Formulations, devices, and methods for lowering intraocular pressure

Abstract

Devices and methods for lowering intraocular pressure are disclosed, including applying a cooling device to a surface of the eye of the patient, the cooling device including a housing, a contact element, and a cold slurry, the contact element is at or below a certain temperature when applied to the surface of the eye, the contact element is applied to the eye for period of time, and the application of the cooling device causes a lowering of the intraocular pressure of the eye.

Description

FORMULATIONS, DEVICES, AND METHODSFOR LOWERING INTRAOCULAR PRESSURE RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 717,690 entitled “FORMULATIONS, DEVICES, AND METHODS FOR LOWERING INTRAOCULAR PRESSURE,” filed November 7, 2024, which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates generally to apparatuses, systems, and methods for creating and administering a cold therapy to the ocular surface to lower intraocular pressure. More particularly, the present disclosure relates to apparatuses, systems and methods for treating ocular hypertension by lowering the temperature of a subject’s ocular surface and / or of target tissue beneath the ocular surface to a particular temperature range for a particular period of time, thus reducing intraocular pressure, in a safe and effective manner.BACKGROUND

[0003] Glaucoma is a group of eye diseases characterized by progressive damage to the optic nerve, commonly associated with elevated intraocular pressure (IOP). This condition can lead to irreversible vision loss if left untreated, making it one of the leading causes of blindness worldwide. Glaucoma typically progresses without noticeable symptoms until significant damage has occurred, necessitating early detection and long-term management to preserve vision. Currently approved treatments aim to lower IOP to prevent further optic nerve damage.

[0004] The build-up of pressure in the eye (IOP, or intraocular pressure) can negatively affect the optic nerve and can result from various clinical conditions. The increase in IOP is gradual and because it is largely painless, it usually goes unnoticed by the patient until irreversible damage to the retina has occurred. Left untreated, significantly elevated IOP, regardless of cause, can result in a permanently reduced visual field and loss of vision.

[0005] IOP plays a critical role in the development and progression of glaucoma. Elevated IOP occurs when there is an imbalance between the production and drainage of aqueous humor, the fluid inside the eye. When this fluid cannot drain properly through the trabecular meshworkor other outflow pathways, pressure within the eye increases. Chronic elevation of IOP exerts mechanical stress on the optic nerve head, particularly at the lamina cribrosa, leading to compression and axonal damage. This disrupts the blood flow and nutrient supply to retinal ganglion cells, contributing to their degeneration. Over time, this damage results in a characteristic visual field loss pattern that is seen in glaucoma patients. Ocular hypertension refers to consistently high IOP without detectable optic nerve damage or vision loss, however, ocular hypertension is considered a significant risk factor for developing glaucoma. Although elevated IOP is the primary risk factor, glaucoma can also develop in individuals with normal IOP levels, a condition known as normal-tension glaucoma. Thus, controlling IOP remains the central focus of most therapeutic strategies for preventing glaucoma progression, but evolving strategies also include neuro-protectants to preserve retinal ganglion cells.

[0006] IOP is primarily regulated by the balance between the production and outflow of aqueous humor, a clear saline-like fluid that fills the anterior chamber of the eye. The ciliary body, located behind the iris, plays a central role in aqueous humor production. Specialized epithelial cells in the ciliary processes secrete aqueous humor, which then flows into the posterior chamber of the eye, and then through the pupil into the anterior chamber. Once produced, aqueous humor flows from the posterior chamber through the pupil into the anterior chamber, where it exits the eye primarily through the trabecular meshwork and Schlemm’s canal. Neural control of aqueous humor production involves both sympathetic and parasympathetic pathways. Sympathetic stimulation, via P-adrenergic receptors in the ciliary epithelium, increases aqueous humor production, while a2-adrenergic receptor stimulation inhibits it. Parasympathetic input, primarily through the cholinergic system, influences the contraction of the ciliary muscle but has less direct impact on fluid production. Additionally, the autonomic nervous system controls the tone of the trabecular meshwork and Schlemm’s canal, affecting aqueous humor outflow. Imbalance in either the production or drainage of aqueous humor can lead to elevated IOP, a major risk factor for the development of glaucoma.

[0007] The primary cause of increased IOP is inadequate drainage through the eye’s outflow pathways, particularly the trabecular meshwork and Schlemm’s canal, which may become blocked or dysfunctional. In open-angle glaucoma, drainage becomes less efficient over time without obvious obstruction, while in angle-closure glaucoma, the iris blocks fluid flow by covering the drainage angle. Overproduction of aqueous humor by the ciliary body can also contribute to elevated IOP. Although most causes are idiopathic, certain conditionsincluding trauma, inflammation (e.g., uveitis), medications such as corticosteroids, and certain eye conditions such as pigment dispersion syndrome can lead to the pathogenesis of elevated IOP. Prolonged elevated IOP can damage the optic nerve, leading to vision loss in glaucoma patients, making early detection and intervention essential.

[0008] Current treatments for elevated IOP focus on reducing IOP to prevent the progression of glaucoma, and they include medications, laser therapies, and surgical interventions. Medications are often the first line of treatment, with prostaglandin analogs such as latanoprost and bimatoprost being commonly used. These drugs increase the outflow of aqueous humor through the uveoscleral pathway, effectively lowering IOP by 25-35%. Betablockers such as timolol and betaxolol reduce aqueous humor production by inhibiting beta-adrenergic receptors in the ciliary body. Another class of drugs, carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide), also decrease aqueous humor production by targeting the enzyme carbonic anhydrase in the ciliary body. When medications are insufficient, laser procedures such as trabeculoplasty can improve outflow through the trabecular meshwork. In more severe cases, surgical options such as trabeculectomy or the implantation of drainage devices are considered to create alternative drainage pathways. Additionally, cyclodestructive procedures such as cyclophotocoagulation reduce IOP by selectively destroying the ciliary’ body to decrease aqueous humor production. Despite these treatments, many patients continue to experience disease progression, highlighting the need for novel therapeutic approaches.

[0009] Modern cyclodestructive procedures, also known as cycloablation or cyclophotocoagulation, are a group of glaucoma treatments designed to lower IOP by reducing the production of aqueous humor. These procedures target the ciliary body, which produces aqueous humor, by selectively destroying the ciliary epithelium, thereby reducing its function. Cyclodestructive techniques are often used in advanced or refractory glaucoma cases, or when traditional medical, laser, or surgical treatments have failed. Cyclodestructive methods include diode laser cyclophotocoagulation (CPC), transscleral cyclophotocoagulation, endoscopic cyclophotocoagulation (ECP), and cyclocryotherapy. Historically, cyclocryotherapy was performed using extreme cold to freeze and destroy the ciliary body tissue. This technique uses a cryoprobe, cooled with liquid nitrogen to an approximate temperature of -80°C, and applied externally to the sclera to freeze the underlying ciliary body. The freezing process causes tissue necrosis and atrophy of the ciliary epithelium, thereby reducing aqueous humor production. However, cyclocryotherapy was associated with higher risks of complicationssuch as inflammation, hypotony (excessively low IOP), and damage to surrounding ocular tissues, leading to significant vision loss in some cases. Although cyclocryotherapy can still be used today, particularly in resource-limited settings, its use has largely declined with the advent of laser-based technologies that offer greater precision and control. The introduction of diode laser CPC, which uses a laser with a wavelength of approximately 810 nm, improved the safety and precision of cyclodestructive procedures. Diode CPC can be performed transsclerally (externally) or endoscopically (internally), depending on the clinical context. The laser energy is absorbed by pigmented tissues in the ciliary body, causing coagulative necrosis of the ciliary epithelium and reducing aqueous humor production. By selectively targeting the pigmented tissues, diode CPC minimizes damage to surrounding structures and gradually lowers IOP gradually over several weeks. The reduction in IOP may be permanent or may require repeat treatments. The mechanism of action in both cyclocryotherapy and diode CPC centers on physically ablating the ciliary epithelium to impair aqueous humor production. Cyclocryotherapy achieves this through freezing, while diode CPC uses heat from the laser to induce coagulative necrosis. In both methods, the mechanism of decreased IOP production is believed to be through destruction of ciliary cells. However, in addition to direct thermal effects on the secretory epithelial cells, an additional pressure-lowering mechanism may be observed from effects of the thermal energy on the long ciliary nerves themselves, as these nerves carry autonomic fibers that influence aqueous humor dynamics through their effects on the ciliary body and trabecular meshwork. Disruption of these nerves could theoretically alter parasympathetic or sympathetic innervation to the ciliary body or trabecular outflow pathways, possibly contributing to IOP reduction.

[0010] Significant limitations exist in the field in regard to current therapies for managing elevated IOP. Medications often require lifelong adherence, can cause side effects, and may eventually lose efficacy. Surgical interventions, though more definitive, carry the risk of complications, particularly hypotony, a condition where IOP drops too low, leading to visionthreatening complications such as choroidal effusions. Many glaucoma eye drops contain preservatives, such as benzalkonium chloride (BAK), which are used to prevent contamination and maintain product stability. However, long-term use of these preserved formulations can cause chronic irritation and discomfort to the ocular surface. The preservatives can disrupt the tear film, leading to dry eye symptoms, inflammation, and damage to the corneal and conjunctival cells. To mitigate these effects, preservative-free formulations are sometimes preferred, though these alternatives may be more costly. Additionally, laser-based treatmentsrequire specialized capital equipment. These lasers are an expensive upfront investment for clinics and surgical centers, requiring both the initial purchase and ongoing maintenance. This cost factor can be a barrier for some institutions, particularly in resource-limited settings, where alternatives such as cyclocryotherapy may be used despite their higher complication rates.

[0011] There is a significant need to develop a non-invasive, low-cost technology that is readily available in clinician offices and capable of rapidly and safely lowering IOP. Current treatments, such as medications and surgical interventions, have limitations, including patient non-compliance, side effects, and the risks associated with invasive procedures. A technology' that offers an effective, rapid reduction in IOP without the need for surgery or frequent administration of eye drops would provide a critical solution for both acute and chronic management of glaucoma. Such a tool would enhance accessibility, reduce treatment burdens, and improve outcomes for patients while offering a cost-effective and easily deployable option for clinicians.SUMMARY

[0012] The following embodiments recite non-limiting permutations of combinations of features of the inventions described. Other pennutations of combinations of features are also contemplated and / or described throughout the disclosure. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of the listed order.

[0013] In one aspect, a cooling device for reducing intraocular pressure is described, including a housing; a contact element comprising a thermally conductive material; and a thermal mass; wherein the contact element is configured to be directly or indirectly applied to a target ocular surface of an eye, according to a treatment protocol, to cause a cooling of a target ocular region, and wherein the intraocular pressure of the eye is reduced following the application of the contact element to the target ocular surface.

[0014] In any one of the embodiments di sclosed herein, the treatment protocol compri ses applying the contact element to the target ocular surface when the contact element has a contact element temperature of between -5 and -40 degrees Celsius.

[0015] In any one of the embodiments disclosed herein, the treatment protocol comprises applying the contact element to the target ocular surface when the contact element has a contact element temperature of between -20 and -30 degrees Celsius.

[0016] In any one of the embodiments disclosed herein, the treatment protocol comprises applying the contact element to the target ocular surface for at treatment time, the treatment time being between about 1 to 20 minutes.

[0017] In any one of the embodiments disclosed herein, the treatment protocol comprises applying the contact element to the target ocular surface for at treatment time, the treatment time being between about 2 to 15 minutes.

[0018] In any one of the embodiments disclosed herein, the thermally conductive material comprises a metal.

[0019] In any one of the embodim ents disclosed herein, the thermally conductive material comprises at least one of aluminum, copper, gold, and silver, or a combination thereof.

[0020] In any one of the embodiments disclosed herein, the thermally conductive material comprises aluminum.

[0021] In any one of the embodiments disclosed herein, prior to the application to the target ocular surface of the eye, the device is stored at a temperature of between about -10 to about -90 degrees Celsius.

[0022] In any one of the embodiments disclosed herein, the thermal mass comprises a mixture of water and glycerol.

[0023] In any one of the embodiments disclosed herein, the thermal mass comprises a plurality of ice particles.

[0024] In another aspect, a method of lowering intraocular pressure of an eye of a patient is disclosed, the method comprising the following steps:applying a cooling device to a surface of the eye of the patient adjacent to a corneal limbus,wherein the cooling device comprises a housing, a contact element comprising a thermally conductive material, and a cold slurry;wherein the contact element is at or below a temperature of -5 degrees Celsius when applied to the surface of the eye, and the contact element is applied to the eye for at least 2 minutes; andwherein the application of the cooling device causes a lowering of the intraocular pressure of the eye.

[0025] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 4 minutes.

[0026] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 3 minutes.

[0027] In any one of the embodiments disclosed herein, the contact element is applied to the eye for between 3-10 minutes,

[0028] In any one of the embodiments disclosed herein, the contact element is applied to the eye for between 5-15 minutes.

[0029] In any one of the embodiments disclosed herein, the contact element is at or below a temperature of -25 degrees Celsius when applied to the surface of the eye.

[0030] In any one of the embodiments disclosed herein, the contact element is at or below a temperature of -30 degrees Celsius when applied to the surface of eye.

[0031] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 4 minutes.

[0032] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 5 minutes.

[0033] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 10 minutes.

[0034] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 15 minutes.

[0035] In any one of the embodiments disclosed herein, the contact element is applied to the eye for at least 20 minutes.

[0036] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below 0 degrees Celsius.

[0037] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -1 degrees Celsius.

[0038] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -2 degrees Celsius.

[0039] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -3 degrees Celsius.

[0040] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -4 degrees Celsius.

[0041] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -5 degrees Celsius.

[0042] In any one of the embodiments disclosed herein, the cooling device is applied until a target region of the eye reaches at or below -10 degrees Celsius.

[0043] In any one of the embodiments disclosed herein, the cooling device is applied to the surface of the eye in at least two locations, each of the at least two locations being on opposite sides of a cornea of the eye.

[0044] In any one of the embodiments disclosed herein, the at least two locations are at 0 and 180 degrees with respect to the cornea of the eye.

[0045] In any one of the embodiments disclosed herein, the cold slurry comprises a mixture of water and glycerol.

[0046] In any one of the embodiments disclosed herein, the cold slurry comprises a plurality of ice particles.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] For a more complete understanding of various embodiments of the disclosed subject matter, reference is now made to the following descriptions taken in connection with the accompanying drawings, in which:

[0048] FIG. 1 illustrates a freezing point curve for glycerine and water solutions, according to one or more embodiments disclosed herein.

[0049] FIG. 2A illustrates a cooling device, according to one or more embodiments disclosed herein.

[0050] FIG. 2B illustrates a cooling device, according to one or more embodiments disclosed herein.

[0051] FIG. 3 illustrates results from a study on intraocular pressure, according to one or more embodiments disclosed herein.

[0052] FIG. 4A illustrates a cooling device, according to one or more embodiments disclosed herein.

[0053] FIG. 4B illustrates a cooling device, according to one or more embodiments disclosed herein.

[0054] FIG. 5A illustrates a protocol for application of a cooling device, according to one or more embodiments disclosed herein.

[0055] FIG. 5B illustrates a protocol for application of a cooling device, according to one or more embodiments disclosed herein.

[0056] FIG. 6A illustrates regions of an ocular surface, according to one or more embodiments disclosed herein.

[0057] FIG. 6B illustrates regions of an ocular surface, according to one or more embodiments disclosed herein.

[0058] While the disclosure is amenable to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and are described in detail below. The intention, however, is not to limit the disclosure to the particular embodiments described. On the contrary, the disclosure is intended to cover all modifications, equivalents, and alternatives falling within the scope of the disclosure as described and as defined by the appended claims.DETAILED DESCRIPTION

[0059] According to some embodiments disclosed herein, IOP may be treated by lowering the temperature of the ocular surface, either by direct application of a cold slurry to the ocular surface, or by the application of a device configured to cool the ocular surface, for a period of time. The device may, for example, contain a cold slurry or solid ice and have a thermally conductive material designed to draw heat away from the ocular surface. In some embodiments herein, the targeted application of the slurry and / or device may cool the ocular surface for a period of time. Ocular surface cooling in this manner, according to some embodiments, can cause surprisingly lasting and effective reduction in IOP. This approach is beneficial because it does not injure tissues in the eye that are not targeted for treatment and can be considered non-destructive.

[0060] Most IOP -lowering technologies either aim to reduce the inflow of aqueous humor into the eye, or to increase the outflow of aqueous humor from the eye. The ciliary body epithelium is the main structure responsible for producing aqueous humor. According to some embodiments, treatment approaches described herein may reduce IOP by lowering perfusion in or around the eye, including ciliary bodies. A reduction in perfusion may cause a drop in aqueous humor production, thereby leading to reduced IOP. Certain embodiments described herein target a measured reduction of perfusion throughout the patient’s eye. For example, in some embodiments, an impact on the ciliary body is targeted with cold temperatures which may have a suppressing effect on its ability to produce aqueous humor.

[0061] In some embodiments, the impact to the ciliary body may be related to the direct application of cold to the area on or around the ciliary body. This may be due to cooling of the ciliary body, or a reduction of blood flow (hypoperfusion) due to impacting the blood vessels that supply the ciliary body. In some embodiments, to make this impact significant and repeatable, several factors may be considered, tested, and controlled. For example, chronic ocular surface pain (COSP) is likely impacted by the long ciliary nerves, which are roughly 0.75mm below the surface of the eye. The ciliary body is farther below the ocular surface than ciliary’ nerves. According to some methods, COSP may be impacted and / or treated due to crystallization of the myelin sheath, which may happen below about 5 degrees Celsius. In some embodiments, impacting the ciliary’ body may require temperatures as cold as, or colder than, those impacting the ciliary nerves.

[0062] According to some embodiments of the present disclosure, the devices and methods disclosed herein relate to the application of non-destructive cold therapy to the eye or periocularregion to lower IOP through mechanisms that include and extend beyond direct modulation of blood flow to the ciliary body. Specifically, such methods may induce localized vasoconstriction in the episcleral vasculature, thereby reducing episcleral venous pressure (EVP) and facilitating enhanced aqueous humor outflow. For instance, exposure to cold (e.g., air at temperatures ranging from approximately -19°C to 0°C for durations of 5-40 minutes) has been shown to decrease EVP by 1-2 mmHg, correlating with a proportional IOP reduction of 1-2 mmHg, without altering aqueous humor production or total outflow facility. This EVP-lowering effect arises from hypothermia-induced arteriolar vasoconstriction, which diminishes regional blood flow and venous pressure, establishing a new steady-state IOP equilibrium. Additionally, cold therapy may influence surrounding vascular structures, such as collector channels and downstream episcleral veins, by promoting vasoconstriction that reduces fluid leakage and edema, further supporting IOP reduction. These approaches may be implemented via devices delivering controlled cold air, compresses, masks, or direct cold application to the eye via contact surfaces, and may be particularly advantageous for managing glaucoma or ocular hypertension in patients where sustained, non-invasive IOP modulation is desired.

[0063] In some embodiments, the devices and methods disclosed here leverage other mechanisms of action to achieve IOP lowering, including potential impacts on corneal physiology and systemic temperature responses that indirectly enhance outflow pathways. For example, mild local cooling may increase corneal thickness (e.g., from 0.52 mm to 0.57 mm), which can mask the true extent of IOP reduction during applanation tonometry measurements, indicating that the actual hypotensive effect -potentially underestimated by 0.5-1 mmHg---stems from enhanced episcleral vasoconstriction and reduced vascular permeability in areas such as the trabecular meshwork and collector channels. In anesthetized or hypothermic states, IOP may exhibit a strong correlation with body temperature fluctuations (e.g., decreasing precipitously with cooling when heat support, is absent), suggesting that cold therapy may modulate IOP via temperature-dependent metabolic slowdowns in ocular tissues, reducing aqueous inflow or increasing uveoscleral outflow. Such methods provide broad therapeutic coverage, including for acute interventions where rapid IOP stabilization is needed, and can be combined with existing ciliary body-targeted approaches to offer synergistic effects without tissue destruction.

[0064] By way of example, selective laser trabeculoplasty (SLT) is a treatment designed to lower IOP through selective photothermolysis. Following SLT, a cascade of biologicalresponses occurs over the following hours and days, including increased cellular activity within the trabecular meshwork and endothelial cell proliferation. This reaction includes cytokine release, recruitment of inflammatory cells such as macrophages, and increased cellular turnover through phagocytosis. These effects collectively enhance the aqueous humor outflow, thereby reducing IOP. Over time, macrophages accumulate in the trabecular meshwork, contributing to a sustained improvement in the outflow facility. Cytokines released during this process are thought to act as growth factors for trabecular cells, potentially reaching Schl emm’s canal and promoting increased fluid flow across the endothelium. Additionally, cytokines may stimulate the expression of specific metalloproteinases, which aid in remodeling the extracellular matrix of the trabecular meshwork, further facilitating aqueous humor drainage over the long term.

[0065] Non-destructive ocular surface cooling, according to some embodiments of the present disclosure, may act via similar mechanisms to SLT. Non-destructive ocular surface cooling of the sclera may induce localized cellular stress that triggers inflammatory processes in adjacent tissues. This cold-induced stress may prompt the release of cytokines and other inflammatory mediators, leading to macrophage recruitment and increased cellular activity, as seen with SLT. These processes potentially contribute to remodeling in adjacent tissues, enhancing aqueous humor outflow and reducing intraocular pressure, thereby mimicking the therapeutic benefits of SLT without inducing thermal damage.

[0066] Methods of using cold slurry (e.g., a mixture of solid ice particles and other liquid materials) to reduce ocular surface discomfort are disclosed in U.S. Patent App. Pub. No. US 2022 / 0079648A1, incorporated by reference herein with respect to methods of administering cold slurry (via topical application or direct injection) and use of a device to cool the ocular surface, and related disclosure. Formulations, devices, and methods for alleviating symptoms of ocular surface discomfort are disclosed in U. S. Patent App. Pub. No. US 2025 / 0177199A1, incorporated by reference herein with respect to the devices and methods for cooling the ocular surface. Devices for use with a cold slurry, according to some embodiments, are disclosed in U. S. Provisional Application No. 63 / 880,593, incorporated by reference herein with respect to the devices and methods for cooling the ocular surface, and related disclosure.

[0067] In some embodiments, a reduction in IOP may occur via an application of a cold slurry, or a cooling device, to a patient’s eye. In some embodiments, one aim of the devices and methods herein is to cool the eye, or specific regions of the eye, for a period of time. Cooling of the eye may decrease the amount of blood flow in that region. Embodimentsdisclosed herein relate to devices and methods that are designed to selectively cool regions of a patient’s eye to cause a reduction in blood flow (i.e., perfusion) and a corresponding reduction in aqueous humor. This aqueous humor reduction may lead to an associated reduction in IOP. Reducing IOP in this manner, according to some embodiments, represents a non-invasive and relatively quick treatment scheme to reduce a patient’s IOP. As discussed herein, devices and methods according to embodiments herein have surprisingly been shown to lead to significant, and lasting, reductions in IOP.

[0068] According to some embodiments, the device may be applied to an eye of a patient according to a treatment protocol designed to reduce IOP. In some embodiments, the device may have a contact element that is designed to contact the patient’s eye. The contact element may comprise a thermally conductive material to enable heat transfer from the eye to the device, including to a cold slurry or ice that may be contained in the device. The contact element can be coupled to the device and / or formed integrally with the device or at least one of the device’s components. The contact element may comprise a metal or a polymer. The contact element may specifically comprise a metal such as aluminum, copper, gold, silver, or combinations thereof. There may be more than one contact element, for example two or three contact elements. The contact element(s) may be designed to contact specific regions of the eye, for example certain areas of therapeutic effect. For example, the region of therapeutic effect may be the sclera or posterior limbus of the eye.

[0069] The treatment protocol designed to reduce IOP may be designed according to one or more of several different parameters. For example, in some embodiments, the device may be cooled to a target temperature in a freezer or refrigerator before use. In some embodiments, after removal from a freezer or refrigerator, the device may be allowed to reach a target temperature (for example, a temperature that is warmer than that of the refrigerator or freezer) before use. In some embodiments, the device may be applied to the eye until portions of the eye reach a certain temperature, or are at or below a certain temperature (or within a temperature range) for a predetermined amount of time. In some embodiments, the device may be applied to the eye of a patient for a predetermined amount of time.

[0070] The treatment protocol may target a specific portion of the eye, such as the sclera, the corneal limbus, regions of the limbus including posterior to the limbus, or other target regions. The target regions may be on the surface of the eye or beneath the surface of the eye. The target regions may be selected based on the proximity, or density, of blood vessels relativeto the target region. In some embodiments, the ciliary body, ciliary processes, blood vessels under the ocular surface, and / or the aqueous outflow channels may be targeted. In some embodiments, the target regions may be targeted through the surface of the eye, where the surface and the underlying regions of the eye are cooled by applying the cooling device to the surface of the eye. In some embodiments, the eye may be targeted outside of the cornea, for example at 0 and 180 degree positions (see Figure 6B), In some embodiments, a different position, or positions, may be targeted depending on the targeted region to be cooled.

[0071] The treatment protocol may aim to use a cold slurry that is at a certain temperature, or within a certain temperature range, before application to the eye. There may also be a target temperature for the cold slurry following application to the eye for a specified treatment time. Further, the treatment time may not be specified, rather, the treatment time may be determined based on the temperature of the cold slurry, the device, or the eye. For example, if there is a specified temperature for the cold slurry at the beginning of treatment, the treatment may only end when the cold slurry reaches a specified temperature that is warmer than the initial temperature.

[0072] According to some embodiments, treatment protocol parameters when applying a device to cool the ocular surface can be considered in four categories: the device storage temperature, the contact element temperature, the contact element material, and the treatment time. These categories are discussed throughout this application, and more specifically discussed in order below. Generally speaking, the amount of cooling that occurs at the ocular surface or in the eye can be modified by changing one or more of these categories. For example, in some embodiments, more cooling of the eye can occur by one or more of the following: decreasing the device storage temperature, decreasing the contact element temperature, increasing the treatment time, and / or increasing the thermal conductivity of the contact element material.

[0073] In some embodiments, the device storage temperature refers to the temperature that the device, including the cold slurry or ice within the device and the device’s contact elements, is stored at. For example, this temperature can refer to the temperature of a freezer that the device is stored in prior to treatment. The device may be stored in the freezer for different durations, ranging from a few seconds to several years. In some embodiments the device is stored in the freezer until the device reaches, or comes close to reaching, the ambient temperature in the freezer. A freezer is used herein as an example, but in some embodimentsthe device may be stored in a different apparatus, including a refrigerator or a different apparatus designed to cool its contents such as, for example, a point of use freezing system.

[0074] Temperatures described herein, unless stated otherwise, are in degrees Celsius. Temperatures with apreceding them represent negative temperatures. For example, a temperature of “-1” is intended to represent negative 1 degrees Celsius, unless stated otherwise.

[0075] In some embodiments, the device storage temperature may be from about -22 to about -18 or about -30 to about -25. In some embodiments, the device storage temperature may also be within 5 degrees of 0, -5, -10, -15, -20, -25, -30, -35, -40, -45, -50, -55, -60, -65, -70, -75, -80, -85, -90, -95, or -100. The device storage temperature may also be within a range of any values disclosed herein.

[0076] In some embodiments, a contact element temperature can be selected. The contact element temperature may refer to the temperature of the contact element at the time of application to the patient’s eye. For example, in some embodiments the contact element temperature may be slightly warmer than the device storage temperature, since the device and the contact element may warm up once removed from the freezer used to maintain the device storage temperature. In some embodiments, the contact element temperature may be about -20. The contact element temperature may also be about -30 to about -25. In some embodiments, the contact element temperature may also be within 5 degrees of 0, -5, -10, -15, -20, -25, -30, -35, -40, -45, -50, -55, -60, -65, -70, -75, -80, -85, -90, -95, or -100. The contact element temperature may also be within a range of any values disclosed herein.

[0077] In some embodiments, the contact element temperature after treatment may also be considered. For example, the contact element temperature may refer to the temperature of the contact element after it has been applied to the patient’s eye during treatment. Typically, the contact element temperature after treatment may be warmer than the contact element temperature before treatment, due to heat transfer from the eye. The difference in contact element temperature before and after treatment may be utilized to, for example, calculate a specific or an approximate amount of energy that has been removed from the eye. In some embodiments, the contact element temperature after treatment may be within 5 degrees of 30, 25, 20, 15,10, 5, 0, -5, -10, -15, -20, -30, -35, -40, -45, -50, -55, -60, -65, -70, -75, -80, -85, -90, -95, or -100.

[0078] In some embodiments, a target temperature of the target region, including a region on the ocular surface and / or a region below the ocular surface, may be a goal of the procedure. For example, the target region of the ocular surface, where the cooling device may be applied, can be cooled to at or below 0 C. In some embodiments, a region below the ocular surface, such as the ciliary body, can be cooled to be at or below 0 C. When the target region is below the ocular surface, in some embodiments, the ocular surface itself may need to be cooled below the target temperature of the target region in order to cool the target region to its desired temperature. The target temperature for the target region may be one of 0, -1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, or may be a range between any of these temperatures.

[0079] In some embodiments, the rate of cooling that occurs in the eye may vary based on the treatment protocol. In some embodiments, the rate of cooling can also be targeted or specified in the treatment protocol. For example, the rate of cooling of eye tissue may be about 0.45°C / second. In some embodiments, the rate of cooling can be any rate in the range of 0.1°C / second to 50°C / second.

[0080] According to some embodiments, the temperature of the cold slurry, which may impact the contact element temperature and the amount of cooling that occurs to the eye, may be based on the glycerol -water curve seen in Figure I. Figure 1 depicts the freezing point of the cold slurry compared to the varying percentages of glycerin in water, which represent the cold slurry in some embodiments. In some embodiments, the cold slurry comprises glycol or propylene glycol.

[0081] In some embodiments, the contact element (or elements) can comprise different materials. The contact element may consist of, or comprise, a metal, a polymer, or other materials. For example, the contact element may comprise aluminum, copper, gold, silver, or combinations of any of these materials. In some embodiments, the thermal conductivity of the contact element material affects the cooling of the eye. For example, as thermal conductivity increases, the contact element material may facilitate more heat transfer from the eye to the cold slurry, thus causing more cooling of the eye.

[0082] In some embodiments, the treatment time refers to the amount of time that the device, including the contact element (or elements) is applied to the patient’s eye. The treatment time may refer to the total time that the device is applied in one continuous period. The treatment time may also refer to the total amount of time that the device is applied to thepatient’s eye, for example over several different applications of the device. In some embodiments, the treatment time may be one or more of 1, 2, 3, 4, 5, 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, and 60 minutes. The treatment time may also be between, or in a range of, any of the times disclosed herein.

[0083] Figure 2A and Figure 2B depict a cooling device according to some embodiments. Referring to Figure 2 A, the device has an ice chamber 101 that is comprised of top ice chamber portion 102, bottom ice chamber portion 104, heat exchanger 106, and contact elements 108, In some embodiments the contact elements 108 may be a part of heat exchanger 106. The ice chamber 101 may house the thermal mass required for the procedure. The heat exchanger 106 and contact elements 108 may transfer heat from the eye to the thermal mass. The heat exchanger and contact elements may comprise a thermally conductive material. The contact element(s) 108 may be thermally conductive surfaces that are contoured to the general shape of the sclera and designed to target specific treatment areas. Since the ocular surface may be relatively warmer than the thermal mass, the contact elements, comprising thermally conductive material, may transfer heat from the ocular surface to the thermal mass, thus cooling the ocular surface. The speculum accessory 110 (see Figure 2B) may keep the eyelids open during the procedure, provide thermal protection for the eyelids, and aid in positioning of the device. The outer shell may comprise the top shell 112 and bottom shell 114, provide a protective layer for the device as well as insulation from the outside environment, and it also may provide cosmetic appearance and an all-around rib for improved grip. The contact surface cover 116 may provide protection for the contact elements and packaging and may also prevent condensation on the contact elements prior to the procedure. The device may be provided sterile in disposable, single-use, packaging.

[0084] In some embodiments, care should be taken to avoid reducing the temperature of the eye, or portions of the eye, below certain temperatures, to avoid harm to the eye. Treatment protocols as described herein may be designed to avoid reducing the eye to these harmful temperatures.

[0085] Exemplary Experimental Protocols and Results

[0086] First Clinical Trial Protocol and Results

[0087] Figure 3 reflects results from an Australian pilot human clinical trial evaluating cooling the ocular surface to treat symptoms of COSP. There, an unexpected secondary finding was observed: a notable decrease in IOP among patients with elevated baseline lOPs.

[0088] Specifically, decreased IOP was observed in 3 out of 4 patients with baseline lOPs >21 mm Hg. In 1 out of 4 subjects IOP mildly increased. The sustained Visual Analogue Scale (VAS) scores post-treatment indicate the IOP reduction is the result of the cooling of the ocular surface.

[0089] Presented below are the results of applying cooling to the ocular surface of four eyes with IOP > 21 mmHg as baseline, where the cooling is applied with the ocular surface cooling device as depicted, for example, in Figure 4A and Figure 4B.

[0090] Figure 3 depicts, according to some embodiments, IOP amounts for different study populations over time showing a decrease in intraocular pressure for treated subjects. The following patients are shown in Figure 3:

[0091] 003-001: Treatment time 3:35; No control arm in study 1. IOP decreased.

[0092] 001-002: 56 y / o female with Dry Eye Disease and menopause. Treatment time 4:04. No change in VAS scores. IOP decreased.

[0093] 001-010 - 38 y / o female with Dry Eye Disease, asthma, hypothyroidism, ADHD, and anxiety. Treatment time 4:08. Significant improvement in VAS scores. IOP slightly increased.

[0094] 001-013 - 38 y / o male with Dry Eye Disease, Depression, ADHD, Asthma. Treatment time 4:03. Significant improvement in VAS scores. IOP decreased.

[0095] Collectively, these findings suggest a potential secondary effect of the device on IOP, possibly reducing the intraocular pressure for patients with glaucoma or ocular hypertension.

[0096] Second Clinical Trial Protocol

[0097] A cooling device, according to some embodiments, may be investigated for its effects on IOP in a second protocol that is explained below.

[0098] According to some embodiments of the present disclosure, a device called the ETX-41433.0 will be used. The ETX 4143 3.0 device is described in further detail above, according to some embodiments, with reference to Figure 2A and Figure 2B. The ETX-4143 3.0 Device is a handheld medical device that may contain an internal at least partially frozen (-20° Centigrade) mixture of purified water and glycerol. The ETX-4143 3.0 device does not contain an active pharmaceutical ingredient. The cold temperature generated by the mixture is transferred topically to the scleral surface via two metallic (aluminum) contact surfaces 102 (see Figure 2A), following instillation of topical anesthetic gel and placement of a speculum accessory used to open and insulate the eyelids and position the device. A cornea shield may be applied after application of the device to protect the cornea during treatment. The device and speculum accessory are provided sterile in disposable, single-use packaging. The different versions of the ETX-4143 device are shown, for example the ETX-4143 2.0 device is shown in Figure 4A and Figure 4B according to some embodiments, and the ETX-4143 3.0 device is shown in Figures 2A and 2B according to some embodiments.

[0099] A summary of the administration steps in this clinical trial are shown in Figure 5 A and Figure 5B.

[0100] In this study, the ETX-4143 3.0 device will be topically applied for a total of 4 minutes in order to cool the target regions of the ocular surface to at or below 0 degrees Celsius. The contact surfaces of the device will be positioned posterior to the limbus at 0 degrees and 180 degrees (see Figures 6A and 6B) directed to the position of the long ciliary nerves in the eye. At the conclusion of the procedure, the physician rinses the ocular surface with balanced salt solution or equivalent saline rinse, and then removes the device, cornea shield, and speculum.

[0101] One end point that will be evaluated during this study is the effect that treatment has on a patient’s IOP.

[0102] The ETX-4143 3.0 device is a handheld medical device that contains a mixture of purified water and glycerol. In some embodiments, the device may be kept in its sterile packaging and placed into a freezer, with a temperature range of -22°C to -18°C, for a minimum of 12 hours prior to the procedure until time of use. Other study materials such as the Accessory (silicone lid speculum) and possibly saline will be provided to each clinical site and may be stored at room temperature.

[0103] The device is manufactured, filled with the glycerol and purified water mixture, sterilized, shipped, and stored at room temperature. When it is time to apply treatment, the device is then placed into a medical freezer at the treatment site for at least 12 hours before a procedure to assure that the internal mixture is at the correct temperature and has an adequate amount of frozen ice particles. Within 5 minutes of being removed from the freezer, the device is removed from its packaging and placed directly onto the surface of the eye (conjunctiva) for a duration of 4 minutes. The low (sub-zero °C) temperature of the thermal mass within the device, as well as the capability of the device to transfer heat into that thermal mass, is critical for proper therapeutic benefit.

[0104] The application of the cold device through defined contact elements rapidly removes thermal energy from the ocular surface. The rapid removal of energy causes a significant decrease in the temperature of the targeted tissue, resulting in sub-zero (°C) temperatures for several minutes. Tissue temperature returns to normal following removal of the device. Therapeutic benefit is expected to begin within days to weeks of treatment.

[0105] The device 100 and its components are shown in Figures 2A and 2B, according to some embodiments, and are further described above.

[0106] The sham device is the investigational device but it contains an internal mixture at room temperature. The treatment procedure is the same, using the speculum accessory to open the eyelids and position the device contact surfaces on the conjunctival surface. Study subjects will not be able to determine if they are being treated with the investigational (cold) or sham (room temperature) device due to the application of the topical anesthetic gel. Devices used for sham treatments will be stored at room temperature in a secure cabinet separate from and away from the subject treatment room.

[0107] Third Clinical Trial Protocol

[0108] In a third clinical trial protocol, the ETX-4143 3.0 device, as described above, will be applied at different starting temperatures and for different durations to different cohorts, to investigate the effects of the different approaches on patients’ IOP

[0109] In this study, there will be 4 different groups: (1) Group 1 is the high temperature, short duration cohort, (2) Group 2 is the high temperature, long duration cohort, (3) Group 3 isthe low temperature, short duration cohort, and (4) Group 4 is the low temperature, long duration cohort.

[0110] For Group 1, the device starting temperature (meaning, the temperature of the device just before application to the ocular surface) will be -20, and the device will be applied for 5 minutes. For Group 2, the device starting temperature will be -20 and the device will be applied for 15 minutes. For Group 3, the device starting temperature will be -30 and the device will be applied for 5 minutes. For Group 4, the device starting temperature will be -30 and the device will be applied for 15 minutes. For any of these groups, the device may also be applied for somewhere between 2 and 5 minutes.

Claims

CLAIMSWhat is claimed is:

1. A cooling device for reducing intraocular pressure, the cooling device comprising:a housing;a contact element comprising a thermally conductive material; anda thermal mass;wherein the contact element is configured to be directly or indirectly applied to a target ocular surface of an eye, according to a treatment protocol, to cause a cooling of a target ocular region,and wherein the intraocular pressure of the eye is reduced following the application of the contact element to the target ocular surface.

2. The device of claim 1, wherein the treatment protocol comprises applying the contact element to the target ocular surface when the contact element has a contact element temperature of between -5 and -40 degrees Celsius.

3. The device of any of claims 1-2, wherein the treatment protocol comprises applying the contact element to the target ocular surface when the contact element has a contact element temperature of between -20 and -30 degrees Celsius.

4. The device of any of claims 1 -3, wherein the treatment protocol comprises applying the contact element to the target ocular surface for at treatment time, the treatment time being between about 1 to 20 minutes.

5. The device of any of claims 1-4, wherein the treatment protocol comprises applying the contact element to the target ocular surface for at treatment time, the treatment time being between about 2 to 15 minutes.

6. The device any of claims 1-5, wherein the thermally conductive material comprises a metal.

7. The device any of claims 1-6, wherein the thermally conductive material comprises at least one of aluminum, copper, gold, and silver, or a combination thereof.

8. The device of any of claims 1-7, wherein the thermally conductive material comprises aluminum.

9. The device of any of claims 1-8, wherein prior to the application to the target ocular surface of the eye, the device is stored at a temperature of between about -10 to about -90 degrees Celsius.

10. The device of any of claims 1-9, wherein the thermal mass comprises a mixture of water and glycerol.

11. The device of any of claims 1-10, wherein the thermal mass comprises a plurality of ice particles.

12. A method of lowering intraocular pressure of an eye of a patient, the method comprising:applying a cooling device to a surface of the eye of the patient adjacent to a corneal limbus,wherein the cooling device comprises a housing, a contact element comprising a thermally conductive material, and a cold slurry;wherein the contact element is at or below a temperature of -5 degrees Celsius when applied to the surface of the eye, and the contact element is applied to the eye for at least 2 minutes; andwherein the application of the cooling device causes a lowering of the intraocular pressure of the eye.

13. The method of claim 12, wherein the contact element is applied to the eye for at least 4 minutes.

14. The method of any of claims 12-13, wherein the contact element is applied to the eye for at least 3 minutes.

15. The method of any of claims 12-14, wherein the contact element is applied to the eye for between 3-10 minutes.

16. The method of any of claims 12-15, wherein the contact element is applied to the eye for between 5-15 minutes.

17. The method of any of claims 12-16, wherein the contact element is at or below a temperature of -25 degrees Celsius when applied to the surface of the eye.

18. The method of any of claims 12-17, wherein the contact element is at or below a temperature of -30 degrees Celsius when applied to the surface of eye.

19. The method of any of claims 12-18, wherein the contact element is applied to the eye for at least 4 minutes.

20. The method of any of claims 12-19, wherein the contact element is applied to the eye for at least 5 minutes.

21. The method of any of claims 12-20, wherein the contact element is applied to the eye for at least 10 minutes.

22. The method of any of claims 12-21, wherein the contact element is applied to the eye for at least 15 minutes.

23. The method of any of claims 12-22, wherein the contact element is applied to the eye for at least 20 minutes.

24. The method of any of claims 12-23, wherein the cooling device is applied until a target region of the eye reaches at or below 0 degrees Celsius.

25. The method of any of claims 12-24, wherein the cooling device is applied until a target region of the eye reaches at or below -1 degrees Celsius.

26. The method of any of claims 12-25, wherein the cooling device is applied until a target region of the eye reaches at or below -2 degrees Celsius.

27. The method of any of claims 12-26, wherein the cooling device is applied until a target region of the eye reaches at or below -3 degrees Celsius.

28. The method of any of claims 12-27, wherein the cooling device is applied until a target region of the eye reaches at or below -4 degrees Celsius.

29. The method of any of claims 12-28, wherein the cooling device is applied until a target region of the eye reaches at or below -5 degrees Celsius.

30. The method of any of claims 12-29, wherein the cooling device is applied until a target region of the eye reaches at or below -10 degrees Celsius.

31. The method of any of claims 12-30, wherein the cooling device is applied to the surface of the eye in at least two locations, each of the at least two locations being on opposite sides of a cornea of the eye.

32. The method of any of claims 12-31, wherein the at least two locations are at 0 and 180 degrees with respect to the cornea of the eye.

33. The method of any of claims 12-32, wherein the cold slurry comprises a mixture of water and glycerol.

34. The method of any of claims 12-33, wherein the cold slurry comprises a plurality of ice particles.

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