FIELD OF THE INVENTION

The field of the invention is ophthalmic compositions comprising carbachol and methods therefore, especially as it relates to low-dose carbachol compositions for treatment of night vision disturbance syndrome.

BACKGROUND OF THE INVENTION

The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

Night vision disturbances (NVD), especially after refractive surgery are unfortunately relatively common and adversely affect many ordinary tasks under low-light conditions. Most often, individuals suffering from NVD experience glare, starbursts, double vision, and halo around brighter objects under low-light conditions or darkness. Given the limited time during which an individual experiences NVD, therapeutic interventions should be restricted to those that are acute and transient to provide prompt effect upon administration of a drug, but also of sufficiently short duration so as to not interfere with vision under non-scotopic conditions.

A study performed using aceclidine (1-azabicyclo[2.2.2]octan-3-yl acetate), typically used to treat open-angle glaucoma, provided reduction in some symptoms (seeJ Cataract Refract Surg.2005 September; 31(9): 1764-72) in selected patient after refractive surgery. However, the physiological effect of aceclidine was relatively extended. Moreover, aceclidine is known to have significant side effects, including increased salivation and bradycardia, which significantly limits desirability and compliance once prescribed. In another known example, WO 00/64425 describes the use of miotic agents, such as cholinomimetic active agents and cholinesterase inhibitors, in combination with one or more hypertonic agents, such as sulfacetamide and derivatives thereof to treat visual disorders characterized by reduced contrast sensitivity. Unfortunately, the duration of the drug effect was once more relatively long (up to 14 hours), and thus renders the formulations unsuitable for acute and transient use.

In still further examples, U.S. Pat. No. 8,455,494 and WO 2010/135731 describe the use of drug combinations of one or more parasympathomimetic drugs or cholinesterase inhibitors with one or more alpha agonists or antagonists to temporarily treat presbyopia. However, while such formulations were to at least some degree effective in the treatment of presbyopia, use in the treatment of NVD was not contemplated. Similarly, WO 2020/072971 teaches stable aqueous topical ophthalmic composition comprising about 0.1% to 10% of cevimeline and other agents for treatment of dry eye disease but does not contemplate use of such formulations for acute and transient treatment of NVD.

Carbachol (carbamoylcholine) is a parasympathomimetic agent that stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular administration its principal effects are miosis and increased aqueous humor outflow, and a change in refraction to at least some degree (see e.g.,Investigative Ophthalmology&Visual ScienceApril 1966, Vol. 5, 186-195). Carbachol is primarily used in the treatment of glaucoma and is used during ophthalmic surgery. For example, CARBASTAT (Carbachol Intraocular Solution, USP, Novartis) or MIOSTAT (Carbachol Intraocular Solution, USP, Novartis) are administered at a concentration of 0.1 mg/mL via intraocular injection to produce miosis during surgery and to reduce the intensity of intraocular pressure elevation in the first 24 hours after cataract surgery. Similarly, ISOPTO CARBACHOL (Carbachol Ophthalmic Solution, Alcon; discontinued) was intended for topical administration at a concentration of 1.5% or 3% to treat glaucoma. However, this drug formulation has not been found by the FDA to be safe and effective, and this labeling has therefore not been approved by FDA.

Thus, even though various compositions and methods of treating NVD and other ophthalmic conditions are known in the art, all or almost all of them suffer from several drawbacks, particularly where acute and transient treatment is required. Therefore, there remains a need for improved compositions and methods for acute and transient treatment of ophthalmic conditions, and especially NVD.

SUMMARY OF THE INVENTION

The inventive subject matter is directed to various compositions and methods of use of carbachol at low concentrations to provide acute and transient treatment of NVD. Most typically, such compositions are topically applied and comprise carbachol in quantities of equal or less than about 0.75% (e.g., about 0.5% or about 0.3%) and achieve a prompt miotic effect sufficient to reduce NVD symptoms with a duration of about 3-4 hours. Notably, the so obtained miotic effect will not be sufficient to treat presbyopia.

In one aspect of the inventive subject matter, the inventors contemplate a method of acute and transient treatment of night vision disturbance in an individual. Most typically, such methods will include a step of topically administering a carbachol composition to one or both eyes of an individual, and the carbachol is present in the composition in an amount of equal or less than about 0.75% (e.g., equal or less than about 0.50% or between about 0.3% and 0.50%). It is further generally preferred that in such methods carbachol is the sole miotic agent.

Where desired, it is contemplated that the carbachol composition may also include benzalkonium chloride in an amount that increases delivery of carbachol to the pupillary muscle. For example, benzalkonium chloride may be present in an amount of at least 0.02%. In some embodiments of contemplated methods, the miotic effect is equal or less than 30%, equal or less than 20% reduction in pupillary diameter, or equal or less than 15% reduction in pupillary diameter, or equal or less than 10% reduction in pupillary diameter. Most typically, the treatment will reduce glare, starburst, halo, and/or double vision under low-light conditions or in darkness. While contemplated methods are suitable for all individuals (e.g., healthy individuals, individuals post refractive surgery), it is contemplated that in some embodiments the individual has not undergone refractive surgery.

In further contemplated embodiments, the acute and transient treatment has a duration of equal or less than 3 hours at a reduction of pupillary diameter of about 2 mm, or has a duration of equal or less than 2 hours at a reduction of pupillary diameter of about 2 mm, or has a duration of equal or less than 1 hours at a reduction of pupillary diameter of about 2 mm. Preferably, but not necessarily, the acute and transient treatment is an on-demand and non-curative treatment.

Therefore, in another aspect of the inventive subject matter, the inventors also contemplate a topical ophthalmic composition for acute and transient treatment of night vision disturbance that comprises carbachol in an amount of equal or less than about 0.75%. Most typically, carbachol is the sole miotic agent in such compositions.

For example, the topical ophthalmic composition may comprise carbachol in an amount of equal or less than about 0.50%, or in an amount of between about 0.3% and 0.50%. Preferably, but not necessarily, benzalkonium chloride may be included in an amount of at least 0.0001%, or in an amount of at least 0.02%. Thus, it is noted that benzalkonium chloride may be present in an amount that increases delivery of carbachol to the pupillary muscle.

Preferably, but not necessarily, the topical ophthalmic composition will have a pH of between 6.0 and 7.0, and/or may comprise a buffer. Where a buffer is present, it is contemplated that the buffer will preferably have a concentration of between 10 mM and 100 mM. It is further generally preferred that the topical ophthalmic composition will have a viscosity of between 10 cP and 250 cP (e.g., between 150 cP and 200 cP).

Therefore, and viewed from a different perspective, the inventors contemplate the use of carbachol as sole active agent in acute and transient treatment of night vision disturbance. For example, such acute and transient treatment may a duration of equal or less than 4 hours or equal or less than 3 hours. For example, in some embodiments the acute and transient treatment has a duration of equal or less than 3 hours at a reduction of pupillary diameter of about 2 mm. Most typically, contemplated compositions comprise carbachol in an amount of equal or less than about 0.75% or equal or less than about 0.50%. Such compositions will reduce at least one of glare, starburst, halo, and double vision, typically in an on-demand and non-curative manner.

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

