Compositions and methods for treating presbyopia, hyperopia, astigmatism, reduced stereopsis, and reduced contrast sensitivity - Patents.com

Abstract

Methods and compositions for treating impaired vision due to presbyopia, hyperopia, or astigmatism, and for enhancing contrast sensitivity and stereopsis, are disclosed. Typically, a topical composition comprising about 0.05-10 wt% of a methylated xanthine and about 1-10 wt% of an ophthalmic miotic is applied to the outer surface of at least one eyelid of a subject.

Description

[Technical Field]

[0001] The present disclosure relates generally to methods and compositions for the treatment of impaired vision due to presbyopia, hyperopia, or astigmatism, as well as methods and compositions for enhancing contrast sensitivity and stereopsis. [Background technology]

[0002] Background to the disclosure Presbyopia is a major cause of visual impairment in otherwise healthy eyes. It is a series of age-related changes in which the eye's natural lens gradually thickens and loses flexibility. These age-related changes occur within proteins in the lens, causing it to become stiffer and less elastic over time. Age-related changes also occur in the muscle fibers surrounding the lens. This reduced elasticity makes it difficult for the eye to focus on nearby objects.

[0003] A properly functioning eye in a young person can see at close distances, an ability that deteriorates with age. Presbyopia typically develops as people age and is associated with a natural, progressive loss of accommodation. The presbyopic eye loses the ability to quickly and easily focus on objects at close distances.

[0004] The most common treatment for presbyopia is the use of reading glasses, which can be purchased without a doctor's prescription. Reading glasses allow the eye to focus on nearby objects and maintain a clear image. This approach is similar to that used to treat hyperopia, or farsightedness.

[0005] Contact lenses and intraocular lenses (IOLs) have also been used to treat presbyopia, for example by relying on monovision (one eye corrected for distance vision and the other eye corrected for near vision) correction or bilateral correction using either bifocal or multifocal lenses. Laser ablation has also been used to treat presbyopia. These methods either attempt to correct the problem for long-term purposes using drastic measures (surgery, laser ablation, etc.) or require the wearing of corrective lenses.

[0006] Hyperopia, or farsightedness, is a common visual condition in which distant objects can appear clear, but close objects can appear blurred. The degree of hyperopia affects the eye's ability to focus. People with severe hyperopia have blurred vision for both close and distant objects, while people with mild hyperopia usually have blurred vision for distant objects and severely blurred vision for close objects.

[0007] In most cases, hyperopia is present from birth and tends to be inherited. Hyperopia is easily corrected with glasses or contact lenses. Another treatment option is surgery.

[0008] Astigmatism is a type of refractive error in which the eye does not focus light evenly on the retina, resulting in distorted or blurred vision, regardless of distance. Other symptoms may include eye strain, headaches, and difficulty driving at night. If astigmatism occurs in childhood, it can lead to amblyopia later in life. The cause of astigmatism is unclear, but it is thought to be partly related to genetic factors. The underlying mechanisms include irregular curvature of the cornea or abnormalities in the eye's lens.

[0009] Astigmatism can be corrected with glasses, contact lenses, or refractive surgery. Glasses are the easiest and safest, but contact lenses provide a wider field of vision. Refractive surgery can completely eliminate the need to wear corrective lenses by permanently changing the shape of the eye, but like any elective surgery, it carries both greater risks and costs than non-invasive options.

[0010] Contrast sensitivity is the visual ability to distinguish an object from its background; it is not the same as visual acuity. Poor contrast sensitivity is common in many visual disorders, including cataracts, diabetic retinopathy, and many retinal disorders. Contrast sensitivity in these patients is usually treated by using high-contrast filters, improving lighting, and using clearer, high-contrast materials. In patients with cataracts, surgical removal of the cataract can significantly decrease contrast sensitivity.

[0011] Stereopsis refers to the perception of depth and three-dimensional structure achieved by individuals with normally developed binocular vision based on visual information from both eyes. The most common cause of reduced stereopsis is reduced near or distance vision due to refractive errors. Poor binocular vision due to strabismus (eye deviation) or amblyopia, in which one eye fails to produce sufficient information to the visual cortex, and anisometropia are other less common causes of stereopsis.

[0012] Photopic vision is achieved under sufficiently bright conditions (luminance level 10-10 8 cd / m 2 ) is the visual perception of the eye under light. In humans and many other animals, photopic vision confers cone-mediated color perception, as well as significantly higher acuity and temporal resolution than that afforded by scotopic vision. In most elderly people, light-adapted spatial contrast sensitivity declines; adults in their 70s require approximately three times the contrast to perceive high spatial frequencies compared to adults in their 20s.

[0013] Scotopic vision is achieved at low light levels (brightness level 10-6 ~10 -3.5 cd / m 2 ) is the ability of the eye to see in low light. In the human eye, cone cells do not function in conditions of low visible light. Dark vision is provided exclusively by rod cells, which are most sensitive to wavelengths around 498 nm (green-blue) and insensitive to wavelengths longer than about 640 nm (reddish-orange). This condition is called the Purkinje effect.

[0014] Visual adaptation is much faster under photopic vision; for example, the transition from light to dark adaptation can take 30 minutes in photopic vision.

[0015] Mesopic vision depends on both the amount of external light and the rate of biochemical processes that provide the energy to keep the rod system fully operational. Problems in mesopic vision are related to the pathological transition from photopic to scotopic vision and can manifest clinically as night blindness.

[0016] Currently, there are no approved pharmaceutical therapies available to correct presbyopia, hyperopia, astigmatism, or poor contrast sensitivity or reduced stereopsis. Thus, there remains a need to improve or alleviate these visual conditions in patients who do not want to undergo surgery, wear corrective glasses or contact lenses, or modify their environment to accommodate for poor vision. Summary of the Invention

[0017] Disclosure Overview In one aspect of the present disclosure, provided is a method for treating impaired vision, reduced contrast sensitivity or reduced stereopsis in a subject in need thereof, comprising: applying a topical composition comprising methylated xanthine and a cholinergic agonist to at least one eyelid of the subject, thereby improving visual acuity, contrast sensitivity, stereopsis or a combination thereof.In certain embodiments, impaired vision is presbyopia, hyperopia or astigmatism.

[0018] In some embodiments, the treatment of impaired vision, contrast sensitivity, or reduced stereopsis improves at least one parameter of vision for at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, or longer.In certain embodiments, the composition is applied to at least one eyelid at least once a day or at least twice a day.In certain embodiments, the composition is applied to at least one eyelid of both eyes of the subject.

[0019] In certain embodiments, the methylated xanthine is caffeine, theophylline, dyphylline, theobromine, aminophylline, pentoxifylline, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cholinergic agonist is pilocarpine, carbachol, cevimeline, or physostigmine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises a methylated xanthine selected from caffeine, theophylline, dyphylline, theobromine, aminophylline, pentoxifylline, and a pharmaceutically acceptable salt thereof, and a cholinergic agonist selected from pilocarpine, carbachol, cevimeline, physostigmine, and a pharmaceutically acceptable salt thereof. In certain embodiments, the composition to be applied to the eyelid comprises 0.05 to 10 wt% of the methylated xanthine. In certain embodiments, the composition comprises about 0.05-1 wt% methylated xanthine, such as caffeine, and about 3-8 wt% pilocarpine, 1-3 wt% carbachol, 0.25-3 wt% physostigmine, or 4-15 wt% cevimeline.

[0020] In another aspect of the present disclosure, a method for treating presbyopia, hyperopia, astigmatism, reduced contrast sensitivity, or reduced stereopsis and reducing the incidence of at least one adverse event associated with the application of an ophthalmic miotic to a subject's eye is provided, comprising applying a topical composition comprising 0.05 to 10 wt% methylated xanthine in combination with an ophthalmic miotic to the outside of the subject's eyelid. In certain embodiments, the one or more adverse effects are selected from the group consisting of ciliary spasm, ciliary-caused eyebrow pain, ciliary-caused headache, ocular redness, blurred vision, decreased distance vision, myopia, miosis, ocular blurring, ocular discomfort, ocular pain, decreased distance vision, and light sensitivity. In certain embodiments, the improvement in at least one parameter of vision selected from the group consisting of visual acuity, contrast sensitivity, and stereopsis occurs in the substantial absence of miosis and myopia.

[0021] In certain embodiments of this aspect, the miotic is selected from carbachol, pilocarpine, physostigmine, and cevimeline, or pharmaceutically acceptable salts thereof. In certain embodiments, the methylated xanthine is selected from caffeine, theophylline, dyphylline, theobromine, aminophylline, and pentoxifylline, and pharmaceutically acceptable salts thereof.

[0022] In certain embodiments, the at least one parameter of vision that is improved is selected from increased accommodation, increased distance visual acuity, increased near visual acuity, increased contrast sensitivity, increased stereopsis, or a combination thereof.

[0023] In certain embodiments of this aspect of the disclosure, the composition comprises about 3-8 wt% pilocarpine, 1-3 wt% carbachol, 0.25-3 wt% physostigmine, or 4-15 wt% cevimeline. In certain embodiments, the composition comprises about 0.05-1 wt% caffeine or pentoxifylline.

[0024] In certain embodiments, the composition comprises about 0.05-1 wt% caffeine, theophylline, or pentoxifylline, and about 3-8 wt% pilocarpine.

[0025] In certain embodiments, the composition comprises about 0.05-1 wt% caffeine, theophylline, or pentoxifylline, and about 1-3 wt% carbachol.

[0026] In certain embodiments, the composition comprises about 0.05-1 wt% caffeine, theophylline, or pentoxifylline, and about 0.25-1 wt% physostigmine.

[0027] In another aspect of the present disclosure, there is provided a topical composition for treating astigmatism, presbyopia, hyperopia, reduced contrast sensitivity or reduced stereopsis, comprising methylated xanthine and an ophthalmic miotic, wherein applying the composition to the outer surface of at least one eyelid of a subject in need thereof improves at least one visual parameter that is affected by astigmatism, presbyopia, hyperopia or reduced contrast sensitivity, respectively, without causing substantial miosis or myopia.In certain embodiments, the methylated xanthine is selected from caffeine, theophylline, dyphylline, theobromine, aminophylline and pentoxifylline, and their pharmaceutically acceptable salts.In certain embodiments, the ophthalmic miotic is pilocarpine, carbachol, physostigmine or cevimeline. [The present invention 1001] An ophthalmic miotic agent for use in treating impaired vision, decreased contrast sensitivity, or reduced stereopsis in a subject in combination with at least one methylated xanthine or a pharmaceutically acceptable salt or ester thereof, wherein the combination is formulated for topical application to at least one eyelid of the subject. [The present invention 1002] Ophthalmic miotics for use in accordance with the present invention 1001, including pilocarpine, carbachol, cevimeline, or physostigmine. [The present invention 1003] 1001. An ophthalmic miotic for use in accordance with the present invention, wherein the combination comprises 1-10 wt% pilocarpine, 1-3 wt% carbachol, 4-15 wt% cevimeline, or 0.25-3 wt% physostigmine. [The present invention 1004] Ophthalmic miotics for use in accordance with the present invention 1001, including pilocarpine. [The present invention 1005] An ophthalmic miotic for use in accordance with the present invention 1001, comprising carbachol. [The present invention 1006] The ophthalmic miotic for use in accordance with the present invention is physostigmine. [The present invention 1007] The ophthalmic miotic for use in the present invention 1001 is cevimeline. [The present invention 1008] An ophthalmic miotic for use in any of claims 1001 to 1007, wherein the methylated xanthine is selected from caffeine, theophylline, dyphylline, theobromine, aminophylline, and pentoxifylline, and pharmaceutically acceptable salts thereof. [The present invention 1009] The ophthalmic miotic for use in accordance with the present invention 1008, wherein the methylated xanthine is caffeine. [The present invention 1010] An ophthalmic miotic for use in accordance with the present invention 1008, wherein the methylated xanthine is pentoxifylline. [The present invention 1011] The ophthalmic miotic for use in accordance with the present invention 1008, wherein the methylated xanthine is theophylline. [The present invention 1012] An ophthalmic miotic for use in accordance with the present invention 1008, wherein the methylated xanthine constitutes 0.05 to 10 wt% of the combination. [The present invention 1013] An ophthalmic miotic for use in accordance with the present invention 1012, wherein the methylated xanthine is caffeine. [The present invention 1014] An ophthalmic miotic for use in accordance with the present invention 1012, wherein the methylated xanthine is pentoxifylline. [The present invention 1015] An ophthalmic miotic for use in accordance with the present invention 1012, wherein the methylated xanthine is theophylline. [The present invention 1016] An ophthalmic miotic for use in any of claims 1001 to 1015, wherein the combination results in improvement of at least one parameter related to vision. [The present invention 1017] An ophthalmic miotic for use in accordance with the present invention 1016, wherein at least one parameter relating to vision is improved for at least 4 hours. [The present invention 1018] An ophthalmic agent for use according to the present invention 1016 or 1017, wherein the improvement in at least one parameter related to vision is selected from improved accommodation, improved distance vision, increased near vision, improved contrast sensitivity, improved stereopsis, and combinations thereof. [The present invention 1019] An ophthalmic miotic for use in any of inventions 1001 to 1018, wherein the combination results in a lower incidence of at least one adverse event selected from the group consisting of blurred vision, ocular discomfort, eye pain, eyebrow pain, blurred vision, light sensitivity, myopia, night blindness, and decreased distance vision, compared to administration to the eye of a composition containing the ophthalmic miotic. [The present invention 1020] The ophthalmic preparation for use according to any one of claims 1001 to 1019, wherein the impaired vision is hyperopia, presbyopia, or astigmatism. [The present invention 1021] A composition for treating presbyopia, hyperopia, astigmatism, decreased contrast sensitivity, or reduced stereopsis in a subject, comprising a methylated xanthine in combination with an ophthalmic miotic agent, wherein the combination is formulated for topical application to the eyelid of the subject. [The present invention 1022] The composition of the present invention 1021, wherein treating with said ophthalmic miotic agent results in a reduction in the incidence of at least one adverse event associated with the use of said ophthalmic miotic agent when applied to the eye, said adverse event being selected from the group consisting of blurred vision, eye discomfort, eye pain, eyebrow pain, blurred vision, light sensitivity, miosis, myopia, night blindness, and decreased distance vision. [The present invention 1023] The composition of the present invention 1021, wherein said combination results in an improvement in at least one parameter related to vision. [The present invention 1024] The composition of claim 1023, wherein said improvement in at least one parameter related to vision occurs in the substantial absence of miosis and induced myopia. [The present invention 1025] The composition for use of the present invention 1021, wherein the methylated xanthine is selected from the group consisting of caffeine, theophylline, dyphylline, theobromine, aminophylline, and pentoxifylline, and pharmaceutically acceptable salts thereof. [The present invention 1026] 1021. The composition of the present invention, comprising 1-10 wt% pilocarpine, 1-3 wt% carbachol, 4-15 wt% cevimeline, or 0.25-3 wt% physostigmine. [The present invention 1027] 1026. The composition of claim 1026, wherein the methylated xanthine constitutes 0.05 to 10 wt% of the composition. [The present invention 1028] The composition of any one of claims 1021 to 1027, wherein the methylated xanthine comprises caffeine and the ophthalmic miotic comprises carbachol. [The present invention 1029] The composition of any one of claims 1021 to 1027, wherein the methylated xanthine comprises caffeine and the ophthalmic miotic comprises pilocarpine. [The present invention 1030] A composition for use in any one of claims 1021 to 1027, wherein the methylated xanthine is pentoxifylline and the ophthalmic miotic is carbachol. [The present invention 1031] A composition for use in any one of claims 1021 to 1027, wherein the methylated xanthine is pentoxifylline and the ophthalmic miotic is pilocarpine. [The present invention 1032] A composition for use in any of claims 1021 to 1027, wherein the methylated xanthine is pentoxifylline and the ophthalmic miotic is physostigmine. DETAILED DESCRIPTION OF THE INVENTION

[0028] Detailed Description of the Disclosure definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains.

[0029] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0030] The term "visual acuity" means the sensitivity or acuity of vision, determined by the sensitivity of the retinal focus in the eye, and measured as the ability to distinguish letters or numbers from a given distance according to established criteria.

[0031] As used herein, "impaired vision" means a reduced ability to see without corrective glasses or contact lenses. "Vision impairment" or "impaired vision" is best-corrected visual acuity worse than 20 / 40 or 20 / 60. As used herein, the term "impaired vision" does not refer to blindness or legal blindness, the latter being 20 / 200 or worse.

[0032] The term "therapeutically effective amount" refers to an amount that is effective when administered to an individual to treat presbyopia, hyperopia, astigmatism, reduced contrast sensitivity, or reduced stereopsis as needed, or to improve at least one visual parameter. The degree of visual improvement and / or success in treating presbyopia, hyperopia, astigmatism, reduced contrast sensitivity, or reduced stereopsis when a therapeutically effective amount of a composition is administered to an individual for each condition will be readily determinable by one of ordinary skill in the art, as described herein.

[0033] The term "myopia" refers to a condition of the eye in which the visible image is focused in front of the retina, resulting in nearsightedness, a particular defect in seeing distant objects.

[0034] As used herein, the term "presbyopia" refers to a visual condition in which the loss of elasticity of the crystalline lens of the eye leads to a defect in accommodation, resulting in an inability to focus sensitively for near vision.Presbyopia is a condition in which the ability to refocus from far to near vision progressively decreases with age, resulting in a decline in the function of intermediate and near reading.Presbyopia usually occurs, especially in middle age.

[0035] As used herein, the terms "hyperopia" or "farsightedness" refer to an eye condition in which incident light rays strike the retina before converging into a focused image, resulting in difficulty seeing nearby objects clearly. The primary difference between presbyopia and hyperopia is the cause of each condition. While aging leads to presbyopia, hyperopia has a genetic component. Hyperopia is present from birth, and visual correction mechanisms deteriorate with age, resulting in blurred vision. Hyperopia is often not significantly affected by age, whereas presbyopia occurs in most people over the age of 40.

[0036] As used herein, the term "astigmatism" means a visual abnormality in which an uneven curvature of one or more refractive surfaces of the eye, usually the cornea, prevents light rays from being sharply focused to a single point on the retina, resulting in blurred vision.

[0037] As used herein, the term "contrast sensitivity" refers to the ability to detect subtle differences in shade and pattern. Contrast sensitivity is important in detecting objects without sharp edges and distinguishing objects or details from their background. Contrast sensitivity is a measure of how different pattern contrast must be in order to be visible, while "acuity" indicates how large an object must be in order to be visible. Contrast sensitivity is increasingly recognized as an important factor affecting the quality of vision. There is a wide range of variation in both acuity and contrast sensitivity among people with normal vision. Acuity of 0.8 (20 / 25, 6 / 9) is considered the low normal value, while the highest normal value is three times larger, or 2.5 (20 / 8, 6 / 2.5). Criteria for various levels of contrast reduction include severe reduction of less than 0.48 log contrast, severe reduction of 0.52 to 1.00, and moderate reduction of 1.04 to 1.48; normal values ​​for individuals over 60 years of age are 1.52 to 1.76, and normal values ​​for individuals 60 years of age and younger are 1.72 to 1.92 log contrast.

[0038] As used herein, "reduced contrast sensitivity" or "insufficient contrast sensitivity" refers to a reduced contrast sensitivity compared to a subject with "normal vision." Contrast sensitivity can be measured, for example, using the Perry-Robson contrast chart, which is used for most clinical research studies. The Perry-Robson chart displays letters as triplets. Each triplet is 0.08 log units lighter. Criteria for various levels of contrast reduction include a "normal" condition where a patient can read 6-7 rows (12-14 triplets). A moderate contrast reduction is when a patient can only read 4-5 rows. In severe cases, a patient can only read 2-3 rows, and in profound contrast reduction, a patient can only read 1 row or less.

[0039] An alternative to the Perry-Robson chart is the Mars Letter Contrast Sensitivity Test. The Mars test uses a set of three near-vision charts. Each letter is 0.04 log units fainter, allowing for more accurate measurement of contrast reduction than is possible with the Perry-Robson chart. Patients are given a log contrast score based on the number of letters they can see. Unlike the Perry-Robson test, which uses a 1-meter testing distance, the Mars test uses a 50-centimeter testing distance. Criteria for various levels of contrast reduction include severe reduction of less than 0.48 log contrast, severe reduction of 0.52 to 1.00, and moderate reduction of 1.04 to 1.48. Normal values ​​for individuals over 60 years of age are 1.52 to 1.76, and normal values ​​for individuals 60 years of age and younger are 1.72 to 1.92 log contrast.

[0040] The term "sustained release" is used herein in its ordinary sense to mean that the compositions disclosed herein are designed to slowly release a drug over an extended period of time.

[0041] The term "uncorrected near visual acuity" ("UNVA") refers to a person's ability to see details of objects within arm's length of the body (e.g., 33-41 cm from the eye) without the use of any visual aids (e.g., eyeglasses or contact lenses). Similarly, the term "distance-corrected near visual acuity" ("DCNVA") is used herein to refer to a person's ability to see details of objects within arm's length of the body (e.g., 33-41 cm from the eye) with the use of visual aids such as eyeglasses or contact lenses that correct distance vision problems. The terms "near vision," "near visual acuity," and "near visual acuity" may be used interchangeably.

[0042] The term "unaided distance visual acuity" ("UDVA") refers to a person's ability to see fine details in objects that are more than an arm's length away from the body, for example, more than 4 meters from the eye, without the use of any visual aids (e.g., glasses or contact lenses). The terms "distance visual acuity," "far vision," and "distance vision" may be used interchangeably.

[0043] As used herein, the term "comfort score" refers to a score assessing pain sensitivity on a scale of 0 to 10, with higher scores indicating greater pain sensitivity. Comfort scores range from 0 (not comfortable) to 4 (very comfortable). Comfort scores were assessed to measure comfort levels. It is known in the art that comfort levels rapidly decrease with standard cholinergic agonists due to unavoidable accommodative spasms that cause pain. Discomfort and pain caused by ciliary muscle spasm and miosis typically result in ocular pain, periocular pain, headache, tingling, burning, and / or redness within 30 minutes of application of the miotic to the eye.

[0044] The term "visual clarity score" refers to a subject's impression of the overall quality of their vision. Clarity scores range from 0 (poor) to 4 (excellent). Overall visual clarity with current technology using cholinergic agonist therapy is impaired by ciliary muscle spasms, which cause blurred distance vision and myopic near vision at certain distances. As a result, the overall clarity of the visual experience is reduced.

[0045] As used herein, the term "refractive power" refers to a measurement of the eye's ability to focus at a distance. Refraction refers to the bending of light that occurs within the human eye. Refractive errors include myopia (nearsightedness), hyperopia (farsightedness), and astigmatism.

[0046] The terms "intermediate distance visual acuity," "intermediate visual acuity," and "intermediate visual acuity" may be used to refer to a person's ability to see details in objects at distances between the near and far visual ranges. Such distance range is considered to be between a distance roughly greater than an arm's length (about 40-60 cm from the eye) and a distance less than about 4 meters from the eye. The term "distance-corrected intermediate visual acuity" ("DCIVA") may be used to refer to a person's ability to see details in objects located at intermediate distances with the aid of visual aids such as glasses or contact lenses that correct distance vision problems.

[0047] The term "visual parameter" or "visual parameter" refers to any characteristic of a patient's vision that can be measured and improved using the compositions and methods described herein. Vision parameters that can be improved in various embodiments described herein include, but are not limited to, near vision, intermediate vision, distance vision, night vision, daytime vision, optical aberrations (e.g., glare, light scattering), contrast sensitivity, stereopsis, and dysaccadic vision. Vision improvement or visual improvement, including, but not limited to, near vision, intermediate vision, and / or distance vision, contrast sensitivity, stereopsis, and combinations thereof, can be reflected, for example, in an increase in the number of letters correctly read on a visual chart at any time after administration from baseline (i.e., before treatment). Improvement in night vision can be reflected in an improvement in a patient's vision under dim or dark lighting (e.g., under mesopic or scotopic conditions). Improvement in daytime vision can be reflected in an improvement in a patient's vision under bright light or sunlight present during daylight hours (e.g., under photopic conditions). Improved stereopsis can result in improved three-dimensional vision or depth perception. Vision improvement using the compositions and methods described herein can also be achieved when combined with or used with other visual aids and assistive devices, including but not limited to reading glasses, lens-modifying medications, and surgical options for presbyopia, including intraocular lenses (IOLs).

[0048] As used herein, the term "accommodation" refers to the mechanism by which the eye changes focus from a distant image to a near image. Accommodation is the adjustment of the eye's lens to keep an object in focus on the retina as the object's distance from the eye changes. Accommodation is brought about by the ciliary muscle acting on the zonular fibers to change the shape of the crystalline lens. The crystalline lens is most flexible during childhood and young adulthood and gradually loses its ability to change shape with age, resulting in presbyopia.

[0049] The term "miosis" is used herein to mean excessive constriction of the pupil. Miosis can occur as a normal response to increased light, or can be caused by certain drugs, such as miotics, e.g., cholinergic agonists, or by pathological conditions.

[0050] The terms "miotropic drug" or "miotic" or "ophthalmic miotic" or "ophthalmic miotic," used interchangeably herein, refer to any drug or pharmaceutically active agent (API) used to treat visual conditions and that, when applied directly to the eye, constricts the pupil of the eye. Miotics are either parasympathomimetic (cholinergic stimulating) drugs with direct muscarinic action, such as pilocarpine, cevimeline, and carbachol, or anticholinesterase drugs, such as physostigmine, neostigmine, echothiophate, and demecarium, that block the action of acetylcholinesterase, thereby allowing acetylcholine to exert its effects. Some miotics act by blocking α- or β-adrenergic receptors. For example, dapiprazole and thymoxamine block α-adrenergic receptors, and propranolol blocks β-adrenergic receptors. When applied directly to the eye, ophthalmic miotics often cause undesirable and painful side effects, such as accommodation spasm, eye pain, headache, blurred vision, and decreased ability to function in low or dark ambient light.

[0051] As used herein, the term "cholinergic agent" or "cholinergic agonist" refers to a compound that enhances or mimics the action of the neurotransmitter acetylcholine, the primary transmitter of nerve impulses in the parasympathetic nervous system, or butyrylcholine. A substance is cholinergic if it can generate, modify, or release acetylcholine or butyrylcholine ("indirect action"), or mimic the behavior of one or more of the body's acetylcholine receptor types ("direct action") or butyrylcholine receptor types ("direct action"). Such mimetics are called parasympathomimetics or cholinomimetics, and are included in the category of "cholinergic agents" used herein. The term "cholinergic agent" also refers to salts and esters of such compounds. Non-limiting examples of cholinergic agents that can be included in the compositions disclosed herein include ophthalmic miotics, pilocarpine, carbachol, physostigmine, and cevimeline. With respect to pilocarpine, carbachol, physostigmine, and cevimeline, the terms "cholinergic agent," "cholinergic agonist," "miotropic agent," "miotic," "ophthalmic miotic," and "ophthalmic miotic" are used interchangeably herein.

[0052] As used herein, the term "methylated xanthine" or "methylxanthine" refers to compounds within a class of drugs derived from the purine base xanthine, which is naturally produced by both plants and animals. Non-limiting examples of methylxanthines include theophylline, dyphylline, caffeine, theobromine, aminophylline, and pentoxifylline.

[0053] As used herein, the term "eyelid" refers to one of the two flexible folds of protective thin skin that cover each eye, along whose edges are located eyelashes and lash glands and meibomian glands.The upper eyelid and the lower eyelid are separated by the palpebral fissure.In each embodiment of the method of the present invention for treating presbyopia, hyperopia, astigmatism, insufficient contrast sensitivity, or reduced stereopsis, it is understood that the treatment substance is applied to the outer skin surface of the upper eyelid, lower eyelid, or both upper and lower eyelids of one or both eyes, as needed.

[0054] The present inventors have previously discovered that adding methylated xanthine to a topical drug-containing composition for administration to the outer surface of the eyelid can achieve sustained release and enhanced penetration of the drug into the eye. (US9,034,830, the entire contents of which are incorporated herein by reference). Without wishing to be bound by a particular theory, it is believed that methylated xanthine, such as caffeine, can act as a solubilizer for the active substance contained in the composition, thereby increasing the bioavailability of the active substance. It is also believed that methylated xanthine acts on the blinking muscle, causing small, localized involuntary muscle contractions (muscle spasms), which transport the drug contained in the composition into the eyelid and circulatory system.

[0055] The present inventors have now discovered that applying a composition comprising a combination of a methylated xanthine and a cholinergic agonist or other miotic to the eyelids of an individual diagnosed with or suffering from a visual disorder that causes blurred vision, such as hyperopia, astigmatism, presbyopia, or insufficient contrast sensitivity or reduced stereopsis, improves distance vision, peripheral vision, or near vision, or improves contrast sensitivity or stereopsis, depending on the condition being treated, without causing the adverse side effects associated with applying a miotic, such as a cholinergic agonist, to the eye, for example, by eye drops.The disclosed compositions and methods treat presbyopia by improving depth of focus and providing accommodation, without causing eye pain, headache, blurred vision, induced myopia, miosis, reduced distance vision, and / or reduced vision in dim or dark light conditions, by topically applying the disclosed compositions to one or more eyelids of a presbyopic subject.The disclosed compositions and methods treat hyperopia, for example, by improving near vision, and treat astigmatism by improving visual clarity. The compositions and methods of the present invention treat inadequate contrast sensitivity by increasing contrast sensitivity. In treating each of these ocular conditions, topical application to the eyelid of a composition of the present disclosure comprising a combination of a methylated xanthine and a cholinergic agonist or other miotic agent improves vision without producing miosis or myopia.

[0056] The compositions and methods of the present disclosure selectively affect a subject's ability to focus or accommodate without significantly affecting the pupil. The methods of the present disclosure result in the absorption of the compositions of the present invention into the ciliary body. The ciliary body is a ring-shaped tissue thickening inside the eye that separates the posterior chamber from the vitreous body. Absorption into the ciliary body occurs via the vascular system of the eyelid. As a result, the compositions and methods of the present disclosure do not inject large amounts of active ingredients into the anterior chamber of the eye. The methods and compositions of the present disclosure affect a subject's ability to focus without causing ciliary spasm and with little or no significant effect on the pupil. Therefore, the methods and compositions of the present disclosure can maintain pupil size within the physiological range. That is, the pupil diameter remains within the physiological range of pupil size (which varies depending on eye color) after applying the compositions of the present disclosure to the eyelid, thereby avoiding reduced contrast sensitivity, night blindness, or reduced visual acuity.

[0057] While a fully dilated pupil typically measures 4 to 8 millimeters, a constricted pupil typically measures less than 3 mm, typically a pinpoint pupil, i.e., 1.5 to 1.9 mm, or even 2.5 mm. According to the American Academy of Ophthalmology, pupil size is normally in the range of 2 to 8 mm. The disclosed methods and compositions maintain the pupil within this range, whereas application of a miotic drug alone to the eye can cause the pupil to constrict significantly, e.g., to less than 2.5 mm.

[0058] In medicine, the use of cholinergic agonists and other miotic drugs is limited because they tend to cause adverse effects in any organ under the control of the parasympathetic nervous system.Adverse effects include blurred vision, miosis, myopia, muscle spasms and diarrhea, low blood pressure and slow heart rate, nausea and vomiting, excessive salivation and sweating, shortness of breath, and increased urinary frequency.For example, the current use of the cholinergic compound pilocarpine in ophthalmic eye drops is limited by some commonly occurring adverse events.These adverse events include temporal and periorbital headaches (i.e., eyebrow pain), which may be caused at least in part by rapid ciliary muscle contraction, ciliary spasm, the decrease in night vision and mesopic vision due to miosis, the decrease in distance vision, the decrease in contrast sensitivity, and myopia. Pilocarpine also acts on muscarinic cholinergic receptors present on the iris sphincter, causing muscle contraction and pupil constriction (i.e., miosis) (Levin et al., Adler's Physiology of the Eye, 11th edition by Saunders Elsevier (Edinburgh), pp. 56, 57, and 509-510). Because of these adverse effects, pilocarpine is used only in low doses in eye drops, e.g., 1.0-2% w / v, and is applied to only one eye due to reduced distance vision and myopia. Similarly, carbachol, a cholinomimetic compound applied to the eye as a liquid (eye drops) to treat glaucoma, also causes reduced night vision and is applied only in low doses, i.e., approximately 1.0%. Because low doses are required to limit adverse side effects, any beneficial effects of these drugs are short-lived, e.g., 4 hours or less, necessitating multiple applications per day, further exacerbating the adverse effects.

[0059] To combat the adverse side effects often associated with the use of pilocarpine eye drops, the drug is often combined with a cholinergic antagonist, but such combinations often result in new side effects in addition to those associated with pilocarpine use.

[0060] The use of the compositions and methods of the present disclosure eliminates or at least significantly reduces the adverse effects, such as miosis or myopia, observed with the use of eye drops containing cholinergic compounds or other miotics, such as pilocarpine, physostigmine, or carbachol.Furthermore, because the compositions of the present disclosure are formulated for application to the eyelids rather than directly to the eyeball, the cholinergic compounds or other miotics contained therein are slowly released into and across the eyelids and into the eye, allowing the use of high dosages of the active ingredient and therefore long-lasting beneficial effects on vision.

[0061] In one aspect of the present disclosure, there is provided a topical ophthalmic composition for application to eyelids, for treating presbyopia, astigmatism, hyperopia, or insufficient or reduced contrast sensitivity or reduced stereopsis.In the embodiment described herein, the composition comprising a therapeutic amount of cholinergic agonist or other miotic drug in combination with an effective amount of methylated xanthine is topically applied to one or more eyelids of the subject of presbyopia or hyperopia, or the subject of astigmatism, or the subject of insufficient contrast sensitivity or reduced stereopsis, to treat each ocular condition.

[0062] The compositions described herein are formulated for topical application to the eyelids of a subject. As used herein, the term "topical" refers to the use of a composition, as described herein, that is mixed in a suitable pharmaceutical carrier and applied to the outer surface of one or more eyelids. The composition may be applied to the outer surface of one or both eyelids as needed. Typical topical compositions are in a pharmaceutically acceptable form that allows the composition to be applied directly to the outer skin surface of the eyelid. Non-limiting examples of such pharmaceutical forms include ointments, liniments, creams, washes, lotions, pastes, jellies, sprays, and aerosols. These compositions can also be applied via patches or impregnated bandages. The term "ointment" includes formulations with oily, water-soluble, and emulsion-type bases, such as petrolatum, lanolin, polyethylene glycol, and mixtures thereof.

[0063] Methylated xanthines that may be used in the various compositions and methods of the present disclosure include, for example, caffeine, theophylline, dyphylline, or aminophylline for topical application to the eyelid or eyelid margin.

[0064] The cholinergic agent useful for inclusion in the compositions described herein includes, but is not limited to, pilocarpine, carbachol, physostigmine, cevimeline, neostigmine, acetylcholinesterase inhibitors, donepezil, galantamine, tacrine, rivastigmine, metrifonate, pyridostigmine, ambenonium, demarcarium, cevimeline, edrophonium, huperzine A, ladostigil, diisopropylfluorophosphate (Floropryl), phosphonate iodide (echothiophate), and physostigmine (eserine), and pharmaceutically acceptable salts and esters thereof.In certain embodiments of all aspects of the present disclosure, the cholinergic agent is pilocarpine, physostigmine, carbachol, cevimeline, or pharmaceutically acceptable salts or esters thereof, or combinations thereof.

[0065] Typically, the compositions of the present disclosure contain one or more cholinergic agonists or other miotic agents in a therapeutically effective amount that is about 0.1 to about 10 wt% of the composition. Because the compositions described herein are applied to the eyelid rather than directly to the eyeball as in eye drops, larger amounts of active agents, such as cholinergic agonists, can be included in the compositions, thereby further enhancing the beneficial visual effects observed with the use of these agents without the typical side effects seen when these agents are used directly in the eye. For example, application of a cholinergic agonist, such as pilocarpine, in an amount of 1-10 wt%, or 3-8 wt%, or 4-6 wt%, or 6-8 wt%, or carbachol in an amount of 1-3 wt%, or 1.5-2.5 wt%, or 2-3 wt%, or physostigmine in an amount of 0.25-3 wt%, or 0.5-2.5 wt%, or 1-2 wt%, or cevimeline at 4-15 wt%, 4-12 wt%, or 4-10 wt%, applied, for example, to the eyelid, improves visual acuity and near vision, and / or contrast sensitivity and / or stereopsis, without or at least significantly reducing any adverse effects on distance vision, miosis, or myopia observed when the miotic agent is applied alone to the eye. The application of the composition of the present disclosure to the eyelids of the subject in need of treatment results in a lower incidence of at least one or more adverse events, such as blurred vision, eye discomfort, eye pain, eyebrow pain, blurred vision, light sensitivity, night blindness, pinhole vision, decreased contrast sensitivity, myopia, and decreased distance vision, compared with the administration of eye drops containing pilocarpine, carbachol, physiostigmine, or other cholinergic agonists.In addition, the application of the composition described herein to the eyelids results in the sustained release of cholinergic agonists or miotic agents into the eye by including methylated xanthine in the composition.Methylated xanthine causes small, localized involuntary muscle contractions (muscle spasms) in blinking muscles for a sustained period, and delivers active ingredients into the eye for a sustained period, for example, at least 4 hours and at least 10 hours, or at least 12 hours or 24 hours after application.In the embodiments described herein, the composition can be administered once a day, twice a day, or more frequently as needed.In certain embodiments, the composition is administered once a day.When administered, the composition can have a duration of action sufficient for a full day.In some embodiments, the composition can have a duration of action of at least 4 hours, for example, more than 4 hours, for example, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, or up to 24 hours, and all time points in between.Some embodiments can provide a composition with a duration of action of 12 hours or even 24 hours.Duration of action refers to the duration during which the administered composition has a positive effect on at least one visual parameter related to presbyopia, hyperopia, astigmatism, reduced contrast sensitivity, or reduced stereopsis. In certain embodiments of all aspects of the present disclosure, the compositions of the present disclosure can include 1-10 wt %, e.g., 2-9 wt %, 3-9 wt %, 4-9 wt %, 5-9 wt %, or 6-9 wt %, or any amount therebetween, of a cholinergic agonist, e.g., pilocarpine, physostigmine, cevimeline, or any one of carbachol, or a pharmaceutically acceptable salt or ester thereof, in combination with 0.05-10 wt % of a methylated xanthine, e.g., caffeine, theophylline, pentoxifylline, aminophylline, or theobromine. Other examples of compositions of the present disclosure include compositions comprising 6-8 wt% pilocarpine, or 1-3 wt% carbachol, or 0.25-3 wt% physostigmine, or 4-15% cevimeline (or pharmaceutically acceptable salts or esters of these cholinergic agonists) in combination with 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, or 0.5 wt% caffeine or other methylated xanthines.In some embodiments, the amount of methylated xanthine used with either the cholinergic agonist or miotic included in the compositions described herein is between 0.05 and 2.5 wt%, e.g., 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0. The amount of caffeine in the composition of the present disclosure is 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 0.13 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, or 2.5 wt%. In certain embodiments, the amount of caffeine in the composition of the present disclosure is 0.2 to 0.5 wt%, for example, 0.32 wt%. In other embodiments, the amount of pentoxifylline is 0.05 to 1 wt%. In some embodiments, the amount of theophylline contained in the composition disclosed herein is 0.1 to 0.5 wt%.

[0066] Compositions of the present disclosure include, but are not limited to, compositions comprising: 1-10 wt% pilocarpine and 0.05-1 wt% caffeine; 1-10 wt% pilocarpine and 0.05-1 wt% theophylline; 1-10 wt% pilocarpine and 0.05-1 wt% pentoxifylline; 1-3 wt% carbachol and 0.05-1 wt% caffeine; 1-3 wt% carbachol and 0.05-1 wt% theophylline; 1-3 wt% carbachol and 0.05-1 wt% pentoxifylline; 0.25- 3 wt% physostigmine and 0.05 to 1 wt% caffeine; 0.25 to 3 wt% physostigmine and 0.05 to 1 wt% pentoxifylline; 0.25 to 3 wt% physostigmine and 0.05 to 1 wt% theophylline; 4 to 15% cevimeline and 0.05 to 1 wt% caffeine; 4 to 15 wt% cevimeline and 0.05 to 1 wt% theophylline; 4 to 15 wt% cevimeline and 0.05 to 1 wt% pentoxifylline.

[0067] The compositions described herein can be formulated into aqueous solutions, creams, ointments, or physiologically acceptable oils.Depending on the dispenser, these preparations may or may not contain additives such as preservatives, for example, benzalkonium chloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acid, and phenylmercury salts such as nitrates, chlorides, acetates, and borates, or antioxidants, and additives such as EDTA, sorbitol, and boric acid.In addition, aqueous solutions may also contain viscosity-increasing agents, for example, polysaccharides, for example, methylcellulose, mucopolysaccharides, for example, hyaluronic acid and chondroitin sulfate, or polyhydric alcohols, for example, polyvinyl alcohol.For ease of application, the compositions can be formulated into stick applicators or other cosmetic applicators suitable for application to the eyelid or the base of eyelashes, for example, the eyelid margin.

[0068] The present disclosure also provides for the use of a methylated xanthine in combination with an ophthalmic miotic described herein in the manufacture of a medicament for treating a subject exhibiting reduced visual acuity, reduced contrast sensitivity, or reduced stereopsis.

[0069] Kits that comprise one or more compositions disclosed herein are also provided.These kits may comprise the single-use dosage form of compositions disclosed herein, or may comprise, for example, vials that contain multiple doses that are measured out by patient or applicator itself.In addition, kits may comprise the formulations of various therapeutic substances for treating presbyopia, which are intended to be applied to different eyelids or skin areas and / or at different times during treatment regimen.Kits may also, if necessary, comprise instructions for appropriate administration regimen.

[0070] The following examples are illustrative in nature and are not intended to be limiting in any way. [Example]

[0071] Example 1 Immediate effects of treatment A 45-year-old patient who recently noticed problems with close-up vision was treated with a topical composition containing 6 wt% pilocarpine and 0.32 wt% caffeine, which was applied to the eyelids of both eyes.

[0072] Prior to treatment, the following data points were obtained: pupil Refractive power: +25SPH Plano SPH > +1.75ADD Naked eyes near Naked eye DV Comfort (1+~4+) Clarity (1+~4+) Pupil before treatment: 5.0mm Near vision JS Distance vision sc20 / 20 Comfort 3+ Clarity 3+

[0073] The following post-treatment measurements were taken: 1 hour after treatment Pupil 4.5mm Unaided near visual acuity (VA) improved to J2 Unaided distance visual acuity remained 20 / 20 Comfort score improved to 4+ Clarity score improved to 4+ 2 hours after treatment Pupil size 5.0mm Unaided near vision improved to the highest level, J1. Naked eye distance VA 20 / 20 Comfort Score 4+ Clarity score 4+ 3 hours after treatment Pupil size 4.5mm Near visual acuity remained elevated at J1 Distance visual acuity remained 20 / 20 Comfort Score 4+ Clarity score 4+ 4 hours after treatment Pupil size 4.5mm Near visual acuity remained elevated at J1 Distance visual acuity remained at 20 / 20 Comfort Score 4+ Clarity score 4+ Five hours after treatment Pupil size 4.0 Near visual acuity remained optimal at J1. Distance vision remained an excellent 20 / 20 Comfort Score 4+ Clarity score 4+

[0074] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0075] Treatment Summary: Treatment of emmetropic presbyopia with pilocarpine 6% and caffeine 0.32% resulted in spontaneous improvement of near and intermediate vision in each eye while preserving distance vision. Distance vision in the right eye improved.

[0076] Example 2 A 49-year-old woman presented with hyperopic astigmatism and sudden onset of presbyopia and decreased near and distance visual acuity in both eyes. The patient did not want to wear contact lenses due to intolerance. Furthermore, the patient experienced eye strain accompanied by nausea and narrowed visual fields when wearing glasses.

[0077] Before treatment, the patient exhibited the following: Before the procedure: Refractive power: OD: +1.25 +1.25×105 20 / 20, +2.00 ADD OS: +1.75 +0.25×105 20 / 20, +2.00 ADD Before the procedure: Naked Eye Vision: Distance: right eye 20 / 80, left eye 20 / 30 Chikakata: I can't read the reading cards at all. Pupils: Right eye (OD) 5mm, left eye (OS) 4.8mm Comfort Score 2+ Clarity score 0

[0078] The patient was treated with a topical composition containing 0.32 wt% caffeine and 6 wt% pilocarpine, which was applied to the outer surface of both eyelids.

[0079] The composition was applied to the eyelids once daily in the morning for three days. The patient reported that her near vision improved immediately after the first treatment, and this improvement continued throughout the day / night after applying the composition once in the morning. After applying the composition once daily for three days, the following data was obtained: After treatment Naked Eye Vision: Distance visual acuity improved to 20 / 25 in the right eye and 20 / 20 in the left eye. Near vision: J4, at this point I can easily read phone calls and texts Pupils: Right eye 5mm, left eye 4.5mm Comfort increased to 4+, Clarity 4+

[0080] With continued treatment, the patient's reading acuity improved to J2 unaided reading acuity and maintained good improved distance vision in each eye. The patient remained spectacle-free for both distance and near vision during one year of daily treatments.

[0081] Treatment Summary: A patient with astigmatic hyperopia and severe presbyopia (blurred near and intermediate vision) with poor baseline visual acuity was treated with pilocarpine 6% and caffeine 0.32% resulting in significant improvement in distance visual acuity in each eye. Spontaneous reading ability at near and intermediate vision was restored.

[0082] Example 3 A 54-year-old male subject who recently noticed problems with close-up vision was treated with a topical composition containing 8 wt% pilocarpine and 0.10 wt% theophylline. The composition was applied to the eyelids of both eyes.

[0083] Prior to treatment, the following data points were obtained: Pupil 5.0mm Refractive power: OD +0.25 +0.50@015 +2.00 ADD for reading OS +0.25 +0.25@175 +2.00 ADD for reading Before treatment Near visual acuity is J10 with the naked eye, which is 20 / 100 at close range. Unaided distance vision: 20 / 25 in the right eye, 20 / 20 in the left eye Comfort Score 2+ Clarity score 1+

[0084] The following post-treatment measurements were taken: Post-Treatment: One hour after treatment: pupil 4.5 mm; near visual acuity increased to J8; distance visual acuity increased to 20 / 20 in each eye. Comfort Score 3+ Clarity score 1+ Two hours after treatment: pupil size 5.0 mm, near visual acuity again improved to J7; distance visual acuity improved to 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort Score 4+ Clarity score 2+ Three hours after treatment: pupil size 4.5 mm, near visual acuity remained elevated to J5; distance visual acuity was still 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort Score 4+ Clarity score 2+ Four hours after treatment: pupil size 4.5 mm, near visual acuity remained elevated at J4; distance visual acuity remained 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort Score 4+ Clarity score 4+ Hour 5: Pupil size 4.0, near visual acuity was optimal at J1; distance visual acuity remained 20 / 20 in each eye. Comfort Score 4+ Clarity score 4+

[0085] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0086] Example 4 A 56-year-old subject with impaired near vision was treated with a topical composition containing 3 wt% carbachol and 0.16 wt% theophylline. The composition was applied to the eyelids of both eyes.

[0087] Prior to treatment, the following data points were obtained: Before the procedure: Pupil 5.0mm Near visual acuity is J7 with the naked eye, which is 20 / 100 at close range. Unaided distance visual acuity in each eye: 20 / 20 Comfort Score 2+ Clarity score 1+ Refractive power: OD: -0.25sph ADD+2.00 OS: -0.75sph ADD+2.00

[0088] After treatment, hourly measurements were taken: One hour after treatment: pupil 5.0 mm; near visual acuity increased to J5; distance visual acuity remained 20 / 20 in each eye Comfort Score 3+ Clarity score 1+ Two hours after treatment: pupil size 4.5 mm, near visual acuity again increased to J2; distance visual acuity in each eye was 20 / 20 Comfort Score 4+ Clarity score 4+ Three hours after treatment: pupil size 4.5 mm, near visual acuity again increased to J1; distance visual acuity in each eye remained 20 / 20 Comfort Score 4+ Clarity score 4+ Four hours after treatment: pupil size 4.0 mm, near visual acuity remained high at J1; distance visual acuity remained 20 / 20 in each eye. Comfort Score 4+ Clarity score 4+ Five hours after treatment: pupil size 5.0, near visual acuity at this time was optimal at J1; distance visual acuity remained 20 / 20 in each eye. Comfort Score 4+ Clarity score 4+

[0089] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0090] Example 5 Pentoxifylline and two direct-acting cholinergic agonist APIs: pilocarpine and carbachol. Pentoxifylline 0.05% and pilocarpine 8% Pentoxifylline 1.0% and pilocarpine 8% Pentoxifylline 0.05% and carbachol 3% Pentoxifylline 1.0% and carbachol 3%

[0091] Pentoxifylline Dose Range Study: Low-dose pentoxifylline 0.05%: Hyperopia and presbyopia treated with 0.05% pentoxifylline and 8% pilocarpine A 59-year-old patient with poor near vision and blurred distance vision was treated with a topical composition containing 8 wt% pilocarpine and 0.05 wt% pentoxifylline. The composition was applied to the eyelids of both eyes.

[0092] Prior to treatment, the following data points were obtained: Pupil before treatment: 4.0mm Near visual acuity is J8 with the naked eye, which is 20 / 80 at close range. Distance visual acuity with no vision is OD 20 / 40, OS 20 / 25 Comfort Score 2+ Clarity score 1+ OD: Spherical power +1.00, Reading ADD +2.00 OS: Spherical power +1.75, reading ADD +2.00

[0093] The following post-treatment measurements were taken: 1 hour after treatment: Pupil size 4.5mm Near vision improved to J6 Distance visual acuity remained 20 / 40 OD and 20 / 25 OS. Comfort Score 3+ Clarity score 2+ 2 hours after treatment: Pupil size 4.0mm Near visual acuity increased to a more functional level of J4, or 20 / 40. Distance visual acuity improved to 20 / 20 in each eye Comfort Score 4+ Clarity score 4+ 3 hours after treatment: Pupil size 3.5mm Near visual acuity remained elevated at J4 Distance visual acuity remained at an improved 20 / 20 level in each eye. Comfort Score 4+ Clarity score 4+ 4 hours after treatment: Pupil size 3.5mm Near vision has risen sharply to J2 again Distance visual acuity remained elevated at 20 / 20 in each eye Comfort Score 4+ Clarity score 4+ Five hours after treatment: Pupil size 3.5 Near vision reached optimal visual acuity level J1 at this point. Distance visual acuity remained good at 20 / 20. Comfort Score 4+ Clarity score 4+

[0094] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0095] High-dose pentoxifylline 1.0%: Hyperopia and presbyopia treated with 1.0% pentoxifylline and 8% pilocarpine A 59-year-old subject with poor near vision and blurred distance vision was treated with a topical composition containing 8 wt% pilocarpine and 1.0 wt% pentoxifylline. The composition was applied to the eyelids of both eyes.

[0096] Prior to treatment, the following data points were obtained: Pupil before treatment: 4.0mm Near visual acuity is J8 with the naked eye, which is 20 / 80 at close range. Distance visual acuity with naked eyes is OD20 / 40, OS20 / 25 Comfort Score 2+ Clarity score 1+ OD: Spherical power +1.00, Reading ADD +2.00 OS: Spherical power +1.75, reading ADD +2.00

[0097] The following post-treatment measurements were taken: 1 hour after treatment: Pupil size 3.5mm Near vision improved to J4 Distance visual acuity improved to 20 / 25 OD and 20 / 20 OS. Comfort Score 4+ Clarity score 3+ 2 hours after treatment: Pupil size 3.0mm Near visual acuity increased to a near-optimal level of J2, or 20 / 25. Distance vision improved to a sharp 20 / 20 in each eye Comfort Score 4+ Clarity score 4+ 3 hours after treatment: Pupil size 3.5mm Near vision was optimized to J1, or 20 / 20. Distance visual acuity remained optimal at 20 / 20 in each eye Comfort Score 4+ Clarity score 4+ 4 hours after treatment: Pupil size 3.0mm Near vision is stable at J1, or 20 / 20. Distance visual acuity remained elevated at 20 / 20 in each eye Comfort Score 4+ Clarity score 4+ Five hours after treatment: Pupil size 3.5 Near vision stabilized at optimal visual acuity level J1 Distance visual acuity remained good at 20 / 20. Comfort Score 4+ Clarity score 4+

[0098] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0099] Example 6 Pentoxifylline dose range when used with carbachol 3%: Methylxanthine low dose range: Pentoxifylline 0.05% and carbachol 3% A 54-year-old woman presented with mild hyperopic astigmatism and sudden onset of presbyopia and decreased near and distance visual acuity in both eyes. The patient was unable to tolerate contact lens wear, expressed anxiety, and did not wish to undergo contact lens or ophthalmic surgery. Additionally, the patient experienced chronic eye strain accompanied by nausea when wearing glasses.

[0100] Before treatment, the patient exhibited the following: Before the procedure: Refractive power: OD: +0.25 +0.50×105 20 / 20, +2.00 ADD OS :+0.25 +0.25×105 20 / 20, +2.00 ADD Naked Eye Vision: Distance: right eye 20 / 30 +3, left eye 20 / 20 -3 Chikakata: I can't read the reading cards at all. Pupils: 5mm in both eyes Comfort score 0 Clarity score 0

[0101] The patient was treated with a topical composition containing 0.05 wt% pentoxifylline and 3 wt% carbachol, which was applied to the outer surface of both eyelids.

[0102] The composition was applied to the eyelids once daily in the morning for three days. The patient reported that her near vision improved immediately after the first treatment, and this improvement continued throughout the day / night after applying the composition once in the morning. After applying the composition once daily for three days, the following data was obtained: Naked Eye Vision: Distance vision improved to 20 / 25 in the right eye and a sharper 20 / 20 in the left eye. Near vision: J4, at this point you can read phone calls and texts practically Pupils: 4.5mm in both eyes Comfort Core increased to 2+ Clarity score 3+

[0103] The patient was able to go glasses-free for both distance and near vision while undergoing one treatment per day.

[0104] Example 7 Methylxanthine Pentoxifylline High Dose Range: Pentoxifylline 1% and Carbachol 3% The 54-year-old female patient described in Example 6 discontinued treatment for 4 weeks to "cure" the effects of 0.5 wt% pentoxifylline and 3 wt% carbachol. After 4 weeks, the patient was treated with a high dose of pentoxifylline (1 wt%) and 3 wt% carbachol.

[0105] Prior to treatment with 1 wt% pentoxifylline and 3 wt% carbachol, the patient exhibited the following: Refractive power: OD: +0.25 +0.50×105 20 / 20, +2.00 ADD OS: +0.25 +0.25×105 20 / 20, +2.00 ADD Naked Eye Vision: Distance vision: right eye 20 / 30 +3, left eye 20 / 20 -3 Near vision: Unable to read reading cards at all Pupils: 5mm in both eyes Comfort score 0 Clarity score 0

[0106] Subjects were treated with a topical composition containing 1.0 wt% pentoxifylline and 3 wt% carbachol, which was applied to the outer surface of both eyelids.

[0107] The composition is applied to eyelids once a day for three days in the morning.The subject reports that near vision improves immediately after the first treatment, and this improvement continues throughout the day / night after applying the composition once a day in the morning.After applying the composition once a day for three days, the following data is obtained: Naked Eye Vision: Distance vision improved to 20 / 25 in the right eye and a sharper 20 / 20 in the left eye. Near vision: J1, at this point I can easily read menus, phones, and computers, and my VA is 20 / 20. Pupils: 4.0mm in both eyes Comfort score increased to 4+ Clarity score 4+

[0108] The subject was able to go glasses-free for both distance and near vision and had significant ease in reading (described by the subject as "really clear") while receiving the once-daily treatment.

[0109] Example 8 1 wt% physostigmine and 0.32 wt% caffeine A 54-year-old patient who recently noticed problems with close-range vision was treated with a composition containing 1 wt% physostigmine and 0.32 wt% caffeine applied topically to the outer eyelids of both eyes.

[0110] Before treatment, the following data were obtained: Refractive power: OD +0.25 +0.50@015 +2.00 Reading ADD OS +0.25 +0.25@175 +2.00 Reading ADD Pupil before treatment: 5.0mm Near visual acuity is J10 with the naked eye, which is 20 / 100 at close range. Unaided distance vision: 20 / 25 in the right eye, 20 / 20 in the left eye Comfort 2+, Clarity 1+

[0111] The following post-treatment measurements were taken: One hour after treatment, pupil was 4.5mm, near visual acuity increased to J9, and distance visual acuity increased to 20 / 20 in each eye. Comfort 3+, Clarity 1+ At the second hour, pupil size was 5.0 mm, and near visual acuity had again increased to J7; distance visual acuity was 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort 4+, Clarity 2+ At the third hour, pupil size was 4.5 mm, near visual acuity had increased to J5, and distance visual acuity was still 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort 4+, Clarity 2+ At 4 hours, pupil size was 4.5 mm, near visual acuity had increased again to J3, and distance visual acuity remained 20 / 20 in the right eye and 20 / 15 in the left eye. Comfort 4+, Clarity 4+ At 5 hours, pupil size was 4.0, near visual acuity at this time was optimal at J1, and distance visual acuity remained 20 / 20 in each eye. Comfort 4+, Clarity 4+

[0112] The increase in near visual acuity was maintained for 12 hours after a single treatment. No adverse effects were observed.

[0113] Example 9 Three subjects were treated with a composition containing 6 wt% pilocarpine and 0.32 wt% caffeine. A 46-year-old man, a 42-year-old man, and a 53-year-old man all exhibited poor reading vision and required reading glasses. All were hyperopic and emmetropic.

[0114] Subject 1: 46-year-old male Baseline distance visual acuity was 20 / 25, CS 50% (LogCS 0.3) Baseline near visual acuity 20 / 114, Snellen-Jaeger 11, CS 40% Baseline Stereo: No Stereo

[0115] Subjects were treated with a lotion containing 6 wt% pilocarpine and 0.32 wt% caffeine applied to the outer surface of the skin of both eyelids. Visual improvement and improved contrast sensitivity were observed within 3 hours of treatment and remained optimal for 12 hours.

[0116] Near Visual Acuity: Baseline visual acuity was Jaeger 11 at near, Snellen 20 / 114, contrast 39.81% (log CS 0.4) at near. Within 2 hours of treatment in both eyes, visual acuity significantly increased to 20 / 25 at near, Jaeger 2, contrast 15.85% (log CS 0.8). Contrast sensitivity for near vision increased more than twofold compared to baseline, to 260% (2.6 times).

[0117] Distance visual acuity: Baseline visual acuity 20 / 25, contrast sensitivity 50.12% (log 0.3). Distance visual acuity increased to 20 / 20 with treatment, and contrast sensitivity was 39.81% (log 0.4). Distance contrast sensitivity improved to 33% above baseline.

[0118] Stereoscopic vision: Binocular visual acuity improved to a near perfect score of 8 / 9.

[0119] Subject 2: 42-year-old male Baseline distance visual acuity: 20 / 20, CS 39.81% (log 0.4) Baseline near visual acuity: Snellen 20 / 40, Jaeger 4, CS 50.12% (log 0.3) Baseline Stereo: Circle 5 / 5

[0120] Subjects were treated with a lotion containing 6 wt% pilocarpine and 0.32 wt% caffeine applied to the outer surface of the skin of both eyelids. Visual improvement and improved contrast sensitivity were observed within 3 hours of treatment and remained optimal for 12 hours.

[0121] Near Visual Acuity: Baseline near visual acuity: Snellen 20 / 40, Jaeger 4, CS 50.12% (log 0.3). Within 2 hours of treatment in both eyes, the subject's visual acuity increased to 20 / 20 at near, Jaeger 1, with 15.85% CS (log 0.8). Contrast sensitivity for near vision increased more than threefold compared to baseline, to 333% (3.3 times).

[0122] Distance Visual Acuity: Baseline visual acuity 20 / 20, contrast sensitivity 39.81% (log 0.4). Distance visual acuity increased to 20 / 20 with treatment, and contrast sensitivity was 19.95% (log 0.7). Distance contrast sensitivity doubled, or 100% higher than baseline.

[0123] Stereoscopic vision: Binocular visual acuity measurements improved significantly, doubling from baseline to a perfect score, i.e., 9 / 9.

[0124] Subject 3: 53-year-old male Baseline distance visual acuity: 20 / 25, CS 50.12% (log 0.3) Baseline near visual acuity: Snellen 20 / 114, Jaeger 11, CS 79.43% (log 0.1) Stereoscopic vision: Failed chitomus test, no depth perception

[0125] Subjects were treated with a lotion containing 6 wt% pilocarpine and 0.32 wt% caffeine applied to the outer surface of the skin of both eyelids. Visual improvement and improved contrast sensitivity were observed within 3 hours of treatment and remained optimal for 12 hours.

[0126] Near Visual Acuity: Baseline near visual acuity: Snellen 20 / 114, Jaeger 11, CS 50.12% (log 0.3). Within 6 hours of treatment in both eyes, the subject's visual acuity significantly increased to 20 / 30 at near, Jaeger 3, with 25.12% CS (log 0.6). Contrast sensitivity for near vision doubled to 100% (2x) compared to the poor baseline contrast sensitivity at low vision.

[0127] Distance visual acuity: Baseline visual acuity 20 / 25, contrast sensitivity 50.12% (log 0.3). Distance visual acuity improved to 20 / 20 with treatment, and contrast sensitivity was 25.12% (log 0.6). Contrast sensitivity for distance vision doubled, i.e., was 100% higher (2x) than baseline.

[0128] Stereoscopic vision: Binocular visual acuity improved from failure at baseline to a near-perfect score, i.e., 8 / 8 circles.

Claims

1. A topical ophthalmic outer eyelid composition for use in treating impaired vision, decreased contrast sensitivity, or reduced stereopsis in a subject, comprising a miotic agent selected from pilocarpine, carbachol, cevimeline, and physostigmine, in combination with at least one xanthine compound selected from methylated xanthines, dyphylline, pentoxifylline, and pharmaceutically acceptable salts thereof, wherein the topical ophthalmic outer eyelid composition is formulated for topical application to the outer surface of at least one eyelid of the subject, and further wherein said topical application to the outer surface of at least one eyelid of the subject reduces the incidence of at least one adverse event associated with application of a miotic agent to the eye, and wherein the at least one adverse event is miosis or myopia.

2. 10. The topical ophthalmic outer eyelid composition of claim 1, wherein the composition comprises 1-10 wt% pilocarpine, 1-3 wt% carbachol, 4-15 wt% cevimeline, or 0.25-3 wt% physostigmine.

3. 10. The topical ophthalmic outer eyelid composition of claim 1, wherein the miotic agent comprises pilocarpine.

4. 10. The topical ophthalmic outer eyelid composition of claim 1, wherein the miotic agent comprises carbachol.

5. 10. The topical ophthalmic outer eyelid composition of claim 1, wherein the miotic agent is physostigmine.

6. 10. The topical ophthalmic outer eyelid composition of claim 1, wherein the miotic agent is cevimeline.

7. The topical ophthalmic outer eyelid composition of claim 1, wherein the xanthine compound is caffeine.

8. The topical ophthalmic outer eyelid composition of claim 1, wherein the xanthine compound is pentoxifylline.

9. The topical ophthalmic outer eyelid composition of claim 1, wherein the xanthine compound is theophylline.

10. The topical ophthalmic outer eyelid composition of claim 1, wherein said xanthine compound comprises 0.05 to 10 wt % of said topical ophthalmic outer eyelid composition.

11. The topical ophthalmic outer eyelid composition of claim 10, wherein the xanthine compound is caffeine.

12. The topical ophthalmic outer eyelid composition of claim 10, wherein the xanthine compound is pentoxifylline.

13. The topical ophthalmic outer eyelid composition of claim 10, wherein the xanthine compound is theophylline.

14. 14. The topical ophthalmic outer eyelid composition of any one of claims 1 to 13, wherein application of the topical ophthalmic outer eyelid composition to the at least one eyelid results in an improvement in at least one parameter of vision.

15. 15. The topical ophthalmic outer eyelid composition of claim 14, wherein at least one parameter of vision is improved for at least 4 hours.

16. 16. The topical ophthalmic outer eyelid composition of claim 14 or 15, wherein the improvement in at least one parameter of vision is selected from improved accommodation, improved distance vision, improved near vision, improved contrast sensitivity, improved stereopsis, and any combination thereof.

17. 17. The topical ophthalmic outer eyelid composition of any one of claims 1 to 16, wherein the impaired vision is hyperopia, presbyopia, or astigmatism.

18. A pharmaceutical composition for treating a reduced vision condition in a subject selected from presbyopia, hyperopia, astigmatism, reduced contrast sensitivity, and reduced stereopsis, comprising a xanthine compound selected from the group consisting of caffeine, theophylline, dyphylline, theobromine, aminophylline, pentoxifylline, and pharmaceutically acceptable salts thereof, and an ophthalmic miotic selected from pilocarpine, carbachol, cevimeline, and physostigmine, wherein the composition is formulated for topical application to the outer surface of at least one eyelid of the subject, and application of the composition to the outer surface of at least one eyelid results in improvement of the reduced vision condition in the substantial absence of myopia or miosis.

19. 19. The pharmaceutical composition of claim 18, wherein the ophthalmic miotic comprises 1 to 10 wt% pilocarpine, 1 to 3 wt% carbachol, 4 to 15 wt% cevimeline, or 0.25 to 3 wt% physostigmine.

20. The pharmaceutical composition of claim 19, wherein the xanthine compound comprises 0.05 to 10 wt% of the composition.

21. A pharmaceutical composition according to any one of claims 18 to 20, wherein the xanthine compound comprises caffeine and the ophthalmic miotic comprises carbachol.

22. A pharmaceutical composition according to any one of claims 18 to 20, wherein the xanthine compound comprises caffeine and the ophthalmic miotic comprises pilocarpine.

23. A pharmaceutical composition described in any one of claims 18 to 20, wherein the xanthine compound is pentoxifylline and the ophthalmic miotic is carbachol.

24. A pharmaceutical composition described in any one of claims 18 to 20, wherein the xanthine compound is pentoxifylline and the ophthalmic miotic is pilocarpine.

25. A pharmaceutical composition according to any one of claims 18 to 20, wherein the xanthine compound is pentoxifylline and the ophthalmic miotic is physostigmine.