral nerve fibers containing TRPM8 are located in the superficial layer of the epidermis and protrude into the superficial layers of the spinal cord and brainstem. Nerve fiber endings in the cornea and eyelids are also mapped. The TRPM8 neuronal system is clearly separated from nociceptive neurons belonging to the C fiber category. Most TRPM8 nerve fibers are myelinated and are classified into A-δ based on conduction velocity.

[0046] TRPM8 peripheral cold / colafferent nerves were first carefully described in a classic study by Hensel. He mapped the density of "cold spots" in the body, which may be associated with the release of specific nerve fibers when cold air is applied individually. Thermal sensation is closely linked to perceptual and biological response systems. Thus, a hot shower is comfortable at 40°C, but at 43.4°C, an individual will try to escape the heat. 43.4°C is also the point at which activation of heat / pain receptors and C-fiber release, leakage of plasma contents from retrocapillary venules, and abnormal cellular oxygen consumption begin. A similarly precise distinction is made for the sensation of coldness. Thus, at around 18°C, individuals complain of feeling cold, put on more clothes, and begin to activate their thermoregulatory systems. Animals readily perceive a temperature difference of ±1°C in experimental conditions. Chemicals also select a range of cooling intensity. Some are slightly cool and tingly, some are refreshingly cool, and some are simply cold.

[0047] The anti-nociceptive properties of physical coolness / coldness on the body surface reduce irritation, itching, and pain. Therefore, air conditioning, cold water, and ice can be used to alleviate sensory discomfort caused by heat, trauma, pain, and certain types of inflammation. The transfer of heat recovery necessary for coolness / coldness can be achieved using gaseous, liquid, or solid materials, utilizing mechanisms of evaporation, convection, or energy conduction.

[0048] In the brain, regulated interactions exist between inputs from both nociceptive and non-nociceptive neurons. It is also possible to accurately recognize the origin of the input geographically. Witness the precise identification of pain from a tiny needle or the catastrophe of ingrown eyelashes (tricholashosis) or ingrown toenails. Neuropathy of the ocular surface nerve is expected to cause serious consequences, as it can completely disrupt the normal functioning of the body. The pharmacological strategy here is to use TRPM8 neural input to control and block central sensitization of nociceptive perception in the NOP. By interfering with the perception of harmful stimuli, the individual's mental state and anxiety about pain are reduced, and the chronic pain condition is improved overall. The hypothesis stated is that cold / cold signals mediated by Aδ-fibers are utilized to amplify the unpleasant signal and block the subsequent pathogenesis.

[0049] Without being limited by theory, the mechanism proposed here can be likened to three telephone lines within a tissue, each with a different dialing mechanism and cable conduction system. One is for touch and pressure, which conducts quickly. One is for coolness and coldness, which is somewhat slower (Aσ conducts at approximately 2-6 meters / second). One is used for irritation, itching, and pain, which conducts slowly (<2 meters / second, mainly C fibers). To use an analogy, one of the two telephone lines interferes with the transmission of the other signals at a central exchange. The compounds of this discovery, 1-diisopropylphosphinoylnonane (Cryosim-3) or 1-diisopropylphosphinoyloctane (Cryosim-2), have been proposed to be used as a dialing mechanism to stimulate the telephone line involved in coolness and coldness signals. Using this telephone line, it is expected that the generated signal will reduce the amplification of unpleasant signals from the C fiber line, resulting in a beneficial effect on chronic pain.

[0050] Based on the above considerations and the data from Example 1, it is proposed that TRPM8 agonists initiate Aσ fiber input to the central nervous system, altering the flow of nociceptive information. This mode of action is indirect, as there is no interference with the generation or transmission of signal input from nociceptors. Note that cold signals are active in sustained tension at 18°C ​​and constitute 92% of the thermoreceptive input from facial skin. In dorsal horn neurons, 50% of TRPM8 cells are activated in the narrow temperature range of 18-19°C. Therefore, even a slight increase in the release frequency of TRPM8, due to its very large volume, will dominate sensory transmission and integration in the central nervous system. This flood of cold signals can increase sensitization of the nociceptive system.

[0051] In the case of Cryosim, the method of drug delivery is local and concentrated in the receptive field containing nociceptors or the immediately adjacent sensory field. In some embodiments, a DIPA compound dissolved in a liquid vehicle is delivered to the target ocular surface by wiping. In some embodiments, DIPA dissolved in a liquid vehicle is applied to the target ocular surface once, two, three, or four times a day. The mode of antineuropathy is indirect, meaning there is no direct effect on signal transmission. Cyrosim-3 is designed to act on non-keratinized tissue. Its receptive field is the nerve endings of the ocular branch of the trigeminal nerve, particularly the receptive field of the supraorbital nerve. A schematic of this method is shown in Figures 1 and 2. The cooling agent is applied to the receptive field of TRPM8 neurons on the ocular margin (Figure 1). Dedicated TRPM8 fibers are located in the afferent nerves of the supraorbital nerve (green). When these signals reach the trigeminal nucleus in the brainstem, the cooling signal blocks and inhibits nociceptive signals transmitted via the afferent nerves of the ciliary nerve (red) [Figure 2].

[0052] The selection and synthesis method of cryosim used herein is described in Wei16 / 350 559, US2019 / 0105335, published on April 11, 2019. A preferred embodiment for carrying out the present invention is 1-[diisopropyl-phosphinoyl]-nonane (synonym: Cryosim-3, 1-diisopropyl-phosphorylnonane, CAS Registry No. 1503744-37-8-7). Cryosim-3 is a synthetic molecule available in over 97% purity from Phoenix Pharmaceuticals, Inc., Burlingame, Calif., USA.

[0053] In some embodiments, the DIPA compound is a pharmaceutically acceptable salt, polymer, ester, or acid thereof.

[0054] In some embodiments, the DIPA compound may be mixed with other components such as other activators, preservatives, buffers, diluents, salts, pharmaceutically acceptable carriers, or other pharmaceutically acceptable ingredients.

[0055] As used herein, “diluent” refers to a component in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the volume of a potent drug that is too small in mass for manufacture and / or administration. It may also be a liquid for dissolving a drug administered by injection, ingestion, or inhalation. Common forms of diluents in the art, though not limited to these, are buffered aqueous solutions, such as phosphate-buffered saline, which mimics the composition of human blood.

[0056] As used herein, “carrier” refers to a compound that facilitates the uptake of a compound into a cell or tissue. For example, but not limited to, dimethyl sulfoxide (DMSO), ethanol (EtOH), or PEG400 are commonly used carriers that facilitate the uptake of many organic compounds into the target cell or tissue.

[0057] As used herein, the terms “individual,” “patient,” and “subject” are interchangeable. None of these terms require, or are not limited to, a situation characterized by the supervision (e.g., constant or intermittent) of a healthcare professional (e.g., a physician, registered nurse, nurse, physician’s assistant, hospital errand boy, or hospice worker).

[0058] As used herein, “therapeutic effective dose” refers to a sufficient amount of DIPA compound in a reasonable benefit / risk ratio applied to treat neuropathic ophthalmic pain disorder in a subject requiring treatment for the neuropathic ophthalmic pain disorder. However, it is understood that the total daily dose of DIPA compound may be determined by the attending physician or personal supervisor within the bounds of sound medical judgment. The specific effective dose level for any particular subject depends on a variety of factors, including other disorders being treated and their severity, the specific composition used, the subject’s age, weight, general health status, sex and diet, the timing, route of administration, and excretion rate and duration of administration of the DIPA compound used, any drugs used concomitantly or concurrently with the DIPA compound, and factors as well as factors well known in medical technology or sports science. Furthermore, “therapeutic effective dose” is the amount that elicits the biological or medical response in a tissue, system, or subject that the researcher or clinician is seeking.

[0059] Those skilled in the art will recognize that even if the condition is not completely eradicated or prevented, a quantity may be considered “effective” if it or its symptoms and / or effects are partially improved or mitigated in the subject. Various indicators for determining the effectiveness of a method are known to those skilled in the art for treating neurogenic ophthalmopathy disorders in subjects requiring treatment of neurogenic ophthalmopathy disorders.

[0060] As used herein, “focused delivery” means “site-specific delivery” of a small amount of liquid to a designated anatomical site. The active ingredient is expected to remain at or near the administration site. For example, wiping a cotton wipe containing 2 mg / mL of C3 results in an offload of approximately 20–40 microliters to the eyelid margin. This amount reaches the TRPM8 receptors in the transitional epithelium of the eyelid via the eyelashes. Blinking can further distribute C3 to the cornea using the “wiper” action of the eyelid. Overall, this small delivery is concentrated only on the ocular surface.

[0061] In some embodiments, the DIPA compound is dissolved in a liquid vehicle at a concentration of 0.5 to 5 mg / ml therein, and the liquid vehicle delivers the DIPA compound to the ocular surface.

[0062] In some embodiments, the liquid vehicle is an aqueous solution.

[0063] In some embodiments, the liquid vehicle is water or isotonic saline solution.

[0064] In some embodiments, the DIPA compound is dissolved in a liquid vehicle at a concentration of 0.5 to 5 mg / ml.

[0065] The dosage may range broadly depending on the desired effect and therapeutic indication. The dosage may be one or more consecutive doses administered over one or more days, as required by the subject. In some embodiments, the compound is administered over a continuous treatment period of, for example, one week or more, or several months or years. In some embodiments, the DIPA compound or a pharmaceutically acceptable salt thereof may be administered less frequently than the administration frequency of the drug in standard treatment. In some embodiments, the DIPA compound or a pharmaceutically acceptable salt thereof may be administered once daily. In some embodiments, the total duration of the treatment regimen with the DIPA compound or a pharmaceutically acceptable salt thereof may be shorter than the total duration of the treatment regimen with standard treatment.

[0066] As those skilled in the art will understand, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts exceeding, or far exceeding, the preferred dosage range described above, in order to effectively and aggressively treat particularly aggressive diseases or infections.

[0067] It should be noted that the attending physician is familiar with the methods and timing for discontinuing, interrupting, or adjusting administration due to toxicity or organ dysfunction. Conversely, the attending physician is also familiar with adjusting treatment to a higher level if the clinical response is insufficient (excluding toxicity). The amount of dosage administered in the management of the target disease varies depending on the severity of the condition being treated and the route of administration. The severity of the condition can be partially assessed, for example, by standard prognostic assessment methods. Furthermore, the dosage and possibly the frequency of administration also vary depending on the age, weight, and response of the individual patient.

[0068] Peripheral sensory nerves on the ocular surface are defined as the epithelium of the cornea, margin, conjunctiva, and eyelid margin, and originate from the ophthalmic branch of the trigeminal nerve. The eyelids and cornea have a high density of nerve endings, estimated to have about 7,000 nerve endings per square millimeter. This density is about 300 to 600 times that of the skin. These nerve endings are initially myelinated, but lose myelin as they penetrate the corneal epithelium. The nerve plexus contains about 80% unmyelinated C fibers and about 20% myelinated nerve fibers (A-δ fibers). Polymodal nociceptors, 70% of which are unmyelinated C fibers, respond to a wide variety of stimuli, including thermal, mechanical, endogenous, and exogenous inflammatory stimuli. In contrast, myelinated A-δ fibers transmit harmless cooling, particularly on the eyelid surface at the base of the eyelash follicles.

[0069] The complexity and intricate nature of corneal nerve endings are described in a recent paper by Schecterson et al. (Molecular Vision 26:576-587, 2020). Nociceptive fibers are associated with TRP channels called TRPV1 and TRPA1. Another fiber system, TRPM8, is also present. TRPM8 is a membrane-intrinsic protein that is a sensor of cold. Activation of TRPM8 in the skin and respiratory tract transmits site-specific cold signals to the brain. The exact physiological role of TRPM8 in corneal nerve fibers is still unknown.

[0070] In previous research, the inventors of this application found that the application of a designed selective TRPM8 agonist called Cryosim-3 (1-diisopropyl-phosphinoylnonane) alleviates ocular discomfort in patients with mild to moderate dry eye disease (Yang, JM; et al., BMC Ophthalmol 2017, 17, 101). This is an acute, direct antinociceptive effect mediated by sensory nerves, similar to how cold (e.g., from a cold towel) reduces discomfort. Surprisingly, the inventors of this application have found that Cryosim-3 is also effective in NOP patients. It is important to clarify that the antinociceptive effect of a drug does not predict or correlate with its antineuropathy effect. For example, opioids (e.g., morphine) and nonsteroidal anti-inflammatory drugs (NSAIDS, e.g., ibuprofen) have antinociceptive effects, but neither is effective for neuropathic pain, which is a chronic condition lasting more than three months. In conditions such as diabetic ulcers, coolness or cold can exacerbate neuropathic pain. Therefore, the efficacy of Cryosim-3 in NOP was unusual.

[0071] Furthermore, Cryosim-3 appeared to have a disease-modifying effect in treating NOP patients. The quality of life of NOP patients improved significantly, and this effect persisted even after discontinuing Cryosim-3 use. This, too, was unexpected.

[0072] Successful treatment of NOP requires attenuating the sensitization process, i.e., suppressing the amplification of unpleasant signals. Peripheral and central sensitization can be distinguished by the use of local anesthetic eye drops, such as propalacaine hydrochloride solution (Alcaine®). While symptoms are temporarily blocked (less than 30 minutes) by Alcaine in some patients, NOP is known to be primarily caused by central sensitization. That is, NOP patients experience persistent discomfort on the ocular surface and, over time, particularly in the evening, become fixated on and mentally amplify the unpleasant signals. This mental fixation on ocular discomfort, a sign of central sensitization, exacerbates NOP.

[0073] The inventors of this invention discovered that to treat NOP, it is important to apply Cryosim-3 four times a day (qid) for at least one week while wiping the eyes. Further improvement was observed when the treatment was extended to one month. Such regular application and patient education regarding its effects were key to achieving clinical improvement.

[0074] In summary, a novel and effective treatment for NOP has been elucidated based on the regular application of Cryosim-3 to the ocular surface for at least one week. Details of this discovery are provided in Example 1.

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated in their entirety by reference unless otherwise stated. If a term has multiple definitions, the definition in this section shall prevail unless otherwise specified.

[0076] The terms used herein are intended solely to illustrate specific cases and are not intended to be limiting. As used herein, the singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. Furthermore, to the extent that "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or the claims, such terms are intended to be comprehensive in the same manner as the term "comprising."

[0077] "Subject" refers to the animal being treated, observed, or experimented on. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, mollusks, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, monkeys, chimpanzees, and primates such as apes, and humans. In some embodiments, the subject is human.

[0078] The terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily imply the complete cure or elimination of a disease or condition. Any relief of undesirable signs or symptoms of a disease or condition, to any degree, may be considered a treatment and / or therapy.

[0079] Allodynia: Pain caused by stimuli that would not normally cause pain.

[0080] Analgesia: The absence of pain in response to stimuli that would normally cause pain.

[0081] Sensory abnormalities: Unpleasant or abnormal sensations, whether spontaneous or induced.

[0082] Hyperalgesia: Increased pain response to stimuli that normally cause pain.

[0083] Neuropathic pain: Pain caused by lesions or diseases of the somatosensory nervous system.

[0084] Nociception: A neural process that codes for harmful stimuli.

[0085] Nociceptors: High-threshold sensory receptors in the peripheral somatosensory nervous system that can transmit and encode harmful stimuli.

[0086] Nociceptive neurons: Central or peripheral neurons of the somatosensory nervous system that can encode harmful stimuli.

[0087] Nociceptive pain: Pain resulting from actual or potential damage to non-nerve tissue, caused by the activation of nociceptors.

[0088] Nociceptive stimuli: Events that are converted and encoded by nociceptors and cause actual or potential tissue damage.

[0089] Nociceptors: High-threshold sensory receptors in the peripheral somatosensory nervous system that can transmit and encode harmful stimuli.

[0090] Harmful irritation: An irritant that causes or may cause damage to normal tissue.

[0091] Pain threshold: The minimum intensity of a stimulus that is perceived as painful.

[0092] Sensitization: Increased responsiveness of nociceptive neurons to their normal input, and / or supplementation of their response to normal subthreshold input.

[0093] Central sensitization: Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.

[0094] Peripheral sensitization: Increased responsiveness and decreased threshold of peripheral nociceptive neurons to stimulation of their receptive fields.

[0095] Example 1 This example is a pilot study of a topical TRPM8 agonist (cryosim-3) for reducing neuropathic eye pain in human subjects.

[0096] Abstract: Activation of TRPM8, a cold receptor present in the cornea and eyelids, may alleviate neurogenic eye pain (NOP) in dry eye (DE) by suppressing other abnormal nociceptive inputs. The effect of the topical TRPM8 agonist, cryosim-3 (C3), on reducing DE-related NOP was investigated. Methods: A promising pilot study was conducted with 15 patients with DE-related NOP. These patients applied topical C3 to their eyelids four times daily for one month. Patients underwent clinical examinations. They also completed the Opti-Ophthalmic Pain Assessment Survey (OPAS), a validated questionnaire regarding NOP, at baseline, one week after treatment, and one month after treatment. Results: After one week, OPAS scores for eye pain intensity, quality of life (driving / watching TV, general activities, sleep, and enjoying life / relationships), and related factors (burning sensation, photosensitivity, and tearing) showed significant improvement. The total OPAS score for eye pain intensity, quality of life, and related factors remained improved after one month. The Schirmer test score also improved after one month. Conclusion: TRPM8 agonists (C3) may be a novel treatment for DE-associated NOP patients who do not respond to conventional treatments.

[0097] Dry eye (DE) is a multifactorial disorder of the ocular surface characterized by loss of tear film homeostasis and associated ocular symptoms [1]. The prevalence is 10% to 70% [1]. Some DE patients experience severe pain that reduces their quality of life (QoL), even if their visible symptoms are minimal [1]. Topical medications can be applied as part of DE treatment to reduce inflammation and tear film osmotic pressure [2]. Generally, if eye pain does not resolve with topical treatment, other specific causes should be suspected, in particular neuropathic pain may be the underlying cause [3,4]. In DE, if eye pain disproportionately outweighs the clinical symptoms, it suggests an underlying neuropathic ophthalmopathy (NOP) nature [4].

[0098] Transient receptor potential (TRP) cation channels are associated with the perception of chemical and thermal stimuli [5]. Among the TRP family, TRPM8 is a cold receptor located at the nerve terminal of the ophthalmic branch of the trigeminal nerve [6]. Because activation of TRPM8 can suppress other abnormal nociceptive inputs, agents targeting this channel may have the potential to alleviate NOP in DE [7,8]. In particular, TRPM8 is distributed not only in the cornea but also in the eyelids, and therefore can be activated using topical agents applied to the eyelids rather than directly instilled in the cornea [6,9,10]. In our previous study, we showed that topical cryosim-3 (C3), a water-soluble selective TRPM8 agonist, is effective in treating DE by increasing basal tear secretion and reducing ocular discomfort without causing complications [9]. In this pilot study, we aimed to investigate the effect of a topical TRPM8 agonist (C3) on reducing NOP in DE patients.

[0099] method This promising non-randomized pilot study was conducted in accordance with the tenets of the Declaration of Helsinki. Ethical approval was obtained from the Chonnam National University Hospital Institutional Review Board (CNUH-2018-274). Informed consent was obtained from all participating patients. The sample size was calculated using G*Power software (version 3.1.9.4; Heinrich-Heine University, Germany) with a level of α=0.05 and a power of 95% to detect a 2-point difference on the pain scale. Therefore, a sample size of 13 patients was found to be sufficient.

[0100] Patients with deoxyribolytic ocular palsy (DE) presenting with NOP features who were evaluated between January and December 2018 were enrolled. DE was diagnosed based on an OSDI score ≥ 13 and a tear film disintegration time (TBUT) ≤ 7 seconds. Inclusion criteria were as follows: (1) chronic ocular pain unresponsive for more than 3 months to conventional topical medications (e.g., lubricants, anti-inflammatory drugs, secretory stimulants, etc.), (2) discrepancies in pain symptoms and signs of DE with specific descriptors such as burning or stinging, and (3) a Wong-Baker Faces Pain Rating Scale (WBFPS) score ≥ 4. Patients with a history of ocular diseases other than DE, and patients receiving systemic medications that alter pain and mood status, were excluded.

[0101] The patient was treated with conventional topical therapy, supplemented with C3. A C3 sample (2 mg / mL) was diluted with purified water, soaked in gauze, and packaged using an automated system. For one month, the patient applied topical C3 to the edge of their closed eyelids four times a day by wiping the gauze (Figure 1).

[0102] Visual-related QoL was quantified using the OSDI questionnaire, which ranges from 0 to 100. TBUT (tear film disintegration time) was measured three times, from the time interval between the last complete blink to the first appearance of tear film disintegration, and the average value was used for analysis. Corneal staining scores were assessed using an area density index, which is the product of the area and density scores. The Schirmer test score represented the length of wetness and was measured for 5 minutes under local anesthesia (0.5% proparacaine) using a calibrated sterile strip placed at the lateral canthus. Only the right eye score was evaluated.

[0103] The WBFPS was selected to screen the severity of pain in DE patients. Patients selected the face that best represented the pain they were experiencing. At baseline, one week after treatment, and one month after treatment, patients also completed the OPAS. The OPAS is a valid questionnaire for neuropathic pain, as previously mentioned

[11] . The questions were divided into sections for analysis: questions 4-9 concerned the intensity of eye pain (0-60); questions 10-11 concerned pain outside the eye (0-20); questions 13-19 (0-10, total score 0-60) assessed QoL (reading and / or computer use, driving and / or watching television, general activities, mood, sleep, and enjoying life / relationships with others); questions 20-21 (each score 0-1, total score 0-2) assessed aggravating factors (mechanical and chemical irritation); and questions 22-25 (each score 0-1, total score 0-4) assessed related factors (redness; heat; photosensitivity; and tearing). The section concerning symptom relief of OPAS was excluded, and only questions 4-25 were analyzed. The questions were divided into the following five sections: eye pain intensity, pain outside the eye, QoL, aggravating factors, and related factors.

[0104] Statistical analysis was performed using PASW Statistics for Windows, Version 18.0 (SPSS Inc., Chicago, IL, USA). Normality of the distribution was assessed using the Shapiro-Wilk test. Repeated measures ANOVA with Wilcoxon's signed-rank test and Bonferroni's post-hoc test was used to compare parameters before and after treatment. P<0.05 was considered statistically significant.

[0105] result This study enrolled 20 DE patients with NOP characteristics. Five patients (25.0%) discontinued treatment due to drug ineffectiveness or intolerance. The remaining 15 patients (75.0%) were included in the analysis. The mean age was 59.5 ± 13.0 years, and nine patients (60.0%) were female. Five patients had a history of intraocular surgery, and one patient had a history of ocular trauma.

[0106] One week after treatment, eye pain intensity, quality of life (QoL) (driving / watching television, general activities, sleep, and enjoying life / relationships), and related factors (burning, photosensitivity, and tearing) improved. Total Optooth Pain Assessment Survey (OPAS) scores for eye pain intensity, QoL (sleep), and related factors (burning and photosensitivity) remained improved after one month. However, scores for non-ocular pain and aggravating factors did not change after treatment (Table 1). Among clinical DE parameters, OSDI and Schirmer test scores improved one month after treatment (Table 2). There were no significant differences in pain scores based on previously used medications (Table 3). [Table 1-1] [Table 1-2] [Table 2] [Table 3] HA, hyaluronic acid; CsA, cyclosporine A.

[0107] DE is a multifactorial disorder of the ocular surface accompanied by ocular symptoms [1]. The prevalence of DE has increased considerably worldwide over the past 30 years [1]. Some DE patients experience ocular pain that affects their quality of life without any particularly unusual ocular symptoms [1]. The classification of pain is based on the underlying etiology: (1) nociceptive pain due to actual or feared tissue damage by activation of nociceptors, and (2) neuropathic pain due to lesions or diseases of the somatosensory nervous system

[12] . Peripheral sensitization occurs with repeated peripheral nerve damage, and central sensitization begins with prolonged peripheral ectopic pain [4]. If the symptoms of ocular pain are disproportionate to the clinical symptoms, it may suggest an underlying NOP that may require special management, including systemic treatment [4].

[0108] However, chronic NOP associated with DE is a clinical problem that is difficult to treat with conventional medications [4,13]. Conventional topical agents such as cyclosporine A reduce the release of inflammatory neuropeptides and cytokines from injured nerves, thereby affecting nociceptive pain and peripheral sensitization

[13] . However, these topical treatments appeared to have limitations in bringing about improvement in the morphological state of corneal nerves and central sensitization in patients with chronic NOP. Current systemic medications mainly include oral antidepressants, anticonvulsants, or gabapentinoids. However, these systemic treatments have several limitations, including delayed onset, variability in efficacy, and unacceptable side effects [4,13,14]. Furthermore, there is limited data available to support the use of systemic neuropathic pain medications for NOP associated with DE [14-16]. In this regard, there is a need for a fast-acting, effective, and safe topical agent for the treatment of NOP in DE.

[0109] Several members of the TRP superfamily have emerged as important targets for pain control, particularly due to their crucial role in nociception in chronic conditions [5]. TRP receptors have been identified in the cornea (TRPV1-4, TRPA1, TRPC4, and TRPM8), conjunctiva (TRPV1, TRPV2, and TRPV4), and eyelid (TRPM8) [6]. Furthermore, numerous studies have reported associations between TRP channel dysfunction and DE [3,6,17]. TRPM8 is a major receptor associated with the perception of coolness and regulates lacrimal gland function through responses to evaporative cooling and hyperosmolar stimulation [10,18-20]. Several studies have shown that cooling the area around the eye with an ice pack or instilling cold artificial tears may alleviate postoperative eye pain [21,22]. Both TRPM8 agonists and antagonists are considered therapeutic agents for pain control [5-7,23]. TRPM8 antagonists have been shown to improve acute and chronic pain, such as cold aches [23,24]. However, TRPM8 antagonists may reduce basal tear secretion as an undesirable side effect in DE, as shown in experimental results using TRPM8 knockout mice

[20] . TRPM8 agonists may exhibit anti-allodynic activity by overactivating TRPM8 and causing its downregulation

[25] . This type of animal experiment and hypothesis regarding the mechanisms of action of TRPM8 agonists or antagonists [23,24] at the molecular level can lead to a quagmire of confused thinking. The best answers for treating NOP will be found on the basis of empirical merit from clinical trials.

[0110] This pilot study demonstrated that topical application of a TRPM8 agonist (C3) to the eyelids is safe and effective in alleviating NOP in patients with dermal edema (DE). We previously showed that topical application of C3 stimulates basal tear secretion and alleviates ocular discomfort in patients with mild DE [9]. Sensory fibers of TRPM8 innervating the upper eyelid and cornea are located in the ocular branch of the trigeminal nerve [6]. In this study, we hypothesized that TRPM8 signaling across the eyelid margin may be perceived in the brain as a signal from the entire ocular surface, not just the cornea [9]. When TRPM8 is activated, glutamate is released from central synapses, and nociceptive afferent neurotransmission activated by injury is suppressed via inhibitory receptors at nerve terminals (Figure 2) [8]. Furthermore, it is hypothesized that these effects reduce neurogenic sensitization of the posterior horn [8]. In addition, OSDI and Schirmer test scores improved, but TBUT and corneal staining scores remained unchanged after C3 administration. TRPM8 agonists are known to increase basal tear secretion and reduce ocular discomfort via neuronal action, but do not directly act on the tear film.[6,9] These results were consistent with our previous research.[9]

[0111] Local administration of C3 to the eyelid margin minimizes corneal exposure that could cause side effects such as discomfort or paradoxical eye pain [9]. Furthermore, wiping off C3 was more comfortable for patients than the introduction of conventional eye drops, and a painless cooling sensation was observed after about 40 minutes [9]. OPAS scores also decreased within one week after treatment, indicating that the topical drug was more effective than systemic drugs

[14] . In addition, although the effect was temporary, C3 was particularly effective when patients experienced severe pain due to DE, such as while driving or sleeping, which led to an improvement in quality of life.

[0112] Furthermore, although the patients in this example did not respond to conventional treatment for a long period (122.7 days), they showed improvement in eye pain within one week after C3 treatment. This improvement suggests a direct effect of C3 treatment, rather than a delayed effect of previous conventional treatment. Therefore, TRPM8 agonists (C3) may be novel agents for treating NOP in DE patients who do not respond to conventional topical treatments. References 1. Craig, JP; Nichols, KK; Akpek, EK; Caffery, B.; Dua, HS; Joo, C.-K.; Liu, Z.; Nelson, JD; Nichols, JJ; Tsubota, K.; et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017, 15, 276-283, doi:10.1016 / j.jtos.2017.05.008. 2. Jones, L.; Downie, LE; Korb, D.; Benitez-Del-Castillo, JM; Dana, R.; Deng, SX; Dong, PN; Geerling, G.; Hida, RY; Liu, Y.; et al. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017, 15, 575-628, doi:10.1016 / j.jtos.2017.05.006. 3. Belmonte, C.; Nichols, JJ; Cox, SM; Brock, JA; Begley, CG; Bereiter, DA; Dartt, DA; Galor, A.; Hamrah, P.; Ivanusic, JJ; et al. TFOS DEWS II Pain and Sensation Report. The Ocular Surface 2017, 15, 404-437, doi:10.1016 / j.jtos.2017.05.002. 4. Galor, A.; Moein, H.-R.; Lee, C.; Rodriguez, A.; Felix, E.R.; Sarantopoulos, K.D.; Levitt, R.C. Neuropathic Pain and Dry Eye. The Ocular Surface 2018, 16, 31-44, doi:10.1016 / j.jtos.2017.10.001. 5. Brederson, J.-D.; Kym, P.R.; Szallasi, A. Targeting TRP Channels for Pain Relief. European Journal of Pharmacology 2013, 716, 61-76, doi:10.1016 / j.ejphar.2013.03.003. 6. Yang, J.; Wei, E.; Kim, S.; Yoon, K. TRPM8 Channels and Dry Eye. Pharmaceuticals 2018, 11, 125, doi:10.3390 / ph11040125. 7. Fernandez-Pena, C.; Viana, F. Targeting TRPM8 for Pain Relief. TOPAINJ 2013, 6, 154-164, doi:10.2174 / 1876386301306010154. 8. Proudfoot, C.J.; Garry, E.M.; Cottrell, D.F.; Rosie, R.; Anderson, H.; Robertson, D.C.; Fleetwood-Walker, S.M.; Mitchell, R. Analgesia Mediated by the TRPM8 Cold Receptor in Chronic Neuropathic Pain. Current Biology 2006, 16, 1591-1605, doi:10.1016 / j.cub.2006.07.061. 9. Yang, J.M.; Li, F.; Liu, Q.; Ruedi, M.; Wei, E.T.; Lentsman, M.; Lee, H.S.; Choi, W.; Kim, S.J.; Yoon, K.C. A Novel TRPM8 Agonist Relieves Dry Eye Discomfort. BMC Ophthalmol 2017, 17, 101, doi:10.1186 / s12886-017-0495-2. 10. Wei, E.T. Improving Brain Power by Applying a Cool TRPM8 Receptor Agonist to the Eyelid Margin. Med Hypotheses 2020, 142, 109747, doi:10.1016 / j.mehy.2020.109747. 11. Qazi, Y.; Hurwitz, S.; Khan, S.; Jurkunas, U.V.; Dana, R.; Hamrah, P. Validity and Reliability of a Novel Ocular Pain Assessment Survey in Quantification and Monitoring of Corneal and Ocular Surface Pain. Ophthalmology 2016, 123, 1458-1468, doi:10.1016 / j.ophtha.2016.03.006. 12. Loeser, J.D.; Treede, R.-D. The Kyoto Protocol of IASP Basic Pain Terminology. Pain 2008, 137, 473-477, doi:10.1016 / j.pain.2008.04.025. 13. Dieckmann, G.; Goyal, S.; Hamrah, P. Neuropathic Corneal Pain. Ophthalmology 2017, 124, S34-S47, doi:10.1016 / j.ophtha.2017.08.004. 14. Yoon, H.-J.; Kim, J.; Yoon, K.C. Treatment Response to Gabapentin in Neuropathic Ocular Pain Associated with Dry Eye. JCM 2020, 9, 3765, doi:10.3390 / jcm9113765. 15. Ongun, N.; Ongun, G.T. Is Gabapentin Effective in Dry Eye Disease and Neuropathic Ocular Pain? Acta Neurol Belg 2019, doi:10.1007 / s13760-019-01156-w. 16. Galor, A.; Patel, S.; Small, L.R.; Rodriguez, A.; Venincasa, M.J.; Valido, S.E.; Feuer, W.; Levitt, R.C.; Sarantopoulos, C.D.; Felix, E.R. Pregabalin Failed to Prevent Dry Eye Symptoms after Laser-Assisted in Situ Keratomileusis(LASIK) in a Randomized Pilot Study. J Clin Med 2019, 8, doi:10.3390 / jcm8091355. 17. Arcas, J.M.; Gonzalez, A.; Gers-Barlag, K.; Gonzalez-Gonzalez, O.; Bech, F.; Demirkhanyan, L.; Zakharian, E.; Belmonte, C.; Gomis, A.; Viana, F. The Immunosuppressant Macrolide Tacrolimus Activates Cold-Sensing TRPM8 Channels. J Neurosci 2019, 39, 949-969, doi:10.1523 / JNEUROSCI.1726-18.2018. 18. Knowlton, W.M.; Palkar, R.; Lippoldt, E.K.; McCoy, D.D.; Baluch, F.; Chen, J.; McKemy, D.D. A Sensory-Labeled Line for Cold: TRPM8-Expressing Sensory Neurons Define the Cellular Basis for Cold, Cold Pain, and Cooling-Mediated Analgesia. J Neurosci 2013, 33, 2837-2848, doi:10.1523 / JNEUROSCI.1943-12.2013. 19. Quallo, T.; Vastani, N.; Horridge, E.; Gentry, C.; Parra, A.; Moss, S.; Viana, F.; Belmonte, C.; Andersson, D.A.; Bevan, S. TRPM8 Is a Neuronal Osmosensor That Regulates Eye Blinking in Mice. Nat Commun 2015, 6, 7150, doi:10.1038 / ncomms8150. 20. Parra, A.; Madrid, R.; Echevarria, D.; del Olmo, S.; Morenilla-Palao, C.; Acosta, M.C.; Gallar, J.; Dhaka, A.; Viana, F.; Belmonte, C. Ocular Surface Wetness Is Regulated by TRPM8-Dependent Cold Thermoreceptors of the Cornea. Nat Med 2010, 16, 1396-1399, doi:10.1038 / nm.2264. 21. Fujishima, H.; Yagi, Y.; Toda, I.; Shimazaki, J.; Tsubota, K. Increased Comfort and Decreased Inflammation of the Eye by Cooling after Cataract Surgery. Am J Ophthalmol 1995, 119, 301-306, doi:10.1016 / s0002-9394(14)71171-7. 22. Fujishima, H.; Yagi, Y.; Shimazaki, J.; Tsubota, K. Effects of Artificial Tear Temperature on Corneal Sensation and Subjective Comfort. Cornea 1997, 16, 630-634. 23. De Caro, C.; Russo, R.; Avagliano, C.; Cristiano, C.; Calignano, A.; Aramini, A.; Bianchini, G.; Allegretti, M.; Brandolini, L. Antinociceptive Effect of Two Novel Transient Receptor Potential Melastatin 8 Antagonists in Acute and Chronic Pain Models in Rat. Br J Pharmacol 2018, 175, 1691-1706, doi:10.1111 / bph.14177. 24. Fakih, D.; Baudouin, C.; Reaux-Le Goazigo, A.; Melik Parsadaniantz, S. TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease. International Journal of Molecular Sciences 2020, 21, 8756, doi:10.3390 / ijms21228756. 25. 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Claims

1. A pharmaceutical composition for use in the treatment of neurogenic ophthalmic pain disorder in subjects requiring treatment of neurogenic ophthalmic pain disorder, comprising a therapeutically effective amount of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound, wherein the DIPA compound is applied topically to the ocular surface of the subject for at least one week, the DIPA compound is dissolved in a liquid vehicle, the liquid vehicle is adapted to concentrate the delivery of the DIPA compound to the ocular surface, and the DIPA compound is 【Chemistry 1】 A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the DIPA compound is dissolved in the liquid vehicle at a concentration of 0.5 to 5 mg / ml, and the liquid vehicle delivers the DIPA compound to the ocular surface.

3. The pharmaceutical composition according to claim 1 or 2, wherein the liquid vehicle is an aqueous solution.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the liquid vehicle is water or isotonic saline solution.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DIPA compound is dissolved in the liquid vehicle at a concentration of 0.5 to 5 mg / ml.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the DIPA compound dissolved in the liquid vehicle is delivered to the eye surface of the target by wiping.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the DIPA dissolved in the liquid vehicle is applied to the target ocular surface four times a day.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the neurogenic eye pain disorder is caused by a dry eye disease or eye surgery.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the neurogenic ophthalmic pain disorder is caused by an eye injury.

10. A topical agent for treating neurogenic ophthalmic pain disorder in a patient requiring treatment for neurogenic ophthalmic pain disorder, comprising an aqueous solution containing a therapeutically effective amount of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound, wherein the DIPA compound is 【Chemistry 2】 It is a topical medication.

11. The topical agent according to claim 10, wherein the concentration of the DIPA compound in the aqueous solution is 0.5 to 5 mg / mL.

12. The topical agent according to any one of claims 10 to 11, wherein the neurogenic eye pain disorder is caused by a dry eye disease or eye surgery.

13. The topical agent according to any one of claims 10 to 11, wherein the neurogenic ophthalmic pain disorder is caused by eye surgery.

14. The topical agent according to any one of claims 10 to 11, wherein the neurogenic eye pain disorder is caused by psychological trauma.

15. The use of a 1-di-isopropyl-phosphinoyl-alkane (DIPA) compound for manufacturing a pharmaceutical for treating neurogenic ophthalmic pain disorder in a subject requiring treatment for neurogenic ophthalmic pain disorder, wherein the pharmaceutical comprises a therapeutically effective amount of the DIPA compound and a liquid vehicle, the liquid vehicle being adapted for concentrated delivery of the DIPA compound to the ocular surface of the subject, and the DIPA compound is 【Transformation 3】 It is used.

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