Method for alleviating symptoms of ocular surface discomfort using medical ice slurry

Abstract

Disclosed herein is a method for alleviating symptoms of ocular surface discomfort, the method comprising: topically applying a cold slurry adjacent to the limbus of a patient's eye, wherein the cold slurry comprises water and a freezing point depressant, the topical application of the cold slurry being configured to cause a degree of numbness of the cornea of ​​the eye for a period of time, and wherein ocular sensation in the eye is restored after the period of time.

Description

[Technical Field]

[0001] Technical Field The present invention relates generally to devices, systems and methods for producing and administering biomaterials such as cold slurries. More specifically, the present invention relates to systems and methods for administering cold slurries to a subject to treat ocular surface discomfort by causing ocular hypoesthesia in a safe and effective manner. [Background technology]

[0002] background The cornea of ​​the eye is a transparent, avascular tissue measuring approximately 11–12 mm horizontally and 9–11 mm vertically. Sridhar, MS, Anatomy of cornea and ocular surface. Indian Journal of Ophthalmology, 66(2), 190–194 (February 2018). It is the outermost surface of the eye and lies in front of the pupil and iris to refract entering light.

[0003] Innervation of the cornea begins in the brainstem, where a large sensory root branches from the pons and attaches to the trigeminal nucleus caudalis, located in the lateral part of the medulla. From there, the trigeminal nerve divides into three divisions, one of which is the ophthalmic division. This root further divides into three branches, one of which is the elongated pair called the nasociliary nerve. This purely sensory nerve travels along the upper part of the orbital cavity and contributes smaller branches to the cornea. Two divisions from this nerve are called the short ciliary nerve and the long ciliary nerve. The short ciliary nerve passes through a sensory root to the ciliary ganglion, then exits the nucleus, penetrates the sclera, and enters the extrachoroidal space, where it can travel to the cornea. Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc.

[0004] The extrachoroidal space is located between the sclera, the outermost layer of the eyeball, and the choroid, a highly vascularized layer responsible for providing nutrients to the ocular structures. Approximately 8–10 short ciliary nerves pierce the sclera, but once inside the extrachoroidal space, these nerves branch into approximately 15–20 segments. The long ciliary nerves have over 50 branches that penetrate the sclera and divide again inside the extrachoroidal space. At the limbus, the junction between the sclera and cornea, the nerves lose their myelin sheaths and continue as free nerve endings. The nerves collect sensory signals from the cornea and send them back toward the brainstem. Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc. All details of corneal innervation are not entirely well understood and may vary somewhat from patient to patient. There may be some contribution from other nerve fibers or some normal anatomical variation in the pathway of innervation.

[0005] Free nerve endings are located under the corneal epithelium, the anterior layer that protects the corneal structure, and often contribute to painful eye sensations. When patients suffer from these symptoms, the condition is called dry eye syndrome (DES), also known as ocular surface disease (OSD). The causes of this condition are multifactorial. One important cause is the production of inadequate amounts of aqueous tears, which deprives the eye of hydration and lubrication. Other causes of ocular surface disease may include meibomian gland dysfunction or damage to the corneal epithelium.

[0006] These "dry eye-induced alterations to the properties of corneal afferent neurons and the central processing of corneal inputs may have significant consequences for both tear regulation and ocular pain." McMonnies, CW, The potential role of neuropathic mechanisms in dry eye syndromes, Journal of Optometry, 10, 5-13 (2017). Importantly, some patients continue to have ocular surface pain even after their ocular surface has returned to a clinically normal appearance. This situation presents a clinical challenge because the cause is thought to be somatosensory dysfunction of corneal innervation that persists long after the original insult that irritated the nerve.

[0007] Other causes of corneal discomfort may include postoperative pain after photorefractive keratomileusis, a procedure used to treat refractive errors that requires removal of the corneal epithelium before applying excimer laser ablation. Other surgical procedures, such as procedures that do not necessarily involve removal of the epithelium but in which the epithelium experiences mild to moderate drying during the procedure, can also cause corneal discomfort. Patients may also experience ocular discomfort after ocular trauma (e.g., corneal abrasion) and laser in situ keratomileusis (LASIK) surgery.

[0008] There are three different types of nociceptors that innervate the cornea. 20% of corneal nociceptors are Aδ mechanoreceptors, which are responsible for fast-conducting, sharp, painful stimuli caused by aggression against the ocular surface. 70% of corneal nociceptors are polymodal, which are stimulated by corneal nerve injury and cause neuropathic pain and "reflex tearing." Levitt, AE, et al., "Chronic dry eye symptoms after LASIK: parallels and lessons learned from other persistent post-operative pain disorders," Molecular Pain, 11:21 (2015). The remaining 10% of corneal nociceptors are C-fiber cold receptors, which play a critical role in maintaining basal tear secretion. These receptors are highly sensitive to temperature changes within the corneal tissue, and LASIK surgery can affect C-fiber signaling by causing tear evaporation at the tear film surface, decreasing temperature by approximately 0.3°C per second. (Levitt et al., 2015).

[0009] Many mechanisms, such as dryness, previous surgery, eyelid gland dysfunction, or previous chemical irritation, can cause the clinical symptoms of OSD, which are marked by signs of ocular irritation and symptoms characterized by dryness, burning, or discomfort. Even after the initial injury has resolved, i.e., normal ocular lubrication is restored, patients may still report significant symptoms of ocular surface discomfort, suggesting a component of hypersensitivity or allodynia, even though their ocular surface shows only minimal signs of disease. Indeed, a literature reference cautions that "ocular surface condition alone is not sufficient to understand ocular dryness; corneal somatosensory function must be considered when evaluating patients with dry eye." Spierer O, Felix ER, McClellan AL, et al. Corneal mechanical thresholds negatively associate with dry eye and ocular pain symptoms. Invest Ophthalmol Vis Sci. 57:617-625 (2016). This situation presents a challenge to the treating physician - patients have residual pain and discomfort with a normal-appearing ocular surface (corneal somatosensory dysfunction). Additional lubrication and other treatments targeted to improve the ocular surface are no longer of any help to these patients, as might be expected.

[0010] Current treatments for pain associated with dry eye syndrome / ocular surface disease, PRK or LASIK surgery, or corneal somatosensory dysfunction are either of limited temporary value or associated with negative side effects. Dry eye syndrome is most commonly treated with warm compresses, over-the-counter artificial tears, or prescription eye drops that target increased tear production or reduce inflammation. Physicians may also recommend topical eye lubricants, which are hygiene products that remove debris from just below the eyelid. These methods work by softening meibum, an oily, lipid-rich secretion from the meibomian glands, to help spread tear production across the cornea. A limitation of these treatments is their short-term relief and the need for continuous application. While lubricants or artificial tears may soothe irritation, they do not actually address the cause of eye dryness and may also contribute to increased debris collecting under the eyelid. Shen Lee, B., et al., Managing dry eye disease and facilitating realistic patient expectations: A review and appraisal of current therapies, Clinical Ophthalmology, 14 119-126 (January 2020).

[0011] Topical NSAIDs and soft bandage contact lenses are the most common treatments for postoperative pain management after photorefractive keratomileusis and LASIK eye surgery. NSAID medications prevent the production of prostaglandins, hormone-like substances associated with inflammation following corneal tissue injury. Pathak, A.K., & Karacal, H., (2019). Pain reduction after photoablation. EyeWiki by the American Academy of Ophthalmology. Topical NSAIDs carry the risk of corneal damage, such as erosion, defects, delayed corneal epithelial healing, or corneal melting (which can result in vision loss). Using soft bandage contact lenses, this method can stimulate epithelial cell regrowth and act as a delivery system for antibiotics or topical NSAIDs. However, bandage contact lenses can promote bacterial growth and are often ineffective at reducing pain. Shetty, R., et al., Pain management after photorefractive keratectomy, Journal of Cataract Refract Surgery, 45(7):972-976 (2019).

[0012] Acute ocular pain can also be treated with topical ophthalmic anesthetic drops, such as proparacaine hydrochloride and tetracaine hydrochloride. These aqueous solutions are given as short-term pain treatment, or to measure intraocular pressure, remove foreign bodies, relieve intracorneal sutures, or as preoperative anesthetics for eye surgery. Local anesthetics can block the corneal nerves from transmitting pain impulses for approximately 15 to 20 minutes per dose. While this short-term pain relief requires continuous application, chronic use can ultimately lead to corneal toxicity. Toxic effects on the cornea include damage to stromal keratocytes, cells that play a critical role in healing trauma to the cornea. If epithelial cells cannot migrate across the cornea, the epithelium eventually begins to slough, resulting in chronic failure of the corneal epithelium to heal.

[0013] However, maintaining some pain perception is important for the normal function of a healthy cornea. Neuropathic keratopathy, also known as neurotrophic keratitis, is a syndrome in which the ocular surface undergoes a progression from tear film abnormalities to epitheliopathy and ultimately to stromal lysis due to pathological deficits in corneal and conjunctival sensation. For true neuropathic keratopathy, the eye must have corneal and conjunctival sensory deficits due to pathological destruction of the trigeminal nerve, which can result from surgery intended to treat trigeminal neuralgia, acoustic neuroma surgery, or infections such as herpes zoster ophthalmicus or leprosy. Other forms of neuropathic keratopathy result from the misuse of local anesthesia. In a rabbit model, typical trophic changes in the corneal epithelium have been demonstrated after controlled thermal coagulation of the trigeminal ganglion in rabbits. This denervation was found to significantly affect the proliferative activity of the epithelium, resulting in a paucity of mitoses.

[0014] As explained above, the cornea is highly sensitive to pain or discomfort. There are many human clinical conditions that cause mild to severe corneal pain and discomfort, all of which could potentially be addressed by developing a safe and effective treatment for corneal pain. Current topical numbing drops only numb the cornea for a few minutes, and chronic use is associated with severe morbidity, such as corneal infection and melting. Furthermore, conventional approaches to treating ocular pain result in complete anesthesia of the eye, which can be very problematic in chronic settings due to the risk of developing neuropathic keratopathy. Furthermore, in chronically inflamed and painful eyes, corneal somatosensory dysfunction becomes a dominant feature of the pain syndrome. In summary, many patients experience debilitating ocular surface discomfort that may be associated with active corneal pathology or may persist long after the original injury without detectable progressive pathology. Clearly, there is a large unmet clinical need for the development of longer-acting, safer corneal anesthetic therapies that partially block corneal sensation and significantly reduce patient discomfort. Summary of the Invention

[0015] overview In one aspect, the present invention provides a method for alleviating symptoms of ocular surface discomfort, the method comprising: topically applying a cold slurry adjacent to the limbus of a patient's eye, the cold slurry comprising water and a freezing point Descent Topical application of the medicated, cold slurry is configured to cause a degree of numbness of the cornea of ​​the eye for a period of time, with ocular sensation in the eye being restored after a period of time.

[0016] In some embodiments, the cold slurry is applied posterior to the limbus.

[0017] In some embodiments, the period of time is greater than about 2 days without topically applying the cold slurry for an additional period on any day after the first day of topical application.

[0018] In some embodiments, the period of time is greater than about 7 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application.

[0019] In some embodiments, the freezing point Descent The drug is glycerol.

[0020] In some embodiments, ocular sensation in the eye is restored about 21 days after topical application of the cold slurry.

[0021] In some embodiments, the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C upon topical application of the cold slurry.

[0022] In some embodiments, the cold slurry is applied topically for about 5 minutes to about 15 minutes.

[0023] In some embodiments, an additional amount of cold slurry is topically applied again about every 90 seconds.

[0024] In some embodiments, the method further comprises placing a contact lens on the patient's eye prior to topically applying the cold slurry.

[0025] In some embodiments, the cold slurry is configured to be a paste consistency.

[0026] In another aspect, the present invention provides a method for alleviating symptoms of ocular surface discomfort, the method comprising: placing a protective covering over the cornea of ​​a patient's eye; and topically applying a cold slurry to the bulbar conjunctiva of the patient's eye, wherein the topical application of the cold slurry causes a prolonged reduction in pain in the patient's eye, and wherein partial sensation in the cornea of ​​the patient's eye is preserved during the prolonged reduction in pain.

[0027] In some embodiments, the cold slurry is applied posterior to the limbus.

[0028] In some embodiments, the cold slurry is applied onto a protective cover.

[0029] In some embodiments, the prolonged reduction in pain lasts for more than about 7 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application.

[0030] In some embodiments, the prolonged reduction in pain lasts for more than about 2 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application.

[0031] In some embodiments, the prolonged reduction in pain lasts for more than about 14 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application.

[0032] In some embodiments, the symptoms are due to dry eye syndrome or corneal somatosensory dysfunction.

[0033] In some embodiments, the sclera of the patient's eye is cooled to a temperature of about −6° C. to about 4° C. during topical application of the cold slurry.

[0034] In some embodiments, the protective covering is a contact lens, which protects the cornea of ​​the eye from freezing.

[0035] In another aspect, the present invention provides a method for alleviating symptoms of ocular surface discomfort, the method comprising: administering a cold slurry to the patient's eye, the cold slurry comprising water and a percentage of ice particles, wherein administration of the cold slurry causes prolonged ocular hypoesthesia, ocular sensation in the eye is restored after the prolonged ocular hypoesthesia, and wherein administration of the cold slurry does not cause permanent damage to the cornea of ​​the eye.

[0036] In some embodiments, the present invention further relates to the treatment of dry eye syndrome, chronic ocular pain, post-surgical pain, post-optical refractive surgery pain, post-LASIK pain, post-cataract surgery pain, and eyeball This includes treating a condition selected from the group consisting of pain after open globe injury recovery, pain after corneal injury, corneal somatosensory dysfunction, allodynia, and pain from acute injury.

[0037] In some embodiments, the cold slurry is administered via injection.

[0038] In some embodiments, the cold slurry is injected into the subconjunctival space.

[0039] In some embodiments, the cold slurry is administered via topical application.

[0040] In some embodiments, the percentage of ice particles is about 20% to 40%.

[0041] In some embodiments, the temperature of the cold slurry is from about -20°C to about -5°C.

[0042] In another aspect, the present invention provides a method for alleviating symptoms of ocular surface discomfort, the method comprising: topically applying a cold slurry to or proximal to the ocular surface of a patient's eye, wherein the topical application of the cold slurry causes prolonged corneal hypoesthesia of the eye, wherein ocular sensation in the eye is restored following the prolonged hypoesthesia, and wherein the topical application of the cold slurry does not cause permanent damage to the cornea of ​​the eye.

[0043] In some embodiments, the cold slurry is applied proximal to the limbus.

[0044] In some embodiments, the prolonged hypoesthesia lasts for more than about 1 day after a single treatment of topical application of the cold slurry.

[0045] In some embodiments, ocular sensation in the eye is restored by about 30 days after topical application of the cold slurry.

[0046] In some embodiments, the cold slurry is topically applied for about 5 minutes to about 15 minutes.

[0047] In some embodiments, the method further comprises placing a contact lens on the patient's eye prior to topically applying the cold slurry, wherein the contact lens prevents freezing of the cornea of ​​the eye. [Brief explanation of the drawings]

[0048] BRIEF DESCRIPTION OF THE DRAWINGS The following figures illustrate exemplary embodiments of the present invention. [Figure 1] FIG. 1 shows freezing point depression graphs for liquid water, a solution containing 10% glycerin volume / volume (v / v), and a solution containing 20% ​​glycerin (v / v). [Figure 2] FIG. 2 is a table showing the degradation by volume and weight of components of exemplary biomaterials that may form injectable cold slurries. [Figure 3]FIG. 3 is a graph showing the ice content characterization of cold slurries having crystallization set points of −5.5° C. and −8.1° C. [Figure 4A] FIG. 4 shows a diagram of the human eye showing different regions of the eye (4A) and powers relative to anatomical references (4B). [Figure 4B] FIG. 4 shows a diagram of the human eye showing different regions of the eye (4A) and powers relative to anatomical references (4B). [Figure 5] FIG. 5 is a graph showing real-time scleral temperature monitoring in rabbits following ocular administration of topically applied (solid line) and injected (dashed line) cold slurry. [Figure 6] FIG. 6 is a graph showing the loss of sensation in rabbit eyes over time following administration of injected cold slurry (diamonds), topically applied cold slurry (triangles), and topically applied slurry at room temperature (squares) to the exposed cornea of ​​the eye. [Figure 7] FIG. 7 is a graph showing hypoesthesia in rabbit eyes over time following administration of topically applied cold slurry to the eye without exposing the cornea. [Figure 8] FIG. 8 shows fluorescently stained images of rabbit corneas showing corneal healing over time after an intentional 8 mm corneal abrasion (8A) and topical application of cold slurry (8B) as a control group. [Figure 9] 9 is a graph showing the decrease in sensation in the eyes of six rabbits over time after a combination treatment in which cold slurry was first applied topically and then injected. In three rabbits (indicated by diamonds, squares, and triangles), the injected slurry did not contain liposomes, while in the other three rabbits (indicated by "X," stars, and circles), the injected slurry contained liposomes. DETAILED DESCRIPTION OF THE INVENTION

[0049] Detailed Description The present disclosure describes apparatus, devices, systems, and methods for treating ocular surface discomfort using a biological material, such as a cold slurry. In some embodiments, the biological material is a cold slurry (e.g., ice slurry) that can be delivered via topical application or injection to the eye of a human patient or subject (e.g., a non-patient human or non-human animal) for preventive or therapeutic purposes to reduce ocular discomfort. The systems and methods disclosed herein unexpectedly provide long-lasting ocular hypoesthesia. The hypoesthesia can cause long-lasting corneal numbness and subsequent recovery of ocular sensation within days or weeks after application of the cold slurry treatment, without causing permanent damage to the cornea or disrupting the progress of corneal healing.

[0050] In some embodiments, the cold slurry can be applied topically to achieve a desired therapeutic effect, such as amelioration or treatment of ocular surface discomfort through long-term corneal numbing. In some embodiments, the therapeutically effective cold slurry is composed entirely of water and excipient materials (i.e., materials without active pharmaceutical compounds). In other embodiments, the cold slurry further comprises a known active pharmaceutical compound. In some embodiments, a protective layer, such as a contact lens, is applied to the cornea prior to topical application of the slurry. In some embodiments, the eyelids are protected from topical application of the slurry by inserting a speculum of plastic or other thermally non-conductive material into the subject's eye.

[0051] In some embodiments, the length of time the slurry is applied to the subject's eye can be varied to induce greater or more gradual hypoesthesia. In some embodiments, the temperature of the slurry applied or injected into the subject's eye can be varied to induce greater or more gradual hypoesthesia. In some embodiments, hypoesthesia decreases over time to the point where it is no longer noticeable. In other embodiments, if the subject's eye may be particularly sensitive, greater hypoesthesia is induced to numb more of the nerves in the subject's eye.

[0052] In some embodiments, the container (e.g., vial, syringe) containing the biomaterial is received for clinical administration. The biomaterial may be received in a crystallized (or partially crystallized) state. In some embodiments, the final product, which is administered to a human patient or subject (e.g., a non-patient human or non-human animal) via topical application or injection, contains sterile ice particles of water and varying amounts of excipients or additives, such as freezing point Descent A cold slurry comprising a drug is used. For example, the percentage of ice particles in the cold slurry can comprise less than about 10% by weight of the slurry, about 10% to about 20% by weight, about 20% to about 30% by weight, about 30% to about 40% by weight, about 40% to about 60% by weight, or more than about 60% by weight. The size of the ice particles is controlled to allow flow through various sized containers (e.g., needle gauge sizes of about 7 to about 43), as described in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), incorporated herein by reference. Additionally, other methods can be used to adjust the size of the ice particles to allow flow through various sized containers. In some embodiments, the majority of the ice particles have a diameter less than about half the inner diameter of the lumen or container used for injection. For example, the ice particles can be about 1.5 mm or less in diameter for use with a 3 mm catheter.

[0053] There are a variety of techniques that can be used to prepare the cold slurry, and the present disclosure is not limited to any particular method or technique.

[0054] In some embodiments, one or more excipients may be included in the cold slurry. An excipient is any substance that is not itself a therapeutic agent but is used as a diluent, adjuvant, and / or vehicle for delivery of a therapeutic agent to a subject or patient, and / or added to a composition to improve its handling, stability, or storage characteristics. The excipient may constitute less than about 10% volume / volume (v / v) of the cold slurry, from about 10% v / v to about 20% v / v, from about 20% v / v to about 30% v / v, from about 30% v / v to 40% v / v, or more than about 40% v / v. Various added excipients may be used to alter the phase change temperature of the cold slurry (e.g., reduce the freezing point), alter the ice percentage of the cold slurry, alter the viscosity of the cold slurry, prevent agglomeration of ice particles, prevent dendritic ice formation (i.e., crystals with multiple branched "tree-like" morphologies such as those found in snowflakes), maintain separate ice particles, increase the thermal conductivity of the fluid phase, or improve the overall prophylactic, therapeutic, or anesthetic effect of the cold slurry.

[0055] More than one freezing point Descent Drugs can be added as excipients to form cold slurries with freezing points below 0°C. By lowering the freezing point of the slurry, the slurry can retain its flowability and remain injectable while still containing a significant proportion of ice particles. Descent The agent may include salts (e.g., sodium chloride, Betadex sulfobutylether sodium), ions, lactated Ringer's solution, sugars (e.g., glucose, sorbitol, mannitol, hetastarch, sucrose, (2-hydroxypropyl)-β-cyclodextrin, or combinations thereof), biocompatible surfactants such as glycerol (also known as glycerin or glycerine), other polyols (e.g., polyvinyl alcohol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol), other sugar alcohols, or urea. Other exemplary freezing points DescentThe agent is disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference in its entirety. In another embodiment, a slurry paste is formed having the consistency of toothpaste, a consistency optimal for topical application.

[0056] freezing point Descent The concentration of the drug determines the proportion of ice particles in the cold slurry and its flowability and injectability. The degree of freezing point depression is determined by the following formula, as described in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference: ΔT F = K F bi where ΔT F is the freezing point depression (T F (純粋溶媒) -T F (溶液) ), K F is the freezing point depression constant, b is the molality, and i is the van't Hoff coefficient, which represents the number of ionic particles per individual molecule of solute. Other methods of calculating freezing point depression may also be used, as disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011).

[0057] Referring to FIG. 1, a graph of freezing point depression is shown for pure water T1, a mixture of water and 10% (v / v) glycerin T2, and a mixture of water and 20% (v / v) glycerin T3. In this graph, all materials were placed in a freezer with a constant temperature of -20°C. Temperatures were measured using thermometers placed within each material. The graph shows that the water and glycerin mixture has a different freezing point than pure water, meaning that the solution can be cooled below 0°C and only partially crystallize. The graph shows that upon cooling, pure water T1 crystallizes at its equilibrium freezing point of 0°C. This is indicated by the time that pure water T1 remains at a temperature of approximately 0°C from about 1.3 hours to about 4.4 hours, starting shortly after it passes its supercooling point of approximately -6°C. Having an equilibrium window of crystallization (i.e., the "flat, straight line" portion of pure water T1 in FIG. 1) is typical for pure solvents. For 10% glycerin solution T2, upon cooling, the solution begins to crystallize at a first freezing point of about −3° C. after about 2.2 hours, and crystallization continues as the solution's temperature further decreases to about −8° C. after about 6 hours. Initial crystallization occurs shortly after 10% glycerin solution T2 passes the supercooling point of about −8° C. (which may vary from sample to sample, e.g., from about −15° C. to about −3° C.), indicated at about 2.2 hours. Having a descending temperature window of crystallization for 10% glycerin solution T2 is typical for solutions (i.e., impure mixtures). Similarly, for 20% glycerin solution T3, upon cooling, the solution begins to crystallize at a first freezing point of about −7° C. after about 3.5 hours (which may vary from sample to sample, e.g., after the first supercooling point of about −25° C. to about −5° C.), and crystallization continues as the solution's temperature further decreases to about −11° C. after about 6 hours and continues to decrease over the next 6.5 hours. The first crystallization occurs shortly after the 20% glycerin solution T3 passes the supercooling point of about −14° C., shown at about 3.5 hours. Similar to the trace for the 10% glycerin solution T2, the falling temperature window of crystallization for the 20% glycerin solution T3 is typical for the solution.

[0058] Referring to FIG. 2, this chart shows the components of an exemplary biomaterial that can form a cold slurry. This chart shows how the ice percentage for an exemplary biomaterial can be calculated for a particular temperature. An exemplary slurry contains 30% ice by mass (weight / weight; w / w) at -10°C. This exemplary slurry has 80 mL of saline (0.9% NaCl) and 20 mL of glycerol (i.e., glycerin). By weight, such a slurry contains approximately 79.6 g of purified water, approximately 0.72 g of sodium chloride, and approximately 25.2 g of glycerol (approximately 20% v / v). In other embodiments, the slurry can contain a higher or lower percentage of glycerol by adjusting the relative volume of glycerol to the saline solution. For example, other suitable slurries contain about 10% glycerol (v / v), about 10% to about 20% glycerol, about 30% glycerol, or more than about 30% glycerol. Thus, when an active pharmaceutical compound is added to the slurry, the concentration of saline can be adjusted to maintain the desired concentration of excipients, such as glycerol. The percentage of ice will vary depending on the composition of the biomaterial.

[0059] Referring to Figure 3, different slurry compositions (batches) are characterized with respect to their temperature profile and ice content. The different slurry batches were placed on a copper plate heated to 40°C and had thermocouple wires measuring the change in temperature of the slurry over time. The plotted data shows the temperature change over time for three different slurry batches. The temperature was measured at two different locations for each slurry: the inside of the copper plate (trace A). C , B C and C C ) and the middle of the copper plate exposed on the outside of the plate (trace A M , B M and C M The temperature traces show three separately made slurry batches: a slurry composition with 15% glycerin (with a temperature setpoint of -8.1°C) is shown in trace A; C and A MTwo different slurry batches (with a freezing temperature of -5.5°C), both with 10% glycerin, are shown in trace B. C and B M and Trace C C and C M When the slurry batch is first introduced to the copper plate, the thermocouple wire (trace A) embedded inside the plate C , B C and C C ) is first measured by the heated plate (e.g., trace A at time 0). C A warm temperature of about 31 °C was measured, followed by a lower temperature (e.g., trace A at about 2 min) due to the cooling effect of the introduced slurry. C On the other hand, for a thermocouple wire placed in the middle of the plate, when the slurry is first introduced to the copper plate, the wire is exposed, so the slurry immediately comes into contact with the thermocouple wire. This results in a negative temperature reading at the middle position initially (e.g., 0°C for trace A at time 0) due to the crystallized slurry coming into contact with the wire. M about -5 °C), then when the slurry begins to melt on a heated plate at a warmer temperature (e.g., trace A at about 4 min). M Allow the plate to equilibrate at 18°C ​​(approximately 18°C). M , B M and C M ) can be used to detect phase transitions during the melting of a crystallized slurry. The graph shows that the two slurry compositions with 10% glycerin melt at similar time points (trace B). M About 4 minutes later, trace C M (approximately 2.7 minutes for the phase transition of the 15% glycerin slurry) M The graph also shows that the same composition (10% glycerin: Trace B) reaches its phase transition at a different time (occurring at approximately 0.2 min for C and B M and Trace C C and C MThe results show that two slurry batches with different compositions (15% glycerin, trace A) reach equilibrium in a similar time frame and at similar temperatures of approximately 15°C to 19°C depending on the thermocouple position (middle / bottom) (as measured by two thermocouple wire positions). C and A M The slurry with ) has a different temperature profile than the other two and reaches equilibrium faster at a temperature of about 19°C to 22°C depending on the thermocouple location (middle / bottom). Figure 3 therefore shows that slurries of different compositions have different temperature profiles and that there is consistency from batch to batch across slurries with the same composition (e.g., B C and B M and C C and C M The slurry represented by A C and A M (having a similar temperature profile that is different from the temperature profile of the slurry represented by

[0060] Referring to Figure 4A, a diagram of an eye is shown showing scleral zone 2, scleral zone 3, cornea 1, and limbus (the dotted line between cornea 1 and scleral zone 2). Figure 4A is reproduced from Andreoli CM, Gardiner MF. Open globe injuries: Emergent evaluation and initial management. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Figure 4B shows a diagram of the eye with a superimposed protractor indicating the angle in degrees (°) relative to the eye. In this diagram, 90° represents the most superior position along the eye.

[0061] In some embodiments, the cold slurries described herein can be applied topically or alternatively injected to achieve long-lasting hypoesthesia, reducing discomfort on the ocular surface. Hypoesthesia refers to a reduction in ocular discomfort or pain without complete blockage of ocular sensation. Hypoesthesia is therefore distinct from anesthesia, which is characterized by a more pronounced blockage of ocular sensation. Hypoesthesia can include corneal anesthesia, which causes a reduction in pain response while maintaining normal ocular function, including otherwise normal healing processes. On the other hand, anesthesia can cause abnormal ocular function due to the loss of all corneal sensation. Corneal sensation is important for normal ocular functions, such as the initiation of protective mechanisms such as blinking and tear production.

[0062] One approach is to apply drops of cold slurry to the ocular surface, which can vary in volume from 1 to 100 microliters, preferably about 10 to 80 microliters. As drops, the formulation can be administered directly to the ocular surface. Alternatively, the cornea can be scraped first, followed by administration of the drops. In some embodiments, the topically applied cold slurry has a more fluid paste consistency, and larger volumes (3 to 50 ml) can be applied topically to the ocular surface as a treatment.

[0063] In some embodiments, the cold slurry described herein is applied topically posterior to the limbus, e.g., in the area shown as scleral zone 2 in FIG. 4A, for a period of about 1 minute to about 20 minutes. In some embodiments, the cold slurry is applied for a period of about 5 minutes to about 10 minutes. In some embodiments, the cold slurry is administered to each eye every 1 to 10 seconds for a period of 1 to 20 minutes. This treatment may be repeated several times over a short period of time (e.g., 5 to 20 minutes). In some embodiments, the cold slurry is applied topically posterior to the limbus for about 10 minutes, with fresh slurry being reapplied every 90 seconds until the 10-minute period is reached.

[0064] In some embodiments, during topical application, sensitive ocular structures are protected from encountering the cold slurry to limit potential side effects. Protection of the corneal surface can limit some or all corneal cell damage or refractive changes caused by freezing the corneal tissue. Protection of the palpebral conjunctiva and eyelids can prevent redness, swelling, and inflammation unrelated to the therapeutic effect. By selectively applying ice to the ocular surface posterior to the limbus on the bulbar conjunctiva (corresponding to the anterior anatomical region known as zone 2, FIG. 4A ), potential adverse effects on the cornea can be minimized.

[0065] In some embodiments, a protective contact lens or other protective covering may be applied over the cornea to protect it from damage. In some embodiments, the corneal covering completely prevents the cold slurry from directly contacting the corneal surface. In some embodiments, a lid speculum is used to hold the eyelids open during topical cold slurry application. In some embodiments, the lid speculum is made of a thermally non-conductive material, such as plastic or another non-conductive material known in the art. A thermally non-conductive material may be used for the lid speculum to prevent the eyelids (inside and outside) from freezing during cold slurry treatment, which could cause damage to the eyelids. In some embodiments, the cold slurry is applied only to the sclera, and the cornea is protected from freezing. In some embodiments, protecting the cornea from freezing ensures faster corneal healing.

[0066] A device can be used to limit exposure to the cold slurry to only the bulbar conjunctiva / sclera, so that the cold slurry does not physically contact or freeze adjacent tissues not related to the desired clinical effect. In some embodiments, the cold slurry formulation does not have any direct contact with the ocular surface. The cold slurry formulation can be contained within a thermally conductive material, such as a small metal or polymer donut-shaped or other protective ring, providing a barrier to direct contact between the formulation and the ocular surface while still providing the necessary cooling. In some embodiments, to minimize undesirable side effects (e.g., potential ocular irritation due to direct application of a hyperosmotic solution to the eye), the device directs cooling only to the area of ​​potential therapeutic effect, preventing the device / cooling from contacting and affecting adjacent tissues.

[0067] In some embodiments, the cold slurry described herein is injected as a subconjunctival bolus approximately every 2 minutes. Each injection may provide approximately 0.5 to 1.5 ml of frozen slurry and may be repeated approximately every 2 minutes for the desired duration of treatment, or a total of approximately 10 minutes. In some embodiments, the cold slurry is injected directly closer to the axons of the ciliary nerve. The ciliary nerve is located approximately at 0° and 180° of the eye (Figure 4B).

[0068] In some embodiments, a standard syringe is used to inject the slurry. Alternatively, a syringe may be used to condition the slurry for injection. In some embodiments, the syringe may have a needle of about 18G to about 25G.

[0069] In some embodiments, real-time temperature sensing is performed on the surface of the eye during treatment (e.g., cold slurry injection or topical application). In some embodiments, the cold slurry is applied to cool the tissue (e.g., the corneal surface, conjunctiva, or any other part of the eye) to below about 0°C, below about -1°C, below about -2°C, below about -3°C, below about -4°C, or below about -5°C. In some embodiments, the cold slurry is applied for about 1 minute, preferably about 2 minutes to about 10 minutes. The temperature of the cooled tissue and the length of time the slurry is applied can be varied to alter the reduced sensation experienced by the subject.

[0070] In some embodiments, the cold slurry is periodically re-administered to the eye of the subject over time to maintain the therapeutic effect.There is a range of possible frequencies for topical administration and / or injection.For example, treatment can be administered at any one of the following times: once every two weeks; once a month; once every two months; once every three months, etc.

[0071] In some embodiments, the cold slurry is used as a safe corneal numbing therapy to treat corneal discomfort or pain. Various formulations of cold slurry can be used with the methods described herein, such as those described above. Further specific embodiments of cold slurries are described with reference to Figures 5-9. "ECT-4143" is a slurry formulation containing 15% glycerol, 30% L-α-phosphatidylcholine liposomes, and 0.9% saline (or phosphate-buffered saline). In some embodiments, ECT-4143 is administered to the eye (topically or via injection) at a temperature of about -25°C to -10°C (the temperature of the slurry). In some embodiments, ECT-4143 is administered to the eye (topically or via injection) at a temperature of about -18°C (the temperature of the slurry, such as in the embodiments described below with reference to Figures 5-9). ECT-4143 is administered at about 2-3 ml per application approximately every 90 seconds until a total treatment time of 10 minutes is reached.

[0072] "ECT-1719" is a slurry formulation containing 15% glycerol and 0.9% saline (or phosphate-buffered saline). In some embodiments, ECT-1719 is administered to the eye (topically or via injection) at a temperature of about -20°C to -5°C or about -15°C to about -10°C (the temperature of the slurry). In some embodiments, ECT-1719 is administered to the eye (topically or via injection) at a temperature of about -11°C (the temperature of the slurry, such as in the embodiments described below with reference to Figures 5-9). In some embodiments, ECT-1719 is injected in a volume of 0.7 ml per injection, for a total of four injections, for a total injection volume of 2.8 ml. ECT-1719 is administered approximately every 120 seconds until a total treatment of 10 minutes is reached.

[0073] Referring to Figure 5, real-time scleral temperature monitoring was performed in rabbits after ocular administration of topically applied cold slurry (ECT-4143, solid line) in one rabbit and injected cold slurry (ECT-1719, dashed line) in a second rabbit. Temperature monitoring was achieved by cannulating the subtenon space with a 25 g needle containing a temperature probe at its distal end. As can be seen in Figure 5, the scleral temperature of the rabbit receiving injected cold slurry (ECT-1719) varied from approximately 0 °C to approximately 8 °C throughout the duration of the procedure (approximately 0 seconds after cold slurry injection to approximately 463 seconds after cold slurry injection). The sharp line on the graph at approximately 463 seconds represents the end of the study after 7.5 minutes and the removal of the temperature probe from the ocular tissue. The scleral temperature of rabbits receiving topically applied cold slurry (ECT-4143) was lower than that of injected cold slurry, fluctuating between approximately -6°C and approximately 4°C for the majority of the time during which temperatures were recorded (approximately 0 seconds after topical application to approximately 600 seconds after topical application). After topical application, the scleral temperature continued to decrease from approximately 4°C at the time of application (approximately 0 seconds in Figure 5) to approximately 0°C after approximately 120 seconds. After the initial period of scleral cooling, the temperature remained relatively stable at approximately 0°C to -5°C from approximately 120 seconds after topical application to approximately 520 seconds after topical application. Furthermore, for the duration of approximately 220 seconds to approximately 520 seconds after topical application, the scleral temperature remained stable at approximately -2°C to approximately -3°C, with very little variability. Approximately 620 seconds after topical application, treatment was terminated and the temperature probe was removed, indicating a sharp increase in the measured temperature, as shown in Figure 5.

[0074] The hypoesthesia effect after cold slurry treatment is measured as the response to ocular contact stimulation using a monofilament / anesthesiometer. Starting with a 6 cm filament length, the eye is probed three times at each length, decreasing in 0.5 cm increments, until a blink response is elicited. As the filament shortens, it becomes stiffer, so more pressure is applied to the eye when probing. Hypoesthesia for each time point is based on a given length of monofilament. At each time point, the specific monofilament length recorded is the shortest length (highest pressure) that does not elicit a blink response. For example, starting with the longest monofilament at 6 cm, if the rabbit does not blink when probed, the next monofilament at 5.5 cm is used to probe the eye. If the rabbit does not blink again, the next monofilament length at 5 cm is used. If the rabbit now blinks, the previous length of 5.5 cm is recorded, as this was the shortest length that did not elicit a blink response (reflecting some degree of hypoesthesia). The deepest level of hypoesthesia is when the rabbit does not blink when probed with the shortest filament length (e.g., 0.5 cm). 0 degree hypoesthesia (no pain block / no numbness) is when the rabbit blinks when probed with the longest filament length (e.g., 6 cm). Filament length is related to the pressure (g / mm 2 ) and a 6cm filament can be converted to 0.4g / mm 2 pressure (lowest pressure), while the 0.5 cm filament produces 15.9 g / mm 2 The pressure recorded is therefore the pressure corresponding to the shortest filament length at which there is no blink response.

[0075] Referring to Figure 6, the hypoesthesia effect (degree of corneal numbness measured using a contact stimulus as described herein) was measured over time in rabbits following administration of injected cold slurry (ECT-1719, 3 rabbits in this group, indicated by diamonds), topically applied cold slurry (ECT-4143, 3 rabbits in this group, indicated by triangles), and room temperature topically applied slurry (ECT-4143, 1 rabbit in this group, indicated by squares) to the exposed cornea of ​​the eye. In Figure 6, the degree of hypoesthesia was measured at the highest possible pressure (i.e., 15.9 g / mm 2 The degree of hypoesthesia is shown as a percentage of the recorded pressure (i.e., based on the shortest monofilament used, corresponding to a pressure of 0.5 cm) (i.e., based on the shortest monofilament with a lack of blink response). The degree of hypoesthesia is shown on days 1, 7, 14, and 28 after cold slurry administration. For injected cold slurry (ECT-1719, indicated by diamonds), the hypoesthesia effect was approximately 20% on day 1, reached baseline levels by day 14, and continued to decrease (error bars overlap 0%). For topically applied cold slurry (ECT-4143 applied at 18°C, indicated by triangles), the hypoesthesia effect was 100% on day 1 (maximum corneal numbness that could be measured), then continued to decrease and gradually ceased on day 28, during which time the pain response returned to baseline levels (error bars overlap 0%). For slurry applied topically at room temperature (ECT-4143, indicated by squares), no hypoesthesia effect could be observed at any time point after treatment. Thus, Figure 6 shows an unexpectedly strong anesthesia effect for topically applied cold slurry, which produced long-lasting anesthesia (nearly one month). Injected cold slurry produced moderate anesthesia that also lasted longer than expected (e.g., approximately one to two weeks). Importantly, for both topical and injection methods, cold slurry treatment produced long-lasting anesthesia that normalized back to baseline levels without causing a permanent numbing effect.

[0076] Figure 7 shows the anesthetic effect over time in rabbits after ocular administration of topically applied cold slurry (6 rabbits, ECT-4143) similar to that shown in Figure 6, except that the cornea was not exposed (protected by a contact lens). The anesthetic effect was measured in the same manner as described above for Figure 6. The anesthetic effect is shown on days 1, 7, 14, 21, and 28 after treatment with the topically applied cold slurry. The anesthetic effect was approximately 50% on day 1 and gradually decreased, slowly reaching baseline levels by day 21 (error bars overlap 0%). Thus, Figure 7 shows an unexpected moderate to strong anesthetic effect for the topically applied cold slurry (with corneal protection), which produced long-lasting anesthetic reduction (approximately 3 weeks) without causing permanent corneal numbness or any corneal damage.

[0077] Referring to Figure 8, representative images of rabbit corneas using fluorescein staining show corneal healing over time after intentional 8 mm corneal abrasion applied in both the control group (Figure 8A) and after topical application of cold slurry in the treatment group where protection was applied to the cornea and eyelid (Figure 8B). The progression of the injury was determined by measuring the size of the injury over time. As can be seen in Figure 8A, corneal healing in the control group (3 rabbits) progressed by 1.31 mm in the first 24 hours after the abrasion. 2 / hour, and 0.62 mm 24 to 60 hours after corneal abrasion 2 Corneal healing occurred at an average rate of 1.09 mm / hr. Unexpectedly, as shown in Figure 8B, corneal healing was not impaired for rabbits receiving topically applied cold slurry (ECT-4143) compared to the control group. In this group (3 rabbits), corneal healing after cold slurry treatment improved by 1.09 mm / hr in the first 24 hours after cold slurry treatment. 2 / hour, and 0.63 mm 24 to 60 hours after cold slurry treatment 2 The average healing rate was 1 / hour.

[0078] Referring to Figure 9, a graph shows the anesthetic effect over time in six rabbits after a combination treatment in which cold slurry was first applied topically and then injected. In three rabbits (indicated by diamonds, squares, and triangles), the topically applied cold slurry was ECT-1719 without liposomes, followed by an injection of the same cold slurry formulation (ECT-1719). In the other three rabbits (indicated by "X," stars, and circles), the topically applied cold slurry was again ECT-1719 (without liposomes) followed by an injection of cold slurry containing liposomes (ECT-4143). The anesthetic effect is indicated by the maximum pressure at which the rabbit did not blink (as described herein with reference to Figures 6 and 7). As shown in Figure 9, the anesthetic effect continued to increase after treatment and could peak anywhere from days 4 to 11, regardless of the combination treatment (liposome or non-liposome injection). The hypoesthesia effect gradually diminished, returning to baseline levels at about day 17. Surprisingly, a second, less pronounced period of hypoesthesia occurred spontaneously at about day 22, gradually ending with a return to baseline levels by day 26.

[0079] The data presented herein support that cold slurry (topical and injected) is a long-term, safe corneal numbing treatment that produces hypoesthesia without permanent corneal numbness or injury.

[0080] Without being bound by theory, the basic premise is that application of cold slurry stops the transmission of pain stimuli by causing the degeneration of the myelin sheath on the nerve. Myelin is a fatty, lipid-rich substance that transports electrical impulses toward nerve axons in a rapid and efficient manner. By administering cold slurry over both the free nerve endings and the myelinated portions of the nerve, the cold temperature freezes or crystallizes the liquid components of the fat cells, inducing apoptosis and degenerating the myelin sheath, a process known as Wallerian degeneration. This process significantly reduces the ability of the ciliary nerve to transmit pain stimuli from the cornea to the brainstem. Because of the thin volume of distal nerve endings on the surface of the eye, not all peripheral nerves are affected, so not all sensation from the surface of the eye is eliminated, resulting in relative hypoesthesia instead of complete numbness. Furthermore, the effects recede after approximately 4 to 8 weeks, at which point ocular sensation is fully restored. Other options for inducing Wallerian degeneration include radiofrequency ablation and cryoneurolysis (freezing at temperatures reaching -80°C), but these procedures pose the risk of damaging surrounding tissues and structures. Furthermore, the inert vehicle containing ice crystals does not harm other components of the eye, making this a reasonable application for treating nerves that cause pain on the ocular surface. This approach preserves vision and normal function of the ocular surface.

[0081] Without being bound by any particular theory, injection into the subconjunctival space around the limbus distributes the cold slurry around the free nerve endings of the ciliary nerve. There are two main ciliary nerves with free nerve endings that branch into the cornea of ​​both eyes. Each ciliary nerve is myelinated along its axon, located downstream from its free nerve ending in the cornea. Injection of the cold slurry extends downstream to the myelinated ciliary nerve axons. As the cold slurry spreads to the ciliary nerve axons, it causes crystallization and apoptosis of the myelin sheath, demyelining the ciliary nerve. Demyelination prevents the nerve from transmitting pain signals to the brain. Alternatively, the cold slurry may cause Wallerian degeneration of the nerve, which may also prevent pain signals from being transmitted to the brain.

[0082] Cold slurries applied topically and / or injected have advantages over other methods of administration because they do not damage the surface of the cornea.

[0083] The systems and methods disclosed herein are not limited in scope by the specific embodiments described herein. Indeed, various modifications of the devices, systems, and methods in addition to those described will become apparent to those skilled in the art from the foregoing description. [Example]

[0084] Example 1 - In vivo testing of cold slurry treatment for corneal paralysis The results of the studies described in this example can be seen in Figures 5-9. Preclinical animal studies were conducted to determine the efficacy of the treatment, including the best means for delivering the treatment, the duration of the treatment's effect, and to examine any potential side effects. For ocular investigations, New Zealand White rabbits are an ideal model because their cornea and corneal innervation system are very similar to humans, and they are the standard accepted model for corneal testing in the literature.

[0085] Preparation of the procedure The animals were given preanesthesia (rabbit xylazine 1.1 mg / kg IM, buprenorphine HCl 0.01-0.05 mg / kg IM) and pre-surgery antibiotics (cefazolin 25-50 mg / kg IM). The animals were then anesthetized (rabbit ketamine 33 mg / kg IM). The animals were placed on a heating pad and vital signs were monitored. Two drops of proparacaine HCl 0.5% and 5% phenylephrine / 0.5% tropicamide (expanded drops) were administered to the eye to be examined. The animals were subjected to inhalation anesthesia (isoflurane at 1.5-2% concentration) with O2 supplementation.

[0086] Test Procedure The animals are prepped and draped in the usual sterile fashion, including instillation of povidone-iodide drops onto the surface of the eye, an eyelid speculum is placed, and topical or subconjunctival injection of the slurry is administered.

[0087] Injection To evaluate the sensitivity of ECT-1719, approximately 0.7 mL of cold slurry was injected into the subconjunctival space around the limbus. Due in part to corneal pressure, injection force, and the natural potential space, the injected cold slurry was uniformly distributed 360° around the limbus. The injection procedure was repeated every 120 seconds for a total of 10 minutes.

[0088] Control animals received treatment with sterile saline (control) or vehicle control (uncooled slurry). At the end of the procedure, the eyes were carefully examined, the eye speculum removed, the sterile drape removed, and the eyes washed with sterile saline. There was an additional control group in which conventional anesthetic drops were applied to the cornea. All surgical procedures were performed on the left eye only (for control purposes) and lasted approximately 10 minutes.

[0089] The above surgical procedures are commonly performed in humans with the use of injections of a variety of different medications (eg, steroids, antibiotics, etc.) depending on the condition.

[0090] Topical administration To evaluate the ECT-4143 sensitivity-reducing potential, the slurry was applied topically to the ocular surface posterior to the corneal limbus. The cornea was protected with a contact lens and the eyelid with a plastic speculum. Approximately 2-3 mL of cold slurry was applied topically, approximately every 90 seconds, for a total treatment time of 10 minutes. At the end of the procedure, the eye was carefully inspected, the speculum removed, the sterile drape removed, and the eye washed with sterile saline.

[0091] Post-procedures for surviving animals Neomycin / Polymyxin / Bacitracin eye ointment and a few drops of prednisone acetate were applied to the operated eye after surgery. The animals were removed from the operating table and placed on a heating pad. While recovering, the animals were monitored for their vital signs (e.g., heart rate, respiration, SPO2). Monitoring continued until muscle control was restored. The animals were returned to their home cages.

[0092] Post-surgical animal monitoring Animals underwent a comprehensive eye exam one day after surgery, followed by weekly corneal sensation measurements. Intraocular pressure measurements were also performed if beneficial reductions in intraocular pressure could be observed in treated animals. Additionally, slit lamp examinations with fluorescein staining and dilated fundus examinations (i.e., the eyes were dilated with 5% phenylephrine and 0.5% tropicamide) were performed. The animals were placed in a restrictive cage for several seconds while eye drops were applied one at a time.

[0093] Effect of administration Several techniques were used to test the effect of administering the cold slurry.

[0094] The paralytic effect of the cold slurry was tested using an anesthesiometer. A filament with a specific stiffness was stretched from the device. Animals treated with the cold slurry were able to withstand a stronger force from the anesthesiometer than animals in the control group. This was indicated by whether the animals recoiled when the eye was poked with the anesthesiometer filament. The test was performed multiple times over the course of the test to determine the duration of the paralytic effect.

[0095] The effect of the cold slurry on the eye's ability to heal was also examined. Epithelial defects were created in the cornea using a trephine and corneal brush. The wounds were verified with fluorescein staining and photodocumented. Control staining was used to measure wound size and wound progression. The cold slurry did not affect the eye's ability to heal. The present invention includes the following aspects. Item 1 1. A method for relieving symptoms of ocular surface discomfort, comprising the step of topically applying a cold slurry adjacent to the limbus of a patient's eye, the cold slurry comprises water and a freezing point depressant; topical application of the cold slurry is configured to cause some degree of numbness of the cornea of ​​the eye for a period of time; Ocular sensation is restored after a period of time. method. Section 2 Item 1. The method of item 1, wherein the cold slurry is applied posterior to the limbus. Section 3 2. The method of paragraph 1, wherein the period of time is greater than about 7 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application. Section 4 Item 4. The method of item 3, wherein the freezing point depressant is glycerol. Section 5 Item 10. The method of item 1, wherein ocular sensation in the eye is restored approximately 21 days after topical application of the cold slurry. Section 6 Item 1. The method of item 1, wherein the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during topical application of the cold slurry. Section 7 Item 1. The method according to item 1, wherein the cold slurry is applied topically for about 5 minutes to about 15 minutes. Item 8 8. The method of paragraph 7, wherein an additional amount of cold slurry is topically applied again about every 90 seconds. Section 9 Item 1. The method of item 1, further comprising placing a contact lens on the patient's eye before topically applying the cold slurry. Section 10 Item 1, wherein the cold slurry is configured to be a paste consistency. Section 11 placing a protective covering over the cornea of ​​the patient's eye; and 1. A method for relieving symptoms of ocular surface discomfort, comprising topically applying a cold slurry to the bulbar conjunctiva of a patient's eye, topical application of the cold slurry causes prolonged reduction in eye pain in patients; Partial corneal sensation in the patient's eye is maintained during the prolonged reduction in pain; method. Item 12 Item 12. The method of paragraph 11, wherein the cold slurry is applied posterior to the limbus. Section 13 Item 12. The method of item 11, wherein the cold slurry is applied over a protective cover. Section 14 12. The method of paragraph 11, wherein the prolonged reduction in pain lasts for more than about 7 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application. Section 15 15. The method of paragraph 14, wherein the prolonged reduction in pain lasts for more than about 14 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application. Section 16 Item 12. The method according to Item 11, wherein the condition is due to dry eye syndrome or corneal somatosensory dysfunction. Section 17 Item 12. The method of item 11, wherein the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during topical application of the cold slurry. Section 18 Item 12. The method of item 11, wherein the protective cover is a contact lens, and the contact lens prevents freezing of the cornea of ​​the eye. Section 19 1. A method for relieving symptoms of ocular surface discomfort, comprising administering a cold slurry to the eye of a patient, the cold slurry comprises water and a proportion of ice particles; Administration of the cold slurry caused prolonged ocular hypoesthesia, Ocular sensation is restored after prolonged hypoesthesia, Administration of the cold slurry does not cause permanent damage to the cornea of ​​the eye; method. Section 20 20. The method of paragraph 19, further comprising treating a condition selected from the group consisting of dry eye syndrome, chronic ocular pain, post-operative pain, post-photorefractive keratomileusis pain, post-LASIK pain, post-cataract surgery pain, and post-open globe injury repair pain, post-corneal injury, corneal somatosensory dysfunction, allodynia, and pain from acute injury. Section 21 20. The method of paragraph 19, wherein the cold slurry is administered by injection. Section 22 20. The method of paragraph 19, wherein the cold slurry is injected into the subconjunctival space. Section 23 20. The method of paragraph 19, wherein the cold slurry is administered via topical application. Section 24 Item 20. The method according to item 19, wherein the proportion of ice particles is about 20% to 40%. Section 25 Item 20. The method according to Item 19, wherein the temperature of the cold slurry is about -20°C to about -5°C. Section 26 1. A method of relieving symptoms of ocular surface discomfort, comprising topically applying a cold slurry to or proximal to the ocular surface of a patient's eye, topical application of the cold slurry causes prolonged corneal hypoesthesia of the eye; Ocular sensation is restored after prolonged hypoesthesia, Topical application of the cold slurry does not cause permanent damage to the cornea of ​​the eye; method. Section 27 27. The method of paragraph 26, wherein the cold slurry is applied proximal to the limbus. Section 28 27. The method of paragraph 26, wherein the prolonged hypoesthesia lasts for more than about 1 day after a single treatment of topical application of the cold slurry. Section 29 27. The method of paragraph 26, wherein ocular sensation in the eye is restored by about 30 days after topical application of the cold slurry. Section 30 Item 27. The method of item 26, wherein the cold slurry is applied topically for about 5 minutes to about 15 minutes. Section 31 27. The method of paragraph 26, further comprising placing a contact lens on the patient's eye before topically applying the cold slurry, wherein the contact lens prevents freezing of the cornea of ​​the eye.

Claims

1. 1. A cold slurry formulation for use in topical application to the eye in a method for relieving symptoms of ocular surface discomfort, comprising: the cold slurry comprises water and a freezing point depressant; The method includes topically applying the cold slurry adjacent to the limbus of the patient's eye; topical application of the cold slurry is configured to cause some degree of numbness of the cornea of ​​the eye for a period of time; Ocular sensation returns after a period of time Cold slurry formulation.

2. 10. The cold slurry formulation of claim 1, wherein the cold slurry is applied posterior to the limbus.

3. 10. The cold slurry formulation of claim 1, wherein the period of time is greater than about 7 days without topically applying the cold slurry for an additional period of time on any day after the first day of topical application.

4. 4. The cold slurry formulation of claim 3, wherein the freezing point depressant is glycerol.

5. 10. The cold slurry formulation of claim 1, wherein ocular sensation in the eye is restored approximately 21 days after topical application of the cold slurry.

6. 10. The cold slurry formulation of claim 1, wherein the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during topical application of the cold slurry.

7. 10. The cold slurry formulation of claim 1, wherein the cold slurry is applied topically for about 5 minutes to about 15 minutes.

8. 8. The cold slurry formulation of claim 7, wherein an additional amount of cold slurry is topically applied again about every 90 seconds.

9. 10. The cold slurry formulation of claim 1, wherein the method further comprises placing a contact lens on the patient's eye prior to topically applying the cold slurry.

10. 10. The cold slurry formulation of claim 1, wherein the cold slurry is configured to be a paste consistency.

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