WO2022249069A1

WO2022249069A1 - Low-dose carbachol ophthalmic compositions with cumulative effect

Info

Publication number: WO2022249069A1
Application number: PCT/IB2022/054864
Authority: WO
Inventors: Harshil H. Jain; Hari A. ATTLURI; Simon P. Chandler; Tushar HINGORANI; Kumaresh Soppimath
Original assignee: Vyluma Inc.
Priority date: 2021-05-26
Filing date: 2022-05-25
Publication date: 2022-12-01

Abstract

A topical ophthalmological formulation comprises carbachol at a low concentration that effects reduction in pupil diameter over time when repeatedly administered over at least a week. Such formulations are particularly beneficial where carbachol is the sole active agent in the treatment of presbyopia and night vision disturbance. Such and other formulations may also comprise modified carbachol exhibiting improved delivery to the pupillary muscle and will (further) beneficially reduce the required quantity of active agent while still producing a desired pupil size for a predetermined period of time. Moreover, such compositions may not require combination with a penetration enhancer, such as benzalkonium chloride, and will as such be better tolerated.

Description

LOW-DOSE CARBACHOL OPHTHALMIC COMPOSITIONS WITH CUMULATIVE EFFECT

[0001] This application claims priority to our copending US provisional applications with the serial numbers 63/193,210, filed 5/26/2021, and 63/209,524, filed 6/11/2021, both incorporated by refence herein.

Field of the Invention

[0002] The field of the invention is ophthalmic formulations for treatment of presbyopia or night vision disturbance, and especially eye drop formulations comprising carbachol that exhibit a cumulative effect.

Background of the Invention

[0003] 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.

[0004] 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.

[0005] Numerous compositions and methods are known to affect one or more functions of the eye and/or treat diseases of the eye, and the active agent in such compositions can be injected or topically applied. For example, 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. 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 administered at a concentration of 1.5% or 3% to treat glaucoma. However, ISOPTO CARBACHOL has not been found safe and effective by the FDA, and the formulation for this specific indication has therefore not been approved by FDA.

[0006] In still further examples, US 8,455,494 and WO 2010/135731 describe the use of one or more parasympathomimetic drugs or cholinesterase inhibitors in combination with one or more alpha agonists or antagonists to temporarily treat presbyopia. However, such formulations tend to suffer from limited duration and need to be frequently applied. Similarly, carbachol and brimonidine were applied to healthy eyes of volunteers in an effort to correct presbyopia as described elsewhere (Eye and Vision (2016) 3:31). Here, all subjects received 3% carbachol and 0.2% brimonidine in both combined and separate forms, 3% carbachol alone and 0.2% brimonidine (control) alone, and statistically significant improvement in mean near visual acuity (NVA) was achieved in all subjects who received combined 3% carbachol and 0.2% brimonidine in the same formula compared with those who received separate forms or carbachol alone or brimonidine alone. Unfortunately, combination of these agents, particularly at relatively high concentrations are often less well tolerated over extended periods.

[0007] 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.

[0008] A study performed using aceclidine (l-azabicyclo[2.2.2]octan-3-yl acetate), typically used to treat open-angle glaucoma, provided reduction in some symptoms (see J Cataract Refract Surg. 2005 Sep;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.

[0009] In still further examples, US 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.

[0010] Therefore, while administration of various pharmaceutically active agents is known in the art, side effects of such formulations are often undesirable, particularly where higher concentrations are administered. On the other hand, where low concentrations of the pharmaceutical agent are administered, issues associated with relatively poor response remain problematic. In some instances, carbachol can be combined with a penetration enhancer, such as benzalkonium chloride, to enhance drug delivery across otherwise impermeable or limited permeability membranes such as the cornea, acting predominantly on the epithelia. Benzalkonium chloride is a quaternary ammonium cationic surface -acting agent that disrupts the epithelial membrane to improve penetration of carbachol. However, the use of benzalkonium chloride can lead to eye irritation at low concentrations and severe eye damage at high concentrations.

[0011] Thus, even though various systems and methods of treating presbyopia and NVD using topical ophthalmological formulations are known in the art, all or almost all of them suffer from several drawbacks. Therefore, there remains a need for compositions and methods for improved topical ophthalmological formulations for treatment of NVD and presbyopia. There is also a need for compositions and methods for topical ophthalmological compositions that exhibit improved delivery to the pupillary muscle for treatment of presbyopia and NVD

Summary of The Invention

[0012] The inventors have unexpectedly discovered that various topical ophthalmological compositions comprising carbachol at a low concentration or dosage will effect a smaller baseline pupil diameter overtime when administered over several consecutive days. Therefore, such formulations will advantageously reduce the required quantity of carbachol while still producing a desired pupil size for an extended period of time. Moreover, such compositions may not require combination with a second miotic agent and will as such be better tolerated. Notably, the inventors also discovered that a higher proportion of responders (with respect to pupil constriction) was observed after 1 week of daily administration, which advantageously coincides with the period of time typically needed to accommodate a brain response (with respect to visual acuity).

[0013] In addition, the inventors also discovered that various topical ophthalmological compositions comprising a modified carbachol exhibit improved delivery of a miotic agent to the pupillary muscle. Therefore, such compositions will advantageously reduce the required quantity of modified carbachol (as compared to unmodified carbachol) while still producing a desired pupil size for a predetermined period of time depending on the quantity of the modified carbachol and frequency of its use.

[0014] In one aspect of the inventive subject matter, the inventors contemplate a low-dose carbachol ophthalmic formulation that includes a liquid carrier for topical ophthalmic administration and carbachol, wherein the carbachol is present in an amount effective to (a) constrict pupil diameter from a baseline pupil diameter to between 2-3 mm for at least two hours after topical administration to an eye, and (b) constrict baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

[0015] In some embodiments, the liquid carrier is an aqueous carrier comprising a buffer, a tonicity agent, and/or a viscosity modifier, and/or the formulation has a pH of between 3.5 and 8.5. Most typically, carbachol will be present in the formulation at a concentration of less than 3 wt%, or less than 2 wt%, or less than 1 wt% ( e.g ., between 0.60 to 0.85 wt%), or less than 0.5 wt%, or less than 0.3 wt%, or even 0.1 wt% and less.

[0016] In further aspects, the pupil diameter is constricted from the baseline pupil diameter to between 2-3 mm for at least three, or at least four hours after topical administration to an eye, and/or the baseline pupil diameter is constricted by at least 1 mm after consecutive administration over at least seven days. Viewed from a different perspective, carbachol may be present in an amount that improves uncorrected near visual acuity. Where desired, the formulation may also comprise a second pharmaceutically active agent that restricts pupil diameter.

[0017] Therefore, the inventors also contemplate a method of reducing baseline pupil diameter that includes a step of topically administering an ophthalmic formulation to an eye of an individual, wherein the ophthalmic formulation comprises a liquid carrier and carbachol, wherein the carbachol is present in an amount effective to constrict baseline pupil diameter by at least 0.8 mm, or at least 1.0 mm, or at least 1.2 mm after consecutive administration over at least seven days. In at least some of such methods, administration further constricts pupil diameter from a baseline pupil diameter to between 2-3 mm for at least two, or at least three hours after topical administration to an eye. Where desired, the formulation may also comprise a second pharmaceutically active agent that restricts pupil diameter.

[0018] In still further contemplated aspects, the inventors also contemplate a method of enhancing miotic effect of a topical ophthalmic formulation that includes a miotic agent other than carbachol. Such methods will include a step of including into the topical ophthalmic formulation carbachol, wherein the carbachol is present in the topical ophthalmic formulation at a concentration that constricts baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

[0019] In some embodiments, the miotic agent other than carbachol may be a cholinesterase inhibitor, a muscarinic agonist, and/or a parasympathomimetic agent ( e.g ., pilocarpine, neostigmine, rivastigmine, brimonidine, and/or galantamine), and carbachol is present in an amount of less than 3 wt%, or less than 2 wt%, or less than 1 wt% (e.g., between 0.10 to 0.85 wt%). Viewed from a different perspective, it is contemplated that in such methods the carbachol is present in the topical ophthalmic formulation at a concentration that constricts baseline pupil diameter by at least 1.0 mm, or at least 1.2 mm after consecutive administration over at least seven days.

[0020] Consequently, the inventors contemplate a topical ophthalmic formulation that comprises a liquid carrier for topical ophthalmic administration, a first pharmaceutically active agent, and a second pharmaceutically active agent, wherein the first pharmaceutically active agent acutely and transiently constricts pupil diameter upon topical administration to an eye, and wherein the second pharmaceutically active agent cumulatively constricts baseline pupil diameter of the eye after consecutive topical administration over at least seven days. [0021] In some embodiments, the first pharmaceutically active agent is pilocarpine, neostigmine, rivastigmine, brimonidine, and/or galantamine, and/or the second pharmaceutically active agent is carbachol. For example, the first pharmaceutically active agent acutely and transiently constricts pupil diameter to between 2-3 mm for at least three hours upon topical administration to an eye, and/or the second pharmaceutically active agent constricts the baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

[0022] In yet a further aspect of the inventive subject matter, the inventors contemplate an ophthalmic composition that includes a liquid carrier for topical ophthalmic administration and modified carbachol comprising a prodrug of carbachol, a substituted carbachol, or a combination thereof, wherein the modified carbachol exhibits an improved delivery to the pupillary muscle as compared to the delivery of an unmodified carbachol to the pupillary muscle.

[0023] In some embodiments, the liquid carrier is an aqueous carrier comprising a buffer, a tonicity agent, and/or a viscosity modifier, and/or the composition has a pH of between 3.5 and 8.5. Most typically, modified carbachol will be present in the composition at a concentration of less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.% (e.g., between 0.60 to 0.85 wt.%), or less than 0.5 wt.%, or less than 0.3 wt.%, or even 0.1 wt.% and less. In these and other embodiments, the composition is substantially free of benzalkonium chloride.

[0024] In various embodiments, the prodrug of carbachol comprises a promoiety selected from the group of an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof. The lipid may comprise a fatty acid, a glyceride, a phospholipid, or combinations thereof. The amino acid may comprise lysine, valine, alanine, phenylalanine, proline, N,N-dimethylglycine, or combinations thereof.

[0025] In other embodiments, the substituted carbachol comprises a halogen atom, a C2-C8 alkyl group, or a combination thereof. The substituted carbachol may comprise a halogen atom, a C2-C8 alkyl group, or a combination thereof. The substituted carbachol comprising the C2-C8 alkyl group may comprise an N-alkyl carbachol, an N,N-dialkyl carbachol, or a combination thereof. Non-limiting examples of suitable N-alkyl-carbachols and N,N-dialkyl-carbachols have lower alkyl groups, such as methyl, ethyl, propyl, etc. [0026] The modified carbachol, such as the prodrug of carbachol or the substituted carbachol, may have a reduced hydrophilic-lipophilic balance (HLB) index as compared to the HLB index of the unmodified carbachol. The hydrophilic-lipophilic balance (HLB) index may be reduced by at least 0.5, or at least 0.7, or at least 0.9, or at least 1.1, or at least 1.5, or at least 1.7, or at least 2.0 and even higher.

[0027] In still another aspect, the modified carbachol is present in an amount effective to (a) constrict pupil diameter from a baseline pupil diameter to between 2-8 mm for at least two hours after topical administration to an eye, and/or (b) constrict baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

[0028] In further aspects, the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least three, at least four, or at least six hours after topical administration to an eye, and/or the baseline pupil diameter is constricted by at least 1 mm after consecutive administration over at least seven days. Viewed from a different perspective, the modified carbachol may be present in an amount that improves uncorrected near visual acuity.

[0029] Therefore, the inventors also contemplate a method of reducing baseline pupil diameter that includes a step of topically administering an ophthalmic composition to an eye of an individual, wherein the ophthalmic composition comprises a liquid carrier and modified carbachol, wherein the carbachol is present in an amount effective to constrict baseline pupil diameter by at least 0.1 mm, or at least 0.2 mm, or at least 0.3 mm, or at least 0.4 mm, or at least 0.5 mm, or at least 0.6 mm, or at least 0.7 mm, 0.8 mm, or at least 1.0 mm, or at least 1.2 mm, or at least 1.5 mm, or at least 2.0 mm, or at least 3.0 mm, or at least 4.0 mm, or at least 4.5 mm, or at least 5.0 mm, after consecutive administration over at least seven days. In at least some of such methods, administration further constricts pupil diameter from a baseline pupil diameter to between 0.1-8 mm for at least one, at least two, at least three, at least four, at least six hours, at least 8 hours, at least 12 hours, at least 18 hours, or at least 24 hours after topical administration to an eye.

[0030] In another aspect of the inventive subject matter, the inventors contemplate a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein at least one of Ri, R2, R₃, R4, R5, Re, and R7 is a promoiety selected from the group of (i) an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof, (ii) a moiety selected from the group of a halogen atom, a C2-C8 alkyl group, or a combination thereof, or (iii) a combination of (i) and (ii). The compound has the structure of Formula (I) with the proviso that when Ri is not the promoiety or the moiety, Ri is an amine group, a substituted amine, or an alkyl group, when R2 is not the promoiety or the moiety, R2 is oxo group, when R3 is not the promoiety or the moiety, R3 is hydrogen, deuterium, halogen, or an alkyl group, when R4 is not the promoiety or the moiety, R4 is hydrogen, deuterium, halogen, or an alkyl group, when R5 is not the promoiety or the moiety, R5 is an amine group, a substituted amine, or an alkyl group, when Re is not the promoiety or the moiety, Re is an amine group, a substituted amine, or an alkyl group, and when R7 is not the promoiety or the moiety, R7 is an amine group, a substituted amine, or an alkyl group.

[0031] In some embodiments, the compound having the structure of Formula (I) is a prodrug of carbachol, methacholine or a prodrug of methacholine, bethanecol or a prodrug of bethanechol, a substituted carbachol, a substituted methacholine, or a substituted bethanechol.

[0032] 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.

Brief Description of The Drawing

[0033] FIG.l is a graph depicting the proportion on Day 1 of subjects treated with carbachol at two concentrations, pilocarpine, and control that reach a pupil diameter of 2-3 mm.

[0034] FIG.2 is a graph depicting the proportion on Day 8 of subjects treated with carbachol at two concentrations, pilocarpine, and control that reach a pupil diameter of 2-3 mm.

[0035] FIG.3 is a graph depicting pupil diameter on Day 1 of subjects treated with carbachol at two concentrations, pilocarpine, and control. [0036] FIG.4 is a graph depicting pupil diameter on Day 8 of subjects treated with carbachol at two concentrations, pilocarpine, and control.

[0037] FIG.5 is a graph depicting the proportion of responders who achieved at least 3 lines of visual improvement as tested by ETDRS (Early Treatment Diabetic Retinopathy Study).

[0038] FIG.6 is a graph depicting the change in visual improvement as tested by ETDRS.

[0039] FIG.7 is a graph depicting comparative pupil diameter results for subjects treated with 0.75% and 3% carbachol.

[0040] FIG.8 is a graph depicting comparative pupil diameter results for subjects treated with 0.75% and 3% carbachol.

[0041] FIG.9 is a graph depicting reading speed change of subjects treated with carbachol at two concentrations, pilocarpine, and control.

[0042] FIG.10 is a graph depicting pH drift of one exemplary formulation at 10 mM buffer concentration.

[0043] FIG.11 is a graph depicting pH drift and chemical stability of another exemplary formulation at 25 mM buffer concentration.

[0044] FIG.12 is a graph depicting pH drift and chemical stability of a further exemplary formulation at 50 mM buffer concentration.

[0045] FIG.13 is a graph depicting changes in viscosity of various exemplary formulations at two different pH values.

Detailed Description

[0046] The inventors have unexpectedly discovered that various topical ophthalmic compositions comprising a parasympathomimetic agent can be prepared that not only constrict pupil diameter from a baseline pupil diameter to between 2-3 mm for several hours after topical administration to an eye, but that also constrict the baseline pupil diameter by at least 0.8 mm after consecutive administration over several days. Indeed, the inventors noted that the proportion of responders to low-dose carbachol treatment was significantly higher after daily administration of carbachol for a week or longer, and that the time of responders in the target area of pupil constriction was also extended. Consequently, the inventors contemplate that such compositions can advantageously be used for treatment of presbyopia and/or night vision disturbance, and due to the unexpected cumulative effect of the parasympathomimetic agent (e.g., carbachol), the concentration of one or more miotic agents in such compositions can be significantly lower than commonly believed to be required for a specific miotic effect. Preferably, but not necessarily, the concentration of carbachol or the modified carbachol in a topically applied composition is between 0.5% and 2.0% (e.g., 0.5, 0.75%, 1.0%, or 2.0%) for treatment of presbyopia, and between 0.1% and 1.0% (e.g., 0.1, 0.25%, or 0.5%) for treatment of night vision disturbance. In this context and elsewhere throughout the specification and claims, it should be noted that the term “modified carbachol” and “carbachol derivative” are used interchangeably herein.

[0047] As will be readily appreciated, the parasympathomimetic agent (e.g., carbachol or modified carbachol) can be used as a single active miotic agent or can be used in combination with one or more additional agents as is described in more detail below. Therefore, and viewed from a different perspective, the parasympathomimetic agent (e.g., carbachol or modified carbachol) can be included in known miotic formulations to increase the miotic effect and/or reduce the concentration of a miotic agent for the same desired miotic effect.

[0048] For example, an exemplary ophthalmic formulation for treatment of presbyopia includes carbachol or a modified carbachol as described in more detail below at a concentration of about 0.75-0.85 wt%, wherein the carbachol or modified carbachol is dissolved in a buffered aqueous liquid carrier and wherein the formulation has a pH of between 4.0 and 6.5, or between 4.5 and 6.5, or between 5.0 and 6.5, or between 5.5 and 6.5, or between 6.0 and 7.0. For example, boric acid may be used as a suitable buffer, typically at a concentration of about 25- 50 mM at a pH of 6.5 or 7.0. As will be appreciated, a typical formulation will also include a tonicity agent (e.g., NaCl) and a viscosity enhancer (e.g., Hypromellose 2910), and a preservative (e.g., benzalkonium chloride). Notably, and as also described in more detail below, such ophthalmic formulations not only produced pupillary constriction from a baseline pupil diameter to a pupillary diameter of between 2-3 mm (or 2-4 mm, or 2-6 mm, or 2-8 mm) for at least two hours after topical administration to an eye, but also produced a baseline pupillary constriction of at least 0.8 mm after consecutive administration over at least seven days. As used herein, the term “baseline” pupil diameter refers to a pupillary diameter before first administration of an ophthalmic formulation, or before a subsequent administration that is about 24 hours (+/- 6 hours) after a prior administration.

[0049] In another example, an exemplary ophthalmic formulation for treatment of NVD includes carbachol or a modified carbachol as described in more detail below as the principal active agent at a very low concentration of, for example, about equal or less than 0.75%, or about equal or less than 0.50%, or about 0.3% to 0.5%. Unexpectedly, the inventors discovered that such low concentrations afforded a significant therapeutic effect with regard to NVD, typically achieving pupillary constriction of 1-2 mm, while having a controlled limited therapeutic duration, typically between 2-4 hours. Typical compositions and formulations for such treatment include those described in U.S. Patent 11,273,141, which is incorporated by reference herein.

[0050] Of course, it should be appreciated that contemplated formulations need not be limited to those in which the carbachol or modified carbachol is present at a concentration of 0.75 wt%, but various other concentrations are also deemed suitable for use herein, including those that have a carbachol or modified carbachol concentration of equal or less than 3 wt%, equal or less than 2.8 wt%, equal or less than 2.6 wt%, equal or less than 2.4 wt%, equal or less than 2.2 wt%, equal or less than 2.0 wt%, equal or less than 1.8 wt%, equal or less than 1.6 wt%, equal or less than 1.4 wt%, equal or less than 1.2 wt%, equal or less than 1.0 wt%, equal or less than 0.8 wt%, equal or less than 0.6 wt%, equal or less than 0.4 wt%, and equal or less than 0.2 wt%. Therefore, carbachol or modified carbachol concentrations of between 0.1-0.3 wt%, or between 0.2-0.4 wt%, or between 0.3-0.5 wt%, or between 0.4-0.6 wt%, or between 0.5-0.7 wt%, or between 0.6-0.8 wt%, or between 0.7-0.9 wt%, or between 0.8-1.0 wt%, or between 1.0-1.5 wt%, or between 1.5-2.0 wt%, or between 2.0-2.5 wt%, or between 2.5-3.0 wt%, or even higher are contemplated herein.

[0051] Moreover, it should be appreciated that in addition to the (modified) carbachol or as alternative to the (modified) carbachol, various other miotic agents may be used for treatment of presbyopia in methods as contemplated herein, and appropriate miotic agents include various parasympathomimetic agents, cholinesterase inhibitors, muscarinic/alpha adrenergic agonist. For example, additional or alternative miotic agents include pilocarpine, isopilocarpine lactam, amiloride, apraclonidine, acetylcholine, bethanechol, brimonidine, clonidine, detomidine, dexmedetomidine, dipivalylepinephrine, donepezil, epinephrine, guanabenz, guanfacine, isoproterenol, medetomidine, metaproterenol, mephentermine, methacholine, methoxamine, methyldopa, muscarine, naphazoline, norepinephrine, phenylephrine, rilmenidine, salbutamol, terbutaline, tetrahydxozoline, metrifonate, neostigmine, pyridostigmine, ambenonium, demarcarium, rivastigmine, galantamine, donepezil, tacrine (tetrahydroaminoacridine), edxophonium, huperzine A, ladostigil, diisopropyl fluorophosphate (Floropryl), phospholine iodide (echothiophate) or physostigimine (eserine), etc., and their pharmaceutically acceptable salts and prodrugs.

[0052] Furthermore, it is contemplated that in at least some embodiments selected derivatives of carbachol are especially suitable, particularly where the derivatives have an enhanced penetration into and through the cornea. While not wishing to the bound by any theory or hypothesis, the inventors contemplate that at least some of the derivatives will be more hydrophobic than the unmodified carbachol. For example, is some aspects the hydrophobicity may be enhanced by one or more substituents that are added to the carbachol, and thusly modified carbachol molecules may have a reduction in their HLB (hydrophilic-lipophilic balance) index as compared to unmodified carbachol of at least 0.5, or at least 0.7, or at least 0.9, or at least 1.1, or at least 1.5, or at least 1.7, or at least 2.0 and even higher. Alternatively, or additionally, hydrophobicity may be enhanced by replacing one or more hydrogen atoms with a fluorine atom.

[0053] In these and other embodiments, the modified carbachol comprises a prodrug of carbachol, a substituted carbachol, or a combination thereof. It is to be appreciated the that the modified carbachol may be both a prodrug of carbachol and a substituted carbachol. As introduced above, the modified carbachol exhibits improved delivery to the pupillary muscle as compared to the delivery of an unmodified carbachol to the pupillary muscle. The term “delivery” as utilized herein refers to movement of the modified carbachol through the various membranes of the eye, including, but not limited, movement through the comeal membrane.

[0054] In embodiments including the prodrug of carbachol, the prodrug of carbachol comprises a promoiety selected from the group of an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof. However, it is to be appreciated that any promoiety suitable to form a prodrug exhibiting improved delivery to the pupillary muscle may be utilized. For example, the prodrug of carbachol may exhibit increased hydrophobicity as compared to unmodified carbachol. In embodiments when the promoiety is a lipid, the lipid comprises a fatty acid, a glyceride, a phospholipid, or combinations thereof. In embodiments when the promoiety is an amino acid, the amino acid comprises lysine, valine, alanine, phenylalanine, proline, N,N-dimethylglycine, or combinations thereof. However, it is to be appreciated that any amino acid may utilized, and, in certain embodiments, the amino acid has a hydrophobic side chain.

[0055] In embodiments including the substituted carbachol, the substituted carbachol comprises a halogen atom, a C2-C8 alkyl group, or a combination thereof. In embodiments when the substituted carbachol comprises the halogen atom, the halogen atom comprises a fluorine atom, a chlorine atom, a bromine atom, or combinations thereof. In embodiments when the substituted carbachol comprises the C2-C8 alkyl group, the C2-C8 alkyl group comprises an N-alkyl carbachol, an N,N-dialkyl carbachol, or a combination thereof. However, it is to be appreciated that any suitable substitution to carbachol exhibiting improved delivery to the pupillary muscle may be utilized. For example, the substituted carbachol may exhibit increased hydrophobicity as compared to unmodified carbachol.

[0056] In exemplary embodiments, the modified carbachol includes N-alkyl-carbachol (with alkyl being lower alkyl such as methyl, ethyl, propyl, etc.), N,N-dialkyl-carbachol (with alkyl being lower alkyl such as methyl, ethyl, propyl, etc.), various modified carbachol amides in which a hydrophobic amino acid or acyl forms an amide bond with the amino group of carbachol, etc.

[0057] In other embodiments of the invention, the inventors contemplate a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein at least one of Ri, R2, R3, Ry R5, Re, and R7 is a promoiety selected from the group of (i) an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof, (ii) a moiety selected from the group of a halogen atom, a C2-C8 alkyl group, or a combination thereof, or (iii) a combination of (i) and (ii). The compound has the structure of Formula (I) with the proviso that when Ri is not the promoiety or the moiety, Ri is an amine group, a substituted amine, or an alkyl group, when R2 is not the promoiety or the moiety, R2 is oxo group, when R3 is not the promoiety or the moiety, R3 is hydrogen, deuterium, halogen, or an alkyl group, when Ri is not the promoiety or the moiety, Ri is hydrogen, deuterium, halogen, or an alkyl group, when R5 is not the promoiety or the moiety, R5 is an amine group, a substituted amine, or an alkyl group, when Re is not the promoiety or the moiety, Re is an amine group, a substituted amine, or an alkyl group, and when R7 is not the promoiety or the moiety, R7 is an amine group, a substituted amine, or an alkyl group.

[0058] In some embodiments, the compound having the structure of Formula (I) is a prodrug of carbachol, a prodrug of methacholine, a prodrug of bethanechol, a substituted carbachol, a substituted methacholine, or a substituted bethanechol. It is to be appreciated that the description above relating to the modified carbachol can be relevant to the compound having the structure of Formula (I), including any of its species, including but not limited to, the prodrug of carbachol, the prodrug of methacholine, the prodrug of bethanechol, the substituted carbachol, the substituted methacholine, and the substituted bethanechol. Therefore, and among other suitable choices, modified carbachol derivatives include N-alkyl-carbachol (with alkyl being lower alkyl such as methyl, ethyl, propyl, etc.), N,N-dialkyl-carbachol (with alkyl being lower alkyl such as methyl, ethyl, propyl, etc.), various carbachol amides in which a hydrophobic amino acid or acyl forms an amide bond with the amino group of carbachol, etc.

[0059] In addition to the above miotic compounds, further compounds may be employed and will particularly include non-steroidal anti-inflammatory drugs (NSAIDs) as for example, described in US8524758, and still further contemplated compositions are described in WO 2020/252061, both incorporated by reference in their entirety herein.

[0060] The ophthalmic composition which contains the one or more miotic agents may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum-based jelly, ethyl cellulose, ethyl oleate, hydroxypropyl methylcellulose (HPMC, Hypromellose), carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The ophthalmic composition may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, thickening agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, etc. [0061] It is further contemplated that the compositions presented herein will comprise a buffer, and suitable buffers are generally buffers that stabilize the pH of the contemplated liquid formulations in a near-neutral pH range, for example between pH 4.0 and 9.0, or between pH 4.5 and 8.0, and more preferably between pH 6.0 and 7.5. Therefore, and most typically the pH of contemplated formulations will be equal or less than 8.0 and more typically equal or less than 7.5, and most typically less than 7.0, but higher than 4.5, more typically higher than 5.0, and most typically higher than 5.2. For example, suitable carbachol compositions may have a pH of 4.0 (+/- 1.0), or a pH of 5.0 (+/- 0.5), or a pH of 5.5 (+/- 0.5), or a pH of 6.0 (+/- 0.5), or a pH of 6.5 (+/- 0.5), or a pH of 7.0 (+/- 0.5), or a pH of 7.5 (+/- 0.5).

[0062] Most typically, the buffer system and/or buffer may have a buffer strength that is relatively low, for example, equal or less than 100 mM, equal or less than 75 mM, equal or less than 60 mM, equal or less than 50 mM, or between 5 mM and 50 mM (e.g., 10 mM, 20mM, 30mM, 40 mM). Therefore, in exemplary embodiments, the buffering system is in the pharmaceutical composition in a concentration of from about 10 mM to about 75 mM, or from about 10 mM to about 60 mM, or from about 0.1 mM to about 60 mM, or from about 0.1 mM to about 55 mM, or from about 0.1 mM to about 50 mM, or from about 5 mM to about 60 mM, or from about 0.1 mM to about 10 mM, or from about 1 mM to about 10 mM, or from about 9 mM to about 20 mM, or from about 15 mM to about 25 mM, or from about 19 mM to about 29 mM, or from about 24 mM to about 34 mM, or from about 29 mM to about 39 mM, or from about 34 mM to about 44 mM, or from about 39 mM to about 49 mM, or from about 44 mM to about 54 mM, or from about 19 mM to about 54 mM, or from about 25 mM to about 54 mM.

[0063] Of course, it should be appreciated that there are many types of buffer systems and buffers known in the art, and all of those are deemed suitable for use herein, including buffer systems comprising an acid and a salt of the acid, a first and a second salt (e.g., monobasic and dibasic salt), and amphoteric buffer molecules. For example, suitable buffer systems with an acid and a salt of the acid include citric acid/sodium citrate buffers, ethanoic acid/sodium ethanoate buffers, boric acid/sodium borate, while suitable buffers having a first and a second salt include monobasic sodium phosphate/dibasic sodium phosphate, or monobasic sodium phosphate/sodium citrate, etc. Similarly, suitable amphoteric buffer molecules include HEPES, MOPS, PIPES, MES, etc. Furthermore, it should be recognized that various components can also be used as an excipient such as boric acid, sodium borate, citric acid, sodium citrate, etc. [0064] In still further aspects, contemplated ophthalmic compositions may contain a tonicity agent to adjust the preparation to the desired isotonic range. Tonicity agents are known to those skilled in the ophthalmic art, and, while not intending to be limiting, some examples include glycerin, mannitol, sorbitol, propylene glycol, sodium chloride, and other electrolytes. In one embodiment, the tonicity agent is glycerin. In another embodiment, the tonicity agent is a chloride salt. In some embodiments, the ionic content adjusted to about 0.2% to about 1.8%, expressed as sodium chloride equivalents. In these embodiments, the preparation may, in addition to tonicity adjusting ingredients, comprise an ophthalmically acceptable, water- soluble, non-ionic synthetic polymer having a molecular weight within the range of 300 to 250,000, and a non-charged, non-ionic tonicity adjusting agent.

[0065] The exact percentage of the non-ionic synthetic polymer used in the solution will depend on the molecular weight of the selected polymer. However, it is intended that, absent the presence of additional viscosity building agents, the ophthalmic solution will generally have a viscosity between about 1 to about 300 cps. In certain embodiments, the ophthalmic solution has a viscosity of about 2 cps to about 8 cps, or between about 5 cps to about 15 cps, or between about 10 cps to about 25 cps, or between about 15 cps to about 30 cps, at 25° C. In other embodiments, the ophthalmic solution has a viscosity of about 100 cps to about 150 cps, or between about 150 cps to about 250 cps, or between about 200 cps to about 250 cps, or between about 250 cps to about 300 cps, at 25° C. For example, hydroxypropyl methylcellulose, polyvinyl alcohol and/or polyethylene glycol are among those non-ionic polymeric substances that may be incorporated into the preparations of the present invention. When polyvinyl alcohol is added to the solution, it will be present in a concentration of from about 0.1% to about 5%, or even from about 0.25% to about 2%, whereas when polyethylene glycol is used it will comprise from about 0.25% to about 3% of the solution. Such polymers are commercially available, and their composition well known to those skilled in the art.

[0066] In further examples, the formulations may include a salt as a tonicity agent. With respect to suitable salts, it is contemplated that the salt is a pharmaceutically acceptable salt, and especially NaCl, at a concentration of at least 0.2 wt%, or at least 0.4 wt%, or at least 0.5 wt%, or at least 0.7 wt%. For example, suitable salt concentrations are between 0.2 wt% and 1.1 wt%, 0.4 wt% and 0.9 wt%, or 0.3 wt% and 0.7 wt%. Depending on the particular salt concentration, additional tonicity agents may be added, and suitable tonicity agents include glycerol, propylene glycol, mannitol, lactose, and dextrose. The amount of tonicity adjusting agent used can be adjusted to obtain osmolality of the formulations in the range of 260 to 340 mOsm/kg. An osmometer can be used to check and adjust the amount of tonicity adjusting agent to be added to obtain the desired osmolality.

[0067] Where desired, the formulation may also include one or more chelating agents, and particularly metal ion chelators. For example, suitable chelators include various bicarboxylic acids, tricarboxylic acids, and aminopolycarboxylic acids such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis( -aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and penta(carboxymethyl)diethylenetriamine (DTP A), and salts and hydrates thereof. For example, exemplary chelator concentrations are between 10 pg/ml and 50 pg/ml, between 50 pg/ml and 250 pg/ml, and between 100 pg/ml and 1000 pg/ml. Viewed form a different perspective, chelator concentrations of equal or less than 0.03 wt%, or equal or less than 0.02 wt%, or equal or less than 0.01 wt% are especially advantageous.

[0068] Suitable chelating agents include monomeric polyacids such as EDTA, cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), aminotrimethylene phosphonic acid (ATPA), citric acid, ophthalmologically acceptable salts thereof, and combinations of any of the foregoing. Further suitable chelating agents include pyrophosphates, tripolyphosphates, and, hexametaphosphates, chelating antibiotics such as chloroquine and tetracycline, nitrogen- containing chelating agent containing two or more chelating nitrogen atoms within an imino group or in an aromatic ring ( e.g ., diimines, 2,2'-bipyridines, etc.), and various polyamines such as cyclam (1,4,7, 11 -tetraazacyclotetradecane), N-(C1-C30 alkyl (-substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomo-spermine (DEHOP), and deferoxamine (N'-[5- [[4-[[5-(acetylhydroxyamino)pentyl]amino]-l,4-dioxobutyl]hydroxy-amino]pentyl]-N'-(5- aminopentyl)-N-hydroxybutanediamide; also known as desferrioxamine B and DFO).

[0069] As contemplated formulations are used as an ophthalmic formulation, it is generally preferred that the formulation also includes a viscosity modifier to adjust the viscosity of the formulation to a dynamic viscosity of between 100 and 250 cP (centipoise), and more preferably between 150 and 250 cP, and most preferably between 180 to 230 cP. While there are numerous viscosity modifiers known in the art such as various polymers, glycerol, and polysaccharidic polymers (all of which are contemplated herein), especially preferred viscosity modifiers include cellulosic viscosity modifiers. For example, particularly preferred cellulosic viscosity modifiers include modified and unmodified hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose (hypromellose).

[0070] As will be readily appreciated, the exact quantity of the viscosity modifier may vary depending on the type of modifier used and desired final viscosity. For example, where the viscosity modifier is a cellulosic modifier and the final viscosity should be between 1 and 300 cP, suitable quantities of the modifier will typically be in the range of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic (modified) carbachol composition. The person of ordinary skill will be readily able to adjust the viscosity to a desired measure using viscometers ( e.g ., rotational, vibration, etc.) well known in the art.

[0071] Notably, the inventors also discovered that benzalkonium chloride may enhance the miotic effect. While not wishing to be bound by any theory or hypothesis, benzalkonium chloride is thought to assist carbachol to penetrate to the pupillary muscle, and as such the effective concentration of benzalkonium chloride will be higher. Most typically, concentrations of benzalkonium chloride will be higher than those normally used for antimicrobial activity.

[0072] For example, where benzalkonium chloride (BAC; A- Alkyl-A-bcnzyl-AW-di methyl - ammonium chloride) or other quaternary ammonium-based surfactant is being used to enhance carbachol penetration to the pupillary muscle, it should be noted that the concentration of the BAC will typically be above the concentration ordinarily used for antimicrobial effect. Most preferably, the concentration of BAC or other quaternary ammonium-based surfactant in contemplated formulations will be at least 0.010%, or at least 0.012%, or at least 0.014%, or at least 0.016%, or at least 0.018%, or at least 0.020%, or at least 0.022%, or at least 0.024%, or at least 0.026%, or at least 0.028%, or at least 0.030%, or at least 0.033%, or at least 0.036%, or at least 0.039%, or at least 0.042%, or at least 0.045%, or at least 0.050%, or even higher. Therefore, suitable BAC or other quaternary ammonium-based surfactant concentrations may be in the range of between 0.010-0.014%, or between 0.012-0.016%, or between 0.014- 0.018%, or between 0.016-0.020%, or between 0.018-0.022%, or between 0.020-0.024%, or between 0.022-0.026%, or between 0.024-0.028%, or between 0.026-0.030%, or between 0.028-0.032%, or between 0.030-0.035%, or between 0.015-0.025%, or between 0.010- 0.030%, or between 0.015-0.035%. Thus, and viewed form a different perspective, the concentration of BAC or other quaternary ammonium-based surfactant in contemplated formulations will be at least 0.015%, or at least 0.017%, or at least 0.0192%, or at least 0.017%, or at least 0.021%, or at least 0.023%, or at least 0.025%, or at least 0.030%, or even higher. In still further contemplated aspects, the concentration of the BAC or other quaternary ammonium-based surfactant may also be significantly lower, such as for example, about 0.001%, or about 0.002%, or about 0.003%, or about 0.004%, or about 0.005%, or higher. Where desired, contemplated formulations may also be substantially free of BAC (e.g., where a modified carbachol is used, or where the cumulative effect is sufficient for a desired purpose). The phrase “substantially free” as utilized herein with regard to benzalkonium chloride means that benzalkonium chloride may be present in an amount of no greater than 0.01 %, or no greater than 0.001%, based on atotal weight of the composition.

[0073] In still further contemplated aspects, the ophthalmic compositions need not necessarily contain a buffer system, a viscosity agent, and/or a tonicity agent, and it should be appreciated that the particular function of the buffer, the viscosity agent, and/or the tonicity agent may be provided by one or more excipients added to the ophthalmic formulation. For example, where the excipient is boric acid or citric acid, the boric acid or citric acid may also act as a buffer and/or preservative. On the other hand, where a buffer concentration is relatively high, the buffer may act as a tonicity agent.

[0074] The ophthalmic compositions may contain a preservative. Preservatives are used to prevent bacterial contamination in multiple -use ophthalmic preparations, and, while not intending to be limiting, examples include benzalkonium chloride, stabilized oxychloro complexes (otherwise known as Purite®), phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal. In some embodiments, the preservative is Purite®. However, in further contemplated aspects, the formulations may also be devoid of a preservative.

[0075] In still further contemplated aspects of the inventive subject matter it should be appreciated that the formulations presented herein will have a desirable storage stability, maintain the pH within a desirable range, and/or experience only moderate increase or decrease in viscosity over time. For example, where the formulation comprises carbachol as an active ingredient, it is generally preferred that the formulation will contain less than 4%, or less than 3.5%, or less than 3.0%, or less than 2.5%, or less than 2.0%, or less than 1.5%, or less than 1.0%, or less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3% choline (formed from degradation of carbachol) after storage at standard conditions (25 °C, 60% relative humidity) for at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months.

[0076] Similarly, it is contemplated that the formulations presented herein will have a pH excursion or change of no more than 2 pH unit, or no more than 0.9 pH units, or no more than 0.8 pH units, or no more than 0.7 pH units, or no more than 0.6 pH units, or no more than 0.5 pH units, or no more than 0.4 pH units, or no more than 0.3 pH units, or no more than 0.2 pH units, after storage at standard conditions (25 °C, 60% relative humidity) for at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months.

[0077] In still further preferred aspects of the inventive subject matter, it is also contemplated that the formulations presented herein will have a change in viscosity of no more than 100 cPs, or no more than 75 cPs, or no more than 50 cPs, or no more than 25 cPs, or no more than 22 cPs, or no more than 20 cPs, or no more than 18 cPs, or no more than 16 cPs, or no more than 14 cPs, or no more than 12 cPs, or no more than 10 cPs after storage at standard conditions (25 °C, 60% relative humidity) for at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months.

[0078] While numerous container materials are deemed suitable for use herein, it is particularly preferred that the containers that enclose the formulations presented herein will be polymeric containers, and especially preferred polymeric containers include HDPE (high density polyethylene), LDPE (low density polyethylene), and PP (polypropylene) (CoC) containers, which may be configured as single-use (disposable) container or as a multi-use container that contains a volume of the formulation sufficient for at least 2, or at least 4, or at least 10, or at least 20, or at least 30, or at least 60 administrations, or even more.

[0079] With respect to the miotic effect of contemplated ophthalmological formulations it is generally contemplated that the compositions presented herein will have a dual effect, with the first effect being acute and typically observable within one hour or less as calculated from topical administration, and with the second effect being cumulative over daily topical administration over at least several days as calculated from the first topical administration.

[0080] Most typically, the first effect will result in a maximum pupillary constriction within no more than 90 min, or no more than 80 min, or no more than 70 min, or no more than 60 min, or no more than 45 min, or no more than 30 min from the topical administration of the ophthalmic composition. Thus, maximum pupillary constriction may be observed within 20- 45 minutes, or within 45-60 minutes, or within 60-75 minutes, or within 60-90 minutes. In most circumstances, the maximum or desired pupillary constriction will be such that the pupillary diameter is between 1.7-1.9 mm, or between 1.8-2.4 mm, or between 2.0-2.7 mm, or between 2.0-3.0 mm, or between 2.2-2.8 mm. However, it is generally preferred that the target range of pupillary diameter will be between 2.0-3.0 mm.

[0081] With respect to the duration of the first miotic effect in which the pupillary diameter is in the desired target range is at least at least 60 min, or at least 90 min, or at least 120 min, or at least 150 min, 180 min, or at least 190 min, or at least 200 min, or at least 220 min, or at least 240 min, or at least 300 min, or at least 330 min, or at least 360 min, or even more in some cases (such duration can be determined using laser pupillometry in a rabbit eye test model). On the other hand, it is generally preferred that the duration of the first miotic effect between administration and recovery to at 70% of initial pupillary diameter is no longer than 8 hours, or no longer than 7 hours, or no longer than 6 hours, or no longer than 5 hours, and in some cases even shorter.

[0082] Most typically, the first miotic effect produced by contemplated compositions will be produce a reduction in pupillary diameter (as measured from before administration) of at least 5%, or at least 7%, or at least 10%, or at least 12%, or at least 14%, or at least 16%, or at least 18%, or at least 20%, or at least 22%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%, but most typically no more than 30%, or no more than 25%, or no more than 22%, or no more than 20%, or no more than 18%, or no more than 15%. Therefore, contemplated reductions in pupillary diameter (as measured from before administration) will be between 2-5%, or between 5-7%, or between 7-10%, or between 10-12%, or between 12- 15%, or between 15-17%, or between 17-20%, or in some cases even between 20-25%, or between 25-35%, or between 35-45%, or between 45-50%, or even higher.

[0083] With respect to the second miotic effect it is generally contemplated that the second miotic effect is observable after no more than 3 days or no more than four days, or no more than five days, or no more than six days, or no more than seven days following once daily topical administration of contemplated formulations. For example, in most cases the constriction of baseline pupil diameter after consecutive administration over at least seven days will be at least 0.1 mm, or at least 0.2 mm, or at least 0.3 mm, or at least 0.4 mm, or at least 0.5 mm, or at least 0.6 mm, or at least 0.7 mm, or at least 0.8 mm, or at least 0.9 mm, or at least 1.0 mm, or at least 1.1 mm, or at least 1.2 mm, or at least 1.3 mm, or at least 1.4 mm, and in some cases even higher, including at least 1.5 mm, or at least 2.0 mm, or at least 2.5 mm, or at least 3.0 mm, or at least 3.5 mm, or at least 4.0 mm, or at least 4.5 mm, or at least 5.0 mm.

[0084] Therefore, it should be appreciated that due to the cumulative effect of constriction of the baseline pupil diameter, lower concentrations of miotic agents are required as compared to single and acute administration to achieve the same effect. Moreover, the period required to achieve the cumulative effect will in most cases coincide with the time required to achieve an adaptive brain response with respect to visual acuity. Similarly, it should be appreciated that the total miotic effect of formulations may be significantly enhanced by addition of carbachol (or other parasympathomimetic agents with similar action). While not wishing to be bound to any specific theory or hypothesis, the inventors contemplate that the cumulative effect is at least in part dependent on the pH of the formulation, the viscosity of the formulation (and type of viscosity modifier used), the concentration of benzalkonium chloride, and/or the amount and type of tonicity agent. Moreover, it is contemplated that the cumulative effect will also be at least in part dependent on the quantity of carbachol used (typically with higher concentrations achieving a higher cumulative effect).

[0085] Consequently, the inventors also contemplate a method of administering an ophthalmic composition comprising carbachol or a modified carbachol in which the administration has a first (loading) phase and a second (maintenance) phase. Most typically, the first phase is continued until a cumulative effect for the carbachol or modified carbachol is achieved, and the second phase then commences. In preferred embodiments, the dose or concentration of the carbachol or modified carbachol in the ophthalmic composition is higher in the first phase than the dose or the concentration in the second phase.

[0086] Most typically, the dose or concentration in the first phase will be at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 100%, or even higher than the dose or concentration in the second phase. Higher dosages may be achieved from the same formulation by using a different eye dropper that delivers a larger droplet volume, or by instructing a user to apply (an) additional droplet(s) to an eye as compared to the number of droplet(s) in the second phase. Alternatively, higher concentrations may be achieved by providing a separate ophthalmic composition that has a higher concentration than the concentration for the second phase. Most typically, the first phase will last at least three days, or at least four days, or at least five days, or at least six days, or at least 7 days, or at least 8 days or longer, while the second phase will typically last at least one month or at least two months, or at least three months, or at least a half year or even longer.

[0087] Therefore, the inventors also contemplate that various topical ophthalmic compositions comprising a modified carbachol can be prepared that exhibit improved delivery to the pupillary muscle thereby requiring a reduced amount of the modified carbachol as compared to the amount of unmodified carbachol to constrict pupil diameter from a baseline pupil diameter to between 2-8 mm for several hours after topical administration to an eye, and/or to constrict the baseline pupil diameter by at least 0.8 mm after consecutive administration over several days. Beneficially, and at least in some embodiments, such compositions are substantially free of a penetration enhancer, such as benzalkonium chloride. Therefore, the composition may be better tolerated by individuals using the composition while exhibiting at least the same therapeutic effect as compared to conventional compositions comprising the penetration enhancer. Consequently, the inventors contemplate that such compositions can advantageously be used for treatment of presbyopia, and due to the unexpected cumulative effect of the modified carbachol along with the improved delivery to the pupillary muscle, the concentration of modified carbachol in such compositions can be significantly lower than commonly believed to be required for a specific miotic effect.

[0088] As already noted above, the modified carbachol can be used as a single active miotic agent or can be used in combination with one or more additional agents as is described in more detail below. Therefore, and viewed from a different perspective, the modified carbachol can be included in known miotic compositions to increase the miotic effect and/or reduce the concentration of a miotic agent for the same desired miotic effect.

[0089] In various embodiments, the modified carbachol is present in an amount effective to constrict pupil diameter from a baseline pupil diameter to between 2-8 mm for at least two hours, at least three hours, at least four hours, or at least six hours, after topical administration to an eye. The modified carbachol is present in an amount effective to constrict baseline pupil diameter by at least 0.8 or optionally by at least 1.0 mm after consecutive administration over at least seven days. Viewed from a different perspective, the modified carbachol may be present in an amount that improves uncorrected near visual acuity and/or that reduces one or more symptoms associated with night vision disturbance. [0090] With respect to the miotic effect of contemplated ophthalmological compositions it is generally contemplated that the compositions presented herein will have a dual effect, with the first effect being acute and typically observable within one hour or less as calculated from topical administration, and with the second effect being cumulative over daily topical administration over at least several days as calculated from the first topical administration.

[0091] Most typically, the first effect will result in a maximum pupillary constriction within no more than 90 min, or no more than 80 min, or no more than 70 min, or no more than 60 min, or no more than 45 min, or no more than 30 min from the topical administration of the ophthalmic composition. Thus, maximum pupillary constriction may be observed within 20- 45 minutes, or within 45-60 minutes, or within 60-75 minutes, or within 60-90 minutes. In most circumstances, the maximum or desired pupillary constriction will be such that the pupillary diameter is between 1.7-1.9 mm, or between 1.8-2.4 mm, or between 2.0-2.7 mm, or between 2.0-3.0 mm, or between 2.2-2.8 mm. However, it is generally preferred that the target range of pupillary diameter will be between 2.0-3.0 mm.

[0092] With respect to the duration of the first miotic effect in which the pupillary diameter is in the desired target range is at least at least 180 min, or at least 190 min, or at least 200 min, or at least 220 min, or at least 240 min, or at least 300 min, or at least 330 min, or at least 360 min, or even more in some cases (such duration can be determined using laser pupillometry in a rabbit eye test model). On the other hand, it is generally preferred that the duration of the first miotic effect between administration and recovery to at 70% of initial pupillary diameter is no longer than 8 hours, or no longer than 7 hours, or no longer than 6 hours, or no longer than 5 hours, and in some cases even shorter.

[0093] Most typically, the first miotic effect produced by contemplated compositions will be produce a reduction in pupillary diameter (as measured from before administration) of at least 5%, or at least 7%, or at least 10%, or at least 12%, or at least 14%, or at least 16%, or at least 18%, or at least 20%, or at least 22%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%, but most typically no more than 30%, or no more than 25%, or no more than 22%, or no more than 20%, or no more than 18%, or no more than 15%. Therefore, contemplated reductions in pupillary diameter (as measured from before administration) will be between 2-5%, or between 5-7%, or between 7-10%, or between 10-12%, or between 12- 15%, or between 15-17%, or between 17-20%, or in some cases even between 20-25%, or between 25-35%, or between 35-45%, or between 45-50%, or even higher. [0094] With respect to the second miotic effect it is generally contemplated that the second miotic effect is observable after no more than 3 days or no more than four days, or no more than five days, or no more than six days, or no more than seven days following once daily topical administration of contemplated compositions. For example, in most cases the constriction of baseline pupil diameter after consecutive administration over at least seven days will be at least 0.6 mm, or at least 0.7 mm, or at least 0.8 mm, or at least 0.9 mm, or at least 1.0 mm, or at least 1.1 mm, or at least 1.2 mm, or at least 1.3 mm, or at least 1.4 mm, and in some cases even higher.

[0095] Therefore, it should be appreciated that due to the cumulative effect of constriction of the baseline pupil diameter, lower concentrations of miotic agents are required as compared to single and acute administration to achieve the same effect. Moreover, the period required to achieve the cumulative effect will in most cases coincide with the time required to achieve an adaptive brain response with respect to visual acuity. Similarly, it should be appreciated that the total miotic effect of compositions may be significantly enhanced by addition of carbachol (or other parasympathomimetic agents with similar action). While not wishing to be bound to any specific theory or hypothesis, the inventors contemplate that the cumulative effect is at least in part dependent on the pH of the composition, the viscosity of the composition (and type of viscosity modifier used), and/or the amount and type of tonicity agent. Moreover, it is contemplated that the cumulative effect will also be at least in part dependent on the quantity of carbachol used (typically with higher concentrations achieving a higher cumulative effect).

[0096] In some embodiments, the inventors therefore contemplate an exemplary ophthalmic composition for acute and transient treatment of NVD includes the (modified) carbachol as the principal active agent, optionally at a very low concentration of, for example, about equal to or less than 0.75%, or about equal to or less than 0.50%, or about 0.3% to about 0.5%. Unexpectedly, the inventors discovered that such low concentrations afforded a significant therapeutic effect with regard to NVD, typically achieving pupillary constriction of 1-2 mm, while having a controlled limited therapeutic duration, typically between 2-4 hours.

[0097] In other embodiments, the inventors also 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 (modified) carbachol composition to one or both eyes of an individual, and the (modified) 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 the (modified) carbachol is the sole miotic agent.

[0098] As used herein, the term “treat” or “treatment” when used in conjunction with NVD is not intended to mean curative treatment, but refers to alleviation, reduction, or even complete elimination of one or more symptoms of NVD. In this context, it should also be appreciated that the compositions and methods of treatment contemplated herein will affect a temporary reduction of the pupillary diameter of about 10-30%, which would be unsuitable or even entirely ineffective in a treatment of presbyopia. Interestingly, however, such limited reduction in pupillary size (particularly under low light conditions) will typically cover most of the area treated in surgical comeal correction such as LASIK procedures. Therefore, administration of contemplated compounds and compositions is non-curative with respect to the condition that produces NVD.

[0099] The term “acute and transient” when used in conjunction with treatment is meant to refer to a treatment that produces upon administration of a therapeutic agent (e.g., (modified) carbachol compositions as presented herein administered as eye drops) a treatment effect within no more than 60 minutes that lasts no more than 4 hours. Thus, most forms of acute and transient treatments can be implemented as on-demand and temporary measure to reduce one or more symptoms of NVD. The term “NVD” or “night vision disturbance” as used herein refers to perception of glare, starburst, halo, and/or double vision that are noted only under low- light conditions (such as dusk) or darkness (night). Viewed from a different perspective, NVD is typically associated with scotopic vision that is predominantly based on rod cells (non-color vision in human), typically occurring at luminance levels at or below 10³ cd/m².

[00100] It should further be appreciated that contemplated and preferred compositions and methods are intended to treat NVD, which are generally associated with visual disturbances at longer distances (i.e., focal distances well beyond reading distances typically seen in treatment of presbyopia). Such disturbances will typically be at distances of at least 1 m, or at least 5 m, or at least 10 m, or at least 25 m, or at least 50 m, and significantly longer distances. Moreover, contemplated and preferred compositions and methods are intended to treat conditions in low-light environments such as evening and night. Thus, it should be noted that contemplated compositions and methods treat NVD without (substantially) affecting the perception of overall brightness. In addition, it should be appreciated that NVD as contemplated herein need not only be due to refractive surgery, but may have various other etiologies, including ageing, cataracts, excessive sunlight exposure, retinitis pigmentosa, vitamin A and/or zinc deficiency, etc.

[00101] 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.

[00102] 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.

Examples

[00103] The following examples are intended to illustrate various aspects of the inventive subject matter and should not be construed as limiting the invention.

[00104] In a first set of tests, the inventors investigated whether various compounds at selected concentrations could effectively and acutely constrict pupil size. More specifically, the inventors tested pilocarpine and carbachol at two different concentrations (0.75% and 3.0%) and measured pupil diameter over several hours after topical administration, and exemplary results are shown in FIG.l. As is readily apparent, all formulations had significant effect on pupillary size on at least some of the tested individuals where the endpoint was 2-3 mm pupil size post administration. Daily administration was continued in all subjects. Interestingly, and as can be seen from the data in FIG.2 showing results at Day 8, one week of daily dosing with carbachol increased the proportion of subjects with pupil diameter in the target range of 2-3 mm, indicating a cumulative effect, whereas no significant cumulative effect was observed with pilocarpine (which had even a blunting effect at hours 2 and 3).

[00105] Such unexpected cumulative effect over time was also reflected in the pupil size that was achieved after a week of administration, and FIGS. 3 and 4 show exemplary results for Day 1 and Day 8, respectively. More specifically, FIG.3 shows exemplary data for pupil diameter over time for Day 1 with the parasympathomimetic drugs as indicated, while FIG.4 shows corresponding results for Day 8. Here, it should be particularly appreciated that carbachol at both tested concentrations had an increased reduction in pupillary diameter after one week of daily administration, resulting in an extended period of time where the pupil diameter was in the target area of 2-3 mm. Moreover, it was also unexpectedly observed that the baseline pupil diameter for carbachol after one week of daily administration was significantly reduced as compared to vehicle or pilocarpine. Such results once more indicate a cumulative effect. The results for pilocarpine between Day 1 and Day 8 were substantially the same.

[00106] The inventors then evaluated the effect of pupil constriction on binocular uncorrected visual acuity using EDTRS, and exemplary results are shown in FIG.5, indicating that pilocarpine may not be superior to carbachol (due to relatively small study population). FIG.6 shows exemplary results for EDTRS letter score changes for uncorrected visual acuity from baseline. Further investigation and results as to the effect or iris color for Day 1 and Day8 are provided in FIG.7 and FIG.8. As can be taken from the data in FIG.7, the cumulative effect was once again pronounced for both concentrations of carbachol. The individual data further highlight that individuals can be grouped into responders and non-responders, but the effect of carbachol seemed to be independent of iris color. Pilocarpine did not exhibit cumulative effect as shown in FIG.8. Finally, the inventors tested whether the topical formulations would have an effect on reading speed, and exemplary results are shown in FIG.9. As can be seen from the figure, there were no statistically significant differences among the groups tested. Further considerations, methods, and contemplations can be found in US 11,273,141, incorporated by reference herein.

[00107] In still further experiments, the inventors sought to determine the chemical stability of low-concentration carbachol formulations. To that end, the inventors prepared the formulations as listed in Table 1 with varying quantities of boric acid (that at the give pH provided for a buffer).

Table 1

[00108] Unexpectedly, various polymeric containers led after only one month to a rapid decrease in pH in formulations having a low buffer strength at accelerated storage conditions (40 °C, 75% relative humidity), which is adverse to chemical stability of carbachol, whereas the same formulations in glass containers were significantly less affected by a pH drift as can be seen form the results in Table 2 and FIG.10.

Table 2

[00109] Interestingly, when the buffer concentration was increased to 25 mM, a pH drift was now observable in the glass container but was significantly less pronounced in the polymeric containers after one month and two months as can be seen from the data in Table 3 and FIG.ll. Moreover, chemical stability of the carbachol as measured by generation of choline was significant for glass containers, and substantially less in the polymeric containers upon storage a accelerated storage conditions.

Table 3

[00110] Based on these findings, the inventors further increased the buffer concentration to 50 mM and evaluated the pH drift and chemical stability of the formulation for one and two months at accelerated storage conditions, and exemplary results are shown in Table 4 and FIG.12. At this buffer concentration, the pH drift in the formulations was substantially reduced, and the chemical stability was now improved in the polymeric containers vis-a-vis the glass container.

Table 4

[00111] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. Unless stated otherwise, all percentage values provided herein are percent by weight (w/w).

[00112] In still further experiments, the inventors sought out to determine if the buffer strength and/or pH would have an influence on the viscosity in the various containers, and exemplary results are show in FIG.13. Notably, while the UDPE containers exhibited a moderate increase in viscosity over time, containers with PP and glass containers had a significant drop in viscosity over time across all buffer strengths and tested pH values.

[00113] As used herein, the term “administering” a pharmaceutical composition or drug refers to both direct and indirect administration of the pharmaceutical composition or drug, wherein direct administration of the pharmaceutical composition or drug is typically performed by a health care professional (e.g., physician, nurse, etc.), and wherein indirect administration includes a step of providing or making available the pharmaceutical composition or drug to the health care professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.). It should further be noted that the terms “prognosing” or “predicting” a condition, a susceptibility for development of a disease, or a response to an intended treatment is meant to cover the act of predicting or the prediction (but not treatment or diagnosis of) the condition, susceptibility and/or response, including the rate of progression, improvement, and/or duration of the condition in a subject.

[00114] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[00115] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As also used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously.

[00116] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refer to at least one of something selected from the group consisting of A, B, C .... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

CLAIMS What is claimed is:

1. A low-dose carbachol ophthalmic formulation, comprising: a liquid carrier for topical ophthalmic administration and carbachol or a carbachol derivative, wherein the carbachol or carbachol derivative is present in an amount effective to

(a) constrict pupil diameter from a baseline pupil diameter to between 2-3 mm for at least two hours after topical administration to an eye, and

(b) constrict baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

2. The ophthalmic formulation of claim 1, wherein the liquid carrier is an aqueous carrier comprising a buffer, a tonicity agent, viscosity modifier, a preservative, and/or pH adjuster.

3. The ophthalmic formulation of claim 1, wherein the formulation has a pH of between 5.5 and 7.5, and wherein the formulation is in a polymeric container.

4. The ophthalmic formulation of any one of claims 1-3, wherein the carbachol or carbachol derivative is present in the formulation at a concentration of less than 3 wt%.

5. The ophthalmic formulation of any one of claims 1-3, wherein the carbachol or carbachol derivative is present in the formulation at a concentration of less than 2 wt%.

6. The ophthalmic formulation of any one of claims 1-3, wherein the carbachol or carbachol derivative is present in the formulation at a concentration of less than 1 wt%.

7. The ophthalmic formulation of any one of claims 1-3, wherein the carbachol or carbachol derivative is present in the formulation at a concentration of between 0.20 to 0.85 wt%.

8. The ophthalmic formulation of claim 1, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-3 mm for at least three hours after topical administration to an eye.

9. The ophthalmic formulation of claim 1, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-3 mm for at least four hours after topical administration to an eye.

10. The ophthalmic formulation of claim 1, wherein the baseline pupil diameter is constricted by at least 1 mm after consecutive administration over at least seven days.

11. The ophthalmic formulation of claim 1, wherein the baseline pupil diameter is constricted by at least 1 mm after consecutive administration over at least seven days.

12. The ophthalmic formulation of claim 1, wherein the carbachol or carbachol derivative is present in an amount that improves uncorrected near visual acuity and/or that corrects night vision disturbance.

13. The ophthalmic formulation of claim 1, wherein the formulation comprises a second pharmaceutically active agent that restricts pupil diameter.

14. A method of reducing baseline pupil diameter, comprising: topically administering an ophthalmic formulation to an eye of an individual, wherein the ophthalmic formulation comprises a liquid carrier and carbachol or a carbachol derivative; wherein the carbachol or carbachol derivative is present in an amount effective to constrict baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

15. The method of claim 14, wherein the baseline pupil diameter by at least 1.0 mm after consecutive administration over at least seven days.

16. The method of claim 14, wherein the baseline pupil diameter by at least 1.2 mm after consecutive administration over at least seven days.

17. The method of any one of claims 14-16, wherein the administration further constricts pupil diameter from a baseline pupil diameter to between 2-3 mm for at least two hours after topical administration to an eye.

18. The method of any one of claims 14-16, wherein the administration further constricts pupil diameter from a baseline pupil diameter to between 2-3 mm for at least three hours after topical administration to an eye.

19. The method of claim 14, wherein the formulation further comprises a second pharmaceutically active agent that restricts pupil diameter.

20. A method of enhancing miotic effect of a topical ophthalmic formulation comprising a miotic agent other than carbachol, comprising: including into the topical ophthalmic formulation carbachol or a carbachol derivative; wherein the carbachol or carbachol derivative is present in the topical ophthalmic formulation at a concentration that constricts baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

21. The method of claim 20, wherein the miotic agent other than carbachol is a cholinesterase inhibitor, a muscarinic agonist, and/or a parasympathomimetic agent.

22. The method of claim 20, wherein the miotic agent other than carbachol is pilocarpine, neostigmine, rivastigmine, brimonidine, and/or galantamine.

23. The method of any one of claims 20-22, wherein the carbachol or carbachol derivative is present in an amount of less than 3 wt%.

24. The method of any one of claims 20-22, wherein the carbachol or carbachol derivative is present in an amount of less than 2 wt%.

25. The method of any one of claims 20-22, wherein the carbachol or carbachol derivative is present in an amount of less than 1 wt%.

26. The method of any one of claims 20-22, wherein the carbachol or carbachol derivative is present in an amount of between 0.20 to 0.85 wt%.

27. The method of claim 20, wherein the carbachol or carbachol derivative is present in the topical ophthalmic formulation at a concentration that constricts baseline pupil diameter by at least 1.0 mm after consecutive administration over at least seven days.

28. The method of claim 20, wherein the carbachol or carbachol derivative is present in the topical ophthalmic formulation at a concentration that constricts baseline pupil diameter by at least 1.2 mm after consecutive administration over at least seven days.

29. A topical ophthalmic formulation, comprising: a liquid carrier for topical ophthalmic administration, a first pharmaceutically active agent, and a second pharmaceutically active agent; wherein the first pharmaceutically active agent acutely and transiently constricts pupil diameter upon topical administration to an eye; and wherein the second pharmaceutically active agent cumulatively constricts base line pupil diameter of the eye after consecutive topical administration over at least seven days.

30. The ophthalmic formulation of claim 29, wherein the first pharmaceutically active agent is pilocarpine, neostigmine, rivastigmine, brimonidine, and/or galantamine.

31. The ophthalmic formulation of any one of claims 29-30, wherein the second pharmaceutically active agent is carbachol or a carbachol derivative.

32. The ophthalmic formulation of any one of claims 29-31, wherein the first pharmaceutically active agent acutely and transiently constricts pupil diameter to between 2-3 mm for at least three hours upon topical administration to an eye.

33. The ophthalmic formulation of any one of claims 29-31, wherein the second pharmaceutically active agent constricts the baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

34. A method of topically administering carbachol or a carbachol derivative to an eye of a subject in need thereof, comprising: administering in a first phase the carbachol or the carbachol derivative to the eye until a cumulative effect on pupillary constriction is achieved; following the first phase, administering in a second phase the carbachol or the carbachol derivative to the eye; wherein the carbachol or the carbachol derivative is administered to the eye in the first phase at a dosage and/or concentration that is higher than a dosage and/or concentration of the carbachol or the carbachol derivative in the second phase.

35. The method of claim 34, wherein the carbachol or the carbachol derivative is administered to the eye in the first phase at the dosage that is higher than the dosage of the carbachol or the carbachol derivative in the second phase.

36. The method of claim 34, wherein the dosage and/or concentration of the carbachol or the carbachol derivative in the first phase is at least 30% higher than the dosage and/or concentration of the carbachol or the carbachol derivative in the second phase.

37. The method of claim 34, wherein the first phase lasts between four and eight days.

38. The method of claim 34, wherein the carbachol derivative comprises a promoiety selected from the group of an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof.

39. The method of claim 34, wherein the carbachol or the carbachol derivative is administered as treatment for presbyopia.

40. An ophthalmic composition, comprising: a liquid carrier for topical ophthalmic administration; and a modified carbachol comprising a prodrug of carbachol, a substituted carbachol, or a combination thereof; wherein the modified carbachol exhibits an improved delivery to the pupillary muscle as compared to the delivery of an unmodified carbachol to the pupillary muscle.

41. The composition of claim 40, wherein the prodrug of carbachol comprises a promoiety selected from the group of an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof.

42. The composition of claim 40 or 41, wherein the lipid comprises a fatty acid, a glyceride, a phospholipid, or combinations thereof.

43. The composition of claim 40, wherein the amino acid comprises lysine, valine, alanine, phenylalanine, proline, N,N-dimethylglycine, or combinations thereof.

44. The composition of claim 41, wherein the amino acid comprises lysine, valine, alanine, phenylalanine, proline, N,N-dimethylglycine, or combinations thereof.

45. The composition of claim 40, wherein the substituted carbachol comprises a halogen atom, a C2-C8 alkyl group, or a combination thereof.

46. The composition of claim 45, wherein the substituted carbachol comprising the C2-C8 alkyl group comprises an N-alkyl carbachol, an N,N-dialkyl carbachol, or a combination thereof.

47. The composition of claim 40, wherein the composition has equal or less than 0.02% benzalkonium chloride.

48. The composition of claim 40, wherein the modified carbachol has a reduced hydrophilic- lipophilic balance (HLB) index as compared to the HLB index of the unmodified carbachol.

49. The composition of claim 40, wherein the modified carbachol is present in an amount effective to: constrict pupil diameter from a baseline pupil diameter to between 2-8 mm for at least two hours after topical administration to an eye; and constrict baseline pupil diameter by at least 0.8 mm after consecutive administration over at least seven days.

50. The composition of claim 49, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least three hours after topical administration to an eye.

51. The composition of claim 49 or 50, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least four hours after topical administration to an eye.

52. The composition of claim 49, wherein the baseline pupil diameter is constricted by at least 1 mm after consecutive administration over at least seven days.

53. The composition of claim 49, wherein the modified carbachol is present in an amount that improves uncorrected near visual acuity.

54. A method of acute and transient treatment of night vision disturbance in an individual, the method comprising: topically administering a carbachol-based ophthalmic composition comprising a modified carbachol to an eye of an individual, wherein the modified carbachol comprises a prodrug of carbachol, a substituted carbachol, or a combination thereof.

55. The method of claim 54, wherein the modified carbachol is present in an amount effective to constrict pupil diameter from a baseline pupil diameter to between 1-2 mm for no greater than three hours after topical administration to the eye.

56. The method of claims 54 or 55, wherein the modified carbachol is present in the composition in an amount of equal to or less than about 0.75%.

57. The method of claim 54, wherein the modified carbachol is present in the composition in an amount of equal to or less than about 0.50%.

58. The method of claim 54, wherein the modified carbachol is present in the composition in an amount between about 0.25% and about 0.50%.

59. The method of claim 54, wherein a miotic effect of the composition is equal to or less than 20% reduction in pupillary diameter.

60. The method of claim 54, wherein a miotic effect of the composition is equal to or less than 15% reduction in pupillary diameter.

61. The method of claim 54, wherein a miotic effect of the composition is equal to or less than 10% reduction in pupillary diameter.

62. The method of claim 54, wherein the treatment reduces at least one of glare, starburst, halo, and double vision.

63. The method of claim 54, wherein the composition is substantially free of benzalkonium chloride.

64. The method of claim 54, wherein the individual has not undergone refractive surgery.

65. The method of claim 54, wherein the acute and transient treatment has a duration of equal to or less than three hours at a reduction of pupillary diameter of about 2 mm.

66. The method of claim 54, wherein the acute and transient treatment has a duration of equal to or less than two hours at a reduction of pupillary diameter of about 2 mm.

67. The method of claim 54, wherein the acute and transient treatment has a duration of equal to or less than one hour at a reduction of pupillary diameter of about 2 mm.

68. The method of claim 54, wherein the acute and transient treatment is an on-demand and non-curative treatment.

69. A method of treating presbyopia in an individual, the method comprising: topically administering a carbachol-based ophthalmic composition comprising a modified carbachol to an eye of an individual, wherein the modified carbachol comprises a prodrug of carbachol, a substituted carbachol, or a combination thereof.

70. The method of claim 69, wherein the modified carbachol is present in an amount effective to constrict pupil diameter from a baseline pupil diameter to between 2-8 mm for at least two hours after topical administration to the eye.

71. The method of claim 69 or 70, wherein the modified carbachol is present in an amount of equal to or less than about 3 wt.%.

72. The method of claim 69, wherein the carbachol is present in an amount of equal to or less than about 2 wt.%.

73. The method of claim 69, wherein the carbachol is present in an amount of equal to or less than about 1 wt.%.

74. The method of claim 69, wherein the carbachol is present in an amount of between about 0.20 to about 0.85 wt.%.

75. The method of claim 69, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least three hours after topical administration to the eye.

76. The method of claim 69, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least four hours after topical administration to the eye.

77. The method of claim 69, wherein the pupil diameter is constricted from the baseline pupil diameter to between 2-8 mm for at least six hours after topical administration to the eye.

78. The method of claim 69, wherein the modified carbachol is present in an amount that improves uncorrected near visual acuity.

79. A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein at least one of Ri, R2, R3, R4, R5, R6, and R7 is: a promoiety selected from the group of an amide, an imine, a carbamate, a carbonate, an ester, a lipid, a succinate, a phosphate, an amino acid, a glycol, an ether, or combinations thereof, or a moiety selected from the group of a halogen atom, a C2-C8 alkyl group, or a combination thereof, or a combination thereof; with the proviso that: when Ri is not the promoiety or the moiety, Ri is an amine group, a substituted amine, or an alkyl group, when R2 is not the promoiety or the moiety, R2 is oxo group, when R3 is not the promoiety or the moiety, R3 is hydrogen, deuterium, halogen, or an alkyl group, when R4 is not the promoiety or the moiety, R4 is hydrogen, deuterium, halogen, or an alkyl group, when R5 is not the promoiety or the moiety, R5 is an amine group, a substituted amine, or an alkyl group, when Re is not the promoiety or the moiety, Re is an amine group, a substituted amine, or an alkyl group, and when R7 is not the promoiety or the moiety, R7 is an amine group, a substituted amine, or an alkyl group.

80. The compound of claim 79, wherein the compound having the structure of Formula (I) is a prodrug of carbachol, a prodrug of methacholine, a prodrug of bethanechol, a substituted carbachol, a substituted methacholine, or a substituted bethanechol.

81. The compound of claim 79 for use as a medicant or for use in a therapy.

82. The compound of claim 79 for use in a method of the acute and transient treatment of night vision disturbance in an individual.

83. The compound of claim 79 for use in a method of treating presbyopia in an individual.