Topical fixed dosage coformulations for ocular therapy

Abstract

This application provides a stable preservative-free pharmaceutical fixed dosage formulation with reduced side effects and high potency for topical ocular delivery to lower intraocular pressure, that can, for example, treat glaucoma, including but not limited to primary open angle glaucoma (POAG), ocular hypertension (OHT) and normal tension glaucoma (NTG). This stable fixed dose formulation includes a combination of cromakalim, such as levcromakalim, in combination with a prostaglandin agonist such as latanoprost, as further described herein.

Description

[0001] TOPICAL FIXED DOSAGE COFORMULATIONS

[0002] FOR OCULAR THERAPY CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of the U.S.S.N. 63 / 754,428, filed February 5, 2025. The entirety of this application is hereby incorporated by reference herein for all purposes.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. EY021727 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0005] FIELD OF THE INVENTION

[0006] This application provides a stable preservative-free topical ocular fixed dosage clear solution with reduced side effects and high potency for topical ocular delivery to lower intraocular pressure, that can, for example, treat glaucoma, including but not limited to primary open angle glaucoma (POAG), ocular hypertension (OHT) and normal tension glaucoma (NTG). This stable fixed dose formulation includes a combination of cromakalim, typically levcromakalim, in combination with latanoprost or other prostaglandin agonist, as further described herein. This fixed dose formulation also induces posterior ocular vasodilation, which can be used to treat retinal ischemia and other disorders that can benefit from increased blood flow in the posterior segment of the eye, including the retina, choroid and optic nerve (e.g., non-arteritic posterior ischemic optic neuropathy (NA-PION).

[0007] BACKGROUND OF THE INVENTION

[0008] Glaucoma is a complex, multifactorial optic neuropathy and the leading cause of irreversible blindness affecting 80 million people worldwide (Quigley, H. A., and Broman, A. T., “The number of people with glaucoma worldwide in 2010 and 2020”, Br. J. Ophthalmol. 2006, 90, 262-267; Tham, Y. C., et al., “Global prevalence of glaucoma and projections of glaucomaburden through 2040: a systematic review and meta-analysis”, Ophthalmology, 2014, 121, 2081-2090; Weinreb, R. N., et al., “The pathophysiology and treatment of glaucoma: a review”, JAMA, 2014, 311, 1901-1911). Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for the disease (Heijl, A., et al., “Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial,” Arch. Ophthalmol. 2002, 120, 1268-1279; Weinreb, R. N., and Khaw, P. T., “Primary open-angle glaucoma,” Lancet 2004, 363, 1711-1720). If left untreated, elevated IOP damages retinal ganglion cells, leading to optic nerve damage and progressive and irreversible vision loss. All currently approved pharmacologic and surgical treatments for glaucoma are aimed at lowering IOP with the purpose of slowing down disease progression. Unfortunately, about 20% of glaucoma patients do not respond to existing therapeutic agents, and all drugs have considerable side effects. As a result, continued research aimed at developing novel pharmacologic agents for the treatment of glaucoma is a priority for the research community.

[0009] The drugs that are the current standard of care for the treatment of glaucoma include Xalatan, Rocklatan, Vyzulta, Iyuzeh, and Zioptan. Xalatan is a monotherapy eyedrop oflatanoprost (a prostaglandin agonist; see U. S. Pat. 5,422,368). The Xalatan formulation is knownto cause blurry vision, conjunctival hyperemia, itchiness, and darkening of the iris. It works byincreasing the outflow of aqueous fluid through the uveoscleral tract. Rocklatan is a combinationfixed dosage form of netarsudil mesylate (a Rho kinase inhibitor) and latanoprost as a topical drop. The most common side effects of Rocklatan are conjunctival hyperemia (red eye; which can lead to bleeding in the surface layer), pain at site of drop, cornea verticillata (deposits in the cornea, which is the transparent layer in front of the eye that covers the pupil and the iris), pruritus (itching of the eye) and general ocular discomfort. Vyzulta contains a derivative of latanoprost (latanoprostene bunod; a nitrate ester prodrug of latanoprost that releases nitric oxide, a vasodilator). Vyzulta is also known to cause conjunctival hyperemia (red eye), eye irritation and eye pain. Vyzulta may also cause the iris (the colored part of the eye) to become darker. Xalatan, Rocklatan, and Vyzulta include the preservative benzalkonium chloride, that is known to cause ocular irritation. On top of these side effects, target IOP is not achievable in a significant percentage of patients using these standard of care irritating ocular therapies. Iyuzeh is a “preservative free” formulation of latanoprost (does not use benzalkonium chloride (BAK)),which like Xalatan, causes blurry vision, conjunctival hyperemia, itchiness. Zioptan is a monotherapy of prostaglandin agonist tafluprost that, while not needing a preservative, also causes conjunctival hyperemia and eye pain and has also been associated with headache and eye pain.

[0010] Latanoprost is also known to be difficult to formulate and has stability issues. As reported by Ochiai and Danjo (“The stabilization mechanism of latanoprost”; International Journal of Pharmaceutics 410 (2011) 23-30); prostaglandin derivatives are likely to degrade in aqueous solutions and adsorb to containers. Temperature-dependent reduction of the latanoprost concentration has also been reported. Xalatan lacks stability and must be stored in a cold environment and typically protected from light (US 2011 / 0118348).

[0011] Despite available therapies, 75% of patients need more than one drug to reduce progression. This leads to a compliance problem, especially because the side effects are difficult and therefore patients may avoid applying multiple drugs. Further, glaucoma often occurs in the older population, who may forget to take multiple medications or take medications without complying with instructions.

[0012] These difficulties are exacerbated by the fact that up to 27% of patients with glaucoma become blind in at least one eye within 10 years and 38% become blind in at least one eye in 25 years. Given the failure to reach target IOP in these patients and the significant side effects of Xalatan, Rocklatan and Vyzulta, improved medications are warranted.

[0013] Cromakalim is an adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener that has been identified as a modulator of IOP. Cromakalim and its use as an antihypertensive was first described in European Patent EP 0120428B1 that claims priority to applications filed in 1983, issued in 1990 and assigned to the Beecham Group, Inc. Disclosures of cromakalim’ s effects on intraocular pressure and glaucoma were reported in PCT Application WO 89 / 10757; Lin et al., “Effects of Cromakalim and Nicorandil on Intraocular Pressure after Topical Administration in Rabbit Eyes” Journal of Ocular Pharmacology and Therapeutics, 1995, 11, 195; and Chowdhury et al., “Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems” PLOS One, 2015, 10, e0141783. Despite the strong biological activity of cromakalim, it has never beenapproved as a drug. Cromakalim has been tested in human clinical trials for systemic hypertension, but the program was terminated.

[0014] Cromakalim exists as a mixture of stereoisomers in the trans-configuration (a mixture of (3R,4S) and (3S,4R) stereoisomers).

[0015]

[0016] Cromakalim (mixture of trans-stereoisomers)

[0017] The (3S,4R)-stereoisomer is referred to as (-)-cromakalim or levcromakalim and the (3R,4S)-stereoisomer is referred to as (+)-cromakalim or dexcromakalim.

[0018]

[0019] (-)-cromakalim (+)-cromakalim

[0020] levcromakalim dexcromakalim

[0021] The majority of cromakalim’s reported activity stems from the (35,47?)-stereoisomer levcromakalim (Ashwood et al. Synthesis and Antihypertensive Activity of 4-(Cyclic Amido)-2H-1-benzopyrans” J. Med. Chem. 1986, 29, 2194 and Attwood et al. “Synthesis of Homochiral Potassium Channel Openers: Role of the Benzopyranyl 3-Hydroxyl Group in Cromakalim and Pyridine N-Oxides in Determining the Biological Activities of Enantiomers” Bioorg. Med. Chem.Lett. 1992, 2, 229). Levcromakalim is the only treatment for glaucoma that selectively targets episcleral venous pressure (EVP).

[0022] Unfortunately, cromakalim is poorly soluble in water and aqueous buffer formulations and readily crystallizes or co-crystallizes and precipitates from solution. It is also poorly soluble in oil or non-polar hydrophobic solvents. Cromakalim is soluble in highly polar “universal” organic solvents such as DMSO (dimethyl sulfoxide), DMF (dimethyl formamide) or NMP (1-methylpyrrolidone) which are capable of hydrogen bonding interactions and hydrophobic interactions, however these are not preferred solvents for in vivo delivery of drugs. It is also somewhat soluble in alcohol such as ethanol, but these low molecular weight monoalcohols are unsuitable for topical human ocular administration. Cromakalim has been solubilized with DMSO and cremophor, that is also used for the non- water-soluble anti-cancer drug taxol (Cremophor EL, now referred to as Kolliphor EL by BASF). However, cromakalim has exhibited low solubility even in DMSO co-solvent mixtures necessitating the use of a high percentage of DMSO, as demonstrated in Whidden, M.A. et al. J Exerc Nutri Biochem. 2016, 20(2), 58-64 or in combination with Cremophor as demonstrated in Roy Chowdhury, U et al. PLOS ONE. 2015, 10 (11), e0141783.

[0023] WO 2024 / 098043 (PCT / US2023 / 078754) filed by Qlaris Bio and Mayo Foundation for Medical Education and Research describes a topical formulation of (lev)cromakalim that can be delivered topically using a specific combination of excipients. A formulation described in WO 2024 / 098043 that contains (lev)cromakalim is being evaluated in human clinical trials for the treatment of primary open angle glaucoma and ocular hypertension (Osprey trial). A formulation described in WO 2024 / 098043 that contains (lev)cromakalim is also being evaluated in human clinical trials for the treatment of primary open angle glaucoma and ocular hypertension on top of the separate standard of care latanoprost (Xalatan) (Apteryx trial).

[0024] Qlaris and Mayo have filed a patent application describing polymeric controlled release formulations of levcromakalim for medical uses, including ocular delivery. See WO 2023 / 018958 (PCT / US2022 / 040197).

[0025] There is a need to provide new topical ocular therapies to lower intraocular pressure and treat the variety of disorders affected by both elevated IOP and normotensive disorders such asnormal tension glaucoma, and other ocular disorders, that are an improvement for treatment of the patient population. There is an additional need to provide new topical ocular therapies that increase vasodilation in the posterior segment of the eye, to treat retinal ischemia and other ocular disorders that benefit from increased posterior blood flow.

[0026] SUMMARY OF THE INVENTION

[0027] A first-in-class and first-time created fixed dosage combination of levcromakalim and latanoprost (or other prostaglandin agonist as described further herein), including a pharmaceutically acceptable salt of either, has been achieved that combines the efficacy of an ATP-sensitive potassium (KATP) channel opener that selectively targets episcleral venous pressure (EVP) with the prostaglandin agonist that selectively targets uveoscleral outflow in a manner that accomplishes a dramatic decrease in IOP and increases compliance and ease of therapy. Given the severe difficulties of formulating either levcromakalim or latanoprost separately as monotherapies in stable separate dosage forms and their insolubility in many liquids, it is a serious achievement that the present invention allows for the first time these two active therapies to be combined in one stable fixed dosage form for easy delivery that encourages compliance and is highly effective to the host in need thereof, typically a human. Further, the stable fixed dose formulation of levcromakalim and latanoprost (or another prostaglandin agonist, as further disclosed herein) has been achieved without the necessity of a preservative such as benzalkonium chloride, which is an eye irritant. This improved topical clear stable fixed dose combination solution can be used in an effective amount to treat a host such as a human with any of the forms of glaucoma, including those caused by elevated intraocular pressure or normal tension glaucoma. In addition, the improved clear stable fixed dose combination solution can be used in an effective amount for posterior vasodilation and thus for the treatment of a disorder associated with reduced blood flow in the posterior ocular segment, such as the retina, choroid or optic nerve. Examples are retinal ischemia and non-arteritic ischemic optic neuropathy (NAION). The complementary mechanisms of action of this fixed dose combination allow enhanced treatment of primary open angle glaucoma and ocular hypertension.In certain embodiments, therefore, the invention provides an aqueous formulation that comprises, includes, consists essentially of or consists of levcromakalim in a range of 0.001% w / v to 0.10% w / v (including 0.010% to 0.015% w / v or to 0.075% w / v), which may be a pharmaceutically acceptable salt; latanoprost or another prostaglandin agonist as described further herein (which may be in a dosage of 0.001% w / v to 0.010% w / v; for example, 0.005% w / v); a polyoxyl-ethylated castor oil (e.g., an ethoxylated glycerol ester) (such as Kolliphor®, which may be for example, but not limited to, EL, HS, RH, ELP or etc.); a fatty acid esterified ethoxylated furanose, such as a fatty acid esterified ethoxylated sorbitan (including but not limited to, polysorbate 20, 40, 60, 80 or etc.); a polymeric lactam (for example, polyvinylpyrrolidone; which may be, for example, but not limited to, PVP-K30, PVP-K90, etc.); a nonionic triblock copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyethylene (including, but not limited to, poloxamer 407 or etc ); a polyol, for example, mannitol; water, and phosphate buffer. In advantageous embodiments, the fixed dose formulation of the present invention does not include a preservative, for example, benzalkonium chloride (BAK), although it can be included if desired. In typical formulations, a pH agent can be used to adjust the pH to about 5-8, or 6-8, or in some embodiments 5.5-7.5 or 6.5-7.5.

[0028] It was very unexpected to discover that latanoprost can be successfully added to a levcromakalim formulation of WO 2024 / 098043 to form a stable fixed dose combination given the historic difficulties of formulating and stabilizing latanoprost. Latanoprost is an extremely sticky viscous material that is hard to work with. It is practically insoluble in water. It is a lipophilic molecule with weak surfactant qualities, which promotes localization within an oil and at an oil / water interface. It has poor thermal stability, and is recommended to be stored with refrigeration. In climates where the temperatures are hot, and sometimes above 37°C, for example if left outside, in a hot car or a hot house, the drug starts to decompose. Therefore, latanoprost formulations sometimes contain more than the effective dosage to compensate for heat or light degradation (Johnson, et al., J. Ocular Pharmacol. Therapy 2011 Feb 27 (1), 51-59) “Thermal Stability of Bimatoprost, Latanoprost and Travoprost under Simulated Daily Use.”

[0029] Since the provided topical ocular fixed dose coformulation should be prepared to provide a reproducible and specific required dosage, there is little room for loss of material. Latanoprost can stick to stir bars, the side of the container and other mechanical forms of mixing instead ofgoing into solution. It also comes out of solution easily. The stable co-formulation described herein was first required to be prepared by applying latanoprost to a stainless-steel square with a stainless-steel hook system that was submerged into the levcromakalim solution for rapid mixing for one hour, and then the solution was left overnight to continue to mix (Example 2d).

[0030] In primary embodiments, the aqueous formulation is not an emulsion, and certainly not an emulsion that has decreased transparency or is even milky, that may disturb vision. For example, in certain embodiments, the aqueous formulation is clear (e.g., a solution with a percent transmittance of greater than 85%, 90%, or 95%). In additional aspects the levcromakalim latanoprost (or other prostaglandin agonist) fixed dose combination formulation is a clear aqueous solution including but not limited to an aqueous micellar or nanomicellar solution. In certain embodiments, the topical formulation does not include an oil as it is specifically defined below.

[0031] Specifically, this innovative stable fixed dosage combination of (lev)cromakalim and latanoprost can surprisingly achieve a decrease in IOP of 5.5 - 6.5 mm Hg or more in vivo. This compares with a lowering of IOP of 4- 4.5 with (lev)cromakalim alone (see Example 5 and FIG.

[0032] 4). This fixed dose combination provides better IOP lowering efficacy than either drug alone.

[0033] In certain embodiments, the prostaglandin agonist is selected from latanoprost, bimatoprost, travoprost, tafluprost and latanoprostene bunod. Latanoprost (or other prostaglandin agonist, such as bimatoprost, travoprost, tafluprost or latanoprostene bunod) is typically included in its standard of care dosage as described herein. The typical standard of care dosage for latanoprost is 0.005% w / v. The typical standard of care dosage for bimatoprost is 0.01 or 0.03% w / v. The typical standard of care dosage for travoprost is 0.004% w / v. The typical standard of care dosage for tafluprost is 0.0015% w / v. The typical standard of care dosage for latanoprostene bunod is 0.024% w / v. Any of these dosages can be increased or decreased according to the desired healthcare goals, however, increased ocular toxicity and / or irritation might occur when the dosage is increased. Most of the prostaglandin drugs, as currently approved, require refrigeration and typically have a short half-life (usually approximately one month). This can be difficult for patients who are forgetful or non-compliant. Further, most formulations of these commercial drugs use a benzalkonium chloride preservative, which leads to additional irritation. As described above, among the benefits of the presently disclosed fixed dosage combination of (lev)cromakalim andthe selected prostaglandin agonist is that it is more temperature stable than the current commercial mono-formulations, can be stored at room temperature for 1, 2, 3, or 4 months or more without the rapid degradation of the prostaglandin agonist, does not require a preservative and / or encourages compliance since both active compounds are in a single stable topical drop.

[0034] The present topical ocular fixed dose combination of latanoprost (or other prostaglandin agonist) and levcromakalim is very safe. It does not provide an unacceptable hERG signal, CYP inhibition or induction, genotoxicity, mutagenicity or off-target effects. The fixed dose combination did not show any ocular or systemic toxicity in mice. The fixed dosage formulation of the present invention also does not cause or worsen vascular congestion, small bleeds, small punctate bleeds or microhemorrhages when provided to a host in need thereof.

[0035] Typical concentrations of (lev)cromakalim in the fixed dose combination range from 0.001-0.010% w / v; such as, for example, 0.001% w / v, 0.005% w / v, 0.010% w / v, 0.015% w / v, 0.020% w / v, 0.030% w / v, 0.075% w / v, or 0.10% w / v). Notably a dosage of 0.015% w / v performs advantageously. In certain aspects of the embodiments, the topical pharmaceutical ocular formulation that can be used as an eye drop includes 0.005-0.030% w / v. Latanoprost is typically included in its standard of care dosage of 0.005% w / v; however, more or less of this active can be used (for example, but not limited to 0.001- 0.010% w / v) if it achieves the desired effect. Where weight / volume (e.g., mg / mL) concentrations are used herein, the active compound is measured without regard to any salt form.

[0036] The fixed dosage formulation of the present invention can be administered, for example, using QD or BID dosing. As variations, the topical drop may be administered QAM or QPM. This innovative fixed dose combination avoids ocular surface irritations caused or aggravated by preservatives and the resultant poor tolerability and loss of compliance or limited efficacy which can necessitate a costly change in regimen or a surgical intervention. An advantageous dosage amount and dosage regimen for the (lev)cromakalim monotherapy formulation has been confirmed in the Osprey human clinical trials (see Example 44). It has been discovered that a dosage of 0.015% w / v concentration of levcromakalim with a once-daily QPM (i.e., administered at night) dose is favorable, and has an excellent safety profile with no clinically relevant adverse events.Alternatively, QAM or BID regimens can be used. This can be carried over to the present topical ocular fixed dose formulation.

[0037] In the Apteryx clinical trial, the levcromakalim formulation demonstrated significant mean reductions from baseline at the three tested concentrations (0.015%, 0.030%, and 0.075%) over latanoprost alone, using the commercial Xalatan formulation (Examples 45). The formulations of 0.015% levcromakalim administered QPM or BID demonstrated additive reductions of 3.2 and 3.6 mm Hg from baseline of 19.8 mm Hg.

[0038] Critically, the fixed dose combination exhibits two to three times the efficacy of either Vyzulta or Rocklatan. The cromakalim / latanoprost fixed dose combination also showed no adverse events in the animal studies described herein, which is superior to Rocklatan. Rocklatan exhibited hyperemia in more than half of the patients (59% hyperemia, see Rocklatan FDA Label, March 2019, NDA 208259). As noted above, hyperemia drives patient discontinuation and creates worse outcomes with added costs and healthcare visits. The presently disclosed fixed dose coformulation is a non-inflammatory, preservative-free, once daily formulation improves long-terms patient adherence by preventing ocular surface disease caused by preservatives.

[0039] In other embodiments, instead of a prostaglandin agonist, a different second active agent is included in the pharmaceutical formulation of the present invention. In certain embodiments the second active agent is an alpha agonist including but not limited to brimonidine or apraclonidine; or a carbonic anhydrase inhibitor (CAI) including but not limited to di chlorphenamide, methazolamide, or acetazolamide.

[0040] The topical ocular fixed dose clear coformulation of the present invention includes levcromakalim which lowers IOP by relaxing vessels of the vascular and vascular-like tissues distal to the trabecular meshwork (TM), thereby reducing the distal outflow resistance and lowering episcleral venous pressure (EVP). Current therapies target only three of the four components of IOP, namely the aqueous humor inflow rate, uveoscleral outflow rate, and conventional outflow facility. The (lev)cromakalim formulation of the present invention targets the fourth component, reduction of EVP. This fills the gap in the potential to maximally lower IOP as EVP can be the largest determinant of overall IOP, while maintaining normal vascular integrity of the venous system without causing hyperemia.Unexpectedly, the fixed-dose combination formulation of the present invention comprising levcromakalim and latanoprost (or other prostaglandin agonist), when combined, causes retinal vasodilation (increase in retinal blood vessel diameter, Example 47). Treatment with latanoprost monotherapy alone provided a vasoconstriction (reduction in the retinal blood vessel diameter) of about 3%, whereas treatment with levcromakalim mono-therapy provided the opposite— a vasodilation (about 18% increase for 0.015% w / v levcromakalim; about 21% increase for 0.075% w / v levcromakalim). The fixed dose combination (FDC 1) (0.015% w / v levcromakalim + 0.005% latanoprost) and FDC 3 (0.075% w / v levcromakalim + 0.005% latanoprost) provided vasodilation of about 18% and about 23%, respectively (Table 82), which indicated that the latanoprost negative effect on blood flow (vasoconstriction) was not observed in the new fixed dose combination of the present invention.

[0041] In certain embodiments, the topical fixed dose formulation of (lev)cromakalim and latanoprost can be transformational to ocular healthcare because it has superior efficacy, minimal toxicity and promotes compliance as a single drop administration. This invention does not require micro- or nano-particle formulation or the manufacture of a covalent prodrug.

[0042] The present topical ocular fixed dose combination formulation in an aqueous liquid is stable under ambient conditions for at least two, three, four or even five months without significant crystallization or undue separation of (lev)cromakalim and / or latanoprost from the liquid and does not include DMSO, DMF or NMP or another unacceptable topical carrier for human use. In additional aspects of these embodiments, the topical pharmaceutical ocular formulation for humans is stable under ambient conditions for at least six, seven, eight or nine months. The term “significant” when used in this context means that the cromakalim, or levcromakalim, or its pharmaceutically acceptable salt, does not crystallize or separate enough to materially decrease the concentration below + / -5% from the initial concentration.

[0043] In certain embodiments, the present fixed dose combination of (lev)cromakalim and prostaglandin agonist such as latanoprost exhibits a stability of at least 4 months, and typically 5, 6 or 7 or more months under ambient conditions (i.e., without significant crystallization or separation from the formulation that reduces the concentration independently of cromakalim or latanoprost, below + / - 5% or below + / - 10% of the original amount). The components of theformulation have achieved stability with each other for the same time period under ambient conditions.

[0044] In addition, the (lev)cromakalim formulation of the present invention optionally exhibits an osmolarity between about 200 and 400 Osm / L, and more typically, between about 250 and 350 Osm / L. This is a measure of the total solute concentration within a specific volume of a solvent expressed in osmoles per liter (Osm / L). Hyperosmolarity can damage ocular tissue and stimulate epithelial cell death, which then initiates an inflammatory cascade which can lead to cell death via apoptosis.

[0045] In certain aspects, the fixed dose combination invention provides an aqueous formulation that comprises, includes, consists essentially of or consists of cromakalim (for example levcromakalim) or a pharmaceutically acceptable salt thereof; lantanoprost or other selected prostaglandin agonist as described herein; polyoxy-ethylated castor oil (e.g., a Kolliphor or Cremophor including but not limited to Kolliphor ELP); an emulsifier such as polyethoxylated furanose fatty acid ester, such as polyethoxylated sorbitan fatty acid ester (including but not limited to polysorbate 40, 60 or 80); a polymeric lactam (including but not limited to a cyclic amide derived from an amino alkanoic acid (including but not limited to a y-lactam such as polyvinyl pyrrolidone); a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene (including but not limited to Poloxamer 407); a polyol such as mannitol; sodium phosphate dibasic (including but not limited to the heptahydrate); sodium phosphate monobasic (including but not limited to the monohydrate); water and HC1 for pH adjustment to approximately 5-8, or 6-8, such as 5.5-7.5 or 6.5-7.5.

[0046] The fixed dose formulation of (lev)cromakalim and latanoprost or other prostaglandin agonist of the present invention can be topically delivered in an effective amount, for example, to treat glaucoma associated with elevated intraocular pressure, including but not limited to primary open angle glaucoma (POAG), (also known as chronic open angle glaucoma, chronic simple glaucoma and glaucoma simplex), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, steroid induced glaucoma, acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.In certain embodiments, the levcromakalim formulation of the present invention can be used in an effective amount to treat elevated intraocular pressure associated with diabetic retinopathy or diabetic retinopathy induced glaucoma.

[0047] In another embodiment, the present formulation is used to treat glaucoma that is not associated with elevated intraocular pressure, including but not limited to normal tension glaucoma (NTG) (also known as low tension glaucoma or normotensive glaucoma).

[0048] An effective amount of the topical fixed dose coformulation of levcromakalim or a pharmaceutically acceptable salt with latanoprost or another prostaglandin agonist or salt thereof of the present inventioncan also be used to treat a host in need thereof either as primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), including but not limited to miniature version of trabeculectomy (microtrabeculectomy), trabecular bypass surgery, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in an alternative embodiment, a Schl emm’s canal stent that dilates Schl emm’s canal, goniotomies, canal oplasties, and laser trabeculoplasties.

[0049] In other aspects, the presently disclosed topical ocular fixed dose coformulation can also be used in an effective amount to treat Sturge Weber Syndrome, which is not limited to but includes glaucoma associated with elevated episcleral venous pressure (EVP). Sturge Weber Syndrome is a congenital disorder that affects the skin, neurological system and sometimes the eyes. It is sometimes referred to as a neurocutaneous disorder. Sturge Weber Syndrome can result in Sturge Weber Syndrome-induced glaucoma, which affects 30-70% of the patients with this disorder.

[0050] BRIEF DESCRIPTION OF FIGURES FIG. 1 shows the High-Performance Liquid Chromatography (HPLC) standard curve of levcromakalim as described in Table 1, Section VII. The graph shows the mean, and the standard deviation of the measurements done in triplicate. The x-axis depicts the concentration of levcromakalim, and the y-axis depicts the area of the levcromakalim peak.

[0051] FIG. 2 illustrates a stainless-steel hook system that can be used to dissolve latanoprost into solution. This stainless-steel hook system is fabricated to submerge the stainless-steel square withlatanoprost, weighed directly onto the stainless-steel square, in a solution of levcromakalim and hold it in place during mixing (see nonlimiting Example 2d).

[0052] FIG. 3 is a bar chart graph showing the average intraocular pressure (IOP) reduction in mmHg in normotensive C57BL / 6J mice following treatment with 0.015% w / v levcromakalim (Formulation 1), 0.075% w / v levcromakalim (Formulation 3), or 0.005% w / v latanoprost (Formulation 4), with vehicle as a negative control, as described in Example 4. The pretreatment IOP values were used as a baseline. The x-axis identifies the formulation and the y-axis provides the change in intraocular pressure in mmHg. Three independent IOP measurements (1 hour, 4 hours, and 24 hours) were averaged to obtain the mean IOP value.

[0053] FIG. 4 is a bar chart graph showing the average intraocular pressure (IOP) reduction in mmHg in normotensive C57BL / 6J mice after treatment with 0.015% w / v levcromakalim (Formulation 1), 0.005% w / v latanoprost (Formulation 4), or 0.015% levcromakalim + 0.005% latanoprost (fixed dose combination batch 1 (FDC 1)), with vehicle as a negative, as described in Example 5. The pretreatment IOP values were used as a baseline. The x-axis identifies the formulation and the y-axis provides the change in intraocular pressure in mmHg. Three independent IOP measurements (1 hour, 4 hours, and 24 hours) were averaged to obtain the mean IOP value.

[0054] FIG. 5 is a bar chart graph showing the average intraocular pressure (IOP) reduction in mmHg in normotensive volunteer subjects after treatment with high dosage of levcromakalim (0.075% w / v levcromakalim) or low dosage of levcromakalim (0.015% w / v levcromakalim), as described in Example 43. The x-axis identifies the time point of IOP measurement and the y-axis provides the change in intraocular pressure in mmHg (*p = 0.003).

[0055] FIG. 6 is a bar chart graph showing the average vessel width in pm in mice after treatment with 0.015% w / v levcromakalim (Formulation 1), 0.075% w / v levcromakalim (Formulation 3), 0.005% w / v latanoprost (Formulation 4), 0.015% w / v levcromakalim + 0.005% w / v latanoprost (FDC 1), or 0.075% w / v levcromakalim + 0.005% w / v latanoprost (FDC 3), compared to baseline, as described in Example 47. The x-axis identifies the formulation and the y-axis provides the measured retinal vessel width in pm.FIG. 7A illustrates the retinal vein image of a mouse subject at baseline measurement (“Baseline,” top row), and after five consecutive days of treatment with 0.015% w / v levcromakalim (Formulation 1) (“Treatment Day 5,” bottom row). The images in the left column are the full retinal vein image and the boxed portion of the left-column image is enlarged and displayed in the right column. Bars are added to accurately measure the diameter of the retinal vein in pm. The measurement was used to calculate the % vasodilation, or increase in retinal vein width.

[0056] FIG. 7B illustrates the retinal vein image of a mouse subject at baseline measurement (“Baseline,” top row), and after five consecutive days of treatment with 0.075% w / v levcromakalim (Formulation 3) (“Treatment Day 5,” bottom row). The images in the left column are the full retinal vein image and the boxed portion of the left-column image is enlarged and displayed in the right column. Bars are added to accurately measure the diameter of the retinal vein in pm. The measurement was used to calculate the % vasodilation, or increase in retinal vein width.

[0057] FIG. 7C illustrates the retinal vein image of a mouse subject at baseline measurement (“Baseline,” top row), and after five consecutive days of treatment with 0.015% w / v levcromakalim + 0.005% w / v latanoprost (FDC 2) (“Treatment Day 5,” bottom row). The images in the left column are the full retinal vein image and the boxed portion of the left-column image is enlarged and displayed in the right column. Bars are added to accurately measure the diameter of the retinal vein in pm. The measurement was used to calculate the % vasodilation, or increase in retinal vein width.

[0058] FIG. 7D illustrates the retinal vein image of a mouse subject at baseline (“Baseline,” top row), and after five consecutive days of treatment with 0.075% w / v levcromakalim + 0.005% w / v latanoprost (FDC 3) (“Treatment Day 5,” bottom row). The images in the left column are the full retinal vein image and the boxed portion of the left-column image is enlarged and displayed in the right column. Bars are added to accurately measure the diameter of the retinal vein in pm. The measurement was used to calculate the % vasodilation, or increase in retinal vein width.

[0059] FIG. 7E illustrates the retinal vein image of a mouse subject at baseline measurement (“Baseline,” top row), and after five consecutive days of treatment with 0.005% w / v latanoprost (Formulation 4) (“Treatment Day 5,” bottom row). The images in the left column are the full retinal vein image and the boxed portion of the left-column image is enlarged and displayed in the rightcolumn. Bars are added to accurately measure the diameter of the retinal vein in pm. The measurement was used to calculate the % vasodilation, or increase in retinal vein width.

[0060] I.Definitions

[0061] “Levcromakalim” refers to cromakalim which is substantially in the (-)-form (usually at least 95%, 98%, or 99% in the lev-form).

[0062] “(Lev)cromakalim” refers to cromakalim which is enantiomerically enriched in the (-)-form, which for the purpose of this invention means greater than 51% levcromakalim.

[0063] Latanoprost

[0064] Latanoprost (common commercial form Xalatan) is an FDA approved prostaglandin agonist. More specifically, latanoprost is the isopropyl ester prodrug of latanoprost free acid (LFA). Latanoprost hydrolyses to the active LFA upon absorption through the cornea to become biologically active. The compound was first approved as a medication to treat high intraocular pressure (IOP), including ocular hypertension (OHT) and open-angle glaucoma (OAG), in the United States and in the European Union in 1996. The structure of latanoprost is shown below.

[0065]

[0066] Latanoprost in vivo metabolizes to latanoprost free acid (LFA). The structure of LFA is shown below.

[0067]

[0068] If desired the latanoprost free acid can be substituted for latanoprost, by equal mole. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.0005% and 0.01% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.001% and 0.01% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.0005% and 0.008% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.001% and 0.008% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.002% and 0.01% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.002% and 0.01% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.002% and 0.008% w / v. In certain embodiments, the concentration of latanoprost in the ophthalmic solution of the present invention is between 0.004% and 0.006% w / v.

[0069] In certain embodiments latanoprost is used at a concentration of about 0.001% w / v. In certain embodiments latanoprost is used at a concentration of about 0.002% w / v. In certain embodiments latanoprost is used at a concentration of about 0.003% w / v. In certain embodiments latanoprost is used at a concentration of about 0.004% w / v. In certain embodiments latanoprost is used at a concentration of about 0.005% w / v. In certain embodiments latanoprost is used at a concentration of about 0.006% w / v. In certain embodiments latanoprost is used at a concentration of about 0.007% w / v.

[0070] Kolliphor® or Cremophor®

[0071] Kolliphor® or Cremophor® (BASF) as used herein is polyoxyl-ethylated castor oil (ethoxylated glycerol ester) made from castor oil and ethylene oxide where fatty acid esters of glycerol represent the hydrophobic portion, and the polyethylene glycol represent the hydrophilic portion. It is used as a surfactant, emulsifier and solubilizer (HLB value = 12 to 14) in drug formulations because it can emulsify and solubilize oils and water-insoluble agents as it is fully soluble in aqueous formulations. An example of ethoxylated glycerol ester, Kolliphor® ELP(cremophor® ELP or polyoxyl-35-castor oil) is a non-ionic polyethoxylated detergent made by reacting castor oil and ethylene oxide in a molar ratio of 1:35. The structure of Kolliphor® ELP is shown below (x + y + z = 35).

[0072]

[0073] OH O Kolliphor® ELP is more viscous than Kolliphor® EL (Cremophor® EL). It forms a clear aqueous solution in water, and dissolves in common organic solvents as it contains free polyethylene glycols and ethoxylated glycols as hydrophilic components, and glycerol polyethylene glycol ricinoleate and fatty esters of polyethylene glycol as lipophilic components. It is used as a purified solubilizer for paclitaxel formulations. In certain non-limiting illustrative embodiments, Kolliphor® ELP is used up to about 5% w / v concentration.

[0074] In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.01% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.05% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.5% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.01% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.05% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.1% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises anethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 0.5% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 2% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises an ethoxylated glycerol ester, for example Kolliphor ELP, at a concentration between 3% and 5% w / v.

[0075] In certain embodiments, Kolliphor ELP is used at a concentration of about 2% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 2.2% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 2.4% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 2.6% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 2.8% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 3% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 3.2% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 3.4% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 3.6% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 3.8% w / v. In certain embodiments, Kolliphor ELP is used at a concentration of about 4% w / v.

[0076] In certain embodiments, the ethoxylated glycerol ester is polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40). In certain embodiments, the ethoxylated glycerol ester is polyoxyethylated 12-hydroxy stearic acid (Kolliphor® HS 15).

[0077] Polysorbate

[0078] Polysorbate as used herein is a class of emulsifiers derived from esterification of ethoxylated furanose sugars, for example ethoxylated sorbitan, with fatty acids. Polysorbates as used herein are oily liquids used to solubilize oils in water-based products. Examples of polysorbates include polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Common brand names of polysorbates are Tween, Scattics, Alkest, and Canarcel. The numeral afterpolysorbate refers to the major fatty acid of the molecule, e g., monolaurate is indicated by 20, monopalmitate is indicated by 40, monostearate by 60, and monooleate by 80. An example of a polysorbate component, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) as described herein is a viscous, non-ionic hydrophilic surfactant derived from polyethoxylated sorbitan and oleic acid with an average molecular weight of about 1310 Da, and HLB value of about 15. The structure of polysorbate 80 is shown below (w + x + y + z = 20).

[0079]

[0080] It is an emulsifier as it contains polyoxyethylene hydrophilic component and polysorbate lipophilic component. Polysorbate 80 shows no carcinogenicity and genotoxicity as it shows no adverse effects at the dose of 2500 mg / kg / day. In certain nonlimiting embodiments, the polysorbate, for example polysorbate 80, is used at a concentration between 0.01% and 10% w / v in the ophthalmic solution of the present invention. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.1% and 10% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.01% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.5% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.1% and 2% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.5% and 2% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.1% and 1.5% w / v. In certain embodiments, the ophthalmic solution of the presentinvention comprises a polysorbate, for example polysorbate 80, at a concentration between 0.5% and 1.5% w / v.

[0081] In certain embodiments, polysorbate 80 is used at a concentration of about 0.1% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.2% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.3% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.4% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.5% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.6% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.7% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.8% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 0.9% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.0% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.1% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.2% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.3% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.4% w / v. In certain embodiments, polysorbate 80 is used at a concentration of about 1.5% w / v.

[0082] Polymeric Lactam

[0083] A lactam as used herein is a cyclic amide derived from amino alkanoic acid. The common five types of lactams are named based on rings size as a-lactam (3-atom rings), P-lactam (4 -atom rings), y-lactam (5-atom rings), 8-lactam (6-atom rings), and s-lactam (7-atom rings). A polymeric lactam can be synthesized in a range of molecular weights and viscosities from a lactam-vinyl monomer. For example, PVP (polyvinylpyrrolidone, povidone, or polyvidone) derived from N-vinylpyrrolidone is a bio-degradable, water-soluble polymer. It is one of the most widely used components in pharmaceutical compositions as it exhibits excellent solubility in solvents of different polarities; and stabilizes suspensions and emulsions. Examples of PVPs are shown below.

[0084]

[0085] Example PVP type Molecular weight

[0086] (kDa)

[0087] K12 3.1-5.7

[0088] K17 7.9-10.8

[0089] K25 23-32

[0090] K30 35-51

[0091]

[0092] K90 900-1300

[0093] Exemplary drawings wherein n is 1, 2, or 3 are provided below for clarification in structure only. The skilled artisan will recognize that PVP is typically higher molecular weight than these structures.

[0094]

[0095] PVP contributes to solubility due to its hydrophilic components as it binds to polar molecules such as phenolic compounds via hydrogen bonding. It is used as a thickening agent because its viscosity is tunable due to its availability at a range of molecular weights (2.5 x 103to 2.5 x 106Da) further described in the table above. It is used in ophthalmic solutions (eye drops or lens packaging solutions) as it acts as a lubricant or wetting agent. In certain non-limiting illustrative embodiments, PVP K-30 is used up to about 2% w / v.

[0096] In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.01% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.05% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.5% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.01% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymericlactam, for example a PVP, at a concentration between 0.05% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.1% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 0.5% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 1% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polymeric lactam, for example a PVP, at a concentration between 1% and 3% w / v.

[0097] In certain embodiments, a PVP is used at a concentration of about 1% w / v. In certain embodiments, a PVP is used at a concentration of about 1.2% w / v. In certain embodiments, a PVP is used at a concentration of about 1.4% w / v. In certain embodiments, a PVP is used at a concentration of about 1.6% w / v. In certain embodiments, a PVP is used at a concentration of about 1.8% w / v. In certain embodiments, a PVP is used at a concentration of about 3% w / v. In certain embodiments, a PVP is used at a concentration of about 2% w / v. In certain embodiments, a PVP is used at a concentration of about 2.2% w / v. In certain embodiments, a PVP is used at a concentration of about 2.4% w / v. In certain embodiments, a PVP is used at a concentration of about 2.6% w / v. In certain embodiments, a PVP is used at a concentration of about 2.8% w / v. In certain embodiments, a PVP is used at a concentration of about 3% w / v.

[0098] Poloxamers

[0099] Poloxamers as used herein are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. Pluronic, as described herein, is a poloxamer that consists of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO), arranged in an A-B-A triblock structure, thus giving PEO-PPO-PEO. An important characteristic of poloxamer solutions is their temperature dependent self-assembling and thermo-gelling behavior. Concentrated aqueous solutions of poloxamers are liquid at low temperature and form a gel at higher temperature in a reversible process. The transitions that occur in these systems depend on the molecular weight andhydrophilic / hydrophobic molar ratio. They can be used to increase the water solubility of hydrophobic, oily substances or otherwise increase the miscibility of two substances with different hydrophobicities.

[0100] An example of a poloxamer is poloxamer 407 that is a hydrophilic non-ionic surfactant which is a polyoxyethylene polymer. Poloxamer 407 can be used up to about 0.1% w / v concentration in ophthalmic solution (drops). The structure of poloxamer 407 is shown below (aavg= 101, bavg= 56).

[0101]

[0102] a b a

[0103] Poloxamer 407 is a triblock copolymer consisting of polypropylene glycol (PPG) as a central lipophilic block with an average length of 56 repeating units, which is flanked on two sides by hydrophilic polyethylene glycol (PEG) blocks with an average length of 101 repeating units. It is listed as a component in the inactive ingredient database (IID) and is approved by FDA. It is used as a hydrophilic non-ionic surfactant to dissolve oily substances in aqueous media and has an HLB value of >18. It has been used as an emulsifier and solubilizer in ophthalmic cleaning solutions at concentrations of up to 0.2%. Ophthalmic gel forming poloxamer 407 and hydroxypropyl methyl cellulose are used for ocular delivery of chloramphenicol.

[0104] In certain embodiments, the ophthalmic solution of the present invention comprises a nonionic triblock copolymer, for example poloxamer 407, at a concentration between 0.01% and 1% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a nonionic triblock copolymer, for example poloxamer 407, at a concentration between 0.1% and.5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a nonionic triblock copolymer, for example poloxamer 407, at a concentration between 0.01% and.5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a nonionic triblock copolymer, for example poloxamer 407, at a concentration between 0.05% and.2% w / v.

[0105] In certain embodiments, poloxamer 407 is used at a concentration of about 0.01% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.02% w / v. In certainembodiments, poloxamer 407 is used at a concentration of about 0.03% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.04% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.05% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.06% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.07% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.08% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.09% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.1% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.2% w / v. In certain embodiments, poloxamer 407 is used at a concentration of about 0.3% w / v.

[0106] Polyols

[0107] A polyol as used herein is an aliphatic, typically alkyl, organic compound containing multiple hydroxyl groups (-OH). Polyols containing two, three and four hydroxyl groups are diols, triols, and tetrols, and can be used in the formulation of the present invention.

[0108] A triol as described herein is an alkyl polyol containing three hydroxyl groups. Glycerol (e g., glycerin) is a viscous, non-toxic triol solvent containing hydrophilic components. It is derived through hydrolysis, saponification with sodium hydroxide, or transesterification of triglycerides (esters of glycerol with long-chain carboxylic acid) extracted from plant and animals. The structure of glycerol is shown below.

[0109] OH

[0110]

[0111] It is miscible in water or alcohol-based solvents and can solubilize emulsions and surfactants due to the polar interactions. Due to its high viscosity while possessing alcohol like solvent properties, it is used as a bulking agent, and osmotic diuretic ophthalmic agent.

[0112] A sugar alcohol as described herein is a polyol derived from the hydrogenation of a sugar and contains one hydroxyl group (-OH) attached to each carbon atom. Sugar alcohols have the general formula HOCH2(CHOH)nCH2OH and exist in differing chain lengths, most commonlyfive- or six-carbon chains as they are derived from pentoses (five-carbon sugars) and hexoses (six-carbon sugars), respectively. They typically can be differentiated by the relative orientation (stereochemistry) of these -OH groups. For example, mannitol and sorbitol only differ in the orientation of hydroxyl group on carbon 2. Mannitol, as described herein, is a type of sugar alcohol derived from reduction of mannose, which produces sorbitol, a 2’ -OH isomer of mannitol as the other product. In certain non-limiting illustrative embodiments, mannitol can be used up to about 10% w / v concentration in ophthalmic solution. The structure of mannitol is shown below.

[0113] OH OH

[0114]

[0115] OH OH

[0116] Sugar alcohols are inert and non-hygroscopic. They are used as an additive and a bulking agent (vehicle) for lyophilized formulations. Other sugar alcohols include but are not limited to erythritol, ethylene glycol, glycerol, threitol, arabitol, xylitol, ribitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, maltitol and lactitol.

[0117] In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.01% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.05% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.1% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.5% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.01% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.05% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.1% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 0.5% and 4% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 1% and 5% w / v. In certain embodiments, the ophthalmicsolution of the present invention comprises a polyol, for example mannitol, at a concentration between 2% and 5% w / v. In certain embodiments, the ophthalmic solution of the present invention comprises a polyol, for example mannitol, at a concentration between 2% and 4% w / v.

[0118] In certain embodiments, mannitol is used at a concentration of about 2% w / v. In certain embodiments, mannitol is used at a concentration of about 2.2% w / v. In certain embodiments, mannitol is used at a concentration of about 2.4% w / v. In certain embodiments, mannitol is used at a concentration of about 2.6% w / v. In certain embodiments, mannitol is used at a concentration of about 2.8% w / v. In certain embodiments, mannitol is used at a concentration of about 3% w / v. In certain embodiments, mannitol is used at a concentration of about 3.2% w / v. In certain embodiments, mannitol is used at a concentration of about 3.4% w / v. In certain embodiments, mannitol is used at a concentration of about 3.6% w / v. In certain embodiments, mannitol is used at a concentration of about 3.8% w / v. In certain embodiments, mannitol is used at a concentration of about 4% w / v.

[0119] Polymeric alkyl or aryl polyols

[0120] Polymeric alkyl or aryl polyols as used herein are liquid polymers of alkyl or aryl alcohol prepared by reaction of alkyl or aryl alcohol with aldehydes, e g., formaldehyde.

[0121] Tyloxapol is a non-ionic liquid polymer of alkyl aryl polyether alcohol. It is formed by reaction of 4-(l,l,3,3-tetramethylbutyl) phenol with formaldehyde, followed by reaction to oxirane.

[0122]

[0123] A polyether alcohol hydrophilic component consists of hydrogen bond donors and acceptors, and the lipophilic alkyl component can emulsify hydrophobic components in aqueous formulations. It is used as a surfactant in ophthalmic formulations to balance hydrophilic-lipophilic mixtures as it has an HLB of 13. WO1998025620A1 describes the use of tyloxapol in manufacturing ophthalmic suspensions.

[0124] Hydroxyalkyl cellulose

[0125] Hydroxyalkyl cellulose as described herein is a hydroxyalkyl ether of cellulose prepared by treating cellulose with sodium hydroxide and reacting with alkylene oxide. It is used as a waterbinder and a thickening agent in pharmaceutical compositions to facilitate hydrophilization. Nonlimiting examples of hydroxyalkyl celluloses include hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), and hydroxypropyl methylcellulose (HPMC or hypromellose).

[0126] Hypromellose (hydroxypropyl methylcellulose) is a non-ionic, partly O-methylated and O-(2-hydroxypropylated) cellulose ether derived semisynthetic polymer containing β-linked D-glucose. The structure of hypromellose is shown below.

[0127] R=H or

[0128] CH3 or

[0129] CH2CH(OH)CH3

[0130]

[0131] Hypromellose is manufactured by reacting alkali cellulose, methyl chloride, and propylene oxide. It is available in various substitution ratios and molecular weight grades, and its HLB value ranges from 10 to 11. It is used as an emulsifier, hydrophilic thickening agent, and stabilizer due to film-foaming ability, biocompatibility, and biodegradability. In ophthalmic solutions it also acts as a lubricant.

[0132] Benzalkonium chloride (BAK)

[0133] Benzalkonium chloride (BAK, Zephiran®) is a preservative that is commonly used in eye drops. In certain embodiments it is also used as a cationic surfactant containing a quaternaryammonium as a cationic head group. It is composed of alkyldimethylbenzylammonium chlorides, with paraffinic chains of 8-18 carbons as lipophilic alkyl residues. The structure of BAK is shown below (n = 8, 10, 12, 16, 18).

[0134]

[0135] BAK can be used to dissolve lipophilic components in aqueous formulations at neutral to slightly alkaline pH, as the aqueous solution containing BAK possesses a low surface tension, exhibiting emulsifying properties. Standard concentrates are manufactured as 50% and 80% w / w solutions. The 50% solution is purely aqueous, while more concentrated solutions incorporate viscosity modifiers (alcohols, etc.) to hinder increasing viscosity and gel formation. In certain embodiments, the formulation of the present invention comprises BAK. In certain embodiments, the formulation of the present invention does not comprise a preservative, for example, but not limited to BAK (preservative free). In certain embodiments, BAK is used at a concentration of about 0.0001 to about 0.001% w / v.

[0136] Carbomer Copolymer A and B

[0137] H2 H H2C I H3

[0138] --c — c — c — c - c=o h°

[0139]

[0140] OHJx>-OR-ly

[0141] R=long-chain alkyl

[0142] Carbomer Copolymer Type A, as used herein for example Premulen™ TR-2 is a copolymer of a hydrophilic acrylic acid and hydrophobic alkyl acrylate co-monomer. Specifically, it is a high molecular weight copolymer of acrylic acid and hydrophobic C10-C30alkyl acrylate crosslinked with allylic pentaerythritol. It is a non-ethoxylated polymer for mild oil in water emulsions. Carbomer Copolymer A (Premulen® TR-2) can generate low-viscosity emulsions and can stabilize 60% oil by weight as it contains higher levels of hydrophobic groups. It forms polyethylene glycol free formulations and resulting formulations do not require HLB calculation.Carbomer Copolymer B, as used herein, for example Premulen™ TR-1 has a similar structure to Carbomer Copolymer A, however, it contains lower levels of hydrophobic groups compared to Carbomer Copolymer A. It can generate high viscosity emulsions and formulate up to 20% oil by weight in pH range of 3-11, and 30% oil by weight in pH range 4-5.5.

[0143] A solubilizer or solubilizing agent is a surfactant that increases the solubility of one agent in another.

[0144] An emulsifier / emulsifying agent is an agent that helps other agents mix and prevent separation. Water in oil (w / o) emulsifiers keep water drops packed in oil, while oil in water (o / w) emulsifiers keep oil drops packed in water.

[0145] A wetting agent is a surface-active molecule capable of reducing surface tension of water. An antifoaming agent is a molecule which reduces or hinders foam (materials formed by trapping gas pockets in liquid) formation.

[0146] It should be realized that whenever the commercial name of a formulation component is used, it is exemplary only and not intended to limit the scope of the invention. Non-limiting examples of the chemical names or chemical classes that can be directly substituted for a commercial product name used are provided above and include but are not limited to: a triol or polyol (typically aliphatic, and more typically alkyl) (for example glycerin); a polyethoxylated furanose fatty acid ester (for example a polysorbate); a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) (for example a poloxamer or Pluronic); an alkyl aryl polyol (for example tyloxapol); an ethoxylated glycerol ester (for example Kolliphor® EL or ELP, Cremophor®, Kolliphor® RH 40 or Kolliphor® HS 15); polyoxyalkylene castor oil; carboxymethyl cellulose / CMC; hypromellose; a polymeric lactam (for example PVP); an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate (for example, Premulen™ such as TR-1 and TR-2); and an ethoxylated alkylphenol (for example octoxynol-40).

[0147] In certain aspects a “micellar solution” is a solution which comprises a dispersion of micelles.In certain aspects a “micelle” is an aggregate of amphipathic lipid molecules dispersed in a liquid.

[0148] In certain aspects a “nanomicellar solution” is a micellar solution containing micelles of less than 100 nm in diameter.

[0149] II.Pharmaceutical Compositions and Dosage Forms for Ocular Delivery

[0150] The fixed dose combination formulation of the present invention can be administered to treat an ocular disorder that can be treated with levcromakalim, including but not limited to decreasing intraocular pressure in the eye of a host in need thereof, treating normal tension glaucoma, or for other indications that can be treated with levcromakalim as described herein.

[0151] In certain aspects the fixed dose combination formulation of the present invention is a fixed dose combination of levcromakalim and latanoprost. For example, a pharmaceutical composition with a concentration of 0.001 to 0.1% w / v (0.01 to 1.0 mg / mL) levcromakalim or a pharmaceutically acceptable salt thereof and a concentration of 0.001 to 0.02% w / v (0.01 to 0.20 mg / mL) latanoprost. In preferred embodiments the fixed dose combination comprises levcromakalim at a concentration of 0.015% w / v (0.15 mg / mL) and latanoprost at a concentration of 0.005% w / v (0.05 mg / mL).

[0152] In certain embodiments the fixed dose combination formulation of the present invention is stable at ambient conditions for at least 5, 6, or 7 months or more and can achieve effective concentrations without the use of a “universal organic solvent” such as DMSO or other excipients that are not pharmaceutically acceptable in the range needed for solubilization.

[0153] In certain embodiments, the fixed dose combination formulation of the present invention comprises 0.005% w / v (0.05 mg / mL) latanoprost in combination with levcromakalim, or a pharmaceutically acceptable salt thereof, at a concentration of at least about 0.001% w / v (0.01 mg / mL), 0.015% w / v (0.15 mg / mL), 0.030% w / v (0.30 mg / mL), 0.075% w / v (0.75 mg / mL), and typically not more than about 0.10% w / v (1.0 mg / mL).

[0154] In certain embodiments, the fixed dose combination formulation of the present invention comprises levcromakalim at a concentration of about 0.001, 0.005, 0.010, 0.015, 0.020, 0.025,0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, or 0.10% w / v. In certain embodiments the fixed dose combination formulation of the present invention comprises levcromakalim at a concentration of about 0.015% w / v. In certain embodiments the fixed dose combination formulation of the present invention comprises levcromakalim at a concentration of about 0.030% w / v. In certain embodiments the fixed dose combination formulation of the present invention comprises levcromakalim at a concentration of about 0.075% w / v.

[0155] In certain embodiments, the fixed dose combination formulation of the present invention comprises latanoprost at a concentration of about 0.001, 0.005, 0.010, 0.015, or 0.020% w / v.

[0156] The average topical drop tends to range from 20 microliters to 50 microliters but can be larger or smaller depending on viscosity and the size of the dropper. An average drop may in certain embodiments be approximately in the range of 30 microliters + / - 25%. In a normal dosage, the patient is asked to administer one drop per eye once, twice, three times or four times a day.

[0157] The fixed dose combination formulation described herein can be provided in any dosage strength that achieves the desired results. In certain illustrative non-limiting embodiments, the pharmaceutical composition is provided in one drop to the eye in a manner that administers levcromakalim, or a pharmaceutically acceptable salt thereof, in a range of from about 0.0001 to about 0.0005 mg, from about 0.0005 to about 0.001 mg, from about 0.001 mg to about 0.005 mg, from about 0.005 mg to about 0.01 mg, from about 0.01 mg to about 0.04 mg, or from about 0.04 mg to about 0.09 mg, and latanoprost in a range from about 0.0005 to about 0.001 mg, from about 0.001 to about 0.005 mg, or from about 0.005 mg to about 0.01 mg of latanoprost.

[0158] In certain embodiments, the fixed dose combination formulation of the present invention has a pH of approximately between 5 and 8, or 6 and 8, or between 5.5-7.5 or 6.5-7.5. In certain embodiments, the formulation comprises a phosphate buffer at a pH around 6.5 to 7. The fixed dose combination formulation of the present invention may further comprise one or more osmotic active components. Suitable osmotic active components used in the pharmaceutical composition according to the invention include but are not limited to sodium chloride, mannitol, and glycerol.

[0159] In preferred embodiments a phosphate buffer is used to control the pH of the formulation, however, in alternative embodiments another buffer can be used. Non-limiting examples ofbuffers, with or without additional components or other additives, include (with illustrative, but not limiting concentrations and pH), BES-buffered saline (2X) (0.05 M, pH 6.95); EBSS (magnesium, calcium, phenol red) (pH 7.0); HBSS (Hank’s Balanced Salt Solution) (pH 7.0 to 7.4); HHBS (Hank’s Buffer with HEPES) (pH 7.4); imidazole-HCl buffer (0.05 M, pH 7.0); MOPS buffer (10X) (0.2 M, pH 7); PBS (phosphate buffered saline) (1 X, pH 7.4)); TBS (1 M, pH 7.4); tris buffer (1 M, pH 7.2); phosphate buffer (pH 5.8 to 8.0); potassium phosphate (pH 5.8 to 8.0); and, trizma® buffer (pH 7.0 to 9.2).

[0160] In certain embodiments, the pH of the ocular formulation of (lev)cromakalim is adjusted using a pharmaceutically acceptable acid or base to the desired pH level for pharmaceutical administration, often between about 5-8 or 6-8, and more typically between 5.5-7.5 or 6.5 and 7.5.

[0161] In certain embodiments, the present invention provides an ocular topical formulation comprising cromakalim, such as levcromakalim or (lev)cromakalim, as defined herein, or a pharmaceutically acceptable salt thereof, and mixtures of selected pharmaceutically acceptable components, which provide at least 0.001% w / v (0.01 mg / mL), 0.015% w / v (0.15 mg / mL), 0.030% w / v (0.30 mg / mL), 0.075% w / v (0.75 mg / mL), and typically not more than about 0.10% w / v (1.0 mg / mL) of levcromakalim or a pharmaceutically acceptable salt thereof in combination with 0.005% w / v (0.005 mg / mL) latanoprost.

[0162] In certain embodiments, levcromakalim can be administered in an ocular formulation as a salt. Pharmaceutically acceptable salts of levcromakalim include but are not limited to:

[0163]

[0164] o

[0165]

[0166] wherein X+and M2+can be any pharmaceutically acceptable cation that achieves the desired results and Z+represents a mixed salt of X+.

[0167] In certain embodiments, the cation is selected from sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethyl pyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, and triethylamine.

[0168] In certain embodiments, X+is Na+or K+. In certain embodiments, X+is Li+. In certain embodiments, X+is Cs+. In certain embodiments, X+is an ammonium ion with a net positive charge of one. Non-limiting examples of ammonium ions with a net positive charge of one include:

[0169]

[0170] In alternative embodiments, the ammonium ion with a net positive charge of one has the formula below:

[0171]

[0172] R1

[0173] wherein R1is C1-C6alkyl, for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tbutyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl,CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, for example, phenyl or napthyl wherein the C1-C6alkyl or aryl can be optionally substituted, for example with a hydroxyl group. In certain embodiments, the ammonium ion is

[0174] ^ 1 /

[0175]

[0176] M2+, for example, may be, but is not limited to an alkaline earth metal cation (magnesium, calcium, or strontium), a metal cation with an oxidation state of +2 (for example, zinc or iron), or an ammonium ion with a net positive charge of two (for example, benzathine, hexamethyl diammonium, and ethylenediamine). In certain embodiments, M2+is Mg2+. In certain embodiments, M2+is Ca2+. In certain embodiments, M2+is Sr2+. In certain embodiments, M2+is Zn2+. In certain embodiments, M2+is Fe2+. In certain embodiments, M2+is an ammonium ion with a net positive charge of two. Non-limiting examples of ammonium ions with a net positive charge of two include:

[0177]

[0178] In alternative embodiments, the ammonium ion with a net positive charge of two has the formula below:

[0179] R1

[0180] N'R1

[0181] R1

[0182]

[0183] wherein

[0184] R1is C1-C6alkyl, for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, for example, phenyl or napthyl wherein the C1-C6alkyl or aryl can be optionally substituted, for example with a hydroxyl group; and, y is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8.In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.015% w / v levcromakalim, about 0.005% w / v latanoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0185] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.030% w / v levcromakalim, about 0.005% w / v latanoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0186] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.075% w / v levcromakalim, about 0.005% w / v latanoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0187] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.015% w / v levcromakalim, about 0.03% w / v Bimatoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0188] In other embodiments, the fixed dose combination formulation of the present invention comprises about 0.030% w / v levcromakalim, about 0.03% w / v Bimatoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasicheptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0189] In some embodiments, the fixed dose combination formulation of the present invention comprises about 0.075% w / v levcromakalim, about 0.03% w / v Bimatoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0190] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.015% w / v levcromakalim, about 0.0015% w / v Tafluprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0191] In other embodiments, the fixed dose combination formulation of the present invention comprises about 0.030% w / v levcromakalim, about 0.0015% w / v Tafluprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0192] In some embodiments, the fixed dose combination formulation of the present invention comprises about 0.075% w / v levcromakalim, about 0.0015% w / v Tafluprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0193] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.015% w / v levcromakalim, about 0.004% w / v Travoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10%w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0194] In other embodiments, the fixed dose combination formulation of the present invention comprises about 0.030% w / v levcromakalim, about 0.004% w / v Travoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0195] In some embodiments, the fixed dose combination formulation of the present invention comprises about 0.075% w / v levcromakalim, about 0.004% w / v Travoprost, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0196] In certain embodiments, the fixed dose combination formulation of the present invention comprises about 0.015% w / v levcromakalim, about 0.024% w / v Latanoprostene Bunod, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0197] In other embodiments, the fixed dose combination formulation of the present invention comprises about 0.030% w / v levcromakalim, about 0.024% w / v Latanoprostene Bunod, about 4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0198] In some embodiments, the fixed dose combination formulation of the present invention comprises about 0.075% w / v levcromakalim, about 0.024% w / v Latanoprostene Bunod, about4.00% w / v Kolliphor ELP, about 1.00% w / v Polysorbate 80, about 2.00% w / v Povidone K30, about 0.10% w / v Poloxamer 407, about 3.30% w / v mannitol, about 0.10% w / v sodium phosphate dibasic heptahydrate, about 0.09% w / v sodium phosphate monobasic monohydrate, quantity sufficient (QS) 1 N hydrochloric acid to pH about 6.5, and QS water for injection to 100% w / v.

[0199] In certain embodiments, the fixed dose combination formulation of the present invention comprises a preservative, for example about 0.005-3% w / v (0.05-30 mg / mL) benzalkonium chloride (BAK), however, in typical embodiments, the fixed dose combination formulation of the present invention does not contain preservative.

[0200] In certain embodiments, the fixed dose combination formulation of the present invention is a clear aqueous solution including but not limited to an aqueous micellar or nanomicellar solution. In other embodiments, the topical formulation is not an emulsion, which for example, could be less clear or even milky and may disturb vision. In another embodiment, the topical formulation does not include an oil as that term is defined specifically below.

[0201] Additional Embodiments

[0202] A1. A fixed dose combination formulation of levcromakalim or (lev)cromakalim or a pharmaceutically acceptable salt thereof and latanoprost or a pharmaceutically acceptable salt thereof, wherein the concentration of levcromakalim or (lev)cromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the formulation further comprises three or more components selected from the group consisting of

[0203] a. a polyol;

[0204] b. a poly ethoxylated furanose fatty acid ester; such as a poly ethoxylated sorbitol fatty acid ester;

[0205] c. a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene (poloxamer);

[0206] d. a polymeric alkyl or aryl polyol;

[0207] e. an ethoxylated glycerol ester;f. a polymeric lactam;

[0208] g. hydroxyalkyl cellulose;

[0209] h. an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate; and

[0210] i. an ethoxylated alkylphenol;

[0211] in an aqueous formulation with a pH between 5 and 8 or 6 and 8.

[0212] A2. The fixed dose combination formulation of embodiment Al, wherein the fixed dose combination formulation comprises four or more components in addition to levcromakalim and latanoprost.

[0213] A3. The fixed dose combination formulation of embodiment Al, wherein the fixed dose combination formulation comprises five or more components in addition to levcromakalim and latanoprost.

[0214] A4. The fixed dose combination formulation of embodiment Al, wherein the fixed dose combination formulation comprises six or more components in addition to levcromakalim and latanoprost.

[0215] A5. The fixed dose combination formulation of any one of embodiments A1-A4, wherein the composition comprises a polyol.

[0216] A6. The fixed dose combination formulation of embodiment A5, wherein the polyol is mannitol.

[0217] A7. The fixed dose combination formulation of embodiment A5, wherein the polyol is glycerin. A8. The fixed dose combination formulation of embodiment A5, wherein the polyol is an alkyl polyol.

[0218] A9. The fixed dose combination formulation of embodiment A8, wherein the alkyl polyol is a triol.

[0219] A10. The fixed dose combination formulation of embodiment A8, wherein the alkyl polyol is a sugar alcohol.

[0220] All. The fixed dose combination formulation of any one of embodiments A1-A10, wherein the composition comprises a polyethoxylated furanose fatty acid ester.A12. The fixed dose combination formulation of embodiment Al l, wherein the polyethoxylated furanose fatty acid ester is polysorbate 80.

[0221] A13. The fixed dose combination formulation of any of embodiments A1-A12, wherein the composition comprises a poloxamer.

[0222] A14. The fixed dose combination formulation of embodiment A13, wherein the poloxamer is poloxamer 407.

[0223] A15. The fixed dose combination formulation of any of the embodiments A1-A14, wherein the composition comprises a polymeric alkyl or aryl polyol.

[0224] A16. The fixed dose combination formulation of any of the embodiments A15, wherein the polymeric alkyl or aryl polyol is tyloxapol.

[0225] Al 7. The fixed dose combination formulation of any of the embodiments Al -Al 6, wherein the composition comprises an ethoxylated glycerol ester.

[0226] A18. The fixed dose combination formulation of embodiment A17, wherein the ethoxylated glycerol ester is a Kolliphor® or Cremophor®.

[0227] A19. The fixed dose combination formulation of embodiment A18, wherein the Kolliphor® or Cremophor® is selected from the group consisting of Kolliphor® ELP, Kolliphor® RH 40, and Kolliphor® HS 15.

[0228] A20. The fixed dose combination formulation of embodiment Al 9, wherein the Kolliphor® or Cremophor® is Kolliphor® ELP.

[0229] A21. The fixed dose combination formulation of embodiment A19, wherein the Kolliphor® or Cremophor® is Kolliphor® RH 40.

[0230] A22. The fixed dose combination formulation of embodiment Al 9, wherein the Kolliphor® or Cremophor® is Kolliphor® HS 15.

[0231] A23. The fixed dose combination formulation of any of the embodiments A1-A22, wherein the composition comprises a polymeric lactam.

[0232] A24. The fixed dose combination formulation of embodiment A23, wherein the polymeric lactam is PVP.

[0233] A25. The fixed dose combination formulation of embodiment A24, wherein the PVP is selected from the group PVP K-30 and PVP K-90.A26. The fixed dose combination formulation of embodiment A25, wherein the PVP is PVP K-30.

[0234] A27. The fixed dose combination formulation of embodiment A25, wherein the PVP is PVP K-90.

[0235] A28. The fixed dose combination formulation of any of the embodiments A1-A27, wherein the composition comprises hydroxyalkyl cellulose.

[0236] A29. The fixed dose combination formulation of embodiment A28, wherein the hydroxyalkyl cellulose is hypromellose.

[0237] A30. The fixed dose combination formulation of any of the embodiments A1-A29, wherein the composition comprises an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate.

[0238] A31. The fixed dose combination formulation of embodiment A30, wherein the oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate is Premulen.

[0239] A32. The fixed dose combination formulation of embodiment A31, wherein the Premulen is PremulenTMTR-1 or PremulenTMTR-2.

[0240] A33. The fixed dose combination formulation of any of the embodiments A1-A32, wherein the composition comprises an ethoxylated alkylphenol.

[0241] A34. The ocular formulation of embodiment A33, wherein the ethoxylated alkylphenol is octoxynol.

[0242] A35. The fixed dose combination formulation of embodiment A34, wherein the octoxynol is octoxynol-40.

[0243] A36. A fixed dose combination formulation of levcromakalim or (lev)cromakalim or a pharmaceutically acceptable salt thereof and latanoprost or a pharmaceutically aceeptable salt thereof, wherein the concentration of levcromakalim or (lev)cromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the formulation further comprises three or more components selected from the group consisting of

[0244] a. polysorbate 80,

[0245] b. poloxamer 407,c. Kolliphor® ELP, Kolliphor® RH 40, or Kolliphor® HS 15, and d. PVP

[0246] in an aqueous formulation with a pH between 5 and 8 or 6 and 8.

[0247] A37. The fixed dose combination formulation of embodiment A36 wherein the ocular formulation consists essentially of (lev)cromakalim, latanoprost, water, and three or more components selected from the group consisting of

[0248] a. polysorbate 80,

[0249] b. poloxamer 407,

[0250] c. Kolliphor® ELP, Kolliphor® RH 40, or Kolliphor® HS 15, and

[0251] d. PVP.

[0252] A38. The fixed dose combination formulation of embodiment A36 wherein the ocular formulation consists essentially of (lev)cromakalim, latanoprost, water, and:

[0253] a. polysorbate 80,

[0254] b. poloxamer 407,

[0255] c. Kolliphor® ELP, and

[0256] d. PVP.

[0257] A39. The fixed dose combination formulation of any one of embodiments A1-A38, comprising polysorbate 80 at a concentration of between 0.5% and 1.5% w / v.

[0258] A40. The fixed dose combination formulation of any one of embodiments A1-A38, comprising polysorbate 80 at a concentration of about 1% w / v.

[0259] A41. The fixed dose combination formulation of any one of embodiments A1-A40, comprising poloxamer 407 at a concentration of between 0.05% and 0.15% w / v.

[0260] A42. The fixed dose combination formulation of any one of embodiments A1-A40, comprising poloxamer 407 at a concentration of about 0.1% w / v.

[0261] A43. The fixed dose combination formulation of any one of embodiments A1-A42, comprising Kolliphor® ELP at a concentration of between 1% and 10% w / v.A44. The fixed dose combination formulation of any one of embodiments Al -A42, comprising Kolliphor® ELP at a concentration of about 4% w / v.

[0262] A45. The fixed dose combination formulation of any one of embodiments A1-A44, comprising PVP at a concentration of between 0.5% and 5% w / v.

[0263] A46. The fixed dose combination formulation of any one of embodiments A1-A44, comprising PVP at a concentration of about 2% w / v.

[0264] A47. The fixed dose combination formulation of any of the embodiments of A1-A46, wherein the formulation is stable at ambient conditions for at least 3 months.

[0265] A48. The fixed dose combination formulation of any of the embodiments of A1-A46, wherein the formulation is stable at ambient conditions for at least 4 months.

[0266] A49. The fixed dose combination formulation of any of the embodiments of A1-A46, wherein the formulation is stable at ambient conditions for at least 5 months.

[0267] A50. The fixed dose combination formulation of any of the embodiments of A1-A46, wherein the formulation is stable at ambient conditions for at least 6 months.

[0268] A51. The fixed dose combination formulation of any of the embodiments of A1-A46, wherein the formulation is stable at ambient conditions for at least 7 months.

[0269] A52. The fixed dose combination formulation of any of the embodiments A1-A51, wherein the formulation is an aqueous formulation of pH of about 6.5 to about 7.5.

[0270] A53. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is between 0.005% w / v and 0.075% w / v.

[0271] A54. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is between 0.005% w / v and 0.05% w / v.

[0272] A55. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is between 0.005% w / v and 0.03% w / v.

[0273] A56. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is about 0.015% w / v.

[0274] A57. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is about 0.03% w / v.

[0275] A58. The fixed dose combination formulation of any of the embodiments A1-A52, wherein the concentration of (lev)cromakalim is about 0.075% w / v.A59. The fixed dose combination formulation of any of the embodiments A1-A58, wherein the concentration of latanoprost is between 0.001% w / v and 0.015% w / v.

[0276] A60. The fixed dose combination formulation of any of the embodiments A1-A58, wherein the concentration of latanoprost is between 0.001% w / v and 0.010% w / v.

[0277] A61. The fixed dose combination formulation of any of the embodiments A1-A58, wherein the concentration of latanoprost is between 0.001% w / v and 0.005% w / v.

[0278] A62. The fixed dose combination formulation of any of the embodiments A1-A58, wherein the concentration of latanoprost is about 0.005% w / v.

[0279] A63. The fixed dose combination formulation of any one of embodiments A1-A62, wherein the formulation is not an emulsion.

[0280] A64. The fixed dose combination formulation of any one of embodiments A1-A63, wherein the formulation is not a gel.

[0281] A65. The fixed dose combination formulation of any one of embodiments A1-A64, wherein the formulation is a clear solution.

[0282] A66. The fixed dose combination formulation of any one of embodiments A1-A65, wherein the formulation is a micellar or nanomicellar solution.

[0283] A67. The fixed dose combination formulation of any one of embodiments A1-A66, wherein the formulation does not include an oil.

[0284] A68. The fixed dose combination formulation of any one of embodiments A1-A67, wherein the formulation has a percent transmittance of greater than 85% when tested with a UV- Vis spectrophotometer.

[0285] A69. The fixed dose combination formulation of any one of embodiments A1-A67, wherein the formulation has a percent transmittance of greater than 90% when tested with a UV- Vis spectrophotometer.

[0286] A70. The fixed dose combination formulation of any one of embodiments A1-A67, wherein the formulation has a percent transmittance of greater than 95% when tested with a UV- Vis spectrophotometer.

[0287] A71. The fixed dose combination formulation of any one of embodiments A1-A70, wherein the formulation comprises levcromakalim.A72. The fixed dose combination formulation of any one of embodiments A1-A70, wherein the formulation comprises cromakalim.

[0288] A73. A method for the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the fixed dose combination formulation of any one of embodiments A1-A72 to a human in need thereof. A74. The method of embodiment A73, wherein the use of the topical formulation results in lower intraocular pressure.

[0289] A75. The method of embodiment A73 or A74, wherein the ocular disorder is a glaucoma. A76. The method of embodiment A75, wherein the glaucoma is glaucoma associated with normal intraocular pressure or normal tension glaucoma (NTG).

[0290] A77. The method of embodiment A75, wherein the glaucoma is glaucoma associated with elevated intraocular pressure selected from the group primary open angle glaucoma (POAG), primary angle closure glaucoma (also known as chronic open angle glaucoma, chronic simple glaucoma and glaucoma simplex), pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge, Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

[0291] A78. The method of embodiment A73 or A74, wherein the ocular disorder is Sturge Weber Syndrome or glaucoma induced by Sturge Weber Syndrome-induced glaucoma.

[0292] A79. The method of embodiment A73 or A74, wherein the ocular disorder is diabetic retinopathy.

[0293] A80. The method of embodiment A73 or A74, wherein the method of treatment is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions of trabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative embodiments, Schlemm’s canal stents that dilate Schlemm’s canal, goniotomies, canaloplasties, and laser trabeculoplasties.A81. The method of embodiment A73 or A74, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic- hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

[0294] A82. The method of any one of embodiments A73-A81, wherein the treatment with topical formulation provides cellular protection and / or neuroprotection to the human in need thereof.

[0295] A83. Use of a fixed dose combination formulation of any one of embodiments A1-A72 in the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the fixed dose combination formulation to a human in need thereof.

[0296] A84. The use of embodiment A83, wherein the use of the topical formulation results in lower intraocular pressure.

[0297] A85. The use of embodiment A83 or A84, wherein the ocular disorder is a glaucoma.

[0298] A86. The use of embodiment A85, wherein the glaucoma is glaucoma associated with normal intraocular pressure or normal tension glaucoma (NTG).

[0299] A87. The use of embodiment A85, wherein the glaucoma is glaucoma associated with elevated intraocular pressure selected from the group primary open angle glaucoma (POAG), primary angle closure glaucoma (also known as chronic open angle glaucoma, chronic simple glaucoma and glaucoma simplex), pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge, Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

[0300] A88. The use of embodiment A83 or A84, wherein the ocular disorder is Sturge Weber Syndrome or glaucoma induced by Sturge Weber Syndrome-induced glaucoma.A89. The use of embodiment A83 or A84, wherein the ocular disorder is diabetic retinopathy. A90. The use of embodiment A83 or A84, wherein the use is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions of trabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative embodiments, Schlemm’s canal stents that dilate Schl emm’s canal, goniotomies, canaloplasties, and laser trabeculoplasties.

[0301] A91. The use of embodiment A83 or A84, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic- hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

[0302] A92. The use of any one of embodiments A83-A91, wherein the treatment with topical formulation provides cellular protection and / or neuroprotection to the human in need thereof.

[0303] Bl. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of levcromakalim and latanoprost, wherein the concentration of levcromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the solution further comprises three or more components selected from the group consisting of

[0304] a. a polyol;

[0305] b. a poly ethoxylated furanose fatty acid ester;

[0306] c. a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene (poloxamer);d. a polymeric alkyl or aryl polyol;

[0307] e. an ethoxylated glycerol ester;

[0308] f. a polymeric lactam;

[0309] g. hydroxyalkyl cellulose;

[0310] h. an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate; and

[0311] i. an ethoxylated alkylphenol;

[0312] in an aqueous solution with a pH between 5 and 8.

[0313] B2. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment Bl comprising four or more components.

[0314] B3. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment Bl comprising five or more components.

[0315] B4. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment Bl, comprising six or more components.

[0316] B5. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B4, wherein the solution comprises a polyol. B6. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B5, wherein the polyol is mannitol.

[0317] B7. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B5, wherein the polyol is glycerin.

[0318] B8. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B5, wherein the polyol is an alkyl polyol.

[0319] B9. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B8, wherein the alkyl polyol is a triol.

[0320] BIO. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B8, wherein the alkyl polyol is a sugar alcohol.

[0321] B 11. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B10, wherein the concentration of the polyol is between 0.1% and 10% w / v.Bl 2. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments Bl -BIO, wherein the concentration of the polyol is between 1% and 5% w / v.

[0322] B 13. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B12, wherein the solution comprises a polyethoxylated furanose fatty acid ester.

[0323] B 14. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B13, wherein the polyethoxylated furanose fatty acid ester is polysorbate 80.

[0324] Bl 5. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments Bl -Bl 4, wherein the concentration of the polyethoxylated furanose fatty acid ester is between 0.1% and 10% w / v.

[0325] B 16. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments Bl -Bl 4, wherein the concentration of the polyethoxylated furanose fatty acid ester is between 0.1% and 3% w / v.

[0326] B 17. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of embodiments Bl -Bl 6, wherein the solution comprises a poloxamer. B18. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B17, wherein the poloxamer is poloxamer 407.

[0327] B 19. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments Bl -Bl 8, wherein the concentration of the poloxamer is between 0.01% and 1% w / v.

[0328] B20. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments Bl -Bl 8, wherein the concentration of the poloxamer is between 0.05% and 0.5% w / v.

[0329] B21. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B21, wherein the solution comprises a polymeric alkyl or aryl polyol.

[0330] B22. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B21, wherein the polymeric alkyl or aryl polyol is tyloxapol.B23. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B 1-B22, wherein the solution comprises an ethoxylated glycerol ester.

[0331] B24. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B23, wherein the ethoxylated glycerol ester is selected from the group consisting of polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyethylated 12-hydroxystearic acid.

[0332] B25. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B23, wherein the ethoxylated glycerol ester is polyoxyl-ethylated castor oil.

[0333] B26. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B23, wherein the ethoxylated glycerol ester is polyoxyl 40 hydrogenated castor oil.

[0334] B27. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B23, wherein the ethoxylated glycerol ester is polyoxyethylated 12-hydroxy stearic acid.

[0335] B28. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B27, wherein the concentration of the ethoxylated glycerol ester is between 0.1% and 6% w / v.

[0336] B29. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B27, wherein the concentration of the ethoxylated glycerol ester is between 1% and 5% w / v.

[0337] B30. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B29, wherein the solution comprises a polymeric lactam.

[0338] B31. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B30, wherein the polymeric lactam is a PVP.

[0339] B32. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B31, wherein the PVP is selected from the group consisting of PVP K-30 and PVP K-90.B33. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B31, wherein the PVP is PVP K-30.

[0340] B34. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B31, wherein the PVP is PVP K-90.

[0341] B35. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B34, wherein the concentration of the polymeric lactam is between 0.1% and 10% w / v.

[0342] B36. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B34, wherein the concentration of the polymeric lactam is between 1% and 5% w / v.

[0343] B37. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B36, wherein the solution comprises hydroxyalkyl cellulose.

[0344] B38. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B37, wherein the hydroxyalkyl cellulose is hypromellose.

[0345] B39. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B 1-B38, wherein the solution comprises an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate.

[0346] B40. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B39, wherein the oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate is Carbomer Copolymer.

[0347] B41. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B40, wherein the Carbomer Copolymer is selected from the group consisting of Carbomer Copolymer A and Carbomer Copolymer B.

[0348] B42. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B 1-B41, wherein the solution comprises an ethoxylated alkylphenol.B43. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B42, wherein the ethoxylated alkylphenol is octoxynol.

[0349] B44. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B43, wherein the octoxynol is octoxynol-40.

[0350] B45. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of levcromakalim or a pharmaceutically acceptable salt thereof and latanoprost, wherein the concentration of levcromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the solution further comprises three or more components selected from the group consisting of a. polysorbate 80,

[0351] b. poloxamer 407,

[0352] c. polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, or polyoxyethylated 12-hydroxystearic acid, and

[0353] d. PVP

[0354] in an aqueous solution with a pH between 6 and 8.

[0355] B46. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B45 wherein the ocular solution consists essentially of levcromakalim, latanoprost, water, and three or more components selected from the group consisting of

[0356] a. polysorbate 80,

[0357] b. poloxamer 407,

[0358] c. polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, or polyoxyethylated 12-hydroxystearic acid, and

[0359] d. PVP.

[0360] B47. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of embodiment B45 wherein the ocular solution consists essentially of levcromakalim, latanoprost, water, and:

[0361] a. polysorbate 80,b. poloxamer 407,

[0362] c. polyoxyl-ethylated castor oil, and

[0363] d. PVP.

[0364] B48. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B47, comprising polysorbate 80 wherein the concentration of polysorbate 80 is between 0.1% and 10% w / v.

[0365] B49. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B47, comprising polysorbate 80 wherein the concentration of polysorbate 80 is between 0.5% and 3% w / v.

[0366] B50. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B49, comprising poloxamer 407 wherein the concentration of poloxamer 407 is between 0.01% and 1% w / v.

[0367] B51. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B49, comprising poloxamer 407 wherein the concentration of poloxamer 407 is between 0.01% and 0.5 % w / v.

[0368] B52. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B51, comprising polyoxyl-ethylated castor oil wherein the concentration of polyoxyl-ethylated castor oil is between 0.1% and 6% w / v. B53. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B51, comprising polyoxyl-ethylated castor oil wherein the concentration of polyoxyl-ethylated castor oil is between 1% and 5% w / v. B54. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B53, comprising aPVP wherein the concentration of the PVP is between 0.1% and 10% w / v.

[0369] B55. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B53, comprising PVP wherein the concentration of the PVP is between 1% and 5% w / v.B56. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B55, comprising polysorbate 80 at a concentration of about 1% w / v.

[0370] B57. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B 1-B56, comprising poloxamer 407 at a concentration of about 0.1% w / v.

[0371] B58. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B57, comprising Kolliphor® ELP at a concentration of about 4% w / v.

[0372] B59. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B 1-B58, comprising a PVP at a concentration of about 2% w / v.

[0373] B60. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments of B1-B59, wherein the solution is stable at ambient conditions for at least 3 months.

[0374] B61. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments of B1-B59, wherein the solution is stable at ambient conditions for at least 4 months.

[0375] B62. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments of B1-B59, wherein the solution is stable at ambient conditions for at least 5 months.

[0376] B63. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments of B1-B59, wherein the solution is stable at ambient conditions for at least 6 months.

[0377] B64. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments of B1-B59, wherein the solution is stable at ambient conditions for at least 7 months.

[0378] B65. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B64, wherein the solution is an aqueous solution of pH of about 6.5 to about 7.5.B66. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.075% w / v.

[0379] B67. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.05% w / v.

[0380] B68. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.03% w / v.

[0381] B69. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is about 0.015% w / v.

[0382] B70. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is about 0.03% w / v.

[0383] B71. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B65, wherein the concentration of levcromakalim is about 0.075% w / v.

[0384] B72. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B71, wherein the concentration of latanoprost is between 0.001% w / v and 0.015% w / v.

[0385] B73. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B71, wherein the concentration of latanoprost is between 0.001% w / v and 0.010% w / v.

[0386] B74. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B71, wherein the concentration of latanoprost is between 0.001% w / v and 0.005% w / v.

[0387] B75. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the embodiments B1-B71, wherein the concentration of latanoprost is about 0.005% w / v.B76. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprising

[0388] a. levcromakalim at a concentration of about 0.015% w / v;

[0389] b. latanoprost at a concentration of about 0.005% w / v;

[0390] c. mannitol at a concentration of about 3.3% w / v;

[0391] d. polysorbate 80 at a concentration of about 1% w / v;

[0392] e. poloxamer 407 at a concentration of about 0.1% w / v;

[0393] f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;

[0394] g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; and

[0395] further comprising water and phosphate buffer as aqueous components.

[0396] B77. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprising

[0397] a. levcromakalim at a concentration of about 0.030% w / v;

[0398] b. latanoprost at a concentration of about 0.005% w / v;

[0399] c. mannitol at a concentration of about 3.3% w / v;

[0400] d. polysorbate 80 at a concentration of about 1% w / v;

[0401] e. poloxamer 407 at a concentration of about 0.1% w / v;

[0402] f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;

[0403] g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; and

[0404] further comprising water and phosphate buffer as aqueous components.

[0405] B78. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprising

[0406] a. levcromakalim at a concentration of about 0.075% w / v;

[0407] b. latanoprost at a concentration of about 0.005% w / v;

[0408] c. mannitol at a concentration of about 3.3% w / v;

[0409] d. polysorbate 80 at a concentration of about 1% w / v;

[0410] e. poloxamer 407 at a concentration of about 0.1% w / v;

[0411] f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;

[0412] g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; and

[0413] further comprising water and phosphate buffer as aqueous components.B79. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B78, wherein the solution is not an emulsion. B80. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B79, wherein the solution is not a gel.

[0414] B81. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B80, wherein the solution is a clear solution. B82. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B81, wherein the solution is a micellar or nanomicellar solution.

[0415] B83. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B82, wherein the solution does not include an oil. B84. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B83, wherein the solution does not include a preservative, for example benzalkonium chloride (BAK).

[0416] B85. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B84, wherein the solution further comprises a preservative, for example benzalkonium chloride (BAK) at a concentration of about 0.0005% to about 2% w / v.

[0417] B86. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B84, wherein the solution further comprises a preservative, for example benzalkonium chloride (BAK) at a concentration of about 0.02% w / v.

[0418] B87. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B86, wherein the solution has a percent transmittance of greater than 85% when tested with a UV-Vis spectrophotometer.

[0419] B88. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B86, wherein the solution has a percent transmittance of greater than 90% when tested with a UV-Vis spectrophotometer.B89. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B86, wherein the solution has a percent transmittance of greater than 95% when tested with a UV-Vis spectrophotometer.

[0420] B90. A method for the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B89 to a human in need thereof.

[0421] B91. The method of embodiment B90, wherein the use of the topical solution results in lower intraocular pressure.

[0422] B92. The method of embodiment B90 or B91, wherein the ocular disorder is a glaucoma. B93. The method of embodiment B92, wherein the glaucoma is normal tension glaucoma (NTG).

[0423] B94. The method according to embodiment B92, wherein the glaucoma is primary open angle glaucoma (POAG).

[0424] B95. The method of embodiment B92, wherein the glaucoma is selected from the group consisting of primary open angle glaucoma (POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

[0425] B96. The method of embodiment B90 or B91, wherein the ocular disorder is ocular hypertension (OHT).

[0426] B97. The method of embodiment B90 or B91, wherein the ocular disorder is Sturge Weber Syndrome or Sturge Weber Syndrome-induced glaucoma.

[0427] B98. The method of embodiment B90 or B91, wherein the ocular disorder is diabetic retinopathy.

[0428] B99. The method of embodiment B90 or B91, wherein the method of treatment is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions oftrabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative embodiments, Schlemm’s canal stents that dilate Schl emm’s canal, goniotomies, canaloplasties, and laser trabeculoplasties.

[0429] B100. The method of embodiment B90 or B91, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic- hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

[0430] B101. The method of any one of embodiments B90-B100, wherein the treatment with the topical solution provides cellular protection and / or neuroprotection to the human in need thereof.

[0431] B102. The method of embodiment B90 or B91, wherein the ocular disorder is an ocular-related neurodegenerative disease affecting the posterior segment of the eye.

[0432] B103. The method of embodiment B 102, wherein the ocular-related neurodegenerative disease is ischemia.

[0433] B104. The method of embodiment Bl 02, wherein the ocular-related neurodegenerative disease is non-arteritic anterior ischemic optic neuropathy (NAION).

[0434] B105. The method of embodiment B 102, wherein the ocular-related neurodegenerative disease is retinal ischemia.

[0435] B106. The method of embodiment B 102, wherein the ocular-related neurodegenerative disease is age-related macular degeneration.

[0436] B107. The method of embodiment Bl 06, wherein the age-related macular degeneration is wet age-related macular degeneration.

[0437] B108. The method of embodiment B106, wherein the age-related macular degeneration is dry age-related macular degeneration.B109. The method of embodiment B102, wherein the ocular-related neurodegenerative disease is optic nerve drusen.

[0438] B110. The method of embodiment B102, wherein the ocular-related neurodegenerative disease is an inherited optic neuropathy.

[0439] B111. The method of embodiment B110, wherein the inherited optic neuropathy is selected from the group consisting of Leber’s hereditary optic neuropathy (LHON), dominant optic atrophy, Behr’s syndrome, and Berk-Tabatznik syndrome.

[0440] B112. Use of a aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of embodiments B1-B89 in the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution to a human in need thereof.

[0441] B113. The use of embodiment B112, wherein the use of the topical solution results in lower intraocular pressure.

[0442] B114. The use of embodiment B112 or B113, wherein the ocular disorder is a glaucoma. B115. The use of embodiment B114, wherein the glaucoma is normal tension glaucoma (NTG). B116. The use according to embodiment B114, wherein the glaucoma is primary open angle glaucoma (POAG).

[0443] B117. The use of embodiment B114, wherein the glaucoma is selected from the group consisting of primary open angle glaucoma (POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

[0444] B118. The use of embodiment B112 or B113, wherein the ocular disorder is Sturge Weber Syndrome or glaucoma induced by Sturge Weber Syndrome-induced glaucoma.

[0445] B119. The use of embodiment B112 or B113, wherein the ocular disorder is diabetic retinopathy.B120. The use of embodiment B112 or B113, wherein the use is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions of trabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative embodiments, Schlemm’s canal stents that dilate Schlemm’s canal, goniotomies, canaloplasties, and laser trabeculoplasties.

[0446] B121. The use of embodiment Bl 12 or Bl 13, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic- hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

[0447] B122. The use of any one of embodiments Bl 12-B121, wherein the treatment with the topical solution provides cellular protection and / or neuroprotection to the human in need thereof. B123. The use of embodiment B122, wherein the ocular disorder is an ocular-related neurodegenerative disease affecting the posterior segment of the eye.

[0448] B124. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is ischemia.

[0449] B125. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is non-arteritic anterior ischemic optic neuropathy (NAION).

[0450] B 126. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is retinal ischemia.

[0451] B 127. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is age-related macular degeneration.

[0452] B 128. The use of embodiment Bl 27, wherein the age-related macular degeneration is wet age- related macular degeneration.B129. The use of embodiment Bl 27, wherein the age-related macular degeneration is dry age- related macular degeneration.

[0453] B130. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is optic nerve drusen.

[0454] B131. The use of embodiment B123, wherein the ocular-related neurodegenerative disease is an inherited optic neuropathy.

[0455] B132. The use of embodiment B131, wherein the inherited optic neuropathy is selected from the group consisting of Leber’s hereditary optic neuropathy (LHON), dominant optic atrophy, Behr’s syndrome, and Berk-Tabatznik syndrome.

[0456] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose (such as sorbitol) fatty acid ester, and a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and polymeric alkyl or aryl polyol. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, and an ethoxylated alkylphenol.

[0457] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymericalkyl or aryl polyol. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an ethoxylated alkylphenol.

[0458] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, and an ethoxylated alkylphenol.

[0459] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, and a polymeric lactam. Incertain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0460] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric lactam, and an ethoxylated alkylphenol.

[0461] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0462] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0463] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymeric alkyl or aryl polyol. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim andlatanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a poly ethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an ethoxylated alkylphenol.

[0464] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a poly ethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, and an ethoxylated alkylphenol.

[0465] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution oflevcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0466] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a poly ethoxylated furanose fatty acid ester, a polymeric lactam, and an ethoxylated alkylphenol.

[0467] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0468] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0469] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combinationsolution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated alkylphenol.

[0470] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric lactam, and an ethoxylated alkylphenol.

[0471] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0472] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0473] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylatedglycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0474] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a polymeric lactam, and an ethoxylated alkylphenol.

[0475] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0476] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0477] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a polymeric lactam, and an ethoxylated alkylphenol.In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0478] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0479] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric lactam, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric lactam, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0480] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric lactam, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0481] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0482] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a poly ethoxylated furanose fatty acid ester, a nonionic triblock copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymeric alkyl or aryl polyol. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, a nonionic tri -block copolymer of a central hydrophobicchain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and an ethoxylated alkylphenol.

[0483] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains ofpolyoxyethylene, a polymeric alkyl or aryl polyol, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated alkylphenol.

[0484] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0485] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, an ethoxylated glycerol ester, a polymeric lactam, and an ethoxylated alkylphenol.

[0486] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a polymeric lactam, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim andlatanoprost further comprises a polyol, a polymeric lactam, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0487] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyol, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0488] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated glycerol ester. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, and an ethoxylated alkylphenol.

[0489] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylatedfuranose fatty acid ester, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0490] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, an ethoxylated glycerol ester, a polymeric lactam, and an ethoxylated alkylphenol.

[0491] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric lactam, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a polymeric lactam, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0492] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polyethoxylated furanose fatty acid ester, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0493] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain ofpolyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a polymeric lactam. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, and an ethoxylated alkylphenol.

[0494] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, an ethoxylated glycerol ester, a polymeric lactam, and an ethoxylated alkylphenol.

[0495] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric lactam, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer ofpolyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a polymeric lactam, a hydroxyalkyl cellulose, and an ethoxylated alkylphenol.

[0496] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0497] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, a polymeric lactam, and a hydroxyalkyl cellulose. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, a polymeric lactam, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, an ethoxylated glycerol ester, a polymeric lactam, and an ethoxylated alkylphenol.

[0498] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a polymeric lactam, a hydroxyalkyl cellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a polymeric lactam, a hydroxy alkyl cellulose, and an ethoxylated alkylphenol.

[0499] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric alkyl or aryl polyol, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0500] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a polymeric lactam, a hydroxyalkylcellulose, and an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate. In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a polymeric lactam, a hydroxy alkyl cellulose, and an ethoxylated alkylphenol.

[0501] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises an ethoxylated glycerol ester, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0502] In certain embodiments the fixed dose combination solution of levcromakalim and latanoprost further comprises a polymeric lactam, a hydroxyalkyl cellulose, an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate, and an ethoxylated alkylphenol.

[0503] III.Method of Administration

[0504] The exact amount and dosage of the active compounds in the fixed dose combination formulation of the present invention described herein to be delivered to the host, typically a human, in need thereof will be determined by the health care provider to achieve the desired clinical benefit.

[0505] In certain embodiments, the fixed dose combination formulation of the present invention is administered for at least about one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, two weeks, three weeks, one month, at least two months, at least three months, at least four months, at least five months, at least six months or more, including indefinitely during therapy. In certain embodiments, the fixed dose combination formulation of the present invention is administered once, twice, three, or more times a day.

[0506] The fixed dose combination formulation of the present invention as described herein are administered topically. For topical delivery, the topical dosage form can be administered, for example, once a day (QD), once a day in the morning (QAM), once a day in the evening (QPM) twice a day (BID), three times a day (TID), four times a day (QID), once every other day (Q2D), once every third day (Q3D), as needed, or any dosage schedule that provides treatment of a disorder described herein.In certain embodiments, the fixed dose combination formulation of the present invention is administered for 10, 11, 12, 13, 14, 15, 16, 17, or 18 days. In certain embodiments, the fixed dose combination formulation of the present invention is administered for 14 days.

[0507] In certain embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye once daily in the evening (QPM). In certain embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye once daily in the evening (QPM) for 14 days. In other embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye once daily in the morning (QAM) for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye once daily at noon for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye once daily in the afternoon for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to at least one eye twice daily (BID) for 14 days.

[0508] In certain aspects, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the evening (QPM). In certain embodiments the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the evening (QPM) for 14 days. In other embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the morning (QAM) for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily at noon for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the afternoon for 14 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) twice daily (BID) for 14 days.

[0509] In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the morning (QAM) for 7 days, then to both eyes (OU) once daily in the evening (QPM) for 7 days, then to both eyes (OU) twice daily (BID) for 7 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the morning (QAM) for 7 days, then to both eyes (OU) twice daily (BID) for 7 days, then to both (OU) eyes once daily in the evening (QPM) for 7 days. In certainembodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the evening (QPM) for 7 days, then to both eyes (OU) once daily in the morning (QAM) for 7 days, then to both eyes (OU) twice daily (BID) for 7 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) once daily in the evening (QPM) for 7 days, then to both eyes (OU) twice daily (BID) for 7 days, then to both eyes (OU) once daily in the morning (QAM) for 7 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) twice daily (BID) for 7 days, then to both eyes (OU) once daily in the morning (QAM) for 7 days, then to both eyes (OU) once daily in the evening (QPM) for 7 days. In certain embodiments, the fixed dose combination formulation of the present invention is applied to both eyes (OU) twice daily (BID) for 7 days, then to both eyes (OU) once daily in the evening (QPM) for 7 days, then to both eyes (OU) once daily in the morning (QAM) for 7 days.

[0510] In certain embodiments, topical administration drops are administered through a single use (unit dose) pharmaceutical packaging. In certain embodiments, the unit dose packaging contains at least about 100 μL to about 500 μL, and more typically about 300 μL of the ocular formulation. In certain embodiments, the delivery volume per drop of the formulation delivered through the unit dose packaging is at least about 10 μL to about 50 μL, 20 μL to about 40 μL, and more typically about 30 μL per eye. In certain specific embodiments, as in Example 42 (Table 71), the concentration of the levcromakalim, or a pharmaceutically acceptable salt thereof, in the unit dose packaging is at least about 0.015% w / v (0.045 mg / 0.3 mL), 0.030% w / v (0.090 mg / 0.3 mL), or 0.075% w / v (0.225 mg / 0.3 mL), and typically not more than 0.075% w / v, and the concentration of latanoprost is about 0.005% w / v (0.015 mg / 0.3 mL). In certain specific embodiments, five of the unit dose dropper bottles are dispensed in a single foil packaging. In certain embodiments the concentration of latanoprost is about 0.005% w / v and the concentration of levcromakalim, or a pharmaceutically acceptable salt thereof, is between 0.015% and 0.075% w / v. In certain embodiments the concentration of latanoprost is about 0.005% w / v and the concentration of levcromakalim is between 0.0015% and 0.015% w / v, between 0.015% and 0.040% w / v, or between 0.040% and 0.075% w / v.

[0511] In certain embodiments, the fixed dose combination formulation of the present invention is administered to the eye, for example, as a topical drop, and delivers levcromakalim, incombination with latanoprost, in the eye, for example to the sclera, conjunctiva, optic nerve, cornea, iris, ciliary body, trabecular meshwork, and / or the retina.

[0512] In certain embodiments, the fixed dose combination formulation of the present invention is delivered for storage in ocular tissues and is then released. The release from ocular tissue leads to the efficient absorption and pharmacological effects of levcromakalim and latanoprost, following administration of the fixed dose combination formulation of the present invention.

[0513] The fixed dose combination formulation of the present invention can also be used for ocular therapy using an alternative route, for example, intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in the described immediate release fashion or via an ocular device, or injection. In certain embodiments, the ocular device is a contact lens that immediately releases the fixed dose combination formulation of the present invention.

[0514] Patient compliance and adherence are serious issues, and the fewer times per day that dosing is required, the more likely compliance is achieved. Once daily ocular formulation dosing for glaucoma is advantageous to maintain the ocular pressure in the desired range to minimize optic nerve damage, while also optimizing compliance and adherence. The fixed dose combination formulation of the present invention, in the selected effective dosage in certain embodiments can be administered once-daily (QD) in a topical drop or other convenient manner.

[0515] IV. Use of the Fixed Dose Combination Formulation of the Present Invention

[0516] The present invention provides methods for the use of the fixed dose combination formulation of the present invention to deliver an effective amount of levcromakalim or a pharmaceutically acceptable salt thereof and latanoprost or a pharmaceutically acceptable salt thereof to treat any disorder that can be treated with levcromakalim or a pharmaceutically acceptable salt thereof.

[0517] In certain embodiments, the fixed dose combination formulation of the present invention is used to treat elevated IOP glaucoma, including but not limited to primary open angle glaucoma(POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, iridocorneal endothelial glaucoma (primary open angle glaucoma is also known as chronic open angle glaucoma, chronic simple glaucoma, and glaucoma simplex). In alternative embodiments the fixed dose combination formulation of the present invention is used to treat acute high-pressure glaucoma resulting from advanced cataracts. In another embodiment, the fixed dose combination formulation of the present invention is used to treat acute high-pressure glaucoma resulting from steroid induced glaucoma, uveitic glaucoma, or post-intravitreal injections, or for glaucoma that is not associated with elevated intraocular pressure, including but not limited to normal tension glaucoma (NTG) (also known as low tension glaucoma or normotensive glaucoma). In a nonlimiting illustrative embodiment, the fixed dose combination formulation comprises Kolliphor®, polysorbate, polyvinylpyrrolidone or PVP, poloxamer, and mannitol.

[0518] In certain embodiments, the patient has best corrected visual acuity (BCVA) of 20 / 200 or better before treatment. In certain embodiments, the patient has bilateral primary open angle glaucoma (POAG). In some embodiments, the patient has ocular hypertension (OHT).

[0519] In certain embodiments, the patient has mild to moderate open angle glaucoma (OAG) or OHT in at least one eye. In some embodiments, the patient has mild to moderate open angle glaucoma or OHT in both eyes. In other embodiments, the patient has current, or has had previous, treatment with prostaglandin analogs (PGA). In some embodiments, the patient does not have current, or has not had, previous treatment with PGAs.

[0520] In certain embodiments, the patient has documented historic intraocular pressure (IOP) values greater than 24 mmHg in either eye. In certain embodiments, the patient has documented historic intraocular pressure (IOP) values less than 24 mmHg in either eye. In certain embodiments, the patient is normotensive, for example has normal IOP.

[0521] In certain embodiments, the patient has IOP greater than 19 mmHg at 08:00 hour at qualification visits prior to randomization. In certain embodiments, the patient has IOP less than 19 mmHg at 08:00 hour at qualification visits prior to randomization.In certain embodiments, the patient has a post-washout IOP that is greater than 22 mmHg in the morning on visits two and three. In certain embodiments, the patient has a post-washout IOP that is less than 22 mmHg in the morning on visits one and three.

[0522] In certain embodiments, the patient has a post-washout IOP that is greater than or equal to 18 mmHg at noon on visit two. In certain embodiments, the patient has a post-washout IOP that is less than 18 mmHg at noon on visit two. In certain embodiments, the patient has IOP less than 34 mmHg.

[0523] In certain embodiments, the patient has had selective laser trabeculoplasty (SLT) surgery done no earlier than one year from the study. In certain embodiments, the patient has had SLT surgery done no later than one year from the study. In other embodiments, the patient has had some minimally invasive glaucoma surgeries (MIGS) done no earlier than one year from the study. In certain embodiments, the patient has had some MIGS done no later than one year from the study. In some embodiments, the patient has had MIGS, in combination with cataract surgery, done no less than one year from screening. In certain embodiments, the patient has had MIGS, combined with cataract surgery, done no more than one year from screening.

[0524] In certain embodiments, the patient does not have a history of active ocular disease other than mild to moderate OAG or OHT. In certain embodiments, the patient does have a history of active ocular disease other than moderate OAG or OHT. In other embodiments, the patient does not have moderate to severe glaucomatous damage in either eye. In certain embodiments, the patient does have moderate to severe glaucomatous damage in either eye.

[0525] Intraocular Pressure HOP)

[0526] IOP is dictated by the rate of aqueous humor (AH) production and outflow. One way to specifically quantify these factors is by the modified Goldmann Equation (Lee SS, Robinson MR, Weinreb RN. Episcleral venous pressure and the ocular hypotensive effects of topical and intracameral prostaglandin analogs. J Glaucoma. 2019;28(9): 846-57), shown below, which states that IOP is equal to episcleral venous pressure (EVP) plus the rate of AH inflow (Q) minus the uveoscleral outflow rate (U), divided by the conventional trabecular outflow rate (C) and EVP:

[0527] IOP = EVP + [(Q-U) / C]Currently approved pharmacological therapies for the management of IOP primarily impact ‘Q’, ‘O’, and ‘U’ by affecting the ciliary body, trabecular meshwork (TM), and uveoscleral tissues of the eye, respectively. For example, beta blockers such as timolol, betaxolol, levobunolol, and metipranolol, alpha agonists such as brimonidine, and apraclonidine, and carbonic anhydrase inhibitors such as brinzolamide, dorzolamide, acetazolamide, and methazolamide impact AH inflow rate (Q). Therapeutics targeting the uvescleral outflow rate (U) include prostaglandin analogs such as latanoprost, bimatoprost, travoprost, tafluprost, latanoprostene bunod, and alpha agonists such as brimonidine, and apraclonidine. Conventional trabecular outflow facility (C) is impacted by cholinergics or mitotics such as pilocarpine, and carbachol, and Rho kinase inhibitors such as netarsudil. In contrast, none of the available pharmacological therapies predominantly lower EVP or specifically target tissues and vessels that are distal to the TM such as the collector channels, the deep scleral and intrascleral venous plexus, or the episcleral veins. In some embodiments, the present invention is a fixed dose combination with one or a combination of these standard or (all drugs).

[0528] Of the 4 components of IOP, EVP is typically the largest one, equaling approximately 50 to 60% of the total IOP (Lee SS, Robinson MR, Weinreb RN. Episcleral venous pressure and the ocular hypotensive effects of topical and intracameral prostaglandin analogs. J Glaucoma.

[0529] 2019;28(9): 846-57). Importantly, EVP dictates the lower limit of IOP (typically, 8 to 12 mmHg), setting the “floor” for maximal therapy. For example, a higher EVP places a limit on the therapeutic potential of pharmacological therapies, namely those for NTG and certain surgical modalities such as minimally invasive glaucoma surgery (MIGS) devices, for the treatment of POAG. Notably, EVP has been found to be higher in untreated NTG and POAG compared with age-matched controls (Selbach JM, Posielek K, Steuhl KP, Kremmer S. Episcleral venous pressure in untreated primary open-angle and normal-tension glaucoma. Ophthalmologica.

[0530] 2005;219(6):357-61). Therefore, both NTG and POAG patients could benefit from EVP-lowering agents.

[0531] In certain embodiments, the fixed dose combination formulation of the present invention lowers the intraocular pressure (IOP) by lowering the episcleral venous pressure (EVP) at certain specific concentrations. For example, as described in Example 5, the lowering of IOP in C57BL / 6Jmice is the result of lowering of the EVP and a significant change in TOP is observed in normotensive C57 / BL6J mice.

[0532] Glaucoma

[0533] Glaucoma is a complex, multifactorial optic neuropathy and a leading cause of irreversible blindness that affects over 80 million people worldwide (Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-7; Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311 (18): 1901- 11; and Tham YC, Li X, Wong TY, et al. Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A Systematic Review and Meta-Analysis. Ophthalmology. 2014; 121(11): 2081-90). Historically, elevated intraocular pressure (IOP) has been a leading and the only modifiable risk factor for glaucoma. Lowering IOP is essential to slow down disease progression and vision loss (Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311(18): 1901-11).

[0534] Traditionally, IOP less than 21 mmHg is considered “normal,” whereas pressures above 21 mmHg are considered a clinical warning sign (Dielemans I, Vingerling JR, Algra D, et al. Primary open-angle glaucoma, intraocular pressure, and systemic blood pressure in the general elderly population. The Rotterdam Study. Ophthalmology. 1995;102(l):54-60). Ocular hypertension (OHT) is a condition in which IOP is elevated without glaucomatous findings (e.g., structural changes in cup-to-disc ratio or visual field loss). An economic analysis revealed that subjects with OHT have an overall risk of 10% of developing glaucoma over 5 years (Mansberger SL, Medeiros FA, Gordon M. Diagnostic tools for calculation of glaucoma risk. Surv Ophthalmol.

[0535] 2008;53(SUPPL1): S11-6) and as such are often treated prophylactically as a means of prevention. Results from the pivotal Ocular Hypertension Treatment Study showed that the risk of developing POAG can be reduced through medical treatments that lower IOP. A patient is considered to have POAG only after glaucomatous clinical findings such as changes in cup-to-disc ratio or observation of visual field changes. (Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol.

[0536] 2002; 120(6): 701- 13).IOP is maintained by balanced production and outflow of aqueous humor (AH), a clear fluid that serves as a nutrient source for the avascular tissues in the anterior segment such as the lens and cornea (Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52-9). AH is produced in humans at a rate of 2.4 pL / min and must drain at roughly the same rate in order for IOP to remain within a “normal” and steady homeostatic range. AH can exit the eye through one of two drainage pathways: the conventional outflow pathway, including the trabecular meshwork (TM) and Schl emm’s Canal, or the uveoscleral pathway, in which AH percolates through spaces in the extracellular matrix and ciliary muscle. In middle-aged and older adults, up to 80% of AH exits the eye through the conventional pathway, while the remaining 20% or less leaves via the uveoscleral pathway. If this balance between AH production and conventional outflow is disrupted, IOP can become elevated.

[0537] Open-angle glaucoma is the most common type in the United States, where 9 in 10 people with glaucoma have the open-angle type. Over time, the pressure damages the optic nerve, which affects vision. This can eventually lead to blindness. In primary open angle glaucoma (POAG), the drainage angle formed by the cornea and iris remains open, but there is increased resistance to outflow through the conventional outflow pathway, causing IOP to be increased (Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. N Eng! J Med.

[0538] 2009;360(l 1): 1113-24; and Weinreb RN, Khaw, PT. Primary open-angle glaucoma. Lancet.

[0539] 2004;363(9422): 1711-20). For most patients, elevated IOP over time will closely correlate to the damage of the retinal nerve fiber layer and the optic nerve head, and subsequent gradual but intractable vision loss due to loss of retinal ganglion nerve fibers (Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-7; and Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311(18): 1901-11), which congregate at the optic disc and form the optic nerve. Therefore, lowering IOP still remains a primary treatment goal for POAG, and it can also be “neuroprotective” given the ultimate preservation of the optic nerve fibers (Weinreb RN, Leung CK, Crowston JG, et al. Primary open-angle glaucoma. Nat Rev Dis Primers. 2016;2: 16067).

[0540] Normal -tension glaucoma (NTG) is a type of open -angle glaucoma that happens in people with normal eye pressure. In NTG, the IOP is within the normal range, yet the optic nerve still becomes damaged, and subjects exhibit progressive glaucomatous visual field loss despite“normal” TOP. Although lOP-independent risk factors are believed to play a role in the pathogenesis of NTG, lowering IOP is still a mainstay of treatment as demonstrated in the Collaborative Normal Tension Glaucoma Study (Anderson DR, Normal Tension Glaucoma Study. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol. 2003; 14(2):86-90). NTG is common in the Asian population.

[0541] Angle-closure glaucoma, also called narrow-angle or acute glaucoma is a severe form of glaucoma that constitutes a medical emergency. In this type of glaucoma, the outer edge of the iris blocks fluid from draining out of the front of the eye. The fluid builds up quickly, causing a sudden increase in eye pressure. If it’s not treated, angle-closure glaucoma can cause blindness in just a few days. Another type of angle-closure glaucoma, sometimes called slow or chronic angleclosure. In another type of glaucoma, congenital glaucoma, babies are born with a problem in their eye that keeps fluid from draining normally.

[0542] Glaucoma caused by another medical condition is called secondary glaucoma. Neovascular glaucoma is often caused by diabetes or high blood pressure happens, where the eye makes extra blood vessels that cover the part of eye where fluid would normally drain. Pigmentary glaucoma is a secondary glaucoma where the pigment (color) from your iris (the colored part of your eye) flakes off and blocks fluid from draining out of the eye. Exfoliation glaucoma (sometimes called pseudoexfoliation) is a type of open-angle glaucoma that happens in some people with exfoliation syndrome, a condition that causes extra material to deposit on parts of the eye and block fluid from draining. Uveitic glaucoma can happen in people who have uveitis, a condition that causes swelling and inflammation in the eye. Uveitis can cause inflammation and scar tissue in the middle of the eye. This may damage or block the part of the eye where fluid drains out, causing high eye pressure and leading to uveitic glaucoma and vision loss.

[0543] High intraocular pressure is a common symptom of the most common glaucoma and treatments to lower intraocular pressure slow down glaucoma onset and progression.

[0544] Glaucoma can be treated with the fixed dose combination formulation described herein comprising levcromakalim or a pharmaceutically acceptable salt thereof, and mixtures of selected pharmaceutically acceptable components described herein. In certain embodiments, the fixed dose combination formulation of the present invention can be used to treat glaucoma, wherein reduction in IOP is due to lowering of the EVP.Hyperemia

[0545] In certain embodiments, ocular therapy using an effective amount of the fixed dose combination formulation, that does not result in significantly meaningful hyperemia is provided. Hyperemia is an excess and or prominence of blood in vessels supplying an organ. Ocular hyperemia, also called “red eye”, can include or result in vascular congestion, excessive vascular vasodilation, small bleeds, small punctate bleeds and / or micro hemorrhages. Ocular hyperemia can have a variety of causes, including but not limited to, exogenous irritants, contact lens, inflammation, vessel disruption, conjunctivitis (including infectious or allergic), trauma, endogenous ocular insults, subconjunctival hemorrhage, conjunctival hemorrhage, blepharitis, anterior uveitis, glaucoma, or irritating drugs and environmental irritants (i.e., sun and wind).

[0546] Certain ocular drugs either do not address hyperemia or cause hyperemia. According to the present invention, the use of ocular formulation of levcromakalim does not cause significantly meaningful hyperemia in the patient when used during therapy. Significantly meaningful hyperemia in certain embodiments is that which causes enough discoloration or discomfort to the patient that the patient considers it an adverse effect of the treatment, which can, if significant enough and / or prolonged, lead to poor compliance and even discontinuation of therapy. The present invention can result in an advance in the art by assisting patient compliance and comfort. In certain embodiments, the administration of the fixed dose combination formulation does not significantly induce the expression of at least one protein independently selected from CD31 and VE-Cadherin.

[0547] Sturge Weber Syndrome

[0548] Sturge Weber Syndrome is a congenital disorder that affects the skin, neurological system and sometimes the eyes. It is sometimes referred to as a neurocutaneous disorder. It is a condition that affects the development of certain blood vessels, causing abnormalities in the brain, skin, and eyes from birth. Sturge Weber Syndrome has three major features: a red or pink birthmark called a port-wine birthmark, a brain abnormality called a leptomeningeal angioma, and increased IOP in the eye (glaucoma). In individuals with Sturge Weber Syndrome, glaucoma typically develops either in infancy or early adulthood and can cause vision impairment. In some affected infants, thepressure can become so great that the eyeballs appear enlarged and bulging (buphthalmos). Individuals with Sturge Weber Syndrome can have tangles of abnormal blood vessels (hemangiomas) in various parts of the eye. When these abnormal blood vessels develop into a network of blood vessels at the back of the eye (choroid), it is called a diffuse choroidal hemangioma and occurs in about one-third of individuals with Sturge Weber Syndrome. A diffuse choroidal hemangioma can cause vision loss. When present, the eye abnormalities typically occur on the same side of the head as the port-wine birthmark.

[0549] Another aspect of the present invention is the use of the fixed dose combination formulation for the treatment of glaucoma associated with Sturge Weber Syndrome. Sturge Weber Syndrome-induced glaucoma affects 30-70% of the patients. Managing Sturge Weber Syndrome-induced glaucoma can be complex, and a number of patients need surgery or a drainage device. According to the invention, Sturge Weber Syndrome-induced glaucoma can be treated by administering an effective amount of the fixed dose combination formulation of the present invention.

[0550] In certain embodiments glaucoma can be treated with the fixed dose combination formulation of the present invention.

[0551] Diabetic Retinopathy

[0552] Diabetic retinopathy (DR) is a diabetes complication caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina). The two stages of DR are nonproliferative retinopathy, and proliferative retinopathy. In the nonproliferative stage, the blood vessels swell and leak, which can cause macular edema, and affect vision due to loss of blood supply. In the proliferative / advanced stage DR, abnormal new blood vessels grown on retinal surface, which can break and bleed into the vitreous, and cause vision loss. DR can develop in diabetes type 1 or type 2 due to high blood sugar.

[0553] Another aspect of the present invention is the use of the fixed dose combination formulation for the treatment of elevated intraocular pressure, and glaucoma associated with diabetic retinopathy. According to the invention, elevated intraocular pressure and glaucomaassociated with DR can be treated by administering an effective amount of ocular formulation of levcromakalim.

[0554] In certain embodiments DR can be treated with the fixed dose combination formulation of the present invention.

[0555] Optic Neuropathy Related Mitochondrial Disorders

[0556] Mitochondrial diseases are medical, genetic, and often inherited. The diseases are a clinically heterogeneous group of disorders that result from a dysfunction in the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism, and tissues and organs that are highly dependent on aerobic metabolism are preferentially involved in mitochondrial disorders. While some mitochondrial disorders only affect a single organ, many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondria contain a potassium specific channel (mitoKATP channel) sensitive to ATP. The mitochondrial KATP channel plays an important role in the mitochondrial volume control and in regulation of the components of protonmotive force.

[0557] Inside the mitochondrion is a group of proteins that carry electrons along four chain reactions (Complexes I-IV), resulting in energy production. This chain is known as the Electron Transport Chain. A fifth group (Complex V) churns out the ATP. Together, the electron transport chain and the ATP synthase form the respiratory chain and the process is known as oxidative phosphorylation or OXPHOS. Complex I, the first step in this chain, is the most common site for mitochondrial abnormalities, representing as much as one third of the respiratory chain deficiencies.

[0558] A number of specific mitochondrial disorders have been associated with Complex I deficiency including Leber’s hereditary optic neuropathy, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), and Leigh Syndrome.

[0559] There are many other types of mitochondrial diseases. For example, dominant optic atrophy (DOA) is an inherited optic nerve disorder characterized by degeneration of the optic nerves that typically starts during the first decade of life. Affected people usually develop moderate visual loss and color vision defects. The severity varies and visual acuity can range from normalto legal blindness. Autosomal dominant optic atrophy plus syndrome (ADOA plus) is a rare syndrome that causes vision loss, hearing loss, and symptoms affecting the muscles. The syndrome is associated with optic atrophy. Other symptoms of ADOA plus include sensorineural hearing loss and symptoms affecting the muscles such as muscle pain and weakness. ADOA plus is caused by mutations in the OP Al gene. Both DOA and ADOA are inherited in an autosomal dominant manner. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention, is administered for the treatment of dominant optic atrophy (DOA) or autosomal dominant optic atrophy plus syndrome (ADOA plus).

[0560] Chronic progressive external ophthalmoplegia (CPEO) is a condition characterized mainly by a loss of the muscle functions involved in eye and eyelid movement. Signs and symptoms tend to begin in early adulthood and most commonly include weakness or paralysis of the muscles that move the eye (ophthalmoplegia) and drooping of the eyelids (ptosis). Some affected individuals also have myopathy, which may be especially noticeable during exercise. CPEO can be caused by mutations in any of several genes, which may be located in mitochondrial DNA or nuclear DNA. CPEO can occur as part of other underlying conditions, such as ataxia neuropathy spectrum and Kearns-Sayre syndrome (KSS). KSS is a slowly progressive multi-system mitochondrial disease that often begins with ptosis. Other eye muscles eventually become involved, resulting in paralysis of eye movement. Degeneration of the retina usually causes difficulty seeing in dimly lit environments. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of chronic progressive external ophthalmoplegia or Kearns-Sayre syndrome.

[0561] Leber hereditary optic neuropathy (LHON) is a condition characterized by vision loss. Some affected individuals develop features similar to multiple sclerosis. LHON is caused by mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of Leber hereditary optic neuropathy.

[0562] Mitochondrial enoyl CoA reductase protein associated neurodegeneration (MEPAN) is caused by 2 mutations in the gene MECR (which encodes the protein mitochondrial trans-2-enoyl-coenzyme A-reductase). Characteristics of MEPAN include optic atrophy and childhood-onset dystonia. In certain embodiments, an effective amount of the fixed dose combination formulationof the present invention is administered for the treatment of mitochondrial enoyl CoA reductase protein associated neurodegeneration (MEPAN).

[0563] POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first three years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum (which includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO)); autosomal recessive progressive external ophthalmoplegia; and, autosomal dominant progressive external ophthalmoplegia. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of a POLG-related disorder.

[0564] In certain embodiments Optical Neuropathy can be treated with the fixed dose combination formulation of the present invention.

[0565] Ophthalmic Neuroprotection

[0566] In certain aspects the fixed dose combination formulation of the present invention exhibits neuroprotection in the patient. Neuroprotection is a therapeutic strategy with the goal of maximizing the recovery of neural cells and minimizing neuronal cell death due to injury. The injury can be mechanical, ischemic, degenerative, or caused by radiation. Many neurodegenerative disorders are associated with aging, which can be detrimental for the elderly population. For example, glaucoma is often characterized by the loss of retinal ganglion cells and is a major cause of vision loss and blindness in the elderly.

[0567] In certain embodiments, the fixed dose combination formulation of the present invention is administered to a host in need thereof for the treatment of an ocular-related neurodegenerative disorder. An ocular-related neurodegenerative disorder is any disorder that is associated with thedysfunction or degeneration of neurons or cells, including neural cells, such as retinal ganglion cells.

[0568] In certain embodiments of the present invention, the fixed dose combination formulation is administered as a method for reducing neuronal or cellular damage in the eye of host in need thereof. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered as a method for the treatment for reducing neuronal or cellular damage in the eye of host in need thereof wherein the eye is glaucomatous.

[0569] In certain embodiments, the fixed dose combination formulation of the present invention promotes the survival, growth, regeneration, and / or neurite outgrowth of retinal ganglion cells. In certain embodiments, the fixed dose combination formulation of the present invention prevents the death of damaged neuronal cells.

[0570] Neuronal cell death can also be a result of retinal ischemia, and therefore in certain embodiments, the fixed dose combination formulation of the present invention is administered as a method of reducing neuronal or cellular damage in the eye following retinal ischemia in a host in need thereof.

[0571] Optic neuropathy, which is damage to the optic nerve often characterized by visual loss, results in the loss of retinal ganglion cells. There are many types of optic neuropathies, including ischemic optic neuropathy, optic neuritis, compressive optic neuropathy, infiltrative optic neuropathy, and traumatic optic neuropathy. Nutritional optic neuropathy can also result from under nutrition and / or a vitamin B12deficiency. Toxic optic neuropathy can result from exposure to ethylene glycol, methanol, ethambutol, amiodarone, tobacco, or certain drugs, such as chloramphenicol or digitalis. Certain forms of optic neuropathy can be inherited, including Leber’ s hereditary optic neuropathy (LHON), dominant optic atrophy, Behr’s syndrome, and Berk-Tabatznik syndrome. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered as a method for reducing neuronal or cellular damage in the eye of a host in need thereof with optic neuropathy.

[0572] Additional non-limiting examples of ocular-related neurodegenerative diseases include lattice dystrophy, retinitis pigmentosa, age-related macular degeneration (wet or dry), photoreceptor degeneration associated with wet- or dry-age related macular degeneration, and optic nerve drusen.In certain embodiments, the fixed dose combination formulation of the present invention is administered as a method of treating an ocular-related neurodegenerative disease affecting the posterior segment of the eye. In certain embodiments, the neurodegenerative disease is ischemia. In certain embodiments the neurodegenerative disease is non-arteritic anterior optic neuropathy (NAION). In certain embodiments the neurodegenerative disease is retinal ischemia. In certain embodiments the neurodegenerative disease is age-related macular degeneration. In certain embodiments the neurodegenerative disease is wet age-related macular degeneration. In certain embodiments the neurodegenerative disease is dry age-related macular degeneration. In certain embodiments the neurodegenerative disease is optic nerve drusen. In certain embodiments the neurodegenerative disease is an inherited optic neuropathy. In certain embodiments the neurodegenerative disease is an inherited optic neuropathy, such as Leber’s hereditary optic neuropathy (LHON). In certain embodiments the neurodegenerative disease is an inherited optic neuropathy, such as dominant optic atrophy. In certain embodiments the neurodegenerative disease is an inherited optic neuropathy, such as Behr’s syndrome. In certain embodiments the neurodegenerative disease is an inherited optic neuropathy, such as Berk-Tabatznik syndrome.

[0573] Integrated or Adjunctive Therapy with Microinvasive Glaucoma Surgery (MIGS) Minimally (or Micro) Invasive Glaucoma Surgery (MIGS) has become an innovative procedure in the evolution of glaucoma surgery. Since glaucoma is a disease in which the optic nerve gets damaged primarily due to elevated IOP, the goal of glaucoma surgery is to lower IOP to prevent or reduce damage to the optic nerve.

[0574] Standard glaucoma surgeries are still considered a major surgery and involve trabeculectomy, ExPRESS shunts, or external tube-shunts such as the Ahmed, Molteno, and Baerveldt style valve implants. While such procedures have often been effective at lowering eye pressure and preventing progression of glaucoma, they have numerous potential complications such as double vision, devastating eye infections, exposure of a drainage implant, swelling of the cornea, and excessively low IOP.

[0575] According to Saheb and Ahmed, minimally (or micro) invasive glaucoma surgery refers to a group of procedures which share five preferable qualities:1. an ab interno and / or ab externo approach through a clear corneal incision which may spare the conjunctiva of incision;

[0576] 2. a minimally traumatic procedure to the target tissue;

[0577] 3. an IOP lowering efficacy that justifies the approach;

[0578] 4. a high safety profile avoiding serious complications compared to other glaucoma surgeries, and given lower likelihood of hypotony; and

[0579] 5. an effective recovery with minimal impact on the patient’s quality of life.

[0580] The MIGS group of operations have been developed in recent years to reduce some of the complications of most standard glaucoma surgeries and therefore, in certain embodiments, the fixed dose combination formulation of the present invention is used as an additive in combination with a microinvasive glaucoma surgery (MIGS).

[0581] MIGS is intended to achieve lower IOP in patients with glaucoma with a less invasive surgical procedure, and ideally to achieve a medication sparing effect. MIGS procedures work by using microscopic-sized equipment and tiny incisions, enable controlled outflow and are often conducted at the time of cataract surgery. While they reduce the incidence of complications, some degree of effectiveness is traded for increased safety. (Pillunat, L. E., etal., Clin Ophthalmol. 2017; 11: 1583-1600)

[0582] The MIGS group of operations are divided into several categories:

[0583] 1. Trabecular bypass operations (i.e., angle-based devices and or subconjunctival shunting devices);

[0584] 2. Microtrabeculectomies (miniaturized versions of trabeculectomy);

[0585] 3. Totally internal or suprachoroidal shunts; and,

[0586] 4. Milder, gentler versions of laser photocoagulation.

[0587] Trabecular Surgery (Trabeculotomy) involves the use of a special contact lens on the eye and cutting through the trabecular meshwork with a tiny device under high power microscopic control. This is done without damaging any other tissues in the ocular drainage pathway. The trabecular meshwork can either be destroyed (Trabectome, Trab360, or OMNI Surgical System) or bypassed using a tiny snorkel-like device (the iStent) or using a plug-shaped stent device (iStent Inject). Both procedures are FDA-approved but generally do not reduce eye pressure low enough and are thus useful in early to moderate stages of glaucoma. With these devices, the resistance ofthe trabecular meshwork is obviated, thus primarily leaving distal outflow facility and episcleral venous pressure as limits to further aqueous humor drainage. In certain embodiments, the fixed dose combination formulation of the present invention is used as an additive in combination with Trabectome or Trab360 and / or the iStent / iStent Inject for the treatment of glaucoma by additively lowering IOP via increased distal outflow or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0588] Microtrabeculectomies work by inserting tiny, microscopic-sized tubes into the eye and draining the fluid from inside the eye to underneath the outer membrane of the eye (conjunctiva). The Xen Gel Stent and PRESERFLO are two new devices that can make the trabeculectomy operation safer. Results have shown excellent pressure lowering with improved safety over trabeculectomy in studies done outside the United States. In certain embodiments, the fixed dose combination formulation of the present invention are used as part of the protocols with Xen Gel Stent and / or Preserflo for the treatment of glaucoma by additively lowering IOP via increased distal outflow or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0589] Suprachoroidal Shunts, including the Gold Micro-shunt, iStent Supra, Aquashunt, and STARflo, work by using tiny tubes with very small internal openings, the front of the eye is connected to the suprachoroidal space between the retina and the wall of the eye to augment the drainage of fluid from the eye. This operation has relatively few serious complications and lowers pressures enough to be useful even in moderately severe glaucoma. In certain embodiments, the fixed dose combination formulation of the present invention is used in combination with Suprachoroidal Shunts procedure for the treatment of glaucoma by additively lowering IOP via increased distal outflow or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0590] Trabecular bypass stents and shunts are investigational devices that work to dilate Schlemm’s canal. These procedures facilitate the flow of aqueous into Schlemm's canal by shunting (Eyepass Glaucoma Implant; GMP Companies, Inc., Fort Lauderdale, FL), by stenting the canal itself (iStent; Glaukos Corp., Laguna Hills, CA), or by dilating the canal using viscoelastic (OMNI Surgical System; Sight Sciences, Menlo Park, CA). Other devices such as the Solx Gold Micro-Shunt (OccuLogix, Inc., Mississauga, Ontario, Canada) divert aqueous into thesuprachoroidal space. In certain embodiments, the fixed dose combination formulation of the present invention is used in combination with trabecular bypass stents or shunts procedure for the treatment of glaucoma by additively lowering IOP via increased distal outflow or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0591] Selective laser trabeculoplasty (SLT) is used during the management of glaucoma to help lower IOP. Since the conduct of the LiGHT study, it is being used more often as first line-treatment to help lower IOP, effectively working at the level of the trabecular meshwork to improve outflow. In certain embodiments, the fixed dose combination formulation of the present invention is used alongside and / or in addition to SLT for the treatment of glaucoma by additively lowering IOP via increased distal outflow and / or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0592] Laser photocoagulation was previously reserved for advanced glaucoma that could not be controlled despite trabeculectomy or tube shunts. Endocyclophotocoagulation and micropulse Diode cyclophotocoagulation are two recent advances to the use of laser photocoagulation and have proven useful in cases where glaucoma has yet to become advanced. In certain embodiments, the fixed dose combination formulation of the present invention is used in the endocyclophotocoagulation and micropulse cyclophotocoagulation protocol for the treatment of glaucoma by additively lowering IOP via increased distal outflow and / or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0593] Endocyclophotocoagulation in recent years has become a widely accepted and popular treatment of refractory glaucoma, pediatric glaucoma, and as an adjunct to cataract surgery in both medically controlled and uncontrolled glaucoma in conjunction with phacoemulsification with intraocular lens placement. Endocyclophotocoagulation is performed following lens removal and intraocular lens implantation by inserting an endolaser unit through the cataract incision, across the anterior segment, and into the posterior chamber on the nasal side of the eye. Laser energy is applied to the ciliary processes to destroy ciliary epithelial cells that produce aqueous humor. In certain embodiments, the fixed dose combination formulation of the present invention is used in the endocyclophotocoagulation protocol for the treatment of glaucoma by additively lowering IOP via increased distal outflow and / or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.Micropulse cyclophotocoagulation delivers the laser in short bursts to allow the surgeon to target specific areas of the ciliary body while giving the tissue time to cool down between bursts, minimizing damage. MicroPulse P3 probe and the new Cyclo G6 glaucoma laser system (Iridex) has both been used successfully in retinal diseases, showing excellent safety and efficacy rates. In certain embodiments, the fixed dose combination formulation of the present invention is used in the Micropulse cyclophotocoagulation surgical protocol for the treatment of glaucoma by additively lowering IOP via increased distal outflow and / or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0594] Other devices include Gonioscopy-assisted transluminal trabeculotomy (GATT), Kahook Dual Blade, Ab interno canaloplasty and Hydrus Microstent, i Stent Supra, Xen Glaucoma Treatment System and InnFocus MicroShunt. In certain embodiments, the fixed dose combination formulation of the present invention is used in the surgical protocol of these devices for the treatment of glaucoma as described above.

[0595] Laser Trabeculoplasty, including Selective Laser Trabeculoplasty (SLT), Argon Laser Trabeculoplasty (ALT), Excimer Laser Trabeculostomy and Micropulse Laser Trabeculoplasty (MLT) are surgical laser procedures that help to reduce resistance at the trabecular meshwork by ablating cells of the trabecular meshwork and improving outflow in a manner similar to other forms of trabeculoplasty and certain MIGS devices. In certain embodiments, Excimer Laser Trabeculostomy is used as an additive in combination with Laser Trabeculoplasty for the treatment of glaucoma by additively lowering IOP via increased distal outflow or reduced episcleral venous pressure prior to or after the procedure in an acute or chronic use setting.

[0596] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.In certain embodiments, the fixed dose combination formulation of the present invention is used as an additive to a minimally (or micro) invasive glaucoma surgery as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0597] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to an a-2 adrenergic agonist, such as brimonidine (Alphagan®), epinephrine, dipivefrin (Propine®) or apraclonidine (Lopidine®) and as an additive to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0598] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to a beta-blocker, such as timolol, betaxolol, levobunolol, metipranolol, or carteolol and as an additive to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein.

[0599] In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is atrabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0600] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to a ROCK inhibitor, such as ripasudil, netarsudil (Rhopressa), fasudil, RKI-1447, GSK429286A, or Y-30141 and as an additive to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0601] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to a second ATP-sensitive potassium channel opener, such as minoxidil, diazoxide, nicorandil, or pinacidil and as an additive to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a further embodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0602] In certain embodiments, the fixed dose combination formulation of the present invention is used as a secondary therapy to a carbonic anhydrase inhibitor, such as dorzolamide (Trusopt®), brinzolamide (Azopt®), acetazolamide (Diamox®) or methazolamide (Neptazane®) and as an additive to a minimally (or micro) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is a trabeculotomy. In a further embodiment, the MIGS is a microtrabeculectomy. In a further embodiment, the MIGS is a suprachoroidal shunt. In a furtherembodiment, the MIGS is a trabecular bypass stent or shunt. In a further embodiment, the MIGS is a selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is a laser photocoagulation. In a further embodiment, the MIGS is endocyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculoplasty.

[0603] Other Exemplary Ocular Disorders

[0604] Orbital tumors are benign or malignant space-occupying lesions of the orbit, often leading to dystopia of the eyeball, motility disturbances, diplopia, visual field defects, and sometimes a complete loss of vision. Often orbital tumors are removed via surgery and therefore a medication would be an advantageous therapeutic option. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment or reduction of orbital tumors. In certain embodiments, the fixed dose combination formulation of the present invention is administered topically one time, two times, three times, or more a day. In some embodiments, the fixed dose combination formulation of the present invention is administered prior to or after surgery for the removal or reduction of orbital tumors.

[0605] Episcleral / orbital vein vasculitis is inflammation of the blood vessel wall. The clinical features of the eye vasculitis can vary from conjunctivitis, episcleritis, scleritis, peripheral ulcerative keratitis, proptosis, retinal vasculitis, orbititis to uveitis, depending on the site and distribution of the vessels involved. In certain embodiments, an effective amount the fixed dose combination formulation of the present invention is administered for the treatment of episcleral / orbital vein vasculitis. In certain embodiments, the fixed dose combination formulation of the present invention is administered as a topical drop.

[0606] Carotid-cavernous sinus fistula is an abnormal connection between an artery in the neck and the network of veins at the back of the eye. A fistula can raise the pressure in your cavernous sinuses, which may compress the cranial nerves located around the cavernous sinuses. This compression may damage the nerve function, which is to control your eye movements. Carotid-cavernous sinus fistula can be direct or indirect. Direct carotid-cavernous sinus fistulas are often caused by accidents or injuries that tear the carotid artery wall, while indirect carotid-cavernous sinus fistulas often arise without warning and are associated with high blood pressure, hardened arteries, pregnancy, and connective tissue disorders. In certain embodiments, an effective amountof the fixed dose combination formulation of the present invention is administered for the treatment of carotid-cavernous sinus fistula.

[0607] Dural cavernous sinus shunts are vascular communications in which blood flows through small meningeal branches of the carotid arteries to enter the venous circulation near the cavernous sinus. Often this disorder is congenital, and the onset of clinical abnormalities may be associated with the occurrence of intracranial venous thrombosis. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of dural cavernous sinus shunts.

[0608] Orbital varices are a vascular hamartoma typified by a plexus of low pressure, low flow, thin walled and distensible vessels that intermingle with the normal orbital vessels. Most patients will experience positional proptosis with a head-down position, and intermittent proptosis that is exacerbated by coughing, straining, the Valsalva maneuver, or compression of the jugular veins. In certain embodiments, the fixed dose combination formulation of the present invention is administered for the treatment of orbital varices.

[0609] Branch retinal vein occlusion (BRVO) is the blockage of branches of the retinal vein causing blood and fluid to spill into the retina. Risk factors for BRVO include diabetes, elevated IOP, and high blood pressure. The macula can swell from this fluid, affecting central vision. Eventually, without blood circulation, nerve cells in the eye can die and vision loss can occur. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of branch retinal vein occlusion (BRVO). In certain embodiments, the fixed dose combination formulation of the present invention is administered as a topical drop that is given once, twice, three, or more times a day.

[0610] Non-arteritic anterior ischemic optic neuropathy (NAION) refers to loss of blood flow to the optic nerve and is due to impaired circulation of blood at the optic nerve head. Non-arteritic anterior ischemic optic neuropathy is associated with diabetes, high blood pressure, atherosclerosis, a small optic nerve, elevated IOP, and sleep apnea. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of non-arteritic anterior ischemic optic neuropathy. In certain embodiments, the fixed dose combination formulation of the present invention is administered as a topical drop that is given once, twice, three, or more times a day.In additional aspects of the invention, the fixed dose combination formulation of the present invention is used for the treatment of a selected ocular disorder, as described below.

[0611] Graves’ ophthalmopathy or Graves’ orbitopathy (or thyroid eye disease or thyroid-associated orbitopathy) are autoimmune inflammatory disorders of the orbit and periorbital tissues and typical signs of the diseases include upper eyelid retraction, lid lag, swelling, and bulging eyes. These disorders are orbital autoimmune disorders caused by an overactive thyroid. An effective amount of the fixed dose combination formulation of the present invention can be administered for the treatment of Graves’ ophthalmopathy, Graves’ orbitopathy, or thyroid-associated orbitopathy. The compound can be administered in any manner that achieves the desired effect, including as a topical drop taken as needed to reduce swelling and redness. In certain embodiments, the fixed dose combination formulation of the present invention is taken in combination with a corticosteroid drug or an immune suppression medication (rituximab or mycophenolate).

[0612] Cavernous sinus thrombosis is the formation of a blood clot within the cavernous sinus, a cavity at the base of the brain which drains deoxygenated blood from the brain back to the heart. This is a rare disorder and can be of two types: septic cavernous thrombosis and aseptic cavernous thrombosis. The cause is often secondary to an infection in the nose, sinuses, ears, or teeth. A common disorder secondary to cavernous sinus pathology is superior ophthalmic vein thrombosis, an uncommon orbital pathology that can present with sudden onset proptosis, conjunctival injection, and visual disturbance. In certain embodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of cavernous sinus thrombosis or superior ophthalmic vein thrombosis. In certain embodiments, the fixed dose combination formulation of the present invention is administered in combination or alternation with an antibiotic, heparin, or a steroid. In one aspect, the fixed dose combination formulation of the present invention is administered orally and is given at least once, twice, three, or more times a day as needed.

[0613] Central retinal vein occlusion, also known as CRVO, is a condition in which the main vein that drains blood from the retina becomes blocked partially or completely. This can cause blurred vision and other problems with the eye. Risk factors for CRVO include diabetes, elevated IOP, and high blood pressure. The macula can swell from this fluid, affecting central vision. Eventually, without blood circulation, nerve cells in the eye can die and vision loss can occur. In certainembodiments, an effective amount of the fixed dose combination formulation of the present invention is administered for the treatment of central retinal vein occlusion. In certain embodiments, the fixed dose combination formulation of the present invention is administered as a topical drop that is given once, twice, or three times a day.

[0614] In certain embodiments, the fixed dose combination formulation of the present invention is used to treat vascular disease. In other embodiments, the fixed dose combination formulation of the present invention is used to treat cardiovascular disease. In some embodiments, the fixed dose combination formulation of the present invention is used to treat eye disease. In certain embodiments, the fixed dose combination formulation of the present invention is used to treat glaucoma. In other embodiments, the fixed dose combination formulation of the present invention is used to treat open angle glaucoma (OAG). In certain embodiments, the fixed dose combination formulation of the present invention is used to treat ocular hypertension. In certain embodiments the fixed dose combination formulation of the present invention is used to treat hypertension.

[0615] Retinal vascular diseases comprise disorders that obstruct or dysregulate blood flow in the retina and sometimes the choroid, leading to visual impairment. Vascular abnormalities in the eye contribute significantly to glaucoma and related retinal disorders by reducing ocular perfusion, disrupting autoregulation, and impairing neurovascular coupling, ultimately leading to retinal ganglion cell dysfunction and loss. They are more common in individuals with systemic vascular risk factors such as hypertension, diabetes, hyperlipidemia, aging, and smoking. In certain embodiments, the fixed dose combination formulation of the present invention is used to treat a retinal vascular disease. In certain embodiments, the retinal vascular disease is retinal arterial microaneurysm (RAM). In certain embodiments, the retinal vascular disease is retinal artery occlusion (RAO). In certain embodiments, the retinal vascular disease is retinal vein occlusion (RVO). In certain embodiments, the retinal vascular disease is central retinal vein occlusion. In certain embodiments, the retinal vascular disease is branch retinal vein occlusion. In certain embodiments, the retinal vascular disease is hemiretinal vein occlusion. In certain embodiments, the retinal vascular disease is ocular ischemic syndrome (OIS). In certain embodiments, the retinal vascular disease is neovascularization. In certain embodiments, the retinal vascular disease is vitreous hemorrhage. In certain embodiments, the retinal vascular disease is carotid-cavernous fistula-associated glaucoma.VI. General Synthesis of Levcromakalim

[0616] The following is a general synthesis of levcromakalim.

[0617]

[0618] The reaction of 4-cyanophenol (4-Hydroxybenzonitrile) with 2-hydroxy-2-methyl-3-butyne under phase transfer catalyst probably proceeds to initial formation of a propargyl carbocation. The course of the reaction can be envisaged by assuming that this then attacks the aromatic ring and the resulting allylic cation can then capture the adjacent phenol oxygen and thus form the observed product (3). Treatment of that product with aqueous N-bromosuccinimide leads to the addition of the elements of hypobromous acid and the formation of the brom ohy drin (4) as a mixture of trans stereoisomers. This cyclizes to the epoxide 5 in the presence of sodium hydroxide (5). Ring opening of the oxirane with ammonia gives a mixture of the trans amino alcohols (6). The stereoisomers can then be resolved at this stage and the 35,47?-enantiomer can be used in the next stage. That isomer is next acylated with 4-chrlorobutyl chloride to give the chloroamide (7). The anion from the reaction of the amide with sodium hydride then displaces the chlorine on the end of the chain to form the pyrrolidine ring to afford levcromakalim (8).

[0619] VII. Nonlimiting Illustrative Processes of Manufacture of Fixed Dose Levcromakalim Latanoprost Formulations of the Present Invention

[0620] The fixed dose formulations of the present invention can be prepared according to a variety of processes to achieve the desired solution. In certain embodiments, the fixed dose combination of the present invention is prepared by using a process wherein levcromakalim and excipients are first individually or in groups dissolved in water for injection (WFI), and then latanoprost is added and homogenized or mixed until dissolved, then filtered to yield the fixed dose combination.In certain embodiments, the fixed dose combination of the present invention is prepared by using a process wherein excipients are first individually or in groups dissolved in WFI, then latanoprost is added and dissolved, then levcromakalim is added and homogenized or mixed until dissolved, then filtered to yield the fixed dose combination.

[0621] In certain embodiments, latanoprost is weighed directly onto a stainless-steel square, and a stainless-steel hook system is fabricated to submerge the square in solution and hold it in place during mixing, in combination with an overhead mixer, to provide more turbulent mixing.

[0622] In certain embodiments, the excipient solution comprises water for injection (WFI), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol.

[0623] In certain embodiments, sodium phosphate dibasic heptahydrate is dissolved by mixing at about 400 RPM for no less than 5 minutes at room temperature. In certain embodiments, sodium phosphate monobasic monohydrate is dissolved by mixing at about 400 RPM for no less than 5 minutes at room temperature. In certain embodiments, Kolliphor ELP is dissolved by mixing at about 550 RPM for no less than 15 minutes at room temperature. In certain embodiments, polysorbate 80 is dissolved by mixing at about 550 RPM for no less than 15 minutes at room temperature. In certain embodiments, the povidone is added slowly over no less than 20 minutes and dissolved by mixing at about 650 RPM for no less than 30 minutes at room temperature. In certain embodiments, poloxamer 407 is dissolved by mixing at about 650 RPM for no less than 15 minutes at room temperature. In certain embodiments, mannitol is dissolved by mixing at about 550 RPM for no less than 5 minutes at room temperature.

[0624] In certain embodiments, the excipient solution is heated to 33-40 °C, preferably about 37 °C before the addition of levcromakalim. In certain embodiments, levcromakalim is dissolved by mixing at about 650 RPM for no less than 180 minutes at 33-40 °C, preferably about 37 °C. In certain embodiments, the levcromakalim formulation was mixed at 550 RPM and cooled to no less than 25 °C, then mixed at about 550 RPM for no less than 10 minutes at no less than 25 °C.

[0625] In certain embodiments, the aqueous pharmaceutically acceptable ocular topical formulation of the present invention is prepared using a process wherein levcromakalim, latanoprost, and excipients are first individually or in groups dissolved in ethanol or other low volatile organic solvent(s), mixed and then evaporated under vacuum to produce a film, which isthen resuspended in phosphate buffer and / or deionized water, homogenized or mixed, which is then incubated and filtered to yield the formulation. Optionally, the resuspension can be autoclaved and optionally filtered. In certain embodiments one or more components is added after the film is produced.

[0626] In certain embodiments, the aqueous pharmaceutically acceptable ocular topical formulation of the present invention is prepared by dissolving levcromakalim and latanoprost in a volatile solvent, followed by evaporation and drying under high vacuum to obtain a dry residue, which is then resuspended into combined aqueous solutions of excipients, then incubated, and filtered to yield the formulation. Optionally, the resuspension can be autoclaved and filtered.

[0627] In certain aspects of the specific embodiments, therapeutic levels of levcromakalim in ocular topical formulations of the present invention can be achieved via the encapsulation of levcromakalim into nanomicelles using a variety of processes. In certain embodiments, the nanomicellar formulations of levcromakalim can be prepared using a 2-step encapsulation process. First, the base formulation of levcromakalim and non-aqueous excipients are separately dissolved in ethanol or other compatible low volatile organic solvent(s). These solutions are combined in a glass round-bottom flask, vortexed or stirred to form a homogenous solution, and the solvent removed by rotary evaporation followed by high vacuum to produce a thin film. The film is then hydrated with water, aqueous excipients, latanoprost, and phosphate buffer, homogenized or mixed, incubated, and then filtered through a 0.22pm filter to yield the final formulation. Optionally, the fully hydrated formula can be autoclaved prior to filtration.

[0628] In certain embodiments, the ocular topical levcromakalim / latanoprost fixed dose formulation is prepared by direct dissolution in which a solution of levcromakalim in ethanol is added to a vial or centrifuge, and the ethanol removed under vacuum to leave a fine solid coating. Aqueous solutions of excipients and latanoprost are then individually added to the dried levcromakalim with rapid stirring, sonication, or homogenization. The solution is optionally autoclaved and then filtered through a 0.22pm filter to yield the final formulation.

[0629] In certain embodiments, the nanomicellar formulations of levcromakalim and latanoprost are prepared using the dialysis method which uses semipermeable membranes to selectively allow certain molecules to pass through. A solution of levcromakalim, latanoprost, and excipients is prepared in a water-miscible organic solvent and loaded into a dialysis bag, which is thensubmerged in a larger volume of deionized water. During this process the organic solvent is replaced by water which induces formation of micelles with entrapment of levcromakalim and latanoprost. Unincorporated excipients and unloaded levcromakalim and latanoprost will then diffuse out of the bag into the surrounding solution over time.

[0630] In certain embodiments, the volatile solvent used to dissolve levcromakalim is selected from the group of acetonitrile, acetone, methylene chloride, chloroform, methanol, propanol, or other alcohol or ether-based solvents. In certain embodiments the volatile solvent used to dissolve latanoprost is selected from acetonitrile, ethyl acetate, methanol, ethanol, propanol, or other alcohol or ether-based solvents. Other solvents can be used that do not impart undue toxicity to the final product or leave an unacceptable residue.

[0631] In certain embodiments, the ocular formulation is homogenized or mixed through techniques including but not limited to heating, centrifuging, filtering, incubating, vortexing, standing, stirring, shaking, sonicating, or any combination thereof.

[0632] In certain embodiments, the fixed dose combination formulation of the present invention as described herein is formed by stirring at the temperature of about 120 °C, about 100 °C to 120 °C, about 80 °C to 100 °C, about 60 °C to 80 °C, about 40 °C to 60 °C, or at ambient temperature.

[0633] In certain embodiments, the ocular formulation can be formed by mixing the components together (which may have each or together been prior dissolved in a low volatile solvent including but not limited to ethanol) and then heating to remove the solvents, wherein the heat can include autoclave. In certain embodiments, the ocular formulation can be formed by heating the solution or the emulsion with a heating block.

[0634] In certain aspects of the embodiments, the present invention provides a solution or an emulsion wherein the undissolved components are removed by centrifugation at the speed of at least about 1000 rpm, at least about 1250 rpm, at least about 1500 rpm, at least about 1800 rpm, at least about 2000 rpm, at least about 2500 rpm, and at least about 3000 rpm.

[0635] In certain embodiments, the present invention provides a solution or an emulsion which is fdtered using a filter of the pore size of at least about 0.2 pm, at least about 0.45 pm, at least about 0.7 pm, and at least about 1.2 pm. In certain nonlimiting embodiments the filter membrane may be made of nylon, polytetrafluoroethylene, or PTFE, polyvinylidene difluoride or PVDF, polyethersulfone or PES, cellulose acetate or CA, polypropylene, or PP, and / or glass fiber.Concentrations of levcromakalim in formulations described herein, can be extrapolated using the standard curve method. Table 1 shows the concentration of levcromakalim standards and measurement of area of the peak which indicates elution of levcromakalim. Figure 1 shows the resulting levcromakalim standard curve using plotted as concentration vs area.

[0636] Table 1: HPLC measurements to plot Area vs Standard concentration

[0637] Standard Peak Area Avg Concentration Cone [mM] 1 2 3 (mg / mL)

[0638] 5 4.555 4.296062 5.257081 4.702714 1.43 2.5 2.282 2.324636 2.655283 2.42064 0.715

[0639] 1.25 1.054 1.336725 1.277846 1.222857 0.3575

[0640]

[0641] 0.75 0.541 0.558182 0.692308 0.597163 0.2145

[0642] The following examples are provided to further illustrate aspects of the invention, which include non-limiting examples of levcromakalim fixed dose combination formulations with concentrations of 0.001 to 0.1% w / v levcromakalim or a pharmaceutically acceptable salt thereof and a concentration of 0.001 to 0.02% w / v latanoprost. These illustrative examples are nonlimiting and should not be constructed as limiting any aspect of the invention.

[0643] Buffer Stock Solutions

[0644] PBS Stock Solution: phosphate buffered saline was prepared with the concentration of NaCl: 1.37 M

[0645] KC1: 27 mM

[0646] Na2HPO4: 100 mM

[0647] KH2PO4: 18 mM

[0648] Stock Phosphate Non-Saline Buffer solution: non-saline phosphate buffer was prepared with the concentration of

[0649] Na2HPO4: 70 mM

[0650] NaH2PO4: 25 mMExample 1 Preparation of Stock Solution 1 (vehicle, diluent, and control)

[0651] Table 2: Composition of Stock Solution 1

[0652] Component % Cone.

[0653] Levcromakalim 0.00%

[0654] Latanoprost 0.00%

[0655] Kolliphor ELP 4.00%

[0656] Polysorbate 80 1.00%

[0657] Povidone K30 2.00%

[0658] Poloxamer 407 0.10%

[0659] Mannitol 3.30%

[0660] Sodium Phosphate 0.10%

[0661] Dibasic Heptahydrate

[0662] Sodium Phosphate 0.09%

[0663] Monobasic Monohydrate

[0664] 1 N HCl QS to pH 6.5

[0665] Water for Injection QS to 100%

[0666]

[0667] QS = Quantity Sufficient

[0668] Water for injection (about 60-75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol are combined in a reaction vessel with stirring, and heating (if necessary), until homogeneous. Quantity sufficient (QS) 1N HCl is then added, with mixing at room temperature, to obtain a pH of about 6.5. QS water for injection is then added, with mixing at room temperature, to bring to the final volume such that the concentration of Kolliphor®-ELP is about 4% w / v, polysorbate 80 is about 1% w / v, povidone K30 is about 2% w / v, poloxamer 407 is about 0.1% w / v, mannitol is about 3.3% w / v, sodium phosphate dibasic heptahydrate is about 0.10% w / v, and sodium phosphate monobasic monohydrate is about 0.09% w / v. The solution is then filtered using Millipore Opticap® XL2 Durapore® 0.22 pm capsule filters with a PVDF membrane.Example 2a. Preparation of Levcromakalim Formulation 1

[0669] Table 3: Composition of Formulation 1

[0670] Component % Cone.

[0671] Levcromakalim 0.015%

[0672] Latanoprost 0.00%

[0673] Kolliphor ELP 4.00%

[0674] Polysorbate 80 1.00%

[0675] Povidone K30 2.00%

[0676] Poloxamer 407 0.10%

[0677] Mannitol 3.30%

[0678] Sodium Phosphate 0.10%

[0679] Dibasic Heptahydrate

[0680] Sodium Phosphate 0.09%

[0681] Monobasic

[0682] Monohydrate

[0683] 1 N HCl QS to pH 6.5

[0684] Water for Injection QS to 100%

[0685]

[0686] QS = Quantity Sufficient

[0687] The compositions of Stock Solution 1 (Example 1) and Formulation 3 (Example 2c) were combined and mixed at room temperature for at least 10 minutes to provide Formulation 1. The composition of Formulation 1 was then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[0688] Table 4: Formulation 1 Analytical Results

[0689] Formulation Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0690] Range: 6.2-6.8 Range: 265-315

[0691] mOsm / kg

[0692] Formulation 0.015% 6.4 289 mOsm / kg Levcromakalim: 1 Levcromakalim; 101%

[0693] 0.0%

[0694]

[0695] LatanoprostExample 2b Preparation of Levcromakalim Formulation 2

[0696] Table 5: Composition of Formulation 2

[0697] Component % Cone.

[0698] Levcromakalim 0.030%

[0699] Latanoprost 0.00%

[0700] Kolliphor ELP 4.00%

[0701] Polysorbate 80 1.00%

[0702] Povidone K30 2.00%

[0703] Poloxamer 407 0.10%

[0704] Mannitol 3.30%

[0705] Sodium Phosphate 0.10%

[0706] Dibasic Heptahydrate

[0707] Sodium Phosphate 0.09%

[0708] Monobasic

[0709] Monohydrate

[0710] 1 N HCl QS to pH 6.5

[0711] Water for Injection QS to 100%

[0712]

[0713] QS = Quantity Sufficient

[0714] Water for injection (about 60-75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol are combined in a reaction vessel with stirring, and heating (if necessary), until homogeneous. The reaction vessel is heated to 33.0-40.0 °C, and levcromakalim is then added with stirring until homogeneous. Upon the dissolution of levcromakalim, the solution is cooled to no more than 25.0 °C with mixing on. Quantity sufficient (QS) 1N HCl is then added, with mixing, to obtain a pH of about 6.5. QS water for injection is then added, with mixing, to bring to the final volume such that the concentration of levcromakalim is about 0.030% w / v, Kolliphor®-ELP is about 4% w / v, polysorbate 80 is about 1% w / v, povidone K30 is about 2% w / v, poloxamer 407 is about 0.1% w / v, mannitol is about 3.3% w / v, sodium phosphate dibasic heptahydrate is about 0.10% w / v, and sodium phosphate monobasic monohydrate is about 0.09% w / v. The composition of Formulation 2 is then filtered using Millipore Opticap® XL2 Durapore® 0.22 pm capsule filters with a PVDF membrane.Example 2c Preparation of Levcromakalim Formulation 3 (Levcromakalim stock) Table 6: Composition of Formulation 3

[0715] Component % Cone.

[0716] Levcromakalim 0.075%

[0717] Latanoprost 0.00%

[0718] Kolliphor ELP 4.00%

[0719] Polysorbate 80 1.00%

[0720] Povidone K30 2.00%

[0721] Poloxamer 407 0.10%

[0722] Mannitol 3.30%

[0723] Sodium Phosphate 0.10%

[0724] Dibasic Heptahydrate

[0725] Sodium Phosphate 0.09%

[0726] Monobasic Monohydrate

[0727] 1 N HCl QS to pH 6.5

[0728] Water for Injection QS to 100%

[0729]

[0730] QS = Quantity Sufficient

[0731] Water for injection (75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol were combined in a reaction vessel with stirring at room temperature, until homogeneous. The reaction vessel was heated to 33.0-40.0 °C, and levcromakalim was then added with stirring until homogeneous. After the dissolution of levcromakalim, the solution was cooled to no more than 25.0 °C with mixing on. Quantity sufficient (QS) 1N HCl was then added, with mixing, to obtain a pH of about 6.5. QS water for injection was then added, with mixing, to bring to the final volume such that the concentration of levcromakalim was about 0.075% w / v, Kolliphor®-ELP was about 4% w / v, polysorbate 80 was about 1% w / v, povidone K30 was about 2% w / v, poloxamer 407 was about 0.1% w / v, mannitol was about 3.3% w / v, sodium phosphate dibasic heptahydrate was about 0.10% w / v, and sodium phosphate monobasic monohydrate was about 0.09% w / v. The composition of Formulation 3 was then filtered using Millipore Opticap® XL2 Durapore® 0.22 pm capsule filters with a PVDF membrane.Table 7: Formulation 3 Analytical Results

[0732] Formulation Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0733] Range: 6.2-6.8 Range: 265-315

[0734] mOsm / kg

[0735] Formulation 0.075% 6.4 286 mOsm / kg Levcromakalim: 3 Levcromakalim; 100%

[0736]

[0737] 0.0% Latanoprost

[0738] Example 2d Preparation of Latanoprost Formulation 4 (latanoprost stock)

[0739] Table 8: Composition of Formulation 4

[0740] Component % Cone.

[0741] Levcromakalim 0.00%

[0742] Latanoprost 0.005%

[0743] Kolliphor ELP 4.00%

[0744] Polysorbate 80 1.00%

[0745] Povidone K30 2.00%

[0746] Poloxamer 407 0.10%

[0747] Mannitol 3.30%

[0748] Sodium Phosphate 0.10%

[0749] Dibasic Heptahydrate

[0750] Sodium Phosphate 0.09%

[0751] Monobasic Monohydrate

[0752] 1 N HCl QS to pH 6.5

[0753] Water for Injection QS to 100%

[0754]

[0755] QS = Quantity Sufficient

[0756] An illustrative example for preparing the active agent free vehicle is provided below:

[0757] Water for injection (about 60-75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol are combined in a reaction vessel with stirring, and heating (if necessary), until homogeneous. Quantity sufficient (QS) 1N HCl is then added, with mixing at room temperature, to obtain a pH of about 6.5. QS water for injection is then added, with mixing at room temperature, to bring to the final volume such that the concentration of Kolliphor®-ELP is about 4% w / v, polysorbate 80 is about 1% w / v, povidone K30 is about 2% w / v, poloxamer 407 is about 0.1%w / v, mannitol is about 3.3% w / v, sodium phosphate dibasic heptahydrate is about 0.10% w / v, and sodium phosphate monobasic monohydrate is about 0.09% w / v.

[0758] An illustrative example for how Formulation 4 was prepared is provided below:

[0759] Latanoprost was then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system was fabricated to submerge the square in solution and hold it in place during mixing (Figure 2). An overhead mixer was used, rather than a stir bar, to provide more turbulent mixing. The solution was then left to mix overnight at room temperature. It was noted that the latanoprost visually appeared to be completely removed from the square after approximately 1 hour of mixing. The composition of Formulation 4 was then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[0760] Table 9; Formulation 4 Analytical Results _ _ _ Formulation Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0761] Range: 6.2-6.8 Range: 265-315

[0762] mOsm / kg

[0763] Formulation 0.0% 6.4 287 mOsm / kg Latanoprost: 4 Levcromakalim; 115%

[0764] 0.005%

[0765]

[0766] Latanoprost

[0767] Example 3a Preparation of Fixed Dose Combination Batch 1 (FDC 1)

[0768] Table 10: Composition of FDC 1

[0769] Component % Cone.

[0770] Levcromakalim 0.015%

[0771] Latanoprost 0.005%

[0772] Kolliphor ELP 4.00%

[0773] Polysorbate 80 1.00%

[0774] Povidone K30 2.00%

[0775] Poloxamer 407 0.10%

[0776] Mannitol 3.30%

[0777] Sodium Phosphate 0.10%

[0778]

[0779] Dibasic HeptahydrateSodium Phosphate 0.09%

[0780] Monobasic

[0781] Monohydrate

[0782] 1 N HCl QS to pH 6.5

[0783] Water for Injection QS to 100%

[0784]

[0785] QS = Quantity Sufficient

[0786] The compositions of Formulation 4 (Example 2d) and FDC 3 (Example 3c) were combined and mixed at room temperature for at least 10 minutes to provide FDC 1. The composition of FDC 1 was then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[0787] Table 11: FDC 1 Analytical Results

[0788] FDC Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0789] Range: 6.2-6.8 Range: 265-315 mOsm / kg

[0790] FDC 1 6.4 288 mOsm / kg Levcromakalim:

[0791] 0.015%

[0792] 100% Levcromakalim;

[0793] Latanoprost: 0.005% Latanoprost

[0794]

[0795] 117%

[0796] Example 3b Preparation of Fixed Dose Combination Batch 2 (FDC 2)

[0797] Table 12: Composition of FDC 2

[0798] Component % Cone.

[0799] Levcromakalim 0.030%

[0800] Latanoprost 0.005%

[0801] Kolliphor ELP 4.00%

[0802] Polysorbate 80 1.00%

[0803] Povidone K30 2.00%

[0804] Poloxamer 407 0.10%

[0805] Mannitol 3.30%

[0806] Sodium Phosphate 0.10%

[0807] Dibasic Heptahydrate

[0808] Sodium Phosphate 0.09%

[0809] Monobasic

[0810]

[0811] Monohydrate1 N HCl QS to pH 6.5

[0812] Water for Injection QS to 100%

[0813]

[0814] QS = Quantity Sufficient

[0815] The compositions of Formulation 4 (Example 2d) and FDC 3 (Example 3c) are combined and mixed at room temperature for at least 10 minutes to provide FDC 2. The composition of FDC 2 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[0816] Table 13: FDC 2 Analytical Results

[0817] FDC Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0818] Range: 6.2-6.8 Range: 265-315 mOsm / kg

[0819] FDC 0.030% 6.4 288 mOsm / kg Levcromakalim: 2 Levcromakalim; 102%

[0820] 0.005% Latanoprost Latanoprost:

[0821]

[0822] 114%

[0823] Example 3c Preparation of Fixed Dose Combination Batch 3 (FDC 3)

[0824] Table 14: Composition of FDC 3

[0825] Component % Composition

[0826] Levcromakalim 0.075%

[0827] Latanoprost 0.005%

[0828] Kolliphor ELP 4.00%

[0829] Polysorbate 80 1.00%

[0830] Povidone K30 2.00%

[0831] Poloxamer 407 0.10%

[0832] Mannitol 3.30%

[0833] Sodium Phosphate 0.10%

[0834] Dibasic Heptahydrate

[0835] Sodium Phosphate 0.09%

[0836] Monobasic Monohydrate

[0837] 1 N HCl QS to pH 6.5

[0838] Water for Injection QS to 100%

[0839]

[0840] QS = Quantity SufficientWater for injection (75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol were combined in a reaction vessel with stirring at room temperature, until homogeneous. Quantity sufficient (QS) 1N HCl was then added, with mixing, to obtain a pH of about 6.5. QS water for injection was then added, with mixing, to bring to the final volume such that the concentration of levcromakalim was about 0.075% w / v, Kolliphor®-ELP was about 4% w / v, polysorbate 80 was about 1% w / v, povidone K30 was about 2% w / v, poloxamer 407 was about 0.1% w / v, mannitol was about 3.3% w / v, sodium phosphate dibasic heptahydrate was about 0.10% w / v, and sodium phosphate monobasic monohydrate was about 0.09% w / v.

[0841] Latanoprost was then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system was fabricated to submerge the square in solution and hold it in place during mixing. An overhead mixer was used. The solution was then left to mix 1 hour at room temperature, then warmed to 35-40 °C for the addition of the levcromakalim. The solution was mixed for an additional 3 hours at 35-40 °C to dissolve the levcromakalim. The heat source was removed, and the solution was left overnight with mixing on to cool. After the overnight mixing, both latanoprost and levcromakalim appeared to be visually dissolved. The composition of FDC 3 was then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[0842] Table 15: FDC 3 Analytical Results

[0843] FDC Concentration pH Result Osmolality Result Assay Results Target: 6.5 Target: 285 mOsm / kg

[0844] Range: 6.2-6.8 Range: 265-315 mOsm / kg

[0845] FDC 0.075% 6.5 288 mOsm / kg Levcromakalim: 3 Levcromakalim; 101%

[0846] 0.005% Latanoprost Latanoprost:

[0847]

[0848] 105%

[0849] Example 3d Preparation of Fixed Dose Combination Batch 4A (FDC 4A)

[0850] Table 16: Composition of FDC 4A

[0851] Component % Cone.

[0852] Levcromakalim 0.075%

[0853] Bimatoprost 0.03%

[0854]

[0855] Kolliphor ELP 4.00%

[0856] Polysorbate 80 1.00%

[0857] Povidone K30 2.00%

[0858] Poloxamer 407 0.10%

[0859] Mannitol 3.30%

[0860] Sodium Phosphate 0.10%

[0861] Dibasic Heptahydrate

[0862] Sodium Phosphate 0.09%

[0863] Monobasic

[0864] Monohydrate

[0865] 1 N HCl QS to pH 6.5

[0866] Water for Injection QS to 100%

[0867]

[0868] QS = Quantity Sufficient

[0869] Bimatoprost was added to 50 mL of Formulation 3 (Example 3c) and mixed at room temperature. After 14 minutes of mixing at room temperature, the majority of the Bimatoprost visually appeared dissolved. Approximately three particles were visible in solution. After 51 minutes, only one particle was visible in solution. The solution was left to mix overnight at room temperature, and no visible change was observed in the remaining particle suggesting this was a foreign particulate and not undissolved Bimatoprost. Therefore, it can be concluded that the Bimatoprost was likely fully dissolved in solution after 51 minutes of mixing at room temperature to provide the clear solution FDC 4A.

[0870] Example 3e Preparation of Fixed Dose Combination Batch 4B (FDC 4B)

[0871] Table 17: Composition of FDC 4B

[0872] Component % Cone.

[0873] Levcromakalim 0.015%

[0874] Bimatoprost 0.03%

[0875] Kolliphor ELP 4.00%

[0876] Polysorbate 80 1.00%

[0877] Povidone K30 2.00%

[0878] Poloxamer 407 0.10%

[0879]

[0880] Mannitol 3.30%

[0881] Sodium Phosphate 0.10%

[0882] Dibasic Heptahydrate

[0883] Sodium Phosphate 0.09%

[0884] Monobasic

[0885] Monohydrate

[0886] 1 N HCl QS to pH 6.5

[0887] Water for Injection QS to 100%

[0888]

[0889] QS = Quantity Sufficient

[0890] Bimatoprost is added to 50 mL of Formulation 3 (Example 2c) with mixing at room temperature for about one hour to provide FDC 4B.

[0891] Example 3f Preparation of Fixed Dose Combination Batch 4C (FDC 4C)

[0892] Table 18: Composition of FDC 4C

[0893] Component % Cone.

[0894] Levcromakalim 0.03%

[0895] Bimatoprost 0.03%

[0896] Kolliphor ELP 4.00%

[0897] Polysorbate 80 1.00%

[0898] Povidone K30 2.00%

[0899] Poloxamer 407 0.10%

[0900] Mannitol 3.30%

[0901] Sodium Phosphate 0.10%

[0902] Dibasic Heptahydrate

[0903] Sodium Phosphate 0.09%

[0904] Monobasic

[0905] Monohydrate

[0906] 1 N HCl QS to pH 6.5

[0907] Water for Injection QS to 100%

[0908]

[0909] QS = Quantity Sufficient

[0910] Bimatoprost is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about one hour to provide FDC 4C.Example 3g Preparation of Fixed Dose Combination Batch 5 A (FDC 5 A)

[0911] Table 19: Composition of FDC 5A

[0912] Component % Cone

[0913] Levcromakalim 0.075%

[0914] Tafluprost 0.0015%

[0915] Kolliphor ELP 4.00%

[0916] Polysorbate 80 1.00%

[0917] Povidone K30 2.00%

[0918] Poloxamer 407 0.10%

[0919] Mannitol 3.30%

[0920] Sodium Phosphate 0.10%

[0921] Dibasic Heptahydrate

[0922] Sodium Phosphate 0.09%

[0923] Monobasic

[0924] Monohydrate

[0925] 1 N HCl QS to pH 6.5

[0926] Water for Injection QS to 100%

[0927]

[0928] QS = Quantity Sufficient

[0929] Tafluprost was added to 50 mL of Formulation 3 (Example 3c) and mixed at room temperature. After 15 minutes of mixing at room temperature, one oil undissolved particle was visible in solution. After 62 minutes of mixing, the Tafluprost appeared to be visually dissolved. The solution was left to mix for one additional hour to confirm dissolution. No changes in solution appearance were observed, so it can be concluded that the Tafluprost was likely fully dissolved after 62 minutes of mixing at room temperature to provide the clear solution FDC 5A.

[0930] Example 3h Preparation of Fixed Dose Combination Batch 5B (FDC 5B)

[0931] Table 20: Composition of FDC 5B

[0932] Component % Cone

[0933] Levcromakalim 0.015%

[0934] Tafluprost 0.0015%

[0935] Kolliphor ELP 4.00%

[0936]

[0937] Polysorbate 80 1.00%

[0938] Povidone K30 2.00%

[0939] Poloxamer 407 0.10%

[0940] Mannitol 3.30%

[0941] Sodium Phosphate 0.10%

[0942] Dibasic Heptahydrate

[0943] Sodium Phosphate 0.09%

[0944] Monobasic

[0945] Monohydrate

[0946] 1 N HCl QS to pH 6.5

[0947] Water for Injection QS to 100%

[0948]

[0949] QS = Quantity Sufficient

[0950] Tafluprost is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about one hour to provide FDC 5B.

[0951] Example 3i Preparation of Fixed Dose Combination Batch 5C (FDC 5C)

[0952] Table 21: Composition of FDC 5C

[0953] Component % Cone

[0954] Levcromakalim 0.03%

[0955] Tafluprost 0.0015%

[0956] Kolliphor ELP 4.00%

[0957] Polysorbate 80 1.00%

[0958] Povidone K30 2.00%

[0959] Poloxamer 407 0.10%

[0960] Mannitol 3.30%

[0961] Sodium Phosphate 0.10%

[0962] Dibasic Heptahydrate

[0963] Sodium Phosphate 0.09%

[0964] Monobasic

[0965] Monohydrate

[0966] 1 N HCl QS to pH 6.5

[0967] Water for Injection QS to 100%

[0968]

[0969] QS = Quantity SufficientTafluprost is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about one hour to provide FDC 5C.

[0970] Example 3j Preparation of Fixed Dose Combination Batch 6A (FDC 6A)

[0971] Table 22: Composition of FDC 6A

[0972] Component % Cone.

[0973] Levcromakalim 0.075%

[0974] Travoprost 0.004%

[0975] Kolliphor ELP 4.00%

[0976] Polysorbate 80 1.00%

[0977] Povidone K30 2.00%

[0978] Poloxamer 407 0.10%

[0979] Mannitol 3.30%

[0980] Sodium Phosphate 0.10%

[0981] Dibasic Heptahydrate

[0982] Sodium Phosphate 0.09%

[0983] Monobasic

[0984] Monohydrate

[0985] 1 N HCl QS to pH 6.5

[0986] Water for Injection QS to 100%

[0987]

[0988] QS = Quantity Sufficient

[0989] Travoprost was added to 50 mL of Formulation 3 (Example 3c) and mixed at room temperature. After 15 minutes of mixing at room temperature, several undissolved oil particles were observed in the solution. After 59 minutes of mixing, three undissolved oil particles were observed in the solution. After 174 minutes of mixing at room temperature, it was unclear if one oil particle remained or if the Travoprost was fully dissolved. Mixing was left on overnight to confirm. The next morning, the solution appeared fully dissolved. However, it is possible that the initial dissolution occurred after 174 minutes of mixing and that overnight mixing is not required to provide the clear solution FDC 6A.Example 3k Preparation of Fixed Dose Combination Batch 6B (FDC 6B)

[0990] Table 23: Composition of FDC 6B

[0991] Component % Cone.

[0992] Levcromakalim 0.015%

[0993] Travoprost 0.004%

[0994] Kolliphor ELP 4.00%

[0995] Polysorbate 80 1.00%

[0996] Povidone K30 2.00%

[0997] Poloxamer 407 0.10%

[0998] Mannitol 3.30%

[0999] Sodium Phosphate 0.10%

[1000] Dibasic Heptahydrate

[1001] Sodium Phosphate 0.09%

[1002] Monobasic

[1003] Monohydrate

[1004] 1 N HCl QS to pH 6.5

[1005] Water for Injection QS to 100%

[1006]

[1007] QS = Quantity Sufficient

[1008] Travoprost is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about three hours to provide FDC 6B.

[1009] Example 31 Preparation of Fixed Dose Combination Batch 6C (FDC 6C)

[1010] Table 24: Composition of FDC 6C

[1011] Component % Cone.

[1012] Levcromakalim 0.03%

[1013] Travoprost 0.004%

[1014] Kolliphor ELP 4.00%

[1015] Polysorbate 80 1.00%

[1016] Povidone K30 2.00%

[1017] Poloxamer 407 0.10%

[1018] Mannitol 3.30%

[1019]

[1020] Sodium Phosphate 0.10%

[1021] Dibasic Heptahydrate

[1022] Sodium Phosphate 0.09%

[1023] Monobasic

[1024] Monohydrate

[1025] 1 N HCl QS to pH 6.5

[1026] Water for Injection QS to 100%

[1027]

[1028] QS = Quantity Sufficient

[1029] Travoprost is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about three hours to provide FDC 6C.

[1030] Example 3m Preparation of Fixed Dose Combination Batch 7A (FDC 7A)

[1031] Table 25: Composition of FDC 7A

[1032] Component % Cone.

[1033] Levcromakalim 0.075%

[1034] Latanoprostene Bunod 0.024%

[1035] Kolliphor ELP 4.00%

[1036] Polysorbate 80 1.00%

[1037] Povidone K30 2.00%

[1038] Poloxamer 407 0.10%

[1039] Mannitol 3.30%

[1040] Sodium Phosphate 0.10%

[1041] Dibasic Heptahydrate

[1042] Sodium Phosphate 0.09%

[1043] Monobasic

[1044] Monohydrate

[1045] 1 N HCl QS to pH 6.5

[1046] Water for Injection QS to 100%

[1047]

[1048] QS = Quantity Sufficient

[1049] Latanoprostene bunod was added to 50 mL of Formulation 3 (Example 3c) and mixed at room temperature. After 15 minutes of mixing at room temperature, many undissolved oil particles were observed in the solution. After 63 minutes of mixing at room temperature, at least three undissolved oil particles were observed in the solution. After 120 minutes of mixing, it was unclear if one particle was present or if full dissolution occurred. There was no change in solutionappearance 1 hour later, so the solution was left overnight to mix to confirm dissolution. The next morning, the solution appeared fully dissolved. However, it is possible that the initial dissolution occurred after 120 minutes of mixing and that overnight mixing is not required to provide the clear solution FDC 7A.

[1050] Example 3n Preparation of Fixed Dose Combination Batch 7B (FDC 7B)

[1051] Table 26: Composition of FDC 7B

[1052] Component % Cone.

[1053] Levcromakalim 0.015%

[1054] Latanoprostene Bunod 0.024%

[1055] Kolliphor ELP 4.00%

[1056] Polysorbate 80 1.00%

[1057] Povidone K30 2.00%

[1058] Poloxamer 407 0.10%

[1059] Mannitol 3.30%

[1060] Sodium Phosphate 0.10%

[1061] Dibasic Heptahydrate

[1062] Sodium Phosphate 0.09%

[1063] Monobasic

[1064] Monohydrate

[1065] 1 N HCl QS to pH 6.5

[1066] Water for Injection QS to 100%

[1067]

[1068] QS = Quantity Sufficient

[1069] Latanoprostene bunod is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about two hours to provide FDC 7B.

[1070] Example 3o Preparation of Fixed Dose Combination Batch 7C (FDC 7C)

[1071] Table 27: Composition of FDC 7C

[1072] Component % Cone.

[1073] Levcromakalim 0.03%

[1074] Latanoprostene Bunod 0.024%

[1075]

[1076] Kolliphor ELP 4.00%

[1077] Polysorbate 80 1.00%

[1078] Povidone K30 2.00%

[1079] Poloxamer 407 0.10%

[1080] Mannitol 3.30%

[1081] Sodium Phosphate 0.10%

[1082] Dibasic Heptahydrate

[1083] Sodium Phosphate 0.09%

[1084] Monobasic

[1085] Monohydrate

[1086] 1 N HCl QS to pH 6.5

[1087] Water for Injection QS to 100%

[1088]

[1089] QS = Quantity Sufficient

[1090] Latanoprostene bunod is added to 50 mL of Formulation 3 (Example 3c) with mixing at room temperature for about two hours to provide FDC 7C.

[1091] In certain embodiments a formulation of the present invention comprises a preservative. A non-limiting example includes 0.02% BAK:

[1092] Example 3p Preparation of Fixed Dose Combination Batch 8 (FDC 8)

[1093] Table 28: Composition of FDC 8

[1094] Component % Cone.

[1095] Levcromakalim 0.015%

[1096] Latanoprost 0.005%

[1097] BAK 0.02%

[1098] Kolliphor ELP 4.00%

[1099] Polysorbate 80 1.00%

[1100] Povidone K30 2.00%

[1101] Poloxamer 407 0.10%

[1102] Mannitol 3.30%

[1103] Sodium Phosphate 0.10%

[1104] Dibasic Heptahydrate

[1105] Sodium Phosphate 0.09%

[1106] Monobasic

[1107]

[1108] Monohydrate1 N HCl QS to pH 6.5

[1109] Water for Injection QS to 100%

[1110]

[1111] QS = Quantity Sufficient

[1112] Water for injection (about 60-75% w / v), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, Kolliphor ELP, polysorbate 80, povidone K30, poloxamer 407, and mannitol are combined in a reaction vessel with stirring, and heating (if necessary), until homogeneous. Quantity sufficient (QS) 1N HCl is added, with mixing at room temperature, to obtain a pH of about 6.5. QS water for injection is added, with mixing at room temperature, to bring to the final volume such that the concentration of BAK is about 0.02% w / v, Kolliphor®-ELP is about 4% w / v, polysorbate 80 is about 1% w / v, povidone K30 is about 2% w / v, poloxamer 407 is about 0.1% w / v, mannitol is about 3.3% w / v, sodium phosphate dibasic heptahydrate is about 0.10% w / v, and sodium phosphate monobasic monohydrate is about 0.09% w / v.

[1113] Latanoprost is weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in solution and hold it in place during mixing. An overhead mixer is used. The solution is then left to mix 1 hour at room temperature, followed by warming to 35-40 °C for the addition of the levcromakalim. The solution is mixed for an additional 3 hours at 35-40 °C to dissolve the levcromakalim. The heat source is removed, and the solution is left overnight with mixing on to cool. After the overnight mixing, both latanoprost and levcromakalim are dissolved. The composition of FDC 8 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1114] In some embodiments, a formulation of the present invention does not contain preservative.

[1115] VIII.In Vivo Evaluation

[1116] Example 4 In vivo Assessments of Ocular Formulations 1, 3, and 4 in Mice

[1117] Table 29: Compositions of Formulations 1, 3, and 4

[1118] Component Formulation 1 Formulation 3 Formulation 4 Levcromakalim 0.015% 0.075% 0.00% Latanoprost 0.00% 0.00% 0.005% Kolliphor ELP 4.00% 4.00% 4.00% Polysorbate 80 1.00% 1.00% 1.00% Povidone K30 2.00% 2.00% 2.00%

[1119]

[1120] Poloxamer 407 0.10% 0.10% 0.10%Mannitol 3.30% 3.30% 3.30% Sodium Phosphate

[1121] 0.10% 0.10% 0.10%

[1122] Dibasic Heptahydrate

[1123] Sodium Phosphate

[1124] 0.09% 0.09% 0.09% Monobasic Monohydrate

[1125] 1 N HCl QS to pH 6.5 QS to pH 6.5 QS to pH 6.5

[1126]

[1127] Water for Injection QS to 100% QS to 100% QS to 100%

[1128] QS = Quantity Sufficient

[1129] Species, Strain, Supplier

[1130] Wild-type C57BL / 6J mice (male, 6-8 months old, n=25) were obtained from Jackson Laboratories (Bar Harbor, ME, USA, Catalog #000664). Animals were acclimatized to housing conditions for at least seven days before experiments were initiated. All mice were maintained in the Mayo Clinic Animal Care Facility under a 12-hour light and 12-hour dark cycle and received water and standard rodent food pellets ad libitum. Prior to the initiation of experiments, mice underwent sham IOP measurements daily for at least three days to habituate the animals to handling and pressure recording procedures.

[1131] Protocol

[1132] Protocols were reviewed and approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC). Fifteen mice were randomly assigned to groups 1-3, with each group containing five mice. Mice were administered 5 pL eyedrops of a given treatment (Group 1, Formulation 1; Group 2, Formulation 3; Group 3, Formulation 4). Each treatment dose was applied topically to one eye once daily QAM (-10:00 am CST) for four consecutive days while the contralateral eye received vehicle (Table 30).Table 30: Summary of Example 4 Test Article Administration and Assessments Baseline3Treatment13

[1133] Day 1 2 3 4 5 6 7 Visual assessments, all groups Z Z z z z z IOP, Group 1 (Formulation 1, N=5) Z Z z z z z IOP, Group 2 (Formulation 3, N=5) z z z z z z IOP, Group 3 (Formulation 4, N=5) z A / z z z z a: Baseline IOP (intraocular pressure) was measured at time points that correspond to 1 hour, 4 hours, and 23 hours of the treatment phase.

[1134] b: IOP was measured 1 hour, 4 hours, and 23 hours following treatment.

[1135]

[1136] Assessment

[1137] External visual assessment of eyes of each mouse was performed daily during the experiment (Table 30). Mice were assessed for watery eyes, eye discharge, hyperemia, swelling of the eyelids, changes to corneal structure, and appearance. Mice were also observed for any physical reaction to the application of the eyedrops.

[1138] IOP was measured in live, conscious mice using a hand-held rebound tonometer (Icare® Tonolab; Colonial Medical Supply, Franconia, NH). Briefly, IOP was measured by holding the tonometer perpendicular to the eye and striking the center of the cornea (Roy Chowdhury et al., 2013). For each IOP measurement, the tonometer probe strikes the center of the cornea six times and calculates IOP by using an algorithm based on probe incident velocity and deceleration (Roy Chowdhury et al., 2017). Three independent IOP measurements were averaged to obtain the mean IOP value at a given time point for each eye (Table 30).

[1139] During treatment, IOP was measured in treated and control eyes at 1 hour, 4 hours, and 23 hours following once-daily dosing for four consecutive days. During the pretreatment period, IOP was measured in all animals at time points that corresponded to the treatment phase (1 hour, 4 hours, and 23 hours after the dose) for up to three consecutive days. The average of the pretreatment values was used as baseline IOP.During the data collection phase, three IOP measurements were taken from each eye and noted in a laboratory notebook using a custom-designed chart. Following completion of measurements for all animals at a given time point, IOP recordings for each eye of each animal were typed into an Excel spreadsheet (Microsoft Corporation, Redmond, WA) specifically designed for this purpose. Following the completion of the experiment, data were used for analysis.

[1140] Daily IOP was calculated by taking the average of the 1 hour, 4 hour, and 23 hour time points (i.e., calculating the mean ± SD). Baseline IOP was determined for each eye by calculating the mean ± SD IOP of the daily pretreatment measurements. IOP during the treatment period was determined for each eye by calculating the mean ± SD daily IOP of day 3-4 treatments. Difference between means within a population was assessed using Student’s paired t-test and considered significant with p<0.05.

[1141] Results

[1142] Baseline lOPs for all three groups ranged from 16.1 to 16.4 mm Hg, with no statistical difference between right and left eyes (Table 31, Figure 3). Treatment with Formulation 1 and Formulation 3 lowered IOP by 4.64 ± 0.39 and 3.80 ± 0.47 mm Hg, respectively. Percent change from baseline was 27% with Formulation 1 and 21% with Formulation 3. Treatment with Formulation 4 lowered IOP by 4.02 ± 0.42 mm Hg, a 23% reduction from baseline, indicating that latanoprost maintained its IOP lowering ability of the tested formulation. In vehicle treated eyes, all groups remained within ± 0.3 mm Hg of baseline IOP.Table 31: Summary of Intraocular Pressure Data Following Treatment with Formulations 1, 3, and 4

[1143] Drug Baseline Vehicle Baseline

[1144] Example 4 treatment (OD) treatment (OS)

[1145] (OS) (OD) IOP (mmHg) 16.15 ± 0.20 11.77 ± 0.38 16.16 ± 0.13 16.39 ± 0.11 Group 1

[1146] A IOP (mmHg) (compared

[1147] (Formulation 0 -4.64 ± 0.39 0 0.21 ± 0.11 to baseline)

[1148] 1)

[1149] % change (compared to

[1150] 0 -27.13 ± 2.19 0 1.47 ± 0.94 baseline)

[1151] IOP (mmHg) 16.36 ± 0.19 12.9 ± 0.37 16.36 ± 0.22 16.22 ± 0.15 Group 2

[1152] (Formulation A IOP (mmHg) (compared 0 -3.80 ± 0.47 0 -0.13 ± 0.20 to baseline)

[1153] 3)

[1154] % change (compared to 0 -21.11 ± 2.90 0 -0.85 ± 0.80 baseline)

[1155] IOP (mmHg) 16.36 ± 0.52 12.60 ± 0.11 16.23 ± 0.33 16.40 ± 0.13 Group 3

[1156] A IOP (mmHg) (compared

[1157] (Formulation 0 -4.02 ± 0.42 0 0.13 ± 0.42 to baseline)

[1158] 4)

[1159] % change (compared to

[1160] 0 -22.54 ± 2.05 0 1.08 ± 2.42 baseline)

[1161]

[1162] Example 5 In vivo Assessments of Ocular Formulations 1, 3, and 4 and Fixed Dose Combination Batch 1 (FDC 1) in Mice

[1163] Table 32: Compositions of Formulation 1, Formulation 4, and Fixed Dose Combination Batch 1 (FDC 1) _

[1164] Component Formulation 1 Formulation 4 FDC 1 Levcromakalim 0.015% 0.00% 0.015% Latanoprost 0.00% 0.005% 0.005% Kolliphor ELP 4.00% 4.00% 4.00% Polysorbate 80 1.00% 1.00% 1.00% Povidone K30 2.00% 2.00% 2.00% Poloxamer 407 0.10% 0.10% 0.10% Mannitol 3.30% 3.30% 3.30%

[1165] Sodium Phosphate Dibasic

[1166] 0.10% 0.10% 0.10%

[1167]

[1168] HeptahydrateSodium Phosphate

[1169] 0.09% 0.09% 0.09% Monobasic Monohydrate

[1170] 1 N HCl QS to pH 6.5 QS to pH 6.5 QS to pH 6.5

[1171]

[1172] Water for Injection QS to 100% QS to 100% QS to 100%

[1173] QS = Quantity Sufficient

[1174] Species, Strain, Supplier

[1175] Wild-type C57BL / 6J mice (male, 6-8 months old, n=25) were obtained from Jackson Laboratories (Bar Harbor, ME, USA, Catalog #000664). Animals were acclimatized to housing conditions for at least seven days before experiments were initiated. All mice were maintained in the Mayo Clinic Animal Care Facility under a 12-hour light and 12-hour dark cycle and received water and standard rodent food pellets ad libitum. Prior to the initiation of experiments, mice underwent sham IOP measurements daily for at least three days to habituate the animals to handling and pressure recording procedures.

[1176] Protocol

[1177] Protocols were reviewed and approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC). Group 1 and group 2 each contained five randomly assigned mice. Group 1 mice received Formulation 1 for four days followed by four days of treatment with FDC 1. In group 2, mice initially were treated with Formulation 4 for four days followed by four days of treatment with FDC 1. Each treatment dose was applied topically to one eye once daily QAM (-10:00 am CST) for four consecutive days while the contralateral eye received vehicle. (Table 33a and Table 33b).

[1178] Table 33a: Summary of Example 5 test Article Administration and Assessments (Days 1-5)

[1179] Actions Day 1 Day 2 Day 3 Day 4 Day 5 IOP measurement

[1180] yes yes yes yes yes (OU)

[1181] Group OD None None Vehicle Vehicle Vehicle 1

[1182] Treatment Formulation Formulation Formulation OS None None

[1183] 1 1 1 IOP measurement

[1184] yes yes yes yes yes (OU)

[1185] Group

[1186] OD None None Vehicle Vehicle Vehicle 2

[1187] Treatment Formulation Formulation Formulation OS None None

[1188]

[1189] 4 4 4 IOP - Intraocular pressure, OU - Both eyes. OD - Right eye, OS - Left eye

[1190]

[1191] Table 33b: Summary of Example 5 test Article Administration and Assessments (Days 6-10)

[1192] Actions Day 6 Day 7 Day 8 Day 9 Day 10 IOP measurement

[1193] yes yes yes yes yes (OU)

[1194] Group OD Vehicle Vehicle Vehicle Vehicle Vehicle 1

[1195] Treatment Formulation

[1196] OS FDC 1 FDC 1 FDC 1 FDC 1

[1197] 1

[1198] IOP measurement

[1199] yes yes yes yes yes (OU)

[1200] Group

[1201] OD Vehicle Vehicle Vehicle Vehicle Vehicle 2

[1202] Treatment Formulation

[1203] OS FDC 1 FDC 1 FDC 1 FDC 1

[1204]

[1205] 4

[1206] IOP - Intraocular pressure, OU - Both eyes. OD - Right eye, OS - Left eye

[1207]

[1208] Assessment

[1209] External visual assessment of eyes of each mouse was performed daily during the experiment (Table 33a and Table 33b). Mice were assessed for watery eyes, eye discharge, hyperemia, swelling of the eyelids, changes to corneal structure, and appearance. Mice were also observed for any physical reaction to the application of the eyedrops.

[1210] IOP was measured in live, conscious mice using a hand-held rebound tonometer (Icare® Tonolab; Colonial Medical Supply, Franconia, NH). Briefly, IOP was measured by holding the tonometer perpendicular to the eye and striking the center of the cornea (Roy Chowdhury et al., 2013). For each IOP measurement, the tonometer probe strikes the center of the cornea six times and calculates IOP by using an algorithm based on probe incident velocity and deceleration (Roy Chowdhury et al., 2017). Three independent IOP measurements were averaged to obtain the mean IOP value at a given time point for each eye (Table 33a and Table 33b).

[1211] During treatment, IOP was measured in treated and control eyes at 1 hour, 4 hours, and 23 hours following once-daily dosing for four consecutive days. During the pretreatment period, IOP was measured in all animals at time points that corresponded to the treatment phase (1 hour, 4 hours, and 23 hours after the dose) for up to three consecutive days. The average of the pretreatment values was used as baseline IOP.

[1212] During the data collection phase, three IOP measurements were taken from each eye and noted in a laboratory notebook using a custom-designed chart. Following completion ofmeasurements for all animals at a given time point, IOP recordings for each eye of each animal were typed into an Excel spreadsheet (Microsoft Corporation, Redmond, WA) specifically designed for this purpose. Following the completion of the experiment, data were used for analysis.

[1213] Daily IOP was calculated by taking the average of the 1 hour, 4 hour, and 23 hour time points (i.e., calculating the mean ± SD). Baseline IOP was determined for each eye by calculating the mean ± SD IOP of the daily pretreatment measurements. IOP during the treatment period was determined for each eye by calculating the mean ± SD daily IOP of day 3-4 treatments. Difference between means within a population was assessed using Student’s paired t-test and considered significant with p<0.05.

[1214] Results

[1215] Baseline lOPs for Group 1 and 2 mice were 16.3 and 16.4 mmHg, respectively, with no statistical difference between right and left eyes (Table 34, Figure 4). Group 1 mice treated initially with Formulation 1 showed an IOP reduction of 4.53 ± 0.28 mm Hg, which increased to 6.52 ± 0.53 mm Hg following treatment with the fixed dose combination FDC 1. Percent change in IOP from baseline following fixed dose combination treatment was 40%.

[1216] In Group 2 mice treated initially with Formulation 4, IOP was lowered by 4.09 ± 0.22 mm Hg. IOP in these mice was further reduced to 5.89 ± 0.79 mm Hg following treatment with the fixed dose concentration of FDC 1. Group 2 mice showed a 36% reduction in IOP from baseline following fixed dose combination treatment. The IOP reduction resulting from the fixed dose concentration was statistically significant from baseline in both Groups 1 and 2 (p<0.003) and when compared to individual drug treatments alone (p<0.003). Vehicle treated eyes showed relatively no change from baseline (Group 1, -0.11 ± 0.69; Group 2, 0.04 ± 0.22).

[1217] The fixed dose combination of FDC 1 lowered IOP greater than each drug alone. This additive effect of the levcromakalim / latanoprost fixed dose combination of the present invention is most likely due to the different mechanisms of action of each drug. Daily clinical assessments of tolerability found no differences between individual drug treatments, fixed-dose drug treatments and vehicle-treated mice in either study.G G 12ropropuu

[1218] (i fC) (i fCFl 1lld b FD 1Fl 4lld b FD 1)ttormaonooeormaonooeuwyuwy

[1219] Table 34: Summary of Intraocular Pressure Data Following Treatment with Formulation 1 Form ulation 4, and Fixed Dose Combination Batch 1 (FDC 1) _

[1220] Baseline Drug Baseline Vehicle Example 5 (OD) treatment (OS) treatment (OD) (OS) 16.38 ± 11.84 ± 16.38 ± 16.33 ± IOP (mmHg)

[1221] 0.52 0.61 0.56 0.31 Formulation A TOP (mmHg) (compared

[1222] 0 -4.53 ± 0.28 0 -0.11 ± 0.69 1 to baseline)

[1223] % change (compared to -27.17 ±

[1224] 0 0 -0.56 ± 4.18 baseline) 1.94

[1225] 16.38 ± 16.38 ± 16.33 ± IOP (mmHg) 9.86 ± 0.21

[1226] 0.52 0.56 0.31 A IOP (mmHg) (compared

[1227] FDC 1 0 -6.52 ± 0.53 0 0.00 ± 0.49 to baseline)

[1228] % change (compared to -39.78 ±

[1229] 0 0 0.08 ± 2.98 baseline) 2.18

[1230] 16.33 ± 12.24 ± 16.22 ± 16.27 ± IOP (mmHg)

[1231] 0.21 0.16 0.18 0.15 Formulation A IOP (mmHg) (compared

[1232] 0 -4.09 ± 0.22 0 0.04 ± 0.29 4 to baseline)

[1233] % change (compared to -25.03 ±

[1234] 0 0 0.29 ± 1.78 baseline) 1.17

[1235] 16.33 ± 10.44 ± 16.22 ± 16.38 ± IOP (mmHg)

[1236] 0.21 0.69 0.18 0.11 A IOP (mmHg) (compared

[1237] FDC 1 0 -5.89 ± 0.79 0 0.16 ± 0.27 to baseline)

[1238] % change (compared to -36.03 ±

[1239] 0 0 0.97 ± 1.68 baseline) 4.64

[1240] IOP, intraocular pressure; Lev, levcromakalim; Lat. latanoprost; FDC, fixed

[1241]

[1242] dose combination

[1243] Example 6 Preparation of Fixed Dose Combination Batch 9 (FDC 9)

[1244] Table 35: Composition of FDC 9

[1245] Component % Cone.

[1246] Levcromakalim 0.015%, 0.03%, or 0.075%

[1247] Latanoprost 0.005%

[1248] Pol oxamer 407 0.05%-3%

[1249] PBS Stock 5%-15%

[1250] Solution

[1251]

[1252] Deionized H₂O QS 100%

[1253] QS = Quantity SufficientA solution of levcromakalim in acetonitrile (1 mL of 6 mg / mL stock) is added to a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and then the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. 300 pL of PBS Stock Solution, and poloxamer 407 are then added. The final volume is brought to 3 mL using deionized H2O such that the concentration of levcromakalim is about 0.015%, 0.03%, or 0.075%, poloxamer 407 is about 0.05-3%, PBS stock solution is about 5-15%. The mixture is stirred in a heating block at 80 °C for 20 minutes. Then, the mixture is incubated at room temperature overnight.

[1254] Latanoprost is then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in the solution and hold it in place during mixing. An overhead mixer is used. The solution is then left to mix overnight at room temperature. The composition of FDC 9 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1255] Example 7 Preparation of Fixed Dose Combination Batch 10 (FDC 10)

[1256] Table 36: Composition of FDC 10

[1257] Component % Cone.

[1258] Levcromakalim 0.015%, 0.03%, or 0.075%

[1259] Latanoprost 0.005%

[1260] Tyloxapol 0.05%-3%

[1261] PBS Stock 5-15%

[1262] Solution

[1263]

[1264] Deionized H₂O QS to 100%

[1265] QS = Quantity Sufficient

[1266] A solution of levcromakalim in acetonitrile (1 mL of 6 mg / mL stock) is added to a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and then the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. 300 pL of PBS Stock Solution, and tyloxapol are then added. The final volume is brought to 3 mL using deionized H₂O such that the concentration of levcromakalim is about 0.015%, 0.03%, or 0.075%, Tyloxapol is about 0.05-3.0%, and PBS stock solution is about 5-15%. The mixture is stirred in a heating block at 80 °C for 20 minutes. Then, the mixture is incubated at room temperature overnight.

[1267] Latanoprost is then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in the solution andhold it in place during mixing. An overhead mixer is used. The solution is then left to mix overnight at room temperature. The composition of FDC 10 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1268] Example 8 Preparation of Fixed Dose Combination Batch 11 (FDC 11)

[1269] Table 37: Composition of FDC 11

[1270] Component % Cone.

[1271] Levcromakalim 0.015%, 0.03%, or 0.075%

[1272] Latanoprost 0.005%

[1273] Kolliphor® ELP 1-10%

[1274] PBS Stock 5-15%

[1275] Solution

[1276]

[1277] Deionized H₂O QS to 100%

[1278] QS = Quantity Sufficient

[1279] A solution of levcromakalim in acetonitrile (1 mL of 6 mg / mL stock) is added to a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and then the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. 300 pL of PBS Stock Solution and Kolliphor® ELP are then added. The final volume is brought to 3 mL using deionized H₂O such that the concentration of levcromakalim is about 0.015%, 0.03%, or 0.075%, Kolliphor® ELP is about 1-10%, and PBS stock solution is about 5-15%. The mixture is stirred in a heating block at 80 °C for 20 minutes. Then, the mixture is incubated at room temperature overnight.

[1280] Latanoprost is then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in the solution and hold it in place during mixing. An overhead mixer is used. The solution is then left to mix overnight at room temperature. The composition of FDC 11 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1281] Example 9 Preparation of Fixed Dose Combination Batch 12 (FDC 12)

[1282] Table 38: Composition of FDC 12

[1283] Component % Cone.

[1284] Levcromakalim 0.015%, 0.03%, or 0.075%

[1285] Latanoprost 0.005%

[1286]

[1287] Kolliphor® RH 40 0.05-6%PremulenTMTR-1 0.05-3%

[1288]

[1289] Deionized H₂O QS to 100%

[1290] QS = Quantity Sufficient

[1291] A solution of levcromakalim in ethanol (1 mL of 6 mg / mL stock); and EtOH-based solutions of Kolliphor® RH 40, and PremulenTM TR-1 are combined in a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. The final volume is brought to 3 mL using deionized H₂O such that the concentration of levcromakalim is about 0.015%, 0.03%, or 0.075%, Kolliphor® RH 40 is about 0.05-6%, and Premulen™ TR-1 is about 0.05-3%. The mixture is stirred in a heating block at 80 °C for 20 minutes. Then, the mixture is incubated at room temperature overnight.

[1292] Latanoprost is then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in the solution and hold it in place during mixing. An overhead mixer is used. The solution is then left to mix overnight at room temperature. The composition of FDC 12 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1293] Example 10 Preparation of Fixed Dose Combination Batch 13 (FDC 13)

[1294] Table 39: Composition of FDC 13

[1295] Component % Cone.

[1296] Levcromakalim 0.015%, 0.03%, or 0.075%

[1297] Latanoprost 0.005%

[1298] Hypromellose 0.05-3%

[1299] PBS Stock Solution 5-15%

[1300]

[1301] Deionized H₂O QS to 100%

[1302] QS = Quantity Sufficient

[1303] A solution of levcromakalim in acetonitrile (1 mL of 6 mg / mL stock) is added to a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. 300 pL of PBS Stock Solution, and hypromellose are then added, and final volume is brought to 3 mL using deionized H₂O such that the concentration of levcromakalim is about 0.015%, 0.03%, or 0.075%, hypromellose is about 0.05-3%, and PBS stock solution is about 5-15%. The mixture is stirred ina heating block at 80 °C for 20 minutes. Then, the mixture is incubated at room temperature overnight.

[1304] Latanoprost is then weighed at about 105% of the desired weight directly onto a stainless-steel square. A stainless-steel hook system is fabricated to submerge the square in the solution and hold it in place during mixing. An overhead mixer is used. The solution is then left to mix overnight at room temperature. The composition of FDC 13 is then filtered using 13mm, 0.2 μm Thermo Scientific™ Choice™ PVDF (Hydrophilic) Syringe Filters.

[1305] Example 11 Preparation of Fixed Dose Combination Batch 14 (FDC 14)

[1306] Table 40: Composition of FDC 14

[1307] Component % Cone.

[1308] Levcromakalim 0.015%, 0.03%, or 0.075%

[1309] Latanoprost 0.005%

[1310] Polysorbate 80 0.05-5%

[1311] Glycerin 1-10%

[1312] EDTA 0.05-3%

[1313]

[1314] Deionized H₂O QS to 100%

[1315] QS = Quantity Sufficient

[1316] A solution of levcromakalim in acetonitrile (1 mL of 6 mg / mL stock) is aliquoted to a 5 mL vial. The solvent is removed via evaporation under a stream of nitrogen, and the vial is placed under high vacuum for 24 hours for further evaporation resulting in a thin film. Water-based solutions of polysorbate 80, glycerin, and EDTA are then added; and the final volum...

Claims

CLAIMSWe Claim:

1. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of levcromakalim and latanoprost, wherein the concentration of levcromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the solution further comprises three or more components selected from the group consisting ofj. a polyol;k. a polyethoxylated furanose fatty acid ester;l. a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene (poloxamer);m. a polymeric alkyl or aryl polyol;n. an ethoxylated glycerol ester;o. a polymeric lactam;p. hydroxyalkyl cellulose;q. an oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate; andr. an ethoxylated alkylphenol;in an aqueous solution with a pH between 5 and 8.

2. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 1 comprising four or more components.

3. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 1 comprising five or more components.

4. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 1, comprising six or more components.

5. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-4, wherein the solution comprises a polyol.

6. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 5, wherein the polyol is mannitol.

7. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 5, wherein the polyol is glycerin.

8. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 5, wherein the polyol is an alkyl polyol.

9. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 8, wherein the alkyl polyol is a triol.

10. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 8, wherein the alkyl polyol is a sugar alcohol.

11. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-10, wherein the concentration of the polyol is between 0.1% and 10% w / v.

12. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-10, wherein the concentration of the polyol is between 1% and 5% w / v.

13. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-12, wherein the solution comprises a polyethoxylated furanose fatty acid ester.

14. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 13, wherein the polyethoxylated furanose fatty acid ester is polysorbate 80.

15. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-14, wherein the concentration of the poly ethoxylated furanose fatty acid ester is between 0.1% and 10% w / v.

16. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-14, wherein the concentration of the poly ethoxylated furanose fatty acid ester is between 0.1% and 3% w / v.

17. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of claims 1-16, wherein the solution comprises a poloxamer.

18. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 17, wherein the poloxamer is poloxamer 407.

19. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-18, wherein the concentration of the poloxamer is between 0.01% and 1% w / v.

20. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-18, wherein the concentration of the poloxamer is between 0.05% and 0.5% w / v.

21. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-20, wherein the solution comprises a polymeric alkyl or aryl polyol.

22. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 21, wherein the polymeric alkyl or aryl polyol is tyloxapol.

23. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-22, wherein the solution comprises an ethoxylated glycerol ester.

24. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 23, wherein the ethoxylated glycerol ester is selected from the group consisting of polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyethylated 12-hydroxystearic acid.

25. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 23, wherein the ethoxylated glycerol ester is polyoxyl-ethylated castor oil.

26. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 23, wherein the ethoxylated glycerol ester is polyoxyl 40 hydrogenated castor oil.

27. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 23, wherein the ethoxylated glycerol ester is polyoxyethylated 12- hydroxystearic acid.

28. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-27, wherein the concentration of the ethoxylated glycerol ester is between 0.1% and 6% w / v.

29. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-27, wherein the concentration of the ethoxylated glycerol ester is between 1% and 5% w / v.

30. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-29, wherein the solution comprises a polymeric lactam.

31. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 30, wherein the polymeric lactam is a PVP.

32. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 31, wherein the PVP is selected from the group consisting of PVP K-30 and PVP K-90.

33. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 31, wherein the PVP is PVP K-30.

34. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 31, wherein the PVP is PVP K-90.

35. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-34, wherein the concentration of the polymeric lactam is between 0.1% and 10% w / v.

36. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-34, wherein the concentration of the polymeric lactam is between 1% and 5% w / v.

37. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-36, wherein the solution comprises hydroxyalkyl cellulose.

38. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 37, wherein the hydroxyalkyl cellulose is hypromellose.

39. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-38, wherein the solution comprises an oil in water polymericemulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate.

40. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 39, wherein the oil in water polymeric emulsifier of a block copolymer of polyacrylic acid and a hydrophobic C10-C30alkyl acrylate is Carbomer Copolymer.

41. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 40, wherein the Carbomer Copolymer is selected from the group consisting of Carbomer Copolymer A and Carbomer Copolymer B.

42. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-41, wherein the solution comprises an ethoxylated alkylphenol.

43. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 42, wherein the ethoxylated alkylphenol is octoxynol.

44. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 43, wherein the octoxynol is octoxynol-40.

45. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of levcromakalim or a pharmaceutically acceptable salt thereof and latanoprost, wherein the concentration of levcromakalim is between 0.001% and 0.1% w / v and the concentration of latanoprost is between 0.001% and 0.02% w / v, and wherein the solution further comprises three or more components selected from the group consisting of a. polysorbate 80,b. poloxamer 407,c. polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, or polyoxyethylated 12-hydroxystearic acid, andd. PVPin an aqueous solution with a pH between 6 and 8.

46. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 45 wherein the ocular solution consists essentially of levcromakalim, latanoprost, water, and three or more components selected from the group consisting ofa. polysorbate 80,b. poloxamer 407,c. polyoxyl-ethylated castor oil, polyoxyl 40 hydrogenated castor oil, or polyoxyethylated 12-hydroxy stearic acid, andd. PVP.

47. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of claim 45 wherein the ocular solution consists essentially of levcromakalim, latanoprost, water, and:a. polysorbate 80,b. poloxamer 407,c. polyoxyl-ethylated castor oil, andd. PVP.

48. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-47, comprising polysorbate 80 wherein the concentration of polysorbate 80 is between 0.1% and 10% w / v.

49. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-47, comprising polysorbate 80 wherein the concentration of polysorbate 80 is between 0.5% and 3% w / v.

50. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-49, comprising poloxamer 407 wherein the concentration of poloxamer 407 is between 0.01% and 1% w / v.

51. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-49, comprising poloxamer 407 wherein the concentration of poloxamer 407 is between 0.01% and 0.5 % w / v.

52. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-51, comprising polyoxyl-ethylated castor oil wherein the concentration of polyoxyl-ethylated castor oil is between 0.1% and 6% w / v.

53. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-51, comprising polyoxyl-ethylated castor oil wherein the concentration of polyoxyl-ethylated castor oil is between 1% and 5% w / v.

54. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-53, comprising a PVP wherein the concentration of the PVP is between 0.1% and 10% w / v.

55. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-53, comprising PVP wherein the concentration of the PVP is between 1% and 5% w / v.

56. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-55, comprising polysorbate 80 at a concentration of about 1% w / v.

57. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-56, comprising poloxamer 407 at a concentration of about 0.1% w / v.

58. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-57, comprising Kolliphor® ELP at a concentration of about 4% w / v.

59. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-58, comprising a PVP at a concentration of about 2% w / v.

60. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims of 1-59, wherein the solution is stable at ambient conditions for at least 3 months.

61. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims of 1-59, wherein the solution is stable at ambient conditions for at least 4 months.

62. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims of 1-59, wherein the solution is stable at ambient conditions for at least 5 months.

63. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims of 1-59, wherein the solution is stable at ambient conditions for at least 6 months.

64. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims of 1-59, wherein the solution is stable at ambient conditions for at least 7 months.

65. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-64, wherein the solution is an aqueous solution of pH of about 6.5 to about 7.5.

66. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.075% w / v.

67. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.05% w / v.

68. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is between 0.005% w / v and 0.03% w / v.

69. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is about 0.015% w / v.

70. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is about 0.03% w / v.

71. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-65, wherein the concentration of levcromakalim is about 0.075% w / v.

72. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-71, wherein the concentration of latanoprost is between 0.001% w / v and 0.015% w / v.

73. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-71, wherein the concentration of latanoprost is between 0.001% w / v and 0.010% w / v.

74. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-71, wherein the concentration of latanoprost is between 0.001% w / v and 0.005% w / v.

75. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any of the claims 1-71, wherein the concentration of latanoprost is about 0.005% w / v.

76. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprisinga. levcromakalim at a concentration of about 0.015% w / v;b. latanoprost at a concentration of about 0.005% w / v;c. mannitol at a concentration of about 3.3% w / v;d. polysorbate 80 at a concentration of about 1% w / v;e. poloxamer 407 at a concentration of about 0.1% w / v;f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; andfurther comprising water and phosphate buffer as aqueous components.

77. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprisinga. levcromakalim at a concentration of about 0.030% w / v;b. latanoprost at a concentration of about 0.005% w / v;c. mannitol at a concentration of about 3.3% w / v;d. polysorbate 80 at a concentration of about 1% w / v;e. poloxamer 407 at a concentration of about 0.1% w / v;f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; andfurther comprising water and phosphate buffer as aqueous components.

78. An aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution comprisinga. levcromakalim at a concentration of about 0.075% w / v;b. latanoprost at a concentration of about 0.005% w / v;c. mannitol at a concentration of about 3.3% w / v;d. polysorbate 80 at a concentration of about 1% w / v;e. poloxamer 407 at a concentration of about 0.1% w / v;f. polyoxyl-ethylated castor oil at a concentration of about 4% w / v;g. polyvinylpyrrolidone (PVP) at a concentration of about 2% w / v; andfurther comprising water and phosphate buffer as aqueous components.

79. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-78, wherein the solution is not an emulsion.

80. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-79, wherein the solution is not a gel.

81. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-80, wherein the solution is a clear solution.

82. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-81, wherein the solution is a micellar or nanomicellar solution.

83. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-82, wherein the solution does not include an oil.

84. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-83, wherein the solution does not include a preservative, for example benzalkonium chloride (BAK).

85. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-84, wherein the solution further comprises a preservative, for example benzalkonium chloride (BAK) at a concentration of about 0.0005% to about 2% w / v.

86. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-84, wherein the solution further comprises a preservative, for example benzalkonium chloride (BAK) at a concentration of about 0.02% w / v.

87. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-86, wherein the solution has a percent transmittance of greater than 85% when tested with a UV-Vis spectrophotometer.

88. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-86, wherein the solution has a percent transmittance of greater than 90% when tested with a UV-Vis spectrophotometer.

89. The aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-86, wherein the solution has a percent transmittance of greater than 95% when tested with a UV-Vis spectrophotometer.

90. A method for the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-89 to a human in need thereof.

91. The method of claim 90, wherein the use of the topical solution results in lower intraocular pressure.

92. The method of claim 90 or 91, wherein the ocular disorder is a glaucoma.

93. The method of claim 92, wherein the glaucoma is normal tension glaucoma (NTG).

94. The method according to claim 92, wherein the glaucoma is primary open angle glaucoma (POAG).

95. The method of claim 92, wherein the glaucoma is selected from the group consisting of primary open angle glaucoma (POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

96. The method of claim 90 or 91, wherein the ocular disorder is ocular hypertension (OHT).

97. The method of claim 90 or 91, wherein the ocular disorder is Sturge Weber Syndrome or Sturge Weber Syndrome-induced glaucoma.

98. The method of claim 90 or 91, wherein the ocular disorder is diabetic retinopathy.

99. The method of claim 90 or 91, wherein the method of treatment is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions of trabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative claims, Schlemm’s canal stents that dilate Schlemm’s canal, goniotomies, canal oplasties, and laser trabeculoplasties.

100. The method of claim 90 or 91, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic-hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

101. The method of any one of claims 90-100, wherein the treatment with the topical solution provides cellular protection and / or neuroprotection to the human in need thereof.

102. The method of claim 90 or 91, wherein the ocular disorder is an ocular-related neurodegenerative disease affecting the posterior segment of the eye.

103. The method of claim 102, wherein the ocular-related neurodegenerative disease is ischemia.

104. The method of claim 102, wherein the ocular-related neurodegenerative disease is non- arteritic anterior ischemic optic neuropathy (NAION).

105. The method of claim 102, wherein the ocular-related neurodegenerative disease is retinal ischemia.

106. The method of claim 102, wherein the ocular-related neurodegenerative disease is age- related macular degeneration.

107. The method of claim 106, wherein the age-related macular degeneration is wet age-related macular degeneration.

108. The method of claim 106, wherein the age-related macular degeneration is dry age-related macular degeneration.

109. The method of claim 102, wherein the ocular-related neurodegenerative disease is optic nerve drusen.

110. The method of claim 102, wherein the ocular-related neurodegenerative disease is an inherited optic neuropathy.

111. The method of claim 110, wherein the inherited optic neuropathy is selected from the group consisting of Leber’s hereditary optic neuropathy (LHON), dominant optic atrophy, Behr’s syndrome, and Berk-Tabatznik syndrome.

112. Use of a aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution of any one of claims 1-89 in the treatment of an ocular disorder affecting the anterior or the posterior segment of the eye comprising administering an effective amount of the aqueous clear ocular topical pharmaceutically acceptable fixed dose combination solution to a human in need thereof.

113. The use of claim 112, wherein the use of the topical solution results in lower intraocular pressure.

114. The use of claim 112 or 113, wherein the ocular disorder is a glaucoma.

115. The use of claim 114, wherein the glaucoma is normal tension glaucoma (NTG).

116. The use according to claim 114, wherein the glaucoma is primary open angle glaucoma (POAG).

117. The use of claim 114, wherein the glaucoma is selected from the group consisting of primary open angle glaucoma (POAG), primary angle closure glaucoma, pediatric glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial glaucoma (ICE), uveitic glaucoma, glaucoma associated with diabetic retinopathy, Sturge Weber Syndrome, steroid induced glaucoma, and acute glaucoma resulting from advanced cataracts and / or from intravitreal injections.

118. The use of claim 112 or 113, wherein the ocular disorder is Sturge Weber Syndrome or glaucoma induced by Sturge Weber Syndrome-induced glaucoma.

119. The use of claim 112 or 113, wherein the ocular disorder is diabetic retinopathy.

120. The use of claim 112 or 113, wherein the use is a primary or secondary or adjunctive treatment as part of the protocol for MIGS (Microinvasive Glaucoma Surgery), selected from the group consisting of miniature versions of trabeculectomy (microtrabeculectomies), trabecular bypass surgeries, totally internal or suprachoroidal shunts, milder / gentler versions of laser cyclo photocoagulation, and in alternative claims, Schlemm’s canal stents that dilate Schlemm’s canal, goniotomies, canal oplasties, and laser trabeculoplasties.

121. The use of claim 112 or 113, wherein the ocular disorder is Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital vein vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunts, orbital varices, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), artery occlusive / embolic-hypoperfusion diseases, or optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION).

122. The use of any one of claims 112-121, wherein the treatment with the topical solution provides cellular protection and / or neuroprotection to the human in need thereof.

123. The use of claim 122, wherein the ocular disorder is an ocular-related neurodegenerative disease affecting the posterior segment of the eye.

124. The use of claim 123, wherein the ocular-related neurodegenerative disease is ischemia.

125. The use of claim 123, wherein the ocular-related neurodegenerative disease is non-arteritic anterior ischemic optic neuropathy (NAION).

126. The use of claim 123, wherein the ocular-related neurodegenerative disease is retinal ischemia.

127. The use of claim 123, wherein the ocular-related neurodegenerative disease is age-related macular degeneration.

128. The use of claim 127, wherein the age-related macular degeneration is wet age-related macular degeneration.

129. The use of claim 127, wherein the age-related macular degeneration is dry age-related macular degeneration.

130. The use of claim 123, wherein the ocular-related neurodegenerative disease is optic nerve drusen.

131. The use of claim 123, wherein the ocular-related neurodegenerative disease is an inherited optic neuropathy.

132. The use of claim 131, wherein the inherited optic neuropathy is selected from the group consisting of Leber’s hereditary optic neuropathy (LHON), dominant optic atrophy, Behr’s syndrome, and Berk-Tabatznik syndrome.

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