Compositions and methods for sustained release cromakalim therapy

Abstract

Provided are sustained release pharmaceutical compositions comprising biodegradable microparticle, nanoparticle, or other polymeric formulations of Formula I, Formula II, or Formula III, or pharma- ceutically acceptable salts thereof, that have advantageous properties for in vivo delivery to a patient in need thereof, and that overcome traditional obstacles in the delivery of cromakalim, including levcromakalim.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 232,603, filed August 12, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] The present application is in the field of medical therapy and provides new pharmaceutical compositions and methods of use comprising certain sustained release formulations of cromakalim, including levcromakalim, and pharma-ceutically acceptable salts thereof. [Background technology]

[0003] Cromakalim and its use as an antihypertensive agent was first described in U.S. Patent No. 5,393,633, assigned to Beecham Group, Inc. Disclosures on the effects of cromakalim on intraocular pressure and glaucoma were reported in U.S. Patent No. 5,393,633, ... and U.S. Patent No. 5,393,633.

[0004] Cromakalim and diazoxide were reported to lower blood pressure in Non-Patent Document 3. In addition, publications by Chowdhury et al. and Roy Chowdhury et al. describe the use of diazoxide and nicorandil (Non-Patent Document 4 and Non-Patent Document 5). Cromakalim placed in membrane patches from rabbit mesenteric artery smooth muscle cells reduced the single K ATP The channel open state probability (P open ) by more than nine-fold (Non-Patent Document 6). Other ATP-sensitive potassium channel openers include pinacidil and minoxidil sulfate, which act as vasodilators in vitro and in vivo.

[0005] Cromakalim exists as a mixture of diastereomers in the trans configuration (a mixture of the (3R,4S) diastereomer and the (3S,4R) diastereomer).

[0006] [ka]

[0007] The (3S,4R)-diastereomer is also called (-)-cromakalim or levcromakalim, and the (3R,4S)-diastereomer is also called (+)-cromakalim or dexcromakalim.

[0008] [ka]

[0009] Most of the reported activity of cromakalim comes from its (3S,4R)-diastereomer, levcromakalim (Non-Patent Document 7 and Non-Patent Document 8).

[0010] Additional publications describing the use of cromakalim and levcromakalim prodrugs for the treatment of medical disorders include U.S. Patent Nos. 5,393,633 and 5,453,398, assigned to Qlaris Bio, Inc. and the Mayo Foundation for Medical Education and Research.

[0011] While cromakalim has established activity as a potassium channel opener and vasodilator, it is virtually insoluble in water. Cromakalim's lipophilicity limits its usefulness for certain in vivo applications. Cromakalim is often solubilized with DMSO or cremophor, which is also used for the water-insoluble drug taxol. Cremophor in particular has toxic side effects.

[0012] Cromakalim has been tested in human clinical trials, but these were discontinued due to lack of activity, most likely poor bioavailability.

[0013] In light of the as yet unrecognized potential therapeutic utility of cromakalim, it would be beneficial to have additional methods, compositions, and formulations that increase the bioavailability and activity of cromakalim, particularly levcromakalim, in vivo to enable additional medical therapies. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] European Patent No. 0120428 [Patent Document 2] WO 89 / 10757 [Patent Document 3] International Publication No. 2021 / 158992 [Patent Document 4] International Publication No. 2021 / 119503 [Non-patent literature]

[0015] [Non-Patent Document 1] 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 [Non-Patent Document 2] Roy 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 [Non-Patent Document 3] Quast, U. et al. J Pharmacol Exp Ther 1989, 250, 261

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

[0016] The present invention relates to a compound of formula I, formula II, or formula III: [ka] The present invention provides new medical uses and sustained release formulations of cromakalim, prodrugs of cromakalim, and pharma-ceutically acceptable salts thereof.

[0017] Pharmaceutically acceptable salts of cromakalim (formula I) include: [ka] (In the formula, X + and M 2+ Z can be any pharma- ceutically acceptable cation that achieves the desired result. + X + (representing a mixed salt of

[0018] In certain embodiments, cromakalim can be administered as a mixture of enantiomers and / or a mixture of salts in a sustained release biodegradable polymer formulation. For example, Adderall is a representative example of a mixture of enantiomers and mixed salts of approved drugs. This mixture has an equal part racemic amphetamine and dextroamphetamine salt mixture (sulfate, aspartate, and sugar salt), resulting in an approximately 3:1 ratio between dextroamphetamine and levoamphetamine. The two enantiomers are sufficiently different to give Adderall a different effect profile than the racemate or d-enantiomer. Similarly, in the present invention, cromakalim can be used as any mixture of levcromakalim and dexcromakalim, or as racemic cromakalim, and as a salt in a certain ratio. In formula IB, Z + X + is intended to represent a mixed salt cation of

[0019] Although sometimes drawn without stereochemistry at the C-OH position, cromakalim of any of the formulas shown typically has the stereochemistry of levcromakalim. In alternative embodiments, cromakalim may be used as a mixture of enantiomers, including racemic form.

[0020] [ka]

[0021] 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, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, and triethylamine.

[0022] In one embodiment, X + is Na+ Or K + In one embodiment, X + Li + In one embodiment, X + is Cs + In one embodiment, X + is an ammonium ion having a net positive charge of 1. Non-limiting examples of ammonium ions having a net positive charge of 1 include: [ka] Examples include:

[0023] In an alternative embodiment, the ammonium ion having a net positive charge is represented by the following formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl, where the C1-C6 alkyl or aryl may be optionally substituted, for example, with a hydroxyl group. In one embodiment, the ammonium ion is [ka] It is.

[0024] M 2+ M may be, for example, but is not limited to, an alkaline earth metal cation (magnesium, calcium, or strontium), a metal cation having an oxidation state of +2 (e.g., zinc or iron), or an ammonium ion having a net positive charge of 2 (e.g., benzathine, hexamethyldiammonium, and ethylenediamine).2+ is Mg 2+ In one embodiment, M 2+ Ca 2+ In one embodiment, M 2+ is Sr 2+ In one embodiment, M 2+ Zn 2+ In one embodiment, M 2+ is Fe 2+ In one embodiment, M 2+ is an ammonium ion having a net positive charge of 2. Non-limiting examples of ammonium ions having a net positive charge of 2 include: [ka] Examples include:

[0025] In an alternative embodiment, the ammonium ion having a net positive charge of two has the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl, where C1-C6 alkyl or aryl may be optionally substituted, for example, with a hydroxyl group; and and y is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0026] The present invention includes solving the long-felt need to enable cromakalim therapy, e.g., levcromakalim therapy, by administering selected compounds as described herein in a sustained release formulation, including but not limited to polymer controlled delivery formulations as further described herein, typically, e.g., microparticles or nanoparticles, or alternatively, hydrogels or liposomes. The fact that cromakalim is lipophilic, which is a major disadvantage for direct administration and has hindered positive clinical trial results, is turned into an advantage in the present invention when formulated into a lipophilic sustained release formulation, such as microparticles, nanoparticles, or liposomes. This may allow cromakalim to be used as a therapy for serious diseases as further described.

[0027] In certain embodiments, the sustained release formulation comprises a biodegradable polymer, including, but not limited to, poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), other aliphatic polyesters, poly(caprolactone), polyanhydrides, polyamides, polyamino acids, poly(ester amides), poly(phosphate esters), poly(orthoesters), hyaluronic acid, or polydioxanone. In some embodiments, the biodegradable polymer is end-capped with polyethylene glycol (PEG).

[0028] The term "microparticle" as used herein refers to a particle with a size on the micrometer (μm) scale. Typically, a microparticle has an average diameter of about 1 μm to about 100 μm. In some embodiments, a microparticle has an average diameter of about 0.5 μm to 80 μm, e.g., about 1 μm to 75 μm, about 10 μm to 75 μm, about 20 μm to 60 μm, about 25 μm to 50 μm, more typically at least about 0.5 μm, 1 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm. As used herein, the term "microsphere" refers to a substantially spherical microparticle.

[0029] The term nanoparticle refers to particles with sizes on the nanometer scale, including but not limited to, 0.5 nanometers to 100 nanometers, including at least about 0.5 nm, 1 nm, 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, or 100 nm.

[0030] In some embodiments, the sustained release cromakalim formulation is delivered and retained in tissues, including ocular tissues, and slowly released over time, providing a long-term, continuous, controlled dosing of active cromakalim, and in one embodiment, levcromakalim, following administration of the sustained release formulation.

[0031] Thus, in one embodiment, the present invention provides controlled delivery of levcromakalim by administering a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, to a host, including a human, in need of controlled delivery. In one embodiment, controlled delivery of levcromakalim to the eye is achieved by topical administration of a sustained release formulation of a compound of the present invention. In selected embodiments of the present invention, a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, is administered to the eye, for example, as topical drops, to deliver levcromakalim in the eye, for example, in the sclera, optic nerve, cornea, iris, ciliary body, trabecular meshwork, and / or retina.

[0032] Sustained release delivery leading to long-term delivery of the active compound requires less frequent dosing, which is important for patient compliance, adherence, and better outcomes.

[0033] Furthermore, the effect of levcromakalim on selected biomarkers for perturbation of hyperemia and vascular integrity was established. Levcromakalim did not significantly affect the expression of measured proteins indicative of tissue and vascular integrity. The effect of levcromakalim was compared to Y-27632, a Rho kinase inhibitor, a class of drugs (exemplified by Rhopressa) known to have significant side effects caused by perturbation of vascular integrity (e.g., leakage and vasodilation causing hyperemia, and vascular rupture leading to pinpoint hemorrhages and subconjunctival hemorrhages). Unlike Y-27632, levcromakalim did not significantly alter the protein expression or distribution of these proteins. Thus, in one embodiment, the use of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, does not cause significant hyperemia in patients in need of use during the therapy described further herein, in some embodiments, when used over a chronic therapy of at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. Alternatively, administration of a sustained release formulation of a compound of Formula I, Formula II, or Formula III does not significantly induce expression of at least one protein independently selected from CD31 and VE-cadherin.

[0034] The sustained release cromakalim formulations of formula I, II, or III or pharma- ceutically acceptable salts thereof may contain a cromakalim moiety that is either the (-)(3S,4R)-enantiomer (levcromakalim) or the (+)(3R,4S)-enantiomer (dexcromakalim), or any mixture thereof. The sustained release cromakalim formulations may be formulated with cromakalim as the free acid or as a fully or partially neutralized acid. In one embodiment, the pH of the pharmaceutical formulations comprising the sustained release cromakalim formulations of formula I, II, or III or pharma- ceutically acceptable salts thereof is adjusted to a pH level desired for pharmaceutical administration, often between about 5.5 or 6.5 and 8.5, more typically between 6.5 and 8, using a pharma- ceutically acceptable base.

[0035] The present invention also provides new medical uses for sustained release cromakalim formulations, including vascular disorders, cardiovascular disorders, lymphatic disorders, and erectile dysfunction. When sustained release cromakalim formulations are administered systemically, they can induce peripheral vasodilation, a beneficial side effect that can treat vascular disorders such as Raynaud's disease, ischemic limb syndrome, pulmonary arterial hypertension, or sexual disorders such as erectile dysfunction. Thus, in one embodiment, the sustained release cromakalim formulation is administered to a host in need thereof, e.g., a human, to treat Raynaud's disease. In another embodiment, the sustained release cromakalim formulation is administered to a host in need thereof, e.g., a human, to treat erectile dysfunction.

[0036] The present invention includes at least the following aspects: (i) new sustained release compositions of compounds of formula I, II, or III, or pharma- ceutically acceptable salts thereof, in certain embodiments, the sustained release formulation is a microparticle or nanoparticle, or alternatively a hydrogel or liposome; (ii) a novel medical use of administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, to treat a disorder in a host in need of treatment; (iii) long-term (i.e., at least 6 weeks, 7 weeks, or for at least 2, 3, 4, 5, or 6 months, or indefinitely over the duration of therapy) medical therapy, including, but not limited to, ocular therapy to a host in need of therapy for normal tension glaucoma, comprising administration of an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III described herein, or a pharma- ceutically acceptable salt thereof, in a manner that does not result in significant tachyphylaxis (i.e., loss of activity over time) or, alternatively, induce resistance; (iv) sustained release human dosing using an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof, to treat glaucoma associated with elevated intraocular pressure, including, but not limited to, primary open angle glaucoma (POAG), primary angle-closure glaucoma (also known as chronic open angle glaucoma, chronic simple glaucoma, and simple glaucoma), pediatric glaucoma, pseudoexfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, iridocorneal endothelial glaucoma (ICE), and in alternative embodiments, uveitic glaucoma, steroid-induced glaucoma, and acute glaucoma resulting from progressive cataracts and / or intravitreal injections; (v) ophthalmic therapy using an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof, in a host in need of ophthalmic therapy, which does not result in significant congestion (which may result in "red eye", vascular congestion, small hemorrhages, small pinpoint hemorrhages, or microhemorrhages); (vi) methods of treatment comprising an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof, either as a primary or secondary or adjunctive treatment as part of a protocol for MIGS (minimally invasive glaucoma surgery), including, but not limited to, miniature forms of trabeculectomies (microtrabeculectomies), trabecular bypass surgery, total intrachoroidal or suprachoroidal shunts, gentler, more gentle forms of laser cyclophotocoagulation, and in alternative embodiments, Schlemm's canal stents to dilate Schlemm's canal, goniotomy, canaloplasty, and laser trabeculoplasty; (vii) a formulation for systemic delivery to a host in need of ocular therapy, comprising a sustained release formulation of an effective amount for ocular therapy of a compound of Formula I, Formula II, or Formula III, as described herein, or a pharma- ceutically acceptable salt thereof; (viii) a formulation for local delivery to a host in need of ocular therapy, comprising a sustained release formulation of an effective amount for ocular therapy of a compound of Formula I, Formula II, or Formula III, as described herein, or a pharma- ceutically acceptable salt thereof; (ix) a formulation for parenteral delivery to a host in need of ocular therapy, comprising a sustained release formulation of an effective amount for ocular therapy of a compound of Formula I, Formula II, or Formula III, as described herein, or a pharma- ceutically acceptable salt thereof; (x) a formulation for localized delivery to a host in need of ocular therapy, comprising a sustained release formulation of an effective amount for ocular therapy of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xi) a formulation for topical or transdermal application to a host in need thereof, comprising a sustained release formulation of an effective amount of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein; (xii) treating a cardiovascular disorder in a host, such as hypertension, congestive heart failure, transient ischemic attack, heart attack, acute myocardial infarction, acute and chronic myocardial ischemia, unstable angina or associated chest pain, arrhythmia, or pulmonary arterial hypertension (PAH), cardioprotection in a host experiencing a heart attack or a host undergoing cardiac surgery, cardioprotection for preservation of the heart prior to organ donation, microvascular dysfunction, or endothelial dysfunction, by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutical acceptable salt thereof; (xiii) treating vascular disorders in a host in need of such treatment, e.g., peripheral arterial disease, including Raynaud's disease, chronic and acute lower limb ischemia, and chronic cold hands and / or feet, by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xiv) treating an endocrine disorder, such as hypoglycemia, hyperinsulinism, or diabetes in a host by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein; (xv) treating a skeletal muscle disorder, such as a skeletal muscle myopathy, in a host by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein; (xvi) treating a urological disorder, such as erectile dysfunction or female sexual arousal disorder, by administration of an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xvii) treatment of dermatological disorders, such as hypotrichosis (failure to exhibit normal eyelash growth) or baldness, in a host in need of such treatment by administration of an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xviii) treating neurological disorders, such as neuropathic pain or neurodegenerative diseases (e.g., Parkinson's disease and Huntington's disease) in a host in need of such treatment by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xix) treating lymphatic diseases such as lymphedema, lymphangitis, lymphadenitis, lymphangiomatosis, Castleman's disease, or cancers of the lymphatic system, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, or lymphangiomatosis, in a host in need of such treatment by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xx) treating an ocular lymphatic disorder selected from conjunctival myxoma, dry eye, conjunctival lymphangiectasia, chemosis, mustard gas keratitis, corneal inflammation, orbital cellulitis, chalazion, cutis chalazion, and blepharochalasis by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xxi) treating tumor hypoperfusion or hypoxia in a host in need of such treatment by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein; (xxii) treating mitochondrial disorders by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein; (xxiii) treating ocular disorders in a host, such as Graves' ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid-cavernous sinus fistula, dural cavernous sinus shunt, orbital varicose veins, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), arterial occlusive / embolic disease and / or hypoperfusion disease, optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION)), by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III described herein, or a pharmacologic acceptable salt thereof; (xxiv) A method for providing cytoprotection and / or neuroprotection, comprising administering to a host in need thereof an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; (xxv) treatment of Sturge-Weber syndrome, including, but not limited to, Sturge-Weber syndrome induced glaucoma, in a host in need of such treatment by administering an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III as described herein, or a pharma- ceutically acceptable salt thereof; and (xxvi) A pharmaceutical composition comprising an effective amount of a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, as described herein, for treating any one of the disorders or diseases described in embodiments (i) through (xxii). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] I. Sustained release cromakalim formulations and their pharma- ceutically acceptable salts for medical uses as described herein In one aspect, the present invention provides a compound of formula I, formula II, or formula III: [ka] and pharmacokinetic and pharmacokinetic properties of the compound of formula (I) and their pharmacokinetic and pharmacokinetic properties.

[0038] The present invention comprises advantageous sustained release formulations that exhibit improved pharmacokinetic properties resulting in long-term controlled delivery of cromakalim, and in one embodiment, levcromakalim.

[0039] Pharmaceutically acceptable salts of cromakalim (formula I) include: [ka] (In the formula, X + and M 2+ can be any pharma- ceutically acceptable cation that achieves the desired result.

[0040] 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, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, and triethylamine.

[0041] In one embodiment, X + is Na + Or K + In one embodiment, X + Li + In one embodiment, X + is Cs + In one embodiment, X + is an ammonium ion having a net positive charge of 1. Non-limiting examples of ammonium ions having a net positive charge of 1 include: [ka] Examples include:

[0042] In an alternative embodiment, the ammonium ion having a net positive charge is represented by the following formula: [ka] (In the formula, R 1 is C1-C6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl, where the C1-C6 alkyl or aryl may be optionally substituted, for example with a hydroxyl group. In one embodiment, the ammonium ion is [ka] It is.

[0043] M 2+ M may be, for example, but is not limited to, an alkaline earth metal cation (magnesium, calcium, or strontium), a metal cation having an oxidation state of +2 (e.g., zinc or iron), or an ammonium ion having a net positive charge of 2 (e.g., benzathine, hexamethyldiammonium, and ethylenediamine). 2+ is Mg 2+ In one embodiment, M 2+ Ca 2+ In one embodiment, M 2+ is Sr 2+ In one embodiment, M 2+ Zn 2+ In one embodiment, M 2+ is Fe 2+ In one embodiment, M 2+ is an ammonium ion having a net positive charge of 2. Non-limiting examples of ammonium ions having a net positive charge of 2 include: [ka] Examples include:

[0044] In an alternative embodiment, the ammonium ion having a net positive charge of two has the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl, where C1-C6 alkyl or aryl may be optionally substituted, for example, with a hydroxyl group; and and y is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0045] In certain embodiments, the cation is a lipophilic cation that is more compatible with lipophilic sustained release formulations than metal cations. Examples are quaternary amines, including choline.

[0046] Non-limiting examples of compounds of formula IA include: [ka] Examples include:

[0047] Non-limiting examples of compounds of formula IB include: [ka] Examples include:

[0048] Non-limiting examples of compounds of formula IC include: [ka] Examples include:

[0049] Pharmaceutically acceptable salts of formula II include: [ka] (In the formula, X + and M 2+ is defined above, and and x is an integer selected from 1, 2, 3, 4, or 5.

[0050] Non-limiting examples of compounds of formula IIA include: [ka] Examples include:

[0051] In one embodiment of Formula IIA, x is 1.

[0052] In one embodiment of Formula IIA, x is 2.

[0053] In one embodiment of Formula IIA, x is 3.

[0054] In one embodiment of Formula IIA, x is 4.

[0055] In one embodiment of Formula IIA, x is 5.

[0056] Non-limiting examples of compounds of formula IIB include: [ka] Examples include:

[0057] In one embodiment of formula IIB, x is 1.

[0058] In one embodiment of formula IIB, x is 2.

[0059] In one embodiment of formula IIB, x is 3.

[0060] In one embodiment of formula IIB, x is 4.

[0061] In one embodiment of formula IIB, x is 5.

[0062] Non-limiting examples of compounds of formula IIC include: [ka] Examples include:

[0063] In certain embodiments, x is 1.

[0064] In certain embodiments, x is 2.

[0065] In certain embodiments, x is 3.

[0066] In certain embodiments, x is 4.

[0067] In certain embodiments, x is 5.

[0068] In one embodiment of formula IIC, x is 1.

[0069] In one embodiment of formula IIC, x is 2.

[0070] In one embodiment of formula IIC, x is 3.

[0071] In one embodiment of formula IIC, x is 4.

[0072] In one embodiment of formula IIC, x is 5.

[0073] Pharmaceutically acceptable salts of formula III include: [ka] Examples include:

[0074] Non-limiting examples of compounds of formula IIIA include: [ka] Examples include:

[0075] In one embodiment of Formula IIIA, x is 1.

[0076] In one embodiment of Formula IIIA, x is 2.

[0077] In one embodiment of Formula IIIA, x is 3.

[0078] In one embodiment of Formula IIIA, x is 4.

[0079] In one embodiment of Formula IIIA, x is 5.

[0080] Non-limiting examples of compounds of formula IIIB include: [ka] Examples include:

[0081] In one embodiment of Formula IIIB, x is 1.

[0082] In one embodiment of Formula IIIB, x is 2.

[0083] In one embodiment of Formula IIIB, x is 3.

[0084] In one embodiment of Formula IIIB, x is 4.

[0085] In one embodiment of Formula IIIB, x is 5.

[0086] Non-limiting examples of compounds of formula IIIC include: [ka] Examples include:

[0087] In one embodiment of Formula IIIC, x is 1.

[0088] In one embodiment of Formula IIIC, x is 2.

[0089] In one embodiment of Formula IIIC, x is 3.

[0090] In one embodiment of Formula IIIC, x is 4.

[0091] In one embodiment of Formula IIIC, x is 5.

[0092] The use of selected pharma- ceutically acceptable salts in such sustained release formulations may be useful in medical treatment. In general, pharma- ceutically acceptable salts may increase or decrease the efficacy or toxicity of a drug, or may change its pharmacokinetics or its distribution in the body through tissues. For example, one pharma- ceutical acceptable salt may concentrate in an organ, and another salt may concentrate in a different organ. As another example, after release from a controlled release formulation, an increase in water solubility alone does not guarantee that a compound will penetrate the eye, reach the relevant site of action, achieve sufficient in vivo concentration, or have beneficial pharmacological effects. In the case of topical administration to the eye, the drug must remain on the ocular surface long enough to penetrate the eye. This requires either administering a sustained release formulation to the desired site, or releasing the drug so that it can cross the multiple layers of the ocular surface, including the tear film, cornea, conjunctiva, and sclera, all of which have different degrees of hydrophilicity and hydrophobicity due to cell membranes, cell-cell junctions, and the aqueous, lipid, and protein components of the tear film. Topical administration is complicated by the constant renewal and washing of the ocular surface by tears, which in turn drain through the nasolacrimal (tear) duct. For a compound to enter the eye, it must be able to penetrate before being washed away.

[0093] One aspect of the present invention is that administration of selected disclosed pharma- ceutically acceptable salts in sustained release formulations can achieve a more useful pharmaceutical effect, in particular, that the drug can enter the relevant ocular tissue or chamber in an effective amount to achieve efficacy, for example, by entering the anterior chamber, reaching the trabecular meshwork, entering the vitreous humor, or reaching the retina.

[0094] Thus, another aspect of the present invention is that the sustained release formulations of the present invention generally enable delivery through multiple tissues for local, parenteral, regional, or systemic delivery in a consistent manner in therapeutic amounts over a period of time sufficient to impart a pharmacological effect to the target tissue and alleviate the disorder of interest, as further disclosed herein.

[0095] Additional embodiments of the present invention 1. In certain embodiments, cromakalim of formula I, formula II, or formula III: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in a levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a pharma- ceutically acceptable salt thereof.

[0096] 2. The sustained release pharmaceutical composition of embodiment 1, wherein the compound of formula I, formula II, or formula III is formulated in biodegradable microparticles.

[0097] 3. The sustained release pharmaceutical composition of embodiment 1, wherein the compound of formula I, formula II, or formula III is formulated in biodegradable nanoparticles.

[0098] 4. The sustained release pharmaceutical formulation of embodiment 1, wherein the compound of formula I, formula II, or formula III is formulated in a biodegradable polymer.

[0099] 5. The sustained release pharmaceutical composition according to embodiments 1-4, wherein the biodegradable polymer comprises poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), other aliphatic polyesters, poly(caprolactone), polyanhydrides, polyamides, polyamino acids, poly(ester amides), poly(phosphate esters), poly(ortho esters), hyaluronic acid, Pluronic® polymers, polyvalerolactone, poly(1,3-dioxane-2-one), poly(sebacic anhydride), or polyethylene glycol (PEG).

[0100] 6. The sustained release pharmaceutical composition according to embodiment 5, wherein the biodegradable polymer is end-capped with acyclic polyacetals derived from polyalkylene glycols, carbohydrates, and / or polysaccharides.

[0101] 7. The sustained release pharmaceutical composition according to embodiment 5, wherein the biodegradable polymer is not PEG but is end-capped with PEG.

[0102] 8. Formula I can be represented by formula IA, formula IB, or formula IC: [ka] (In the formula, X + and M 2+ is a pharma- ceutically acceptable cation, and Z + X + The sustained release pharmaceutical composition according to any one of the preceding embodiments, wherein the cation is a mixed salt of

[0103] 9.X + Cations include sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, cesium, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethaneamine, triethylamine, and the formula: [ka] or an ammonium ion of the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, aryl, and is C1-C6 alkyl or aryl).

[0104] 10.M 2+ is an alkaline earth metal cation, a metal cation, or an ammonium ion.

[0105] 11. In certain embodiments, a method of treating an ophthalmic disorder selected from Graves' ophthalmopathy, cavernous sinus thrombosis, orbital venous vasculitis, carotid-cavernous fistula, orbital varicose veins, central retinal vein occlusion, branch retinal vein occlusion, and non-arteritic anterior ischemic optic neuropathy in a host in need of treatment, comprising administering to the host an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0106] 12. The method of embodiment 11, wherein the eye disorder is non-arteritic anterior ischemic optic neuropathy.

[0107] 13. In certain embodiments, a method of treating a vascular disorder selected from Raynaud's disease, peripheral arterial disease, chronic limb ischemia, thrombophlebitis, pulmonary arterial hypertension, and chronic venous insufficiency in a host in need of such treatment, comprising administering to the patient an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0108] 14. The method of embodiment 13, wherein the vascular disorder is Raynaud's disease.

[0109] 15. The method of embodiment 13, wherein the vascular disorder is pulmonary arterial hypertension.

[0110] 16. In certain embodiments, a method for treating a cardiovascular disease selected from chronic or acute myocardial ischemia, microvascular dysfunction, coronary artery disease, arrhythmia, hypertension, endothelial dysfunction, and heart attack in a host in need of such treatment, comprising administering to the patient an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical acceptable carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0111] 17. In certain embodiments, a method for treating erectile dysfunction or female sexual arousal disorder in a host in need of treatment, comprising administering to the host an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutically acceptable carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0112] 18. The method of embodiment 17, for treating erectile dysfunction.

[0113] 19. In certain embodiments, a method for treating a lymphatic disorder selected from lymphadenopathy, lymphangitis, lymphangiectasia, lymphadenitis, and lymphangiomatosis in a host in need of treatment, comprising administering to the host an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutically acceptable carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0114] 20. In certain embodiments, a method of treating an ocular lymphatic disorder selected from conjunctival myxoma, dry eye, conjunctival lymphangiectasia, chemosis, mustard gas keratitis, corneal inflammation, orbital cellulitis, chalazion, cutis chalazion, and blepharochalasis in a host in need of treatment, comprising administering to the patient an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim can be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt thereof.

[0115] 21. The method of any one of embodiments 10-20, wherein an effective amount of a sustained release formulation of a compound of formula I, formula II, or formula III does not cause significant hyperemia.

[0116] 22. The sustained release formulation of a compound of Formula IA, Formula IB, or Formula IC: [ka] (In the formula, X + and M 2+ is a pharma- ceutically acceptable cation, and Z + X + The method of any one of embodiments 10-21, wherein the cation is a mixed salt of Formula I.

[0117] 23. The compound of formula IA is [ka] 23. The method of embodiment 22, wherein said method is selected from the group consisting of

[0118] 24. A compound of formula IB [ka] 23. The method of embodiment 22, wherein said method is selected from the group consisting of

[0119] 25. A compound of formula I.C. [ka] 23. The method of embodiment 22, wherein said method is selected from the group consisting of

[0120] 26. The compound has formula IIA, formula IIB, or formula IIC: [ka] (In the formula, X + and M 2+ is a pharma- ceutically acceptable cation; Z + X + and 22. The method of any one of embodiments 10-21, wherein x is an integer selected from 1, 2, 3, 4, or 5.

[0121] 27. The compound has formula IIIA, formula IIIB, or formula IIIC: [ka] (In the formula, X + and M 2+ is a pharma- ceutically acceptable cation; Z + X + and 27. The method of embodiment 26, wherein x is an integer selected from 1, 2, 3, 4, and 5, and the C—OH bond can be substantially in a levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture.

[0122] 28. The method of any one of embodiments 11 to 27, wherein the host is a human.

[0123] 29. In certain embodiments, cromakalim of formula I, formula II, or formula III, optionally in a pharma- ceutical carrier, for use in treating an ophthalmic disorder selected from Graves' ophthalmopathy, cavernous sinus thrombosis, orbital venous vasculitis, carotid-cavernous fistula, orbital varicose veins, central retinal vein occlusion, branch retinal vein occlusion, or non-arteritic anterior ischemic optic neuropathy in a host in need of treatment: [ka] Sustained release pharmaceutical compositions are provided comprising biodegradable microparticle, nanoparticle, or other polymeric formulations of or a pharma- ceutically acceptable salt thereof.

[0124] 30. The sustained release pharmaceutical composition according to embodiment 29, wherein the eye disorder is non-arteritic anterior ischemic optic neuropathy.

[0125] 31. In certain embodiments, cromakalim of formula I, formula II, or formula III, optionally in a pharma- ceutically acceptable carrier, for use in treating a vascular disorder selected from Raynaud's disease, peripheral arterial disease, chronic limb ischemia, thrombophlebitis, pulmonary arterial hypertension, and chronic venous insufficiency in a host in need of such treatment: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in a levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a pharma- ceutically acceptable salt thereof.

[0126] 32. The sustained release pharmaceutical composition according to embodiment 31, wherein the vascular disorder is Raynaud's disease.

[0127] 33. The sustained release pharmaceutical composition according to embodiment 31, wherein the vascular disorder is pulmonary arterial hypertension.

[0128] 34. In certain embodiments, cromakalim of formula I, formula II, or formula III, optionally in a pharma- ceutically acceptable carrier, for use in treating a disorder or disease described herein in a host in need of treatment: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in a levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a pharma- ceutically acceptable salt thereof.

[0129] 35. An effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical carrier, in the manufacture of a medicament for the treatment of an ophthalmic disorder selected from Graves' ophthalmopathy, cavernous sinus thrombosis, orbital venous vasculitis, carotid-cavernous fistula, orbital varicose veins, central retinal vein occlusion, branch retinal vein occlusion, and non-arteritic anterior ischemic optic neuropathy in a host in need of treatment: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation of a pharmaceutically acceptable salt thereof.

[0130] 36. The use according to embodiment 35, wherein the eye disorder is non-arteritic anterior ischemic optic neuropathy.

[0131] 37. In the manufacture of a medicament for the treatment of a vascular disorder selected from Raynaud's disease, peripheral arterial disease, chronic limb ischemia, thrombophlebitis, pulmonary arterial hypertension, and chronic venous insufficiency in a host in need of treatment, an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutical acceptable carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a sustained release formulation comprising a biodegradable microparticle, nanoparticle, or other polymeric formulation of a pharmaceutically acceptable salt.

[0132] 38. The use according to embodiment 37, wherein the vascular disorder is Raynaud's disease.

[0133] 39. The use according to embodiment 37, wherein the vascular disorder is pulmonary arterial hypertension.

[0134] 40. In certain embodiments, in the manufacture of a medicament for the treatment of a disorder or disease described herein in a host in need of treatment, an effective amount of a cromakalim compound of formula I, formula II, or formula III, optionally in a pharma- ceutically acceptable carrier: [ka] wherein x is an integer selected from 1, 2, 3, 4, and 5, and the cromakalim may be substantially in the levorotatory configuration, or a mixture of levorotatory and dextrorotatory configurations, including a racemic mixture, or a pharma- ceutically acceptable salt thereof.

[0135] 41. In certain embodiments, cromakalim of formula I, formula II, or formula III is administered in an effective amount to treat a host using any of the methods described herein: [ka] Sustained release pharmaceutical compositions are provided comprising biodegradable microparticle, nanoparticle, or other polymeric formulations of or a pharma-ceutically acceptable salt thereof.

[0136] II. Medical Uses of Extended Release Formulations of Compounds of Formula I, Formula II, and Formula III, Particularly Levcromakalim, or Pharmaceutically Acceptable Salts Thereof The present invention provides a novel method of use for delivering sustained release formulations of compounds of formula I to III or pharma- ceutically acceptable salts thereof, including an effective amount of levcromakalim or a salt thereof, and compositions for delivering the same. The present invention includes at least the following aspects:

[0137] A "patient" or "host" or "subject" as used herein is typically a human, and the methods are for human therapy. In appropriate circumstances, the scope may include non-human animals, such as mammals, primates (non-human), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc., in need of treatment or prevention of any of the disorders specifically described herein.

[0138] Long-term therapy without significant tachyphylaxis or resistance In one embodiment, the present invention includes long-term (i.e., at least 6 weeks, 7 weeks, or at least 2 months, 3 months, 4 months, 5 months, or 6 months, or indefinitely during the duration of therapy) medical therapy, including ocular therapy, using sustained release formulations of compounds of Formula I-III, including levcromakalim, or pharma- ceutically acceptable salts thereof, in a manner that does not result in significant tachyphylaxis (i.e., loss of activity over time) or resistance, including, but not limited to, normal tension glaucoma. Tachyphylaxis is a decrease in response to a drug that occurs over time. Tachyphylaxis may occur after the first dose or after a series of doses. Resistance is the need to increase the dose of a drug to produce a given response.

[0139] The present invention provides a method for using sustained release formulations of compounds of formula I, formula II, or formula III, or their pharma- ceutically acceptable salts, including levcromakalim or its salts, for long-term therapy in a manner that does not induce significant tachyphylaxis or, alternatively, tolerance. Loss of activity over time has been noted with many drugs, including ocular therapeutics. For example, tachyphylaxis is a common effect of over-the-counter ocular allergy medications, and is also observed with some drugs for other ocular conditions, including glaucoma. Tachyphylaxis has many causes, including increased or decreased expression of receptors or enzymes. This phenomenon has been noted particularly with beta-adrenergic antagonists and histamine.

[0140] The dose can be once a day or several times a day, at the physician's best discretion and as further described herein. In one embodiment, the dose is delivered as a topical drop for glaucoma, including normal tension glaucoma, or any form of high pressure glaucoma, including those described herein as examples elsewhere. It is advantageous for patients to be able to take a stable dose of drug for an extended period of time without having to change the drug or dosage strength. Although no two patients are the same and patients may show different results based on genetics or disease, in general, long-term therapy can be achieved according to the present invention using an effective amount of sustained release formulation of the compound of formula I, formula II, or formula III, or a pharma- ceutically acceptable salt thereof, in a delivery system appropriate for the disorder being treated.

[0141] Once-daily dosing In another embodiment, a sustained release formulation suitable for once-daily (QD) human dosing is provided to treat high IOP glaucoma, including but not limited to primary open-angle glaucoma (POAG), primary angle-closure glaucoma, pediatric glaucoma, pseudoexfoliation 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 simple glaucoma). In an alternative embodiment, once-daily (QD) human dosing is used to treat acute high-pressure glaucoma resulting from developing cataracts. In a further alternative embodiment, once-daily (QD) human dosing is used to treat acute high-pressure glaucoma resulting from steroid-induced glaucoma, uveitic glaucoma, or post-intravitreal injection. One aspect of the present invention is the ability to treat glaucoma in humans with a once-daily dose using a controlled release formulation (e.g., gel or microparticle or nanoparticle formulation). In a typical embodiment, this is administered using a controlled release formulation in a simple formulation such as, for example, phosphate buffered saline or citrate buffer, optionally with an ophthalmic excipient including, but not limited to, mannitol or another osmotic agent.

[0142] Patient compliance and adherence are serious issues, and the fewer times a day medication is required, the more likely compliance will be achieved.Once-daily human sustained-release medication for glaucoma is advantageous in maintaining intraocular pressure in a desirable range to optimize compliance and adherence while minimizing optic nerve damage.The sustained-release cromakalim formulation of the compound of formula I, formula II, or formula III, or their pharma- ceutically acceptable salts, including levcromakalim, can be administered once a day in topical drops or other convenient manners at an effective dosage selected in certain embodiments.

[0143] Hyperemia In yet another embodiment, an ocular therapy is provided using a sustained release formulation of a compound of formula I, formula II, or formula III, or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim that does not result in significant redness. Redness is excess and / or visible blood in the blood vessels supplying an organ. Ocular redness, also called "red eye," can include or cause blood vessel congestion, excessive vasodilation, small hemorrhages, small pinpoint hemorrhages, and / or microhemorrhages. Ocular redness can have a variety of causes, including, but not limited to, exogenous irritants, contact lenses, inflammation, blood vessel disruption, conjunctivitis (including infectious or allergic), trauma, intrinsic ocular injury, subconjunctival hemorrhage, conjunctival hemorrhage, blepharitis, anterior uveitis, glaucoma, or irritating medications, and environmental irritants (i.e., sunlight and wind).

[0144] Certain ocular drugs either do not respond to or actually cause redness. According to the present invention, the use of a sustained release formulation of a compound of formula I, formula II, or formula III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, when used during therapy, in one embodiment, when used over the long-term therapy described herein, does not cause significant redness in the patient. Significant redness in one embodiment is redness that causes the patient sufficient discoloration or discomfort that the patient considers it an adverse effect of the treatment, which, if sufficiently significant, may lead to reduced compliance or even discontinuation of therapy. The present invention may provide an advancement in the art by aiding in patient compliance and comfort. In one embodiment, administration of a sustained release formulation of a compound of formula I, formula II, or formula III does not significantly induce the expression of at least one protein independently selected from CD31 and VE-cadherin.

[0145] In one embodiment, administration of a sustained release formulation of a compound of Formula I, Formula II, or Formula III does not significantly induce expression of at least one protein independently selected from endothelin, fibronectin, α-SMA, phospho-eNOS, and total eNOS.

[0146] Another aspect of the present invention is a sustained release treatment of glaucoma associated with Sturge-Weber syndrome, a congenital disorder that affects the skin, nervous system, and sometimes the eyes. Sturge-Weber syndrome is sometimes referred to as a neurocutaneous disorder. Sturge-Weber syndrome can cause Sturge-Weber syndrome-induced glaucoma, which affects 30% to 70% of patients who show ocular improvement. Management of Sturge-Weber syndrome-induced glaucoma can be complicated, and many patients require surgery or drainage devices. In accordance with the present invention, Sturge-Weber syndrome-induced glaucoma can be treated by administering a sustained release formulation of a compound of formula I, formula II, or formula III, or a pharma- ceutically acceptable salt thereof, optionally comprising an effective amount of levcromakalim in a pharma- ceutically acceptable carrier as described herein. The patient can continue long-term therapy under the care of a physician.

[0147] Hypoglycemia, hyperinsulinism, and diabetes Hypoglycemia is a condition caused by low glucose levels in the blood. Glucose is the main source of energy for the human body, and many symptoms occur when blood glucose levels are lower than the levels needed by the body to support its energy needs. For example, a patient's blood glucose level may fall to 3.9 mmol per liter or lower. Early symptoms of hypoglycemia include irregular heartbeat, fatigue, pale skin, trembling, anxiety, sweating, hunger, irritability, tingling around the mouth, and / or wheezing during sleep. As blood glucose levels fall further, these symptoms worsen to include confusion, visual impairment, seizures, and loss of consciousness. If blood glucose levels fall too low, death may occur.

[0148] Hypoglycemia can be caused by a disorder of the endocrine system in which blood glucose levels are not properly regulated by the body in an artificial manner. Treatment with sustained release formulations of the compounds of Formula I-III, including levcromakalim, or their pharma- ceutically acceptable salts, can help stabilize the endocrine system and thus reduce the onset or duration of hypoglycemia.

[0149] In one embodiment, the endocrine disorder causing hypoglycemia treated by the sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is hyperinsulinemia. Hyperinsulinemia occurs when the body has above-normal insulin levels in the blood, for example, above 175 pmol per liter when fasting or above 1600 pmol per liter after a meal. Since insulin breaks down glucose, too high levels can cause hypoglycemia and its symptoms.

[0150] Diabetes is a condition in which the body's blood sugar levels are too high. Diabetes is generally divided into two types. Type 1 diabetes is a form of autoimmune disease that occurs when a patient's immune system attacks and destroys the insulin-producing cells of the pancreas, leaving the patient with little or no natural insulin. In type 2 diabetes, the patient's cells become resistant to insulin and the pancreas cannot make enough insulin to overcome this resistance. Regardless of the type of diabetes, possible symptoms include increased thirst, frequent urination, extreme hunger, unexplained weight loss, the presence of ketones in the urine, fatigue, irritability, blurred vision, slow-healing sores, and frequent infections.

[0151] One aspect of the present invention is the ability to administer a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, to a patient in need thereof to treat diabetes. In one embodiment, the compound is used to treat type 1 diabetes. In another embodiment, the compound is used to treat type 2 diabetes.

[0152] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof is administered in an effective amount in a parenteral dosage form to treat hypoglycemia, hyperinsulinemia, or diabetes. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof is administered continuously throughout the day via infusion and pump. In an alternative embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof is administered via an oral dosage form such as a pill, tablet, or capsule. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof is administered at least once, twice, or three times a day.

[0153] In one embodiment, the sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, including levcromakalim, is selected from the group consisting of metformin, sulfonylureas (glyburide (DiaBeta, Glynase), glipizide (Glucotrol) and glimepiride (Amaryl)), meglitinides (repaglinide (Prandin) and nateglinide (Starlix)), DPP-4 inhibitors (sitagliptin (Januvia), saxagliptin (Onglyx)), and combinations thereof. za), and linagliptin (Tradjenta)), GLP-1 receptor agonists (Exenatide (Byetta, Bydureon), liraglutide (Victoza) and semaglutide (Ozempic)), SGLT2 inhibitors (canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance)), or in combination with or alternating with other medications for diabetes, including insulin.

[0154] Skeletal myopathies Skeletal myopathies (also known as myofibrillar myopathies) are disorders in which skeletal muscle fibers contain defects that lead to muscle weakness. For example, muscle fibers may have defects in sarcomeres, which are necessary for muscle contraction and are usually composed of rod-shaped structures called Z-bands. Z-bands connect adjacent sarcomeres to form myofibrils, the basic units of muscle fibers. Defective sarcomeres can form clumps within muscle fibers, greatly reducing their strength.

[0155] One aspect of the present invention is the ability to administer a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, to a patient in need thereof to treat skeletal myopathy. In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III is administered parenterally, orally, or topically to treat skeletal myopathy. In one embodiment, the sustained release formulation is administered intravenously. In one embodiment, the sustained release formulation is administered in combination with or alternating with other biological therapeutics, such as corticosteroids (prednisone), immunosuppressants (azathioprine, methotrexate, cyclosporine A, cyclophosphamide, mycophenolate mofetil, and tacrolimus), adrenocorticotropic hormones, or rituximab or tumor necrosis factor (TNF) inhibitors (infliximab or etanercept).

[0156] In one embodiment, the patient has a mutation in the desmin (DES) gene. In another embodiment, the patient has a mutation in the myotilin (MYOT) gene. In another embodiment, the patient has a mutation in the LIM domain binding 3 (LDB3) gene. In another embodiment, the patient does not have a mutation in DES, MYOT, or LDB3.

[0157] In one embodiment, the myopathy is acquired. Acquired myopathy may be further subclassified as inflammatory myopathy, toxic myopathy, and myopathy associated with a general condition. In one embodiment, the inflammatory myopathy is selected from polymyositis, dermatomyositis, and inclusion body myositis (IBM). Toxic myopathy is a drug-induced myopathy and is a side effect observed with the use of cholesterol-lowering drugs, HIV therapy drugs, antiviral therapy drugs, rheumatic drugs, and antifungal agents (Valiyil et al. Curr Rheumatol Rep. 2010, 12, 213). Thus, in one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat drug-induced toxic myopathy. Non-limiting examples of drugs that induce toxic myopathy include steroids, cholesterol-lowering drugs (e.g., statins, fibrates, niacin, and ezetimibe), propofol, amiodarone, colchicine, chloroquine, antiviral drugs and protease inhibitors, omeprazole, and tryptophan.

[0158] In an alternative embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat a myopathy associated with a systemic condition. Non-limiting examples of systemic diseases include endocrine disorders, systemic inflammatory diseases, electrolyte imbalances, critical illness myopathies, and amyloid myopathies.

[0159] In one embodiment, the myopathy is hereditary. Hereditary myopathy may be further subclassified as muscular dystrophies, congenital myopathies, mitochondrial myopathies, and metabolic myopathies. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat muscular dystrophies, including dystrophinopathies (Duchenne muscular dystrophy), myotonic dystrophy type 1 and myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, or limb-girdle muscular dystrophy. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat congenital myopathies, including nemaline myopathy or central core myopathy. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat metabolic myopathies, including acid maltase deficiency or acid alpha-1,4-glucosidase deficiency (Pompe disease), glycogen storage diseases types 3-11, carnitine deficiency, fatty acid oxidation disorders, or carnitine palmitoyltransferase deficiency. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat mitochondrial myopathy, including Kearns-Sayre syndrome (KSS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited deafness and diabetes mellitus (MIDD), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), or Pearson syndrome.

[0160] Erectile dysfunction and female sexual arousal disorder due to blood flow Erectile dysfunction is a disorder characterized by persistent difficulty in achieving and / or maintaining an erection. Erectile dysfunction can be caused by a variety of factors, including psychological, emotional, and physical problems. One aspect of the present invention is to administer a sustained release formulation of a compound of formula I-III or a pharmaceutically acceptable salt thereof, comprising an effective amount of levcromakalim, to a patient in need thereof to treat erectile dysfunction. In one embodiment, a patient with erectile dysfunction has low blood flow to the pubic area. Thus, in one aspect, the sustained release formulation of a compound of formula I-III or a pharmaceutically acceptable salt thereof, comprising levcromakalim or a pharmaceutically acceptable salt thereof, increases blood flow to the pubic area.

[0161] Female sexual arousal disorder is a disorder characterized by persistent difficulty in becoming and / or maintaining sexual arousal. Female sexual arousal disorder can be caused by a variety of factors, including psychological, emotional, and physical problems. One aspect of the present invention is the ability to administer an effective amount of a sustained release formulation of a compound of formula I-III or a pharmaceutically acceptable salt thereof, including levcromakalim, to a patient in need thereof to treat female sexual arousal disorder. In one embodiment, patients with female sexual arousal disorder have low blood flow to the pubic area. Thus, in one embodiment, a sustained release formulation of a compound of formula I-III or a pharmaceutically acceptable salt thereof, including levcromakalim, increases blood flow to the pubic area.

[0162] In one embodiment, the sustained release formulation of the compound of formula I-III is orally administered in an effective amount required to treat erectile dysfunction or female sexual arousal disorder. In one embodiment, the sustained release formulation can be administered topically in an effective amount as a cream, gel, or ointment to be used as needed to treat erectile dysfunction or female sexual arousal disorder. In certain embodiments, the sustained release formulation of the compound of formula I-III, such as cromakalim, is formulated as the active agent in a lubricant for the treatment of erectile dysfunction and / or female sexual arousal disorder.

[0163] In certain embodiments, the sustained release formulations of the compounds of Formula I-III or pharma- ceutically acceptable salts thereof, including levcromakalim, are administered in an effective amount in combination with or alternation with one or more additional treatments for erectile dysfunction, including, but not limited to, a phosphodiesterase inhibitor (e.g., sildenafil, sildenafil citrate, vardenafil, vardenafil HCl, tadalafil, avanafil), testosterone therapy, penile injections (e.g., ICI or intracavernosal alprostadil), intraurethral agents (e.g., IU or alprostadil), penile implants, combinations of therapeutic agents (e.g., bimix or trimix), or surgery.

[0164] In certain embodiments, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, such as cromakalim, is administered in combination with one or more additional treatments for female sexual arousal disorder, including, but not limited to, estrogen therapy, an estrogen receptor modulator (e.g., ospemifene), androgen therapy, an antidepressant (e.g., flibanserin), or a melanocortin agonist (e.g., bremelanotide).

[0165] Hypotrichosis and baldness Eyebrow and eyelash hypotrichosis is a disorder in which there is little to no hair growth or insufficient amount of hair in the eyebrows and / or eyelashes at the edge of the eyelids.

[0166] One aspect of the present invention is the ability to administer a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, to a patient in need thereof to treat hypotrichosis. In one embodiment, the patient has a genetic mutation that causes hypotrichosis. In another embodiment, the patient does not have a genetic mutation that causes hypotrichosis.

[0167] In one embodiment, the sustained release formulation of the compound of Formula I-III is administered as a topical dosage form applied to the upper eyelid margin at the base of the eyelashes. In one embodiment, the sustained release formulation of the compound of Formula I-III is administered at least once daily or twice daily.

[0168] In certain embodiments, the compounds of the invention are provided in effective amounts in combination or alternation with a prostaglandin analog (eg, bimatoprost).

[0169] Baldness is most typically hair loss or lack of hair on the scalp. Common types of baldness include male or female pattern baldness, alopecia areata, telogen effluvium (hair loss after stressful situations), and anagen effluvium (abnormal hair loss in the first stage of the hair growth cycle). In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to a patient in need thereof to treat baldness. In one embodiment, the baldness is male or female pattern baldness. In one embodiment, the baldness is alopecia areata. In one embodiment, the baldness is telogen effluvium. In one embodiment, the baldness is anagen effluvium.

[0170] Neuropathic pain and neurodegenerative diseases (e.g., Parkinson's disease and Huntington's disease) Neuropathic pain is a disorder that nerve damage or nervous system dysfunction causes electric or burning pain.Neuropathic pain can be acute or chronic, and can be caused by various factors, including alcoholism, amputation, chemotherapy, diabetes, facial nerve problems, AIDS, multiple myeloma, multiple sclerosis, nerve or spinal cord compression, herniated disk, arthritis, shingles, spinal surgery, syphilis, or thyroid problems.Patients with neuropathic pain may experience electric and burning pain, or tingling or numbness.

[0171] One aspect of the present invention is the ability to administer a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, to a patient in need thereof to treat neuropathic pain.

[0172] In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof is administered orally, enterally, or parenterally to treat neuropathic pain. The sustained release formulation may be administered once, twice, or three times daily as directed by a health care provider for as long as necessary.

[0173] In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt thereof is used in combination or alternation with a calcium channel alpha2 delta ligand (e.g., pregabalin or gabapentin), a tricyclic antidepressant (e.g., amitriptyline, nortriptyline, or desipramine), an SNRI antidepressant (e.g., duloxetine or venlafaxine), or an opioid (e.g., tramadol or tapentadol) to treat neuropathic pain.

[0174] Neurodegenerative diseases cause or result from the degeneration of the patient's nerves. The cellular processes include neuroinflammatory responses that involve activation of glial cells, including microglia and astrocytes. Neurodegenerative diseases may cause patients to have difficulty balancing, moving, speaking, breathing, or remembering. Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0175] One aspect of the present invention is to administer an effective amount of a sustained release formulation of a compound of the present invention, such as cromakalim or a pharma- ceutically acceptable salt thereof, to a patient in need thereof to treat a neurodegenerative disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In another embodiment, the neurodegenerative disease is Huntington's disease. In an alternative embodiment, the neurodegenerative disease is Alzheimer's disease.

[0176] Therapies for neurodegenerative diseases include combination or alternating therapy with an effective amount of the compounds disclosed herein. Drugs for Parkinson's disease include amantadine, nilotinib, zonisamide, selegiline, methylphenidate, and salbutamol. Drugs for Huntington's disease include tetrabenazine, tiapride, clozapine, olanzapine, risperidone, quetiapine, and memantine. Drugs for amyotrophic lateral sclerosis (ALS) include mastinibe, dolutegravir, abacavir, lamivudine, retigabine, and tamoxifen. Drugs for Lewy body disease include donepezil, galantamine, and rivastigmine. Drugs for spinal muscular atrophy include nusinersen and onasemnogene abeparvovec.

[0177] Neuroprotective drugs are often administered to prevent damage to the brain and / or spinal cord after ischemia, stroke, convulsion, or trauma. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof containing an effective amount of levcromakalim is administered as a neuroprotective drug. In one embodiment, the sustained release compound is administered after ischemia, stroke, convulsion, or trauma. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof containing an effective amount of levcromakalim is administered as a cytoprotective drug.

[0178] Tumor hypoperfusion and hypoxia In one aspect, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to a patient to treat tumor hypoperfusion or tumor hypoxia. Tumor hypoperfusion refers to reduced blood flow within a tumor. Tumor hypoxia refers to reduced oxygen levels within tumor cells. There may be overlap between the two.

[0179] When a tumor is in a state of hypoperfusion, perhaps because the tumor is growing rapidly, it does not have sufficient blood flow to allow tumor therapeutics to reach the tumor cells. This can lead to resistance to treatment with chemotherapy drugs. In one embodiment, a sustained release formulation of a compound of Formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof is administered to a patient with tumor hypoperfusion, thus making the tumor more easily treatable with antitumor drugs, such as chemotherapy drugs.

[0180] In another embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered to a patient with hypoperfusion of non-tumor tissue, for example as a result of trauma.

[0181] When a tumor is hypoxic, the tumor is hypoxic because of lack of oxygen in cells. Tumors that are hypoxic may be more likely to exhibit metastatic behavior. Thus, in one embodiment, an effective amount of a sustained release formulation of a compound of formula I-III or a pharmaceutically acceptable salt thereof, including levcromakalim, is administered to a patient to treat tumor hypoxia, optionally in combination or alternation with a chemotherapeutic agent or other antitumor therapeutic agent.

[0182] In another embodiment, an effective amount of a sustained release formulation of a compound of the invention, or a pharma- ceutically acceptable salt thereof, optionally in combination with a vascular endothelial growth factor (VEFG) therapeutic, is administered to treat hypoxia or hypoperfusion.

[0183] In an alternative embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof is used in combination or alternation with oxygen therapy (e.g., an oxygen mask or a small tube placed under the nose to give oxygen) or an asthma medication (e.g., fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, montelukast, zafirlukast, zileuton, salmeterol, formoterol, vilanterol, albuterol, levalbuterol, prednisone, methylprednisone, omalizumab, mepolizumab, benralizumab, or reslizumab).

[0184] Selected cardiovascular disorders Unstable angina is a condition in which the heart does not receive enough blood and oxygen due to narrowing of the coronary arteries, causing unexpected chest pain and discomfort. The most common cause of this condition is atherosclerotic coronary artery disease. Angina can be treated with angioplasty and stent placement, or enhanced external counterpulsation. Several medications may improve symptoms, including aspirin, nitrates, beta-blockers, statins, and calcium channel blockers. Many of these drugs have undesirable side effects. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic acceptable salt thereof containing an effective amount of levcromakalim is administered to a patient with unstable angina and associated chest pain.

[0185] In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, such as cromakalim, is administered in combination with angioplasty, stent placement, and / or enhanced external counterpulsation. In another embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, such as cromakalim, is administered in combination or alternation with aspirin, a nitrate, a beta-blocker, a statin, or a calcium channel blocker.

[0186] Congestive heart failure (CHF) is a chronic, progressive condition in which the ventricles of the heart are unable to pump an adequate blood volume to the rest of the body. The most typical form of CHF is left-sided CHF, in which the left ventricle does not pump blood properly, which often progresses to the right side. The four stages of CHF are indicative of the severity of the disease and further determine the various treatment options. If left untreated, blood and other fluids may accumulate in the lungs, abdomen, liver, and lower body, which can be life-threatening. Medications for CHF include ACE inhibitors, beta-blockers, and diuretics. Each of these medications has associated side effects. For example, ACE inhibitors may increase potassium levels in the blood, which may not be tolerated by some patients. Thus, in one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to a patient with CHF. Heart failure may be stage 1, stage 2, stage 3, or stage 4.

[0187] Chronic or acute myocardial ischemia is when blood flow cannot reach the heart, preventing it from receiving enough oxygen. Myocardial ischemia can be caused by atherosclerosis, blood clots, or coronary artery spasm. Myocardial ischemia can cause serious abnormal heartbeats and even lead to heart attacks. Current treatments for myocardial ischemia can include administration of aspirin, nitrates, beta-blockers, ACE inhibitors, or cholesterol-lowering drugs, each of which has varying degrees of side effects and efficacy. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to a patient with chronic or acute myocardial ischemia.

[0188] Microvascular dysfunction (or coronary microvascular disease) is a type of non-obstructive coronary artery disease that causes the small blood vessels that supply the heart muscle to fail. Patients with microvascular dysfunction do not have plaque buildup in their coronary blood vessels, but have damage to the inner walls of the blood vessels, which can cause spasms and reduce blood flow to the heart muscle. In an alternative embodiment of the present invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is provided in an amount effective for treating microvascular dysfunction.

[0189] Coronary artery disease is the buildup of plaque in the walls of the coronary arteries, the blood vessels that supply blood to the heart. This plaque narrows the arteries, slowing blood flow, and if a piece of plaque breaks off and clogs the artery, this can completely block blood flow. Blockage of blood flow to the heart by plaque and / or a blood clot is called acute myocardial infarction, which is often called a heart attack. Symptoms vary but often include a feeling of pressure or tightness in the chest and arms, shortness of breath, and / or sudden dizziness. Emergency medical assistance is typically required. The patient may be given one or a variety of medications, including aspirin, thrombolytics, antiplatelet drugs, blood-thinning drugs, nitroglycerin, beta-blockers, ACE inhibitors, or statins. Possible surgical procedures include angioplasty or bypass surgery. Cardiac rehabilitation is required after a heart attack, including drug therapy to prevent new heart attacks and subsequent complications.

[0190] Given the life-threatening nature of a heart attack, it is advantageous to have many potential therapeutic agents as possible treatment options. Thus, in one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to a patient experiencing a heart attack and / or as a therapeutic agent in cardiac rehabilitation. The drug is administered for a period determined by a health care provider, including but not limited to at least two weeks, one month, two months, three months, or more. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt containing levcromakalim acts as a cardioprotectant during a heart attack. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is used as a cardioprotectant in a host undergoing cardiac surgery. In one embodiment, the host is undergoing an ablation procedure. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat left ventricular failure following acute myocardial infarction (AMI) or a heart attack. In an alternative embodiment of the invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat coronary artery disease.

[0191] In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt thereof, such as cromakalim, is administered in combination or alternation with an ACE inhibitor, a beta blocker, aspirin, a nitrate, a cholesterol-lowering drug, a statin, or a diuretic.

[0192] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt comprising levcromakalim is provided in an amount effective for cardiac preservation prior to organ donation.

[0193] Arrhythmia is an inappropriate (too fast, too slow, or irregular) beating of the heart, which can be caused by a variety of medical conditions including coronary artery disease, high blood pressure, electrolyte imbalance, or damage from a heart attack. Arrhythmia is very common, affecting 3 million people in the United States each year. While the majority of arrhythmias may be harmless, very abnormal arrhythmias can cause serious or fatal symptoms. Left untreated, arrhythmias can affect the heart, brain, and other organs because not enough blood can reach the organs. Implantable devices for the treatment of arrhythmias include pacemakers or implantable cardioverter defibrillators (ICDs). In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic acceptable salt, including levcromakalim, is administered to a patient with arrhythmia. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic acceptable salt, including levcromakalim, is provided in an amount effective to treat or prevent arrhythmias and / or ventricular fibrillation associated with AMI in a host in need of such treatment or prevention.

[0194] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt, such as cromakalim, is administered in combination with a pacemaker or ICD.

[0195] The endothelial layer is a layer of cells that lines all blood vessels and is responsible for the proper expansion and contraction of blood vessels. Endothelial tone is the balance between contraction and expansion, which primarily determines the body's blood pressure. Endothelial dysfunction is the failure of the endothelial layer to regulate expansion / contraction. Endothelial dysfunction is a well-established response to cardiovascular risk factors and often precedes the development of atherosclerosis. Therapeutic agents include ACE inhibitors and statin drugs, although additional drugs are under investigation. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharmacologic acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to a patient with endothelial dysfunction.

[0196] A transient ischemic attack (TIA) is similar to a stroke, but lasts only a few minutes and leaves no permanent damage. Like a stroke, a blood clot in the blood supply travels to the brain. Signs of a TIA include weakness, numbness, paralysis, slurred speech, dizziness, blindness, and / or sudden, severe headache. After a TIA is diagnosed, it is important to try to prevent a new TIA or stroke. Typical medications include antiplatelet drugs, anticoagulants, and thrombolytic agents. Alternatively, angioplasty is often recommended. Antiplatelet drugs and anticoagulants should be taken with caution as they increase the risk of bleeding. Thus, vasodilators are an alternative medication for TIA. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutical acceptable salt containing an effective amount of levcromakalim is administered to a patient diagnosed with a transient ischemic attack.

[0197] Carotid artery disease is the buildup of plaque in the carotid arteries, which run along both sides of the neck and supply blood to the brain, face, and neck. When a portion of the plaque breaks off and causes a clot in the blood vessel leading to the brain, the clot can cause a stroke. In an alternative embodiment of the present invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt containing an effective amount of levcromakalim is administered to a patient diagnosed with a stroke.

[0198] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt, such as cromakalim, is administered in combination or alternation with an antiplatelet agent, an anticoagulant, or a thrombolytic agent.

[0199] Hypertension is a condition in which the force of blood flowing through blood vessels is consistently high. This can often lead to many conditions, including cardiac conditions and strokes, as discussed herein. In an alternative embodiment of the present invention, a sustained release formulation of a compound of formula I-III or a pharmacologic acceptable salt containing an effective amount of levcromakalim is administered to a patient with hypertension as a therapeutic agent for lowering blood pressure.

[0200] Vascular disorders Raynaud's disease is a rare disorder of blood vessels that causes the fingers and toes to go numb in response to cold or stress. This may induce discoloration of the fingers and toes (usually white, then blue) accompanied by a feeling of numbness. This is caused by the arteries of the fingers and toes undergoing vasospasm when exposed to cold or stress, which subsequently narrows the blood vessels and temporarily restricts the blood supply. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to a patient to treat Raynaud's disease. This may be by topical, enteral, or parenteral delivery.

[0201] Peripheral arterial disease (PAD) is a disease in which plaque builds up in the arteries that carry blood to the limbs, heart, and other organs. This narrows the arteries, reducing blood flow from the heart. PAD can cause embolism or thrombosis, which can lead to acute hand-foot disease. Acute hand-foot disease is treatable, but if left untreated (delay of 6 to 12 hours), can lead to amputation and / or death. Symptoms include pain, pallor, and / or paralysis. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat acute lower limb ischemia.

[0202] Chronic limb ischemia is a type of progressive PAD that develops over time and includes muscle pain, patellofemoral pain, and eventual tissue loss due to poor perfusion and hypoxia.Chronic limb ischemia is associated with diabetes, smoking, and hypertension.In one embodiment, an effective amount of a sustained release formulation of a compound of formula I-III or a pharma-ceutical acceptable salt containing levcromakalim is administered to treat chronic limb ischemia.

[0203] Thrombophlebitis is when blood clots form in the veins, slowing the flow of blood through the veins. Thrombophlebitis most often affects the legs, but can also occur in the arms or other veins in the body. Thrombophlebitis can occur just under the skin or deeper in the legs or arms. Types of thrombophlebitis include superficial phlebitis or superficial thrombophlebitis, which occurs just under the surface of the skin, deep vein thrombosis (DVT), which occurs deep in the body, and migratory thrombophlebitis (Trousseau syndrome or migratory thrombophlebitis), when the clot travels back to a different part of the body. In an alternative embodiment of the invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat thrombophlebitis. In one embodiment, the thrombophlebitis is superficial thrombophlebitis. In one embodiment, the thrombophlebitis is deep vein thrombosis. In one embodiment, the thrombophlebitis is migratory thrombophlebitis.

[0204] Chronic venous insufficiency (CVI) is a condition that occurs when the venous walls and / or valves in the veins of the legs do not function effectively, making it difficult for blood to return from the legs to the heart. CVI causes blood to "pool" or collect in these veins, and this pooling is called congestion. If CVI is not treated, pressure and swelling will increase until the smallest blood vessels (capillaries) in the legs burst. When this happens, the overlying skin will become reddish-brownish and very fragile when bumped or scratched. In an alternative embodiment of the present invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat chronic venous insufficiency.

[0205] Pulmonary arterial hypertension (PAH) is a rare disease that usually appears in young adulthood, primarily in women. PAH is a progressive disorder of the pulmonary arteries leading to the lungs and is fatal despite currently available therapies. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to a patient to treat pulmonary arterial hypertension. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt is administered in combination with a PDE-5 inhibitor (e.g., sildenafil or tadalafil), a prostanoid vasodilator (e.g., epoprostenol, treprostinil, or iloprost), a guanylate cyclase stimulator (e.g., riociguat), or an endothelin receptor antagonist (e.g., bosentan, ambrisentan, or macitentan).

[0206] Aspects of the invention include administering the drugs described herein in combination or alternation with a calcium channel blocker (e.g., nifedipine, afeditab, procardia, amlodipine, felodipine, bepridil, diltiazem, nicardipine, nisoldipine, verapamil, and isradipine) or another vasodilator (e.g., hydralazine, nitroglycerin, alprostadil, riociguat, nesiritide, nitroprusside, sildenafil, and minoxidil).

[0207] Lymphatic disorders The lymphatic system helps remove toxins and waste from the body, and its main function is to carry lymph, a fluid that contains white blood cells, throughout the body and fight infections. The system is primarily made up of lymphatic vessels connected to lymph nodes, which filter the lymph. ATP The channel is expressed by lymphatic muscle cells and expresses a specific K ATP Studies have shown that channel openers dilate lymphatic vessels.

[0208] For example, as discussed in a recent study by Garner et al. ("KATP Channel Openers Inhibit Lymphatic Contractions and Lymph Flow as a Possible Mechanism of Peripheral Edema", Journal of Pharmacology and Experimental Therapeutics, October 25, 2020), rhythmic contractions of isolated rat mesenteric lymphatic vessels were induced by KATP channel openers such as cromakalim, minoxidil sulfate, and diazoxide. ATP This gradually abates with exposure to channel openers. Increasing concentrations of cromakalim attenuated the frequency and amplitude of contractions, eventually eliminating vascular constriction and compromising flow through the vessels. Similar effects were observed with minoxidil sulfate and diazoxide when administered at clinically relevant concentrations.

[0209] Inflammation of lymphatic vessels is known as lymphangitis, and symptoms typically include swelling, redness, and / or pain at the site of infection. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt comprising an effective amount of levcromakalim is administered to treat lymphangitis.

[0210] Lymph nodes may also be infected with viruses, bacteria, and / or fungi, which is called lymphadenitis. Symptoms of lymphadenitis also include redness or swelling around the lymph node. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat lymphangitis, in one embodiment, the sustained release formulation of a compound of Formula I-III is administered in combination with an antibiotic or antifungal agent.

[0211] A common cancer of the lymphatic system is Hodgkin's lymphoma, a cancer that originates from white blood cells called lymphocytes. This cancer can occur in any part of the body, and symptoms include painless enlargement of lymph nodes in the neck, armpits, or groin. There are two major types of Hodgkin's lymphoma: classical Hodgkin's lymphoma and nodal lymphocyte-predominant Hodgkin's lymphoma. Treatments for Hodgkin's lymphoma include chemotherapy and / or radiation, the most common treatment being the monoclonal antibody rituximab (Rituxan). In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered in combination with chemotherapy and / or radiation to treat Hodgkin's lymphoma. In one embodiment, the chemotherapy agent is rituximab.

[0212] Non-Hodgkin's lymphoma occurs when the body produces too many abnormal white blood cells called lymphocytes, which lead to tumors. A common subtype of non-Hodgkin's lymphoma is B-cell non-Hodgkin's lymphoma. Symptoms include swollen lymph nodes, fever, and / or chest pain. Non-Hodgkin's lymphoma is treated with chemotherapy and / or radiation. A common treatment is a regimen known as R-CHOP, which consists of the monoclonal antibody Rituximab (Rituxan) in addition to cyclophosphamide, doxorubicin, vincristine, and prednisone. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered in combination with chemotherapy and / or radiation to treat non-Hodgkin's lymphoma. In one embodiment, the chemotherapy consists of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab.

[0213] Castleman disease is a group of lymphoproliferative disorders characterized by lymphadenopathy and has at least three distinct subtypes: monocentric Castleman disease (UCD), human herpesvirus 8-associated multicentric Castleman disease (HHV-8-associated MCD), and idiopathic multicentric Castleman disease (iMCD). In UCD, a single area of ​​lymph node enlargement is seen, whereas in iMCD, multiple areas of lymph node enlargement are seen. HHV-8-associated MCD is similar to iMCD in that multiple areas of lymph node enlargement are seen, but the patient is also infected with human herpesvirus 8.

[0214] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat Castleman's disease, including monocentric Castleman's disease (UCD), human herpesvirus 8-associated multicentric Castleman's disease (HHV-8-associated MCD), and idiopathic multicentric Castleman's disease (iMCD).

[0215] Lymphangiomatosis is a disease in which cysts and / or lesions form from lymphatic vessels. The masses are widespread rather than present as a single localized mass. Lymphangiomatosis is a multisystem disorder in which abnormally proliferating lymphatic channels enlarge and infiltrate surrounding tissues, bones, and organs. Lymphangiomatosis is a rare disease that is most prevalent in children and teenagers. There is no standard treatment, and in many cases, treatment is aimed only at alleviating symptoms. In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharmaceutically acceptable salt thereof is administered to treat or alleviate symptoms associated with lymphangiomatosis.

[0216] Lymphangiectasia, also known as "lymphangiectasia", is a pathological dilation of lymphatic vessels. When lymphangiectasia occurs in the intestine, it causes a disease known as "intestinal lymphangiectasia", characterized by dilation of lymphatic vessels, chronic diarrhea, and loss of proteins such as serum albumin and globulin. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat or alleviate symptoms associated with lymphangiectasia.

[0217] The eye is unique in that certain parts of the eye are rich in lymphatic vessels, whereas other parts of the eye are devoid of lymphatic vessels. Parts of the eye, including the eyelid, lacrimal gland, conjunctiva, limbus, optic nerve sheath, extraocular muscles, and connective tissue of the extraocular cone, are rich in lymphatic vessels, whereas the cornea and retina are devoid of lymphatic vessels. Many lymphatic disorders have been identified in the eye. Ocular lymphatic disorders include, but are not limited to, conjunctival myxoma, dry eye, conjunctival lymphangiectasia, conjunctival edema, mustard gas keratitis, corneal inflammation, orbital cellulitis, chalazion, cutis laxa, and blepharochalasis. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat ocular lymphatic disorders. In one embodiment, the ocular lymphatic disorder is selected from conjunctival myxoma, dry eye, conjunctival lymphangiectasia, chemosis, mustard gas keratitis, corneal inflammation, orbital cellulitis, chalazion, cutis laxa, and blepharochalasis.

[0218] There is also evidence that lymphatic vessels, rather than neovasculature, are important in immune rejection after corneal transplantation (T. Dietrich et al., Journal of Immunology, 2010, 184, 2, 535-539). Thus, in one embodiment, sustained release formulations of compounds of Formula I-III, including levcromakalim, or pharma- ceutically acceptable salts thereof, are administered after corneal transplantation to reduce the risk of immune rejection.

[0219] Mitochondrial disorders Mitochondrial diseases are long-term, hereditary disorders that are often inherited. They are a clinically heterogeneous group of disorders resulting from dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism, and tissues and organs highly dependent on aerobic metabolism are preferentially affected by mitochondrial disorders. Although some mitochondrial disorders affect only a single organ, many affect multiple organ systems and often present with prominent neurological and myopathic features. Mitochondria contain potassium-specific channels sensitive to ATP (mitoKATP channels). Mitochondrial KATP channels play a key role in controlling mitochondrial mass and regulating components of the proton motive force.

[0220] Mitochondria are unique in that they have their own DNA, called mitochondrial DNA or mtDNA. Mutations in this mtDNA or nuclear DNA (DNA found in the nucleus of cells) can cause mitochondrial disorders. Environmental toxins can also cause mitochondrial disease. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat mitochondrial disorders.

[0221] Inside the mitochondria are a group of proteins (complex I-IV) that transport electrons along four chain reactions leading to energy production. This chain is known as the electron transport chain. The fifth group (complex V) produces large amounts of ATP. Together, the electron transport chain and ATP synthase form the respiratory chain, a process known as oxidative phosphorylation or OXPHOS. The first step in this chain, complex I, is the most common site for mitochondrial disorders, accounting for as much as one-third of all respiratory chain deficiencies. Complex I deficiency, which often appears at birth or in childhood, is usually a progressive neurodegenerative disorder that contributes to a variety of clinical symptoms, especially in organs and tissues that require high energy levels, such as the brain, heart, liver, and skeletal muscles. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof, containing an effective amount of levcromakalim, is administered to treat complex I deficiency.

[0222] A number of specific mitochondrial disorders are associated with complex I deficiencies, 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.

[0223] Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) is a progressive neurodegenerative disease that typically begins between the ages of 2 and 15, but may occur in infancy or adulthood. Early symptoms may include stroke-like episodes, seizures, migraines, and recurrent vomiting. Stroke-like episodes, often accompanied by seizures, are the hallmark symptoms of MELAS, causing partial paralysis, vision loss, and focal neurological deficits. The gradual cumulative effect of these episodes often results in various combinations of motor loss (speech, movement, and feeding), sensory impairment (vision loss and loss of bodily sensations), and mental impairment (dementia). MELAS patients may also suffer from additional symptoms, including muscle weakness, peripheral nerve dysfunction, diabetes, hearing loss, cardiac and renal problems, and gastrointestinal abnormalities. Lactic acid typically accumulates at high levels in the blood, cerebrospinal fluid, or both. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat mitochondrial encephalomyopathy-lactic acidosis-stroke-like episodes (MELAS).

[0224] Myoclonic epilepsy with ragged-red fibers (MERRF) is a multisystem disorder characterized by myoclonus, often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia. Symptoms usually first appear during childhood or adolescence after normal early development. In more than 80% of cases, MERRF is caused by a mutation in a mitochondrial gene called MT-TK. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof containing an effective amount of levcromakalim is administered to treat myoclonic epilepsy with ragged-red fibers (MERRF).

[0225] Leigh syndrome is a rare genetic neurodegenerative condition. Leigh syndrome usually appears in infancy, often after a viral infection, and symptoms usually progress rapidly. Early symptoms may include poor sucking ability, loss of head control and motor skills, loss of appetite, vomiting, and seizures. As the condition progresses, symptoms may include weakness and lack of muscle tone, spasticity, movement disorders, cerebellar ataxia, and peripheral neuropathy. Leigh syndrome may be caused by mutations in either mitochondrial DNA or nuclear DNA. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutical acceptable salt thereof containing an effective amount of levcromakalim is administered to treat Leigh syndrome.

[0226] Complex II deficiency, which can range from severe life-threatening symptoms in infancy to muscle disease beginning in adulthood, can be caused by mutations in the SDHA, SDHB, SDHD, or SDHAF1 genes. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat Complex II deficiency.

[0227] Complex III deficiency is a severe multisystem disorder characterized by lactic acidosis, hypotonia, hypoglycemia, poor growth, encephalopathy, and delayed psychomotor development. Visceral involvement, including liver disease and renal tubulopathy, may also occur. It is generally caused by mutations in the BCS1L, UQCRB, and UQCRQ genes in nuclear DNA and is inherited in an autosomal recessive manner. However, complex III deficiency may also be caused by mutations in the MTCYB gene in mitochondrial DNA, either maternally transmitted or sporadically occurring, resulting in a milder form of the condition. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharmacologic acceptable salt thereof containing an effective amount of levcromakalim is administered to treat complex III deficiency.

[0228] Complex IV deficiency, also known as cytochrome C oxidase deficiency (COX deficiency), is a condition that can affect several parts of the body, including skeletal muscle, heart, brain, and liver. There are four types of COX deficiency, differentiated by symptoms and age of onset: benign infantile mitochondrial type, French-Canadian type, infantile mitochondrial myopathy, and Leigh syndrome. Complex IV deficiency is caused by mutations in any of at least 14 genes, with inheritance patterns depending on the gene involved. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat complex IV deficiency.

[0229] There are many other types of mitochondrial diseases. For example, dominant optic atrophy (DOA) is a hereditary optic neuropathy characterized by degeneration of the optic nerve that typically begins in the first decade of life. Affected individuals usually develop moderate vision loss and color vision defects. Severity varies, and vision can range from normal to legally blind. Autosomal dominant optic atrophy plus syndrome (ADOA plus) is a rare syndrome that causes vision loss, hearing loss, and symptoms that affect muscles. This syndrome is associated with optic nerve atrophy. Other symptoms of ADOA plus include sensorineural hearing loss and symptoms that affect muscles, such as muscle pain and weakness. ADOA plus is caused by a mutation in the OPA1 gene. Both DOA and ADOA are inherited in an autosomal dominant manner. In certain embodiments, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat dominant optic atrophy (DOA) or autosomal dominant optic atrophy plus syndrome (ADOA plus).

[0230] Alpers syndrome is a progressive neurological disorder that begins during childhood and is often complicated by severe liver disease. Symptoms include increased muscle tone accompanied by hyperreflexia (spasticity), seizures, and dementia. Most often, Alpers syndrome is caused by a mutation in the POLG gene. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat Alpers syndrome.

[0231] Barth syndrome is a metabolic and neuromuscular disorder that occurs almost exclusively in males, primarily affecting the heart, immune system, muscles, and growth. Barth syndrome will typically manifest during infancy or early childhood. The main hallmarks of the condition include abnormalities of the heart and skeletal muscles (cardiomyopathy and skeletal myopathy), low levels of certain white blood cells called neutrophils that help fight bacterial infections (neutropenia), and growth retardation that can lead to short stature. Other signs and symptoms can include elevated levels of certain organic acids (such as 3-methylglutaconic acid) in urine and blood, and increased thickness of the left ventricle of the heart due to endocardial fibroelastosis, which can lead to heart failure. Barth syndrome is caused by a mutation in the TAZ gene and is inherited in an X-linked recessive manner. In one embodiment, an extended release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to treat Barth syndrome.

[0232] Mitochondrial fatty acid beta-oxidation disorders (FAOD) are a heterogeneous group of abnormalities in fatty acid transport and mitochondrial beta-oxidation. They are inherited as autosomal recessive disorders and have a wide range of clinical manifestations. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat mitochondrial fatty acid beta-oxidation disorders (FAOD). FAOD includes CPT I deficiency, CACT deficiency, CPT II deficiency, LCAD deficiency, LCHAD deficiency, VLCAD deficiency, MCAD deficiency, SCHAD deficiency, and SCAD deficiency.

[0233] Primary carnitine deficiency is a genetic condition that prevents the body from using certain fats for energy, especially during fasting periods. The nature and severity of signs and symptoms vary, but they most often appear in infancy or early childhood and may include severe brain dysfunction (encephalopathy), cardiomyopathy, confusion, vomiting, muscle weakness, and hypoglycemia. This condition is caused by a mutation in the SLC22A5 gene and is inherited in an autosomal recessive manner. In one embodiment, a sustained release formulation of the compound of formula I-III or a pharmacologic acceptable salt thereof containing an effective amount of levcromakalim is administered to treat primary carnitine deficiency.

[0234] Guanidinoacetate methyltransferase deficiency is a genetic disease that affects the brain and muscles. Patients with this disease may begin to show symptoms in early childhood by age 3. Signs and symptoms vary but may include mild to severe intellectual disability, recurrent seizures, speech disorders, and involuntary movements. GAMT deficiency is caused by a mutation in the GAMT gene. The disease is inherited in an autosomal recessive manner. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat guanidinoacetate methyltransferase deficiency.

[0235] Primary coenzyme Q10 deficiency involves a lack of coenzyme Q10 and can affect many parts of the body, especially the brain, muscles, and kidneys.The mildest cases of primary coenzyme Q10 deficiency begin in a person's 60s and often cause cerebellar ataxia, which refers to impaired coordination and balance due to defects in the cerebellum.In one embodiment, a sustained release formulation of the compound of formula I-III or a pharmacologic acceptable salt thereof containing an effective amount of levcromakalim is administered to treat primary coenzyme Q10 deficiency.

[0236] Chronic progressive external ophthalmoplegia (CPEO) is a condition primarily characterized by loss of muscle function 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 eyes (ophthalmoplegia) and drooping of the eyelids (ptosis). Some affected individuals also have myopathy, which can be especially noticeable during movement. CPEO can be caused by mutations in any of several genes that can be located in mitochondrial DNA or nuclear DNA. CPEO can occur as part of the ataxic neuropathy spectrum and other underlying conditions such as Kearns-Sayre syndrome (KSS). KSS is a slowly progressive, multisystem mitochondrial disorder that often begins with ptosis. Eventually other eye muscles become affected, causing paralysis of eye movements. Degeneration of the retina usually causes difficulty seeing in dim light. In certain embodiments, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat chronic progressive external ophthalmoplegia or Kearns-Sayre syndrome.

[0237] Congenital lactic acidosis (CLA) is caused by a mutation in mitochondrial DNA (mtDNA) that causes excess lactic acid to accumulate in the body, a condition called lactic acidosis. Severe cases of CLA appear in the neonatal period, while milder cases caused by mtDNA mutations may not appear until early adulthood. Symptoms in the neonatal period include hypotonia, lethargy, vomiting, and tachypnea. As the disease progresses, it causes developmental delays, cognitive impairment, abnormal facial and head development, and organ failure. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to treat congenital lactic acidosis (CLA).

[0238] Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) is a rare neurological disorder characterized in most patients by slowly progressive cerebellar ataxia (lack of control of movement) and spasticity (reduced position and vibration sense) with dorsal column dysfunction. The disease usually begins in childhood or adolescence, but may not develop until adulthood. Symptoms may include difficulty speaking, epilepsy, learning disabilities, cognitive decline, and decreased consciousness, neurological exacerbations, and fever following mild head trauma. In one embodiment, an effective amount of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing levcromakalim is administered to treat Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL).

[0239] Leber's hereditary optic neuropathy (LHON) is a condition characterized by vision loss. Some affected individuals exhibit features similar to multiple sclerosis. LHON is caused by mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat Leber's hereditary optic neuropathy.

[0240] Glutaric acidemia type II (GA2) is a disorder that impedes the body's ability to break down proteins and fats to generate energy. In most cases, GA2 first appears in infancy or early childhood as a sudden episode of metabolic crisis that can cause weakness, behavioral changes (such as poor feeding and reduced activity) and vomiting. GA2 is inherited in an autosomal recessive manner and is caused by mutations in the ETFA, ETFB, or ETFDH genes. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma-ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat glutaric acidemia type II (GA2).

[0241] Mitochondrial enoyl CoA reductase protein associated neurodegeneration (MEPAN) is caused by two mutations in the gene MECR (encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase protein). Hallmarks of MEPAN include optic atrophy and childhood-onset dystonia. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat mitochondrial enoyl CoA reductase protein associated neurodegeneration (MEPAN).

[0242] Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a clinically heterogeneous group of mitochondrial disorders characterized by a reduction in mtDNA copy number in affected tissues without mutations or rearrangements in mtDNA. MDS are phenotypically heterogeneous and may affect specific organs or combinations of organs, with the main findings described being hepatocerebral (i.e., hepatic dysfunction, psychomotor retardation), myopathic (i.e., hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e., hypotonia, muscle weakness, psychomotor retardation), or neurogastrointestinal (i.e., gastrointestinal motility disorders, peripheral neuropathy). Generally, there are four classes of MDDS: 1) a form that mainly affects muscles, which is associated with mutations in the TK2 gene; 2) a form that mainly affects brain and muscles, which is associated with mutations in the SUCLA2, SUCLG1, or RRM2B genes; 3) a form that mainly affects brain and liver, which is associated with mutations in DGUOK, MPV17, POLG, or TWNK (also called PEO1); and 4) a form that mainly affects brain and gastrointestinal tract, which is associated with mutations in ECGF1 (also called TYMP). In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat mitochondrial DNA (mtDNA) depletion syndrome (MDS).

[0243] Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is a condition that affects several parts of the body, especially the digestive system and the nervous system. The main features of MNGIE disease can appear at any time from infancy to adulthood, but in most cases, signs and symptoms begin by the age of 20. MNGIE disease is also characterized by nervous system abnormalities, but these tend to be milder than gastrointestinal problems. Affected individuals experience tingling, numbness, and weakness in the limbs, especially the hands and feet (peripheral neuropathy). Additional neurological signs and symptoms include drooping eyelids (ptosis), weakness of the muscles that control eye movement (ophthalmoplegia), and hearing loss. Leukoencephalopathy, a type of alteration of brain tissue known as white matter, is a hallmark of MNGIE disease. In one embodiment, an extended release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to treat mitochondrial neurogastrointestinal encephalopathy (MNGIE).

[0244] Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) syndrome is characterized by a variety of signs and symptoms that primarily affect the nervous system. Beginning in childhood or early adulthood, most NARP patients experience numbness, tingling, or pain in the arms and legs (sensory neuropathy), muscle weakness, and impaired balance and coordination (ataxia). Affected individuals may also experience vision loss caused by a condition called retinitis pigmentosa. Mutations in the MT-ATP6 gene cause NARP syndrome. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof, comprising an effective amount of levcromakalim, is administered to treat Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) syndrome.

[0245] Pearson syndrome affects many parts of the body, but especially the bone marrow and pancreas. It affects the cells in the bone marrow that produce red blood cells, white blood cells, and platelets (hematopoietic stem cells). It also affects the pancreas and can cause frequent diarrhea and stomach pain, weight gain problems, and diabetes. Some children with Pearson syndrome may also have damage to the liver, kidneys, heart, eyes, ears, and / or brain. Pearson syndrome is caused by a mutation in mitochondrial DNA. In one embodiment, an extended release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat Pearson syndrome.

[0246] POLG-related disorders include a series of overlapping phenotypes with onset from infancy to late adulthood. Mutations in POLG can cause mitochondrial DNA (mtDNA) depletion syndrome in early childhood or a later-onset syndrome resulting from mtDNA deletion. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. The six major disorders caused by POLG mutations are Alpers-Hutten-Locker syndrome, one of the most severe phenotypes; childhood myoencephalohepatopathy spectrum, which appears within the first 3 years of life; myoclonic epilepsy-myopathy-sensory ataxia; ataxic neuropathy spectrum (including phenotypes previously called mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxic neuropathy-dysarthria-ophthalmoplegia (SANDO)); autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof comprising an effective amount of levcromakalim is administered to treat a POLG-related disorder.

[0247] Pyruvate carboxylase deficiency is a genetic disorder that causes lactate and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, especially the nervous system. There are at least three types of pyruvate carboxylase deficiency, type A, type B, and type C, which are classified according to the severity of signs and symptoms. The condition is caused by a mutation in the PC gene and is inherited in an autosomal recessive manner. In one embodiment, a sustained release formulation of a compound of formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat pyruvate carboxylase deficiency.

[0248] Pyruvate dehydrogenase complex (PDC) deficiency is a type of metabolic disorder in which the body cannot efficiently break down nutrients in food to be used for energy. Symptoms of PDC deficiency include signs of metabolic dysfunction, such as extreme fatigue (lethargy), poor feeding, and rapid breathing (tachypnea). Other symptoms may include developmental delay, periods of uncontrollable movement (ataxia), low muscle tone (hypotonia), abnormal eye movements, and signs of neurological dysfunction, such as seizures. Symptoms usually begin in infancy, but signs may first appear at birth or later in childhood. The most common PDC deficiency is caused by a genetic mutation or pathogenic variant in the PDHA1 gene. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof containing an effective amount of levcromakalim is administered to treat pyruvate carboxylase deficiency.

[0249] Myopathic form of TK2-associated mitochondrial DNA depletion syndrome (TK2-MDS) is an inherited condition that causes progressive myopathy. Signs and symptoms of TK2-MDS typically begin in early childhood. Growth is usually normal in early childhood, but as muscle weakness progresses, TK2-MDS patients lose motor skills such as standing, walking, eating, and speaking. In some affected individuals, the muscles that control eye movement become increasingly weak, causing the eyelids to droop (progressive external ophthalmoplegia). In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof containing an effective amount of levcromakalim is administered to treat myopathic form of TK2-associated mitochondrial DNA depletion syndrome (TK2-MDS).

[0250] Selected Eye Disorders In additional aspects of the invention, sustained release formulations of compounds of Formula I-III, including levcromakalim, or pharma- ceutically acceptable salts, are used to treat selected ocular disorders, as described below.

[0251] Graves' ophthalmopathy or Graves' orbitopathy (or thyroid eye disease or thyroid-associated orbitopathy) is an autoimmune inflammatory disorder of the orbit and periorbital tissues, and typical symptoms of the disease include upper eyelid retraction, eyelid lag, swelling, and exophthalmos. These disorders are orbital autoimmune disorders caused by hyperthyroidism. An effective amount of a sustained release formulation of a compound of formula I-III can be administered to treat Graves' ophthalmopathy, Graves' orbitopathy, or thyroid-associated orbitopathy. The compound can be administered in any form that achieves the desired effect, including as topical drops used as needed to reduce swelling and redness. In one embodiment, a sustained release formulation of a compound of formula I-III is taken in combination with a corticosteroid or immunosuppressant drug (rituximab or mycophenolate).

[0252] Orbital tumors are benign or malignant space-occupying lesions of the orbit that often cause ocular heterotopia, movement disorders, diplopia, visual field defects, and sometimes complete vision loss. In many cases, orbital tumors are removed by surgery, making drug therapy an advantageous treatment option. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic salt thereof containing an effective amount of levcromakalim is administered to treat or reduce orbital tumors. In one embodiment, the compound is administered topically once, twice, three times, or more times per day. In one embodiment, the compound is administered before or after surgery to remove or reduce orbital tumors.

[0253] Cavernous sinus thrombosis is the formation of a blood clot within the cavernous sinus, a cavity at the base of the brain that drains deoxygenated blood from the brain back to the heart. It is a rare disorder and can be of two types: septic cavernous thrombosis and aseptic cavernous thrombosis. Its cause is often secondary to infection in the nose, sinuses, ears, or teeth. A common disorder secondary to cavernous sinus lesions is superior ophthalmic vein thrombosis, which is a rare orbital pathology that can present with sudden-onset proptosis, conjunctival congestion, and visual impairment.

[0254] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat cavernous sinus thrombosis or superior ophthalmic vein thrombosis. In one embodiment, an effective amount is administered in combination or alternation with an antibiotic, heparin, or steroid. In one aspect, the compound is administered orally and given at least once, twice, three times, or more times daily as needed.

[0255] Episcleral / orbital venous vasculitis is inflammation of the blood vessel wall. Clinical features of ocular vasculitis may vary from conjunctivitis, episcleritis, scleritis, marginal ulcerative keratitis, exophthalmos, retinal vasculitis, orbititis to uveitis, depending on the location and distribution of the involved blood vessels. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat episcleral / orbital venous vasculitis. In one embodiment, the prodrug is administered as a topical drop.

[0256] A carotid-cavernous fistula is an abnormal connection between the arteries of the neck and the venous network at the back of the eye. The fistula can increase pressure within the cavernous sinus, compressing the cranial nerves located around the cavernous sinus. This compression can impair the nerve function that controls eye movement. A carotid-cavernous fistula can be direct or indirect. Direct carotid-cavernous fistulas are often caused by accidents or wounds that tear the carotid artery wall, whereas indirect carotid-cavernous fistulas often occur without warning and are associated with hypertension, arteriosclerosis, pregnancy, and connective tissue disorders. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt containing an effective amount of levcromakalim is administered to treat a carotid-cavernous fistula. In one embodiment, the sustained release formulation is administered as an oral dosage form.

[0257] Dural cavernous shunts are vascular connections in which blood flows through small meningeal branches of the carotid artery and enters the venous circulation near the cavernous sinus. In many cases, the disorder is congenital, and the development of clinical abnormalities may be associated with the occurrence of intracranial venous thrombosis. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic acceptable salt containing an effective amount of levcromakalim is administered to treat dural cavernous shunts. In one embodiment, the prodrug is administered as an oral dosage form.

[0258] Orbital varicose veins are vascular hamartomas typified by a low pressure, low flow, thin-walled, distensible vascular plexus intermingling with normal orbital vessels. Most patients will experience positional proptosis in head-down position and intermittent proptosis exacerbated by coughing, straining, Valsalva maneuver, or jugular vein compression. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharmacologic acceptable salt, including levcromakalim, is administered to treat orbital varicose veins. In one embodiment, the prodrug is administered as an oral dosage form.

[0259] Sturge-Weber syndrome 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 main features: red or pink angioma called port-wine stains, brain abnormalities called leptomeningeal angioma, and increased IOP in the eye (glaucoma). In people with Sturge-Weber syndrome, glaucoma typically develops either in infancy or early adulthood and can cause vision problems. In some affected infants, the pressure inside the eye can become so high that the eyeball appears enlarged and bulging (buphthalmos). People with Sturge-Weber syndrome may have abnormal plexuses of blood vessels (angiomas) 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), this is called diffuse choroidal hemangioma, which occurs in about one-third of people with Sturge-Weber syndrome. Diffuse choroidal hemangioma can cause vision loss. When present, the ocular abnormalities typically occur in the same temporal region as the port-wine stains.

[0260] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat Sturge-Weber syndrome. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat Sturge-Weber syndrome-induced glaucoma. In one embodiment, the compound is administered as an oral formulation once, twice, three or more times a day. In one embodiment, the sustained release formulation is administered as a topical ophthalmic formulation, as defined herein, once a day for chronic therapy.

[0261] Central retinal vein occlusion, also known as CRVO, is a condition in which the main vein that drains blood from the retina is partially or completely blocked. This can lead to blurred vision and other eye damage. Risk factors for CRVO include diabetes, elevated IOP, and high blood pressure. This fluid can cause the macula to swell, affecting central vision. Eventually, the lack of blood circulation can lead to the death of nerve cells in the eye and vision loss. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt containing an effective amount of levcromakalim is administered to treat central retinal vein occlusion. In one embodiment, the compound is administered as topical drops given once, twice, or three times daily. In one embodiment, the prodrug is given in combination with an anti-VEGF inhibitor, such as bevacizumab (Avastin™), ranibizumab (Lucentis™), aflibercept (Eylea™), and brolucizumab (Beovu™).

[0262] Branch retinal vein occlusion (BRVO) is when a branch of the retinal vein becomes blocked, causing blood and fluid to leak into the retina. Risk factors for BRVO include diabetes, elevated IOP, and high blood pressure. This fluid can cause the macula to swell and affect central vision. Eventually, the lack of blood circulation can cause nerve cells in the eye to die and vision loss can occur. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat branch retinal vein occlusion (BRVO). In one embodiment, the prodrug is administered as topical drops given once, twice, three times, or more per day.

[0263] Non-arteritic anterior ischemic optic neuropathy (NAION) refers to the loss of blood flow to the optic nerve, due to impaired blood circulation at the optic nerve head. Non-arteritic anterior ischemic optic neuropathy is associated with diabetes, hypertension, atherosclerosis, small optic nerve, elevated IOP, and sleep apnea. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered to treat non-arteritic anterior ischemic optic neuropathy. In one embodiment, the prodrug is administered as topical drops given once, twice, three times, or more times daily.

[0264] In some embodiments, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt comprising an effective amount of levcromakalim is used as a second therapeutic agent to latanoprost to treat the ocular disorders described herein.

[0265] In some embodiments, a sustained release formulation of a compound of Formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt, is administered to a host in need thereof, e.g., (1) Prostaglandin analogues, such as latanoprost (Xalatan), bimatoprost (Lumigan), travoprost (Travatan or Travatan Z), or tafluprost (Zioptan); (2) α2 adrenergic agonists, such as brimonidine (Alphagan™), epinephrine, dipivefrin (Propine™), or apraclonidine (Lopidine™); (3) beta-blockers, such as timolol, levobunolol, metipranolol, or carteolol; (4) ROCK inhibitors, such as ripasudil, netarsudil (Rhopressa), fasudil, RKI-1447, GSK429286A, or Y-30141; (5) a second potassium channel opener, e.g., minoxidil, diazoxide, nicorandil, or pinacidil; (6) Carbonic anhydrase inhibitors, such as dorzolamide (Trusopt®), brinzolamide (Azopt®), acetazolamide (Diamox®), or methazolamide (Neptazane®), (7) PI3K inhibitors, such as wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), d) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazin-2-yl]phenyl]urea) (gedatorisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl) ethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, piraralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, Apitolisib (GDC-0980; RG7422), (8) BTK inhibitors, such as ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics (U.S. Patent Application Publication No. 2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide), LFM-A13 (α-cyano-β-hydroxybutyric acid roxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 (RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), or, (9) Syk inhibitors, such as cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxysilyl)phenyl]pyrazine-1-yl)phenyl) ... phenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl )amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)amino )pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306, 7-azaindole, piceatannol, ER-27319, PRT060318, luteolin, apigenin, quercetin, fisetin, myricetin, morin; It may be useful to administer it in combination with

[0266] In an alternative embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered to a host in need thereof in combination with a nitric oxide donor, including, but not limited to, NCX-470, NCX-1728, NCX-4251, NCX-4016, NCX-434, NCX-667, Vyzulta (latanoprostene ophthalmic solution), or sodium nitroprusside (SNP).

[0267] Ophthalmic nerve protection Neuroprotection is a therapeutic strategy that aims to maximize neuronal recovery and minimize neuronal death due to injury. Injury can be mechanical, ischemic, degenerative, or radiation-induced. Many neurodegenerative disorders are associated with aging and can be detrimental to the elderly. For example, glaucoma is often characterized by loss of retinal ganglion cells and is the leading cause of vision loss and blindness in the elderly.

[0268] In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered to a host in need thereof to treat an ocular-associated neurodegenerative disorder, which is any disorder associated with the dysfunction or degeneration of cells, including nerve cells, such as neurons or retinal ganglion cells.

[0269] In one embodiment of the invention, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered as a method of reducing neuronal or cellular damage in the eye of a host in need of relief. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered as a method of reducing neuronal or cellular damage in the glaucomatous eye of a host in need of relief.

[0270] In another embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing levcromakalim promotes survival, growth, regeneration, and / or neurite outgrowth of retinal ganglion cells. In another embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing levcromakalim prevents death of damaged nerve cells.

[0271] Since neuronal cell death can be a result of retinal ischemia, in one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, is administered as a method of reducing neuronal or cellular damage in the eye following retinal ischemia in a host in need thereof.

[0272] Optic neuropathy, damage to the optic nerve that is often characterized by loss of vision, results in the loss of retinal ganglion cells. There are many types of optic neuropathy, including ischemic optic neuropathy, optic neuritis, compressive optic neuropathy, infiltrative optic neuropathy, and traumatic optic neuropathy. Nutritional deficiencies and / or vitamin B 12 Deficiency may result in nutritional optic neuropathy. Exposure to ethylene glycol, methanol, ethambutol, amiodarone, tobacco, or certain drugs such as chloramphenicol or digitalis may result in toxic optic neuropathy. Certain forms of optic neuropathy may be inherited, including Leber's hereditary optic neuropathy (LHON), dominant optic atrophy, Beer's syndrome, and Berk-Tabatznik syndrome. In one embodiment, a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt containing an effective amount of levcromakalim is administered as a method of reducing nerve or cellular damage in the eye of a host in need of relief associated with optic neuropathy.

[0273] Additional non-limiting examples of neurodegenerative diseases associated with the eye include lattice dystrophies, retinitis pigmentosa, age-related macular degeneration (wet or dry), photoreceptor degeneration associated with wet age-related macular degeneration or dry age-related macular degeneration, and optic nerve drusen.

[0274] Integrated or adjunctive therapy with minimally invasive glaucoma surgery (MIGS) Minimally (or minimally) invasive glaucoma surgery (MIGS) has become an innovative technique in the evolution of glaucoma surgery. Since glaucoma is a disease in which the optic nerve is damaged primarily due to elevated IOP, the goal of glaucoma surgery is to lower IOP to prevent or reduce damage to the optic nerve.

[0275] Standard glaucoma surgery is still considered a major operation and involves trabeculectomy, ExPRESS shunt, or external tube shunts such as Ahmed-style, Molteno-style, and Baerveldt-style valve implants. Although such procedures are often effective in lowering intraocular pressure and halting the progression of glaucoma, they are associated with many potential complications, including double vision, severe eye infections, exposure of the drainage implant, corneal swelling, and excessively low IOP.

[0276] According to Saheb and Ahmed, minimally (or minimally) invasive glaucoma surgery has five favorable qualities: 1. ab interno and / or ab externo approach via a clear corneal incision, which may eliminate the need for a conjunctival incision; 2. Minimally traumatic procedure to the target tissue, 3. IOP-lowering effect that justifies the approach, 4. A high safety profile avoiding serious complications compared to other glaucoma surgeries and given lower ocular hypotony potential, 5. Rapid recovery with minimal impact on the patient's quality of life; Refers to a group of surgical procedures that share a common theme.

[0277] The MIGS group of surgeries have been developed in recent years to alleviate some of the complications of most standard glaucoma surgeries. Thus, in one embodiment, sustained release formulations of compounds of Formula I-III are used as additives in combination with minimally invasive glaucoma surgery (MIGS).

[0278] MIGS aims to achieve lower IOP in patients with glaucoma with a less invasive surgical procedure, ideally achieving a drug-sparing effect. MIGS procedures work by using microscopic instruments and small incisions, allowing for controlled outflow, and are often performed at the time of cataract surgery. They reduce complication rates, but some efficacy comes at the expense of increased safety (Pillunat, LE, et al., Clin Ophthalmol. 2017; 11: 1583-1600).

[0279] MIGS surgery falls into several categories: 1. Trabecular bypass surgery (i.e., angle-based devices and / or subconjunctival shunt devices), 2. Microtrabeculectomies (a miniaturized form of trabeculectomy), 3. Complete internal or suprachoroidal shunt, and 4. A kinder, gentler form of laser photocoagulation, It is classified as follows.

[0280] Trabecular meshwork surgery (trabeculectomy) involves cutting open the trabecular meshwork with a small device under high-powered microscopic control using a special contact lens on the eye. This is done without damaging other tissues in the intraocular drainage pathway. The trabecular meshwork may be destroyed (Trabectome or Trab360) or bypassed using a small snorkel-like device (iStent) or a plug-shaped stent device (iStent Inject). Both techniques are FDA approved, but generally do not lower intraocular pressure as low, making them useful in the early to moderate stages of glaucoma. With these devices, the resistance of the trabecular meshwork is obviated, so distal outflow capacity and episcleral venous pressure remain the main limitations to further aqueous humor drainage. In certain embodiments, sustained release formulations of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, are used as additives in combination with Trabectome or Trab360 and / or iStent / iStent Inject to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0281] Micro trabeculectomy works by inserting a small microscopic tube into the eye and draining from inside the eye under the outer membrane of the eye (conjunctiva). Xen Gel Stent and PRESERFLO are two new devices that can make trabeculectomy surgery safer. Results have shown superior pressure reduction with improved safety over trabeculectomy in studies conducted outside the United States. In certain embodiments, the compounds of the present invention are used as part of a protocol with Xen Gel Stent and / or Preserflo to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0282] Suprachoroidal shunts, including Gold Micro shunt, iStent Supra, Aquashunt, and STARflo, work by using a small tube with a very small internal opening to connect the anterior segment of the eye to the suprachoroidal space between the retina and the eye wall to increase drainage from the eye. This procedure has relatively few serious complications and reduces pressure enough to be useful even in moderate glaucoma. In certain embodiments, sustained release formulations of the compounds of Formula I-III or pharma- ceutical acceptable salts, including levcromakalim, are used in combination with suprachoroidal shunt procedures to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after the procedure in acute or chronic use settings.

[0283] Trabecular meshwork bypass stents and shunts are investigational devices that function to dilate Schlemm's canal. These procedures promote the inflow of aqueous humor into Schlemm's canal by inserting a shunt (Eyepasse Glaucoma Implant, GMP Companies, Inc., Fort Lauderdale, FL) or by inserting a stent into Schlemm's canal itself (iStent, Glaukos Corp., Laguna Hills, CA). Other devices, such as the Solx Gold Micro-Shunt (OccuLogix, Inc., Mississauga, Ontario, Canada), divert aqueous humor into the suprachoroidal space. In certain embodiments, sustained release formulations of the compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used in combination with trabecular meshwork bypass stent or shunt procedures to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after the procedure in an acute or chronic use setting.

[0284] Selective laser trabeculoplasty (SLT) is used during any management to help lower IOP. Since the implementation of the LiGHT study, SLT is now more frequently used as a first-line treatment to help lower IOP, effectively acting at the level of the trabecular meshwork to improve outflow. In certain embodiments, sustained release formulations of the compounds of Formula I-III or pharma-ceutically acceptable salts, including levcromakalim, are used together or in addition to SLT to treat glaucoma by additively lowering IOP via increasing distal outflow and / or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0285] Laser photocoagulation was previously reserved for advanced glaucoma that could not be controlled despite trabeculectomy or tube shunt. Endoscopic cyclophotocoagulation and micropulse diode cyclophotocoagulation are two recent advances in the use of laser photocoagulation and have proven useful in cases where glaucoma has not yet progressed. In certain embodiments, sustained release formulations of the compounds of formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used in endoscopic cyclophotocoagulation and micropulse cyclophotocoagulation protocols to treat glaucoma by additively lowering IOP via increasing distal outflow and / or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0286] In recent years, endoscopic cyclophotocoagulation has become a widely accepted and popular treatment for refractory glaucoma, pediatric glaucoma, in combination with phacoemulsification with intraocular lens placement, as an adjunct to cataract surgery in both medically controlled and uncontrolled glaucoma. Endoscopic cyclophotocoagulation is performed 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, followed by lens removal and intraocular lens implantation. Laser energy is applied to the ciliary processes to destroy the aqueous humor-producing ciliary epithelial cells. In certain embodiments, sustained release formulations of the compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used in endoscopic cyclophotocoagulation protocols to treat glaucoma by additively lowering IOP via increasing distal outflow and / or reducing episcleral venous pressure before or after the procedure in an acute or chronic use setting.

[0287] Micropulse cyclophotocoagulation delivers the laser in short bursts, allowing the surgeon to target specific areas of the ciliary body while allowing the tissue time to cool between bursts, minimizing damage. Both the MicroPulse P3 probe and the new Cyclo G6 Glaucoma Laser System (Iridex) have been successfully used in retinal diseases and have shown excellent safety and efficacy rates. In certain embodiments, sustained release formulations of the compounds of Formula I-III or pharma-ceutically acceptable salts, including levcromakalim, are used in micropulse cyclophotocoagulation surgical protocols to treat glaucoma by additively lowering IOP via increasing distal outflow and / or reducing episcleral venous pressure before or after the procedure in acute or chronic use settings.

[0288] Other devices include Gonioscopy-assisted transluminal trabeculotomy (GATT), Kafuk Dual Blade, Ab interno tubular grafting and Hydrus Microstent, iStent Supra, Xen Glaucoma Treatment System, and InnFocus MicroShunt. In certain embodiments, sustained release formulations of the compounds of formula I-III or pharma- ceutical acceptable salts, including levcromakalim, are used in the surgical protocols of these devices to treat the above glaucoma.

[0289] Laser trabeculoplasty, including selective laser trabeculoplasty (SLT), argon laser trabeculoplasty (ALT), excimer laser trabeculoplasty, and micropulse laser trabeculoplasty (MLT), is a surgical laser procedure that serves 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 trabeculoplasty is used as an additive in combination with laser trabeculoplasty to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in an acute or chronic use setting.

[0290] In one embodiment, sustained release formulations of compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used as second-line therapy to prostaglandin analogs, such as latanoprost (Xalatan), bimatoprost (Lumigan), travoprost (Travatan or Travatan Z), latanoprost bunod (Vyzulta), or tafluprost (Zioptan), and as an adjunct to minimally (or minimally) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation.In a further embodiment, the MIGS is laser trabeculotomy.

[0291] In one embodiment, sustained release formulations of compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used as second-line therapy to latanoprost (Xalatan) and as an adjunct to minimally (or minimally) invasive glaucoma surgery as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy.

[0292] In one embodiment, sustained release formulations of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, are used as a second-line therapy to an alpha 2 adrenergic agonist, such as brimonidine (Alphagan™), epinephrine, dipivefrin (Propine™), or apraclonidine (Lopidine™), and as an adjunct to minimally invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy.

[0293] In one embodiment, sustained release formulations of compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used as second-line therapy to beta-blockers, such as timolol, levobunolol, metipranolol, or carteolol, and as an adjunct to minimally (or minimally) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is microtrabeculotomy. 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy. In a further embodiment, the MIGS is trabeculotomy. In further embodiments, the MIGS is microtrabeculectomy. In further embodiments, the MIGS is a suprachoroidal shunt. In further embodiments, the MIGS is a trabecular bypass stent or shunt. In further embodiments, the MIGS is selective laser trabeculoplasty (SLT). In further embodiments, the MIGS is laser photocoagulation. In further embodiments, the MIGS is cyclophotocoagulation. In further embodiments, the MIGS is laser trabeculotomy.

[0294] In one embodiment, sustained release formulations of compounds of Formula I-III or pharma- ceutically acceptable salts, including levcromakalim, are used as second-line therapy to ROCK inhibitors, such as ripasudil, netarsudil (Rhopressa), fasudil, RKI-1447, GSK429286A, or Y-30141, and as an adjunct to minimally (or minimally) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy.

[0295] In one embodiment, sustained release formulations of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, are used as a second-line therapy to a second potassium channel opener, such as minoxidil, diazoxide, nicorandil, or pinacidil, and as an adjunct to minimally (or minimally) invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy.

[0296] In one embodiment, sustained release formulations of a compound of Formula I-III or a pharma- ceutically acceptable salt, including levcromakalim, are used as second-line therapy to carbonic anhydrase inhibitors, such as dorzolamide (Trusopt™), brinzolamide (Azopt™), acetazolamide (Diamox™), or methazolamide (Neptazane™), and as an adjunct to minimally invasive glaucoma surgery (MIGS) as described herein. In a further embodiment, the MIGS is trabeculotomy. In a further embodiment, the MIGS is 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 selective laser trabeculoplasty (SLT). In a further embodiment, the MIGS is laser photocoagulation. In a further embodiment, the MIGS is cyclophotocoagulation. In a further embodiment, the MIGS is laser trabeculotomy.

[0297] III. Pharmaceutical Compositions and Dosage Forms Extended-release formulations In some embodiments, sustained release formulations, e.g., microparticles or nanoparticles, of the compounds of formula I, II, or III of the invention described herein, e.g., levcromakalim, or a pharma- ceutically acceptable salt thereof, may comprise biodegradable polymers for controlled delivery of the selected compound, including, but not limited to, Pluronic® polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3-dioxane-2-one)), polyanhydrides (e.g., poly(sebacic anhydride)), polyethers (e.g., polyethylene glycol), polyurethanes, polymethacrylates, polyacrylates, and polycyanoacrylates. In some embodiments, the selected polymer may be modified, e.g., end-capped, with acyclic polyacetals derived from polyethylene glycol (PEG), carbohydrates, and / or polysaccharides. See, for example, Papisov, 2001, ACS Symposium Series, 786:301, incorporated herein by reference.

[0298] Techniques for producing microparticles and nanoparticles are well known. These techniques include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low-temperature casting. The following is a brief description of suitable methods for particle formulation. Optionally, pharma-ceutically acceptable excipients, including pH adjusters, disintegrants, preservatives, and antioxidants, can be incorporated into particles during their formation.

[0299] In some embodiments, the particles are obtained by a solvent evaporation method. In this method, a compound described herein (or a polymer matrix and one or more compounds described herein) is dissolved in a volatile organic solvent such as methylene chloride. The organic solution containing the compound described herein is then suspended in an aqueous solution containing a surfactant such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent has evaporated, leaving solid nanoparticles or microparticles. The resulting nanoparticles or microparticles are washed with water and dried overnight in a freeze dryer. This method can result in microparticles or nanoparticles with various sizes and morphologies.

[0300] Pharmaceutical compositions containing labile polymers, such as certain polyanhydrides, may degrade in the presence of water during the manufacturing process. For these polymers, particles can be made using methods carried out in completely or substantially anhydrous organic solvents.

[0301] Solvent removal can also be used to prepare particles from hydrolytically unstable compounds. In this method, the compound (or the polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent, such as methylene chloride. This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion. Solid particles are formed from the emulsion, which can then be separated from the supernatant. The external morphology of the spheres produced using this technique depends largely on the identity of the drug.

[0302] In certain embodiments, the compounds of formula I, II, or III, including levcromakalim, of the present invention described herein, or pharma- ceutically acceptable salts, are administered to a patient in need thereof as particles formed by solvent removal. In another embodiment, the present invention provides particles formed by solvent removal, comprising a compound of the present invention and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particles formed by solvent removal comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment, the particles formed by solvent removal comprise a compound of the present invention, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by solvent removal can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed by solvent removal are formulated into a tablet, but the tablet is not coated.

[0303] In certain embodiments, the particles are obtained by spray drying. In this method, the compound (or the polymer matrix and one or more compounds) is dissolved in an organic solvent such as methylene chloride. This solution is pumped through an atomizing nozzle driven by a compressed gas flow, and the resulting aerosol is suspended in a heated air cyclone, where the solvent evaporates from the microdroplets to form particles. Using this method, microparticles and nanoparticles can be obtained.

[0304] In other embodiments, the compounds of formula I, II, or III, including levcromakalim, of the present invention as described herein, or pharma- ceutically acceptable salts, are administered to a patient in need thereof as a dispersion spray dried (SDD). In another embodiment, the present invention provides a dispersion spray dried (SDD) comprising a compound of the present invention and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the SDD comprises a compound of the present invention and an additional therapeutic agent. In a further embodiment, the SDD comprises a compound of the present invention, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the dispersion spray dried described can be coated to form a coated tablet. In an alternative embodiment, the dispersion spray dried is formulated into a tablet but is not coated.

[0305] Phase inversion method can be used to form particles from the active compounds described herein.In this method, the compound (or polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and this solution is poured into a strong non-solvent for the compound, which spontaneously generates microparticles or nanoparticles under favorable conditions.Using this method, nanoparticles of a wide range of sizes, including, for example, nanoparticles to microparticles, typically have a narrow size distribution, can be produced.

[0306] In some embodiments, the sustained release formulation of the compound of formula I, formula II, or formula III, including levcromakalim, or a pharma- ceutically acceptable salt of the present invention described herein is administered to a patient in need thereof as particles formed by phase inversion. In another embodiment, the present invention provides particles formed by phase inversion comprising a compound of the present invention and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particles formed by phase inversion comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment, the particles formed by phase inversion comprise a compound of the present invention, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed by phase inversion are formulated into a tablet, but the tablet is not coated.

[0307] Techniques for forming particles using coacervation are known in the art, for example as described in GB 929406, GB 929401, and U.S. Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves the separation of a compound (or a polymer matrix and one or more compounds) solution into two immiscible liquid phases. One phase is a dense coacervate phase that contains a high concentration of the compound, while the other phase contains a low concentration of the compound. Within the dense coacervate phase, the compound forms nano- or micro-scale droplets that harden into particles. Coacervation can be induced by temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer that forms an interpolymer complex (complex coacervation).

[0308] In one embodiment, the compound of formula I, formula II, or formula III, including levcromakalim, of the present invention as described herein, or a pharma- ceutically acceptable salt, is administered to a patient in need thereof as a sustained release particle formed by coacervation. In another embodiment, the present invention provides a particle formed by coacervation comprising a compound of the present invention and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particle formed by coacervation comprises a compound of the present invention and an additional therapeutic agent. In a further embodiment, the particle formed by coacervation comprises a compound of the present invention, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particle formed by coacervation is formulated into a tablet, but the tablet is not coated.

[0309] A method for cryogenic casting of controlled release microspheres is described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, the compound is dissolved in a solvent. This mixture is then sprayed into a container containing a liquid non-solvent at a temperature below the freezing point of the drug solution causing droplets of the compound to freeze. When the droplets and the non-solvent for the compound are warmed, the solvent in the droplets melts and is extracted into the non-solvent, causing the microspheres to harden.

[0310] In one embodiment, the selected compound of formula I, formula II, or formula III, including levcromakalim of the present invention as described herein, or a pharma- ceutically acceptable salt, is administered to a patient in need thereof as a particle formed by cold casting. In another embodiment, the present invention provides a particle formed by cold casting, comprising a compound of the present invention and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particle formed by cold casting comprises a compound of the present invention and an additional therapeutic agent. In a further embodiment, the particle formed by cold casting comprises a compound of the present invention, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by cold casting can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particle formed by cold casting is formulated into a tablet, but the tablet is not coated.

[0311] In one aspect of the present invention, the selected compounds of formula I, formula II, or formula III, including levcromakalim of the present invention described herein, or pharma- ceutically acceptable salts, are incorporated into nanoparticles, for example, for convenient delivery and / or sustained release delivery. The use of nanoscale materials offers the ability to modify basic physical properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and / or immunogenicity. Many nanoparticle-based therapeutic and diagnostic agents have been demonstrated to be useful in the treatment of cancer, diabetes, pain, asthma, allergies, and infectious diseases. These nanoscale agents may provide more effective and / or more convenient routes of administration, reduce therapeutic toxicity, extend product life cycles, and ultimately reduce healthcare costs. As a therapeutic delivery system, nanoparticles may enable targeted delivery and controlled release.

[0312] In addition, nanoparticle-based compound delivery can be used to release compounds at a sustained rate, allowing for less frequent dosing, targeted drug delivery to minimize systemic side effects, or combination therapy to deliver two or more drugs simultaneously to create synergistic effects and reduce drug resistance. Many nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drug and polymer-based conjugates account for the majority of the products. See Zhang, L., et al. "Nanoparticles in Medicine: Therapeutic Applications and Developments)", Clin. Pharm. and Ther., 83(5):761-769, 2008.

[0313] Methods for making nanoparticles are known in the art, see, for example, Muller, RH, et al., Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art, Eur. H. Pharm. Biopharm., 50:161-177, 2000; U.S. Patent No. 8,691,750 to Consien et al.; WO 2012 / 145801 to Kanwar.; U.S. Patent No. 8,580,311 to Armes, S. et al.; Petros, RA and DeSimone, JM, Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews / Drug Discovery, vol. 9:615-627, 2010; U.S. Patent No. 8,465,775; U.S. Patent No. 8,444,899; U.S. Patent No. 8,420,124; U.S. Patent No. 8,263,129; U.S. Patent No. 8,158,728; U.S. Patent No. 8,268,446; Pellegrino et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13:3843 (all of which are incorporated herein by reference). Additional methods are described in the literature (e.g., Doubrow, Ed., "Microcapsules and Nanoparticles in Medicine and Pharmacy," CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S. Pat. Nos. 5,578,325 and 6,007,845; P. Paolicelli et al., "Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" Nanomedicine. 5(6):843-853 (2010)), U.S. Pat. No. 5,543,158 to Gref et al., or WO 2009 / 051837 by Von Andrian et al.; Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc., 115:11010). 121:5633; and Zhou et al., 1990, Macromolecules, 23:3399). Examples of these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), ポ(4-ヒドロキシ-L-プロリンエステル) (Putnam et al., 1999, Macromolecules, 32:3658; and びLim et al., 1999, J. Am. Chem. Soc., 121:5633) and びポリ(4-ヒドロキシ-L-プロリンエステル) (Putnam et al., 1999, Macromolecules, 32:3658; Lim et al., 1999, J. Am. Chem. Soc., 121:5633; U.S. Patent No. 6,123,727; U.S. Patent No. 5,804,178; U.S. Patent No. 5,770,417; U.S. Patent No. 5,736,372 ; U.S. Patent No. 5,716,404; U.S. Patent No. 6,095,148; U.S. Patent No. 5,837,752; U.S. Patent No. 5,902,599; U.S. Patent No. 5, 696,175; U.S. Patent No. 5,514,378; U.S. Patent No. 5,512,600; U.S. Patent No. 5,399,665; U.S. Patent No. 5,019,379 ;U.S. Patent No. 5,010,167; U.S. Patent No. 4,806,621; U.S. Patent No. 4,638,045; U.S. Patent No. 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480;Lim et al., 2001, J. Am. Chem. Soc., 123:2460;Langer, 2000, Acc. Chem. Res., 33:94;Langer, 1999, J. Control. Release, 62:7; Uhrich et al., 1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, Ed.by Goethals, Pergamon Press, 1980;Principles of Polymerization by Odian, John Wiley & Sons, Fourth Edition, 2004;Contemporary Polymer Chemistry by Allcock et al., Prentice-Hall, 1981;Deming et al., 1997, Nature, 390:386;and U.S. Patent Nos. 6,506,577, 6,632,922, 6,686,446 and 6,818,732;C. Astete et al., "Synthesis and characterization of PLGA nanoparticles" J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006);K. Avgoustakis "Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery" Current Drug Delivery 1:321-333 (2004); C. Reis et al., "Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles" Nanomedicine 2:8-21 (2006); P. Paolicelli et al., "Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" Nanomedicine. 5(6):843-853 (2010); U.S. Patent No. 6,632,671 to Unger (October 14, 2003), all of which are incorporated herein by reference.

[0314] In some embodiments, the polymer particles are between about 0.1 nm and about 10,000 nm, between about 1 nm and about 1000 nm, between about 10 nm and 1000 nm, between about 1 nm and 100 nm, between about 1 nm and 10 nm, between about 1 nm and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm. In one embodiment, the microparticles are about 0.1 nm or less, 0.5 nm or less, 1.0 nm or less, 5.0 nm or less, 10 nm or less, 25 nm or less, 50 nm or less, 75 nm or less, 100 nm or less, 150 nm or less, 200 nm or less, 250 nm or less, 300 nm or less, 400 nm or less, 450 nm or less, 500 nm or less, 550 nm or less, 600 nm or less, 650 nm or less, 700 nm or less, 750 nm or less, 800 nm or less, 850 nm or less, 900 nm or less, 950 nm or less, 1000 nm or less, 1250 nm or less, 1500 nm or less, 1750 nm or less, or 2000 nm or less.

[0315] In some embodiments, the compounds described herein may be covalently coupled to the polymers used in nanoparticles, such as PLGA particles, PLA particles, PGA, or other polymers that covalently bond to hydroxyls in the compounds of Formula I, Formula II, or Formula III. Methods for covalently binding active compounds to biodegradable polymers are well known and published.

[0316] Method of administration The sustained release formulations of the selected compounds of formula I, II, or III, including levcromakalim, or pharma- ceutically acceptable salts of the invention described herein may be administered in an effective amount to a host, typically a human, in need of administration for any of the indications described herein. Although sustained release formulations may be provided without a carrier, they are more typically administered as a pharmaceutical composition comprising a sustained release formulation of a compound of formula I, II, or III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, in a pharma- ceutically acceptable carrier, in an effective amount for a host, typically a human, in need of such treatment. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of a sustained release formulation of a compound of formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, together with at least one pharma- ceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may comprise the compound or a salt thereof as the only active agent, or in alternative embodiments, may comprise the compound or a salt thereof and at least one additional active agent.

[0317] The exact amount of the active compound or pharmaceutical composition in a sustained release formulation described herein delivered to a host in need thereof, typically a human, will be determined by a healthcare provider to achieve the desired clinical benefit.

[0318] The pharmaceutical compositions contemplated herein typically include a carrier, which is further described below. The carrier must have sufficiently high purity and sufficiently low toxicity so as to be suitable for administration to the patient to be treated. The carrier may be inert or have its own medicinal effect. The amount of the carrier used with the compound is sufficient to provide a practical amount of the substance to be administered per unit dose of the compound. Representative carriers include solvents, diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, isotonicity agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier.

[0319] One or more viscosity agents can be added to pharmaceutical compositions to increase the viscosity of the composition as required.Examples of useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamides, polyvinyl alcohols (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, their derivatives and their mixtures.

[0320] The solutions, suspensions or emulsions for administration may be buffered with an effective amount of a buffering agent required to maintain a suitable pH for the selected administration. Suitable buffering agents are known to those skilled in the art. Some examples of useful buffering agents are acetate, borate, carbonate, citrate and phosphate buffers.

[0321] The sustained release formulations of the compounds of formula I, formula II, or III, including levcromakalim, of the present invention described herein, or pharma- ceutically acceptable salts thereof, may be provided in any dosage strength that achieves the desired results and further depends on the route of administration. In certain exemplary non-limiting embodiments, the pharmaceutical composition is present in a dosage form that includes from about 0.01 mg to about 2000 mg, from up to about 1 mg, 5 mg, or 10 mg to about 1000 mg, from up to about 100 mg to about 800 mg, or from up to about 200 mg to about 600 mg of active compound, and optionally from up to about 0.1 mg to about 2000 mg, from up to about 10 mg to about 1000 mg, from up to about 100 mg to about 800 mg, or from up to about 200 mg to about 600 mg of additional active agent in a unit dosage form. Examples are dosage forms containing at least about 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1400 mg, 1500 mg, or 1600 mg of an active compound or salt thereof. In certain embodiments, the dosage form has at least about 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of active compound or a salt thereof. The amount of active compound in the dosage form is calculated without reference to the salt.

[0322] In alternative embodiments, the pharmaceutical composition is in a dosage form comprising a compound of a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising about 0.005 mg to about 5 mg, about 0.003 mg to about 3 mg, about 0.001 mg to about 1 mg, about 0.05 mg to about 0.5 mg, about 0.03 mg to about 0.3 mg, or about 0.01 mg to about 0.1 mg, or about 0.01 mg to about 0.05 mg of levcromakalim. In one embodiment, the dosage form has at least about 0.01 mg, 0.02 mg, 0.025 mg, or 0.05 mg of the active compound or a salt thereof.

[0323] As a non-limiting embodiment, the therapeutically effective amount of the compound in a pharmaceutical dosage form may range, for example, from about 0.001 mg / kg to about 100 mg / kg or more per day. For example, in a non-limiting embodiment, a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from about 0.1 mg / kg of patient to about 35 mg / kg of patient per day, depending on the pharmacokinetics of the agent in the patient. In an alternative embodiment, a sustained release formulation of a compound of Formula I, Formula II, or Formula III, or a pharma-ceutically acceptable salt thereof, including levcromakalim, may be administered in an amount ranging from about 0.01 mg / kg of patient to about 3.5 mg / kg of patient per day, depending on the pharmacokinetics of the agent in the patient.

[0324] In certain embodiments, the sustained release formulation of a compound of formula I, II, or III, or a pharma- ceutically acceptable salt thereof, including levcromakalim, is administered for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more, including indefinitely during therapy. In certain embodiments, the sustained release formulation of a compound of formula I, II, or III, or a pharma-ceutically acceptable salt thereof, including levcromakalim, is administered once, twice, three times, or more, daily.

[0325] Non-limiting examples of buffers, with or without additional excipients or other additives, that may be used as pharma- ceutically acceptable formulations for the appropriate indications described herein include, for example (at illustrative but non-limiting concentrations and pH), acetate buffer (0.1 M, pH 5.0), BES buffered saline (2x) (0.05 M, pH 6.95), bicine (1 M, pH 8.26), CAPS (1 M, pH 10.4), CHES (1 M, pH 10.5), and acetylated saline (1 M, pH 10.5). H9.5), citrate buffer (0.1M, pH6.0), citrate phosphate buffer (0.15M, pH5.0), diethanolamine (1M, pH9.8), EBSS (magnesium, calcium, phenol red) (pH7.0), glycine-HCl buffer (0.1M, pH3.0), glycine-sodium hydroxide buffer (0.08M, pH10), HBSS (Hank's Balanced Salt Solution), HEPPSO (1M, pH7.85), H HBS (Hank's buffered saline solution containing Hepes), hydrochloric acid-potassium chloride buffer (0.1 M, pH 2.0), imidazole-HCl buffer (0.05 M, pH 7.0), MES (0.5 M, pH 6), MOPS buffer (10x) (0.2 M, pH 7), PBS (phosphate buffered saline) (1x, pH 7.4), sodium borate buffer (1 M, pH 8.5), TAE (1 M, pH 8.6), TAE buffer (50x) (0.04 M, pH 8 .5), TBS (1M, pH 7.4), TE buffer (10x); tricine (1M, pH 8.05), Tris buffer (1M, pH 7.2), acetate buffer (pH 3.6-5.6), carbonate-bicarbonate buffer (pH 9.2-10.6), citrate buffer (pH 3.0-6.2), phosphate buffer (pH 5.8-8.0), potassium phosphate (pH 5.8-8.0), and Trizma™ buffer (pH 7.0-9.2).

[0326] Formulations for ocular, topical, enteral and parenteral delivery are described in more detail below.

[0327] ocular delivery When used in ophthalmic therapy, an effective amount of the sustained release formulation of the compound of Formula I, Formula II, or Formula III, including levcromakalim, of the present invention herein, or a pharma- ceutically acceptable salt thereof, may be administered as a topical formulation, such as, for example, a solution, suspension, or emulsion. Topical formulations typically include a pharma- ceutically acceptable carrier, which may be an aqueous carrier or a non-aqueous carrier.

[0328] Examples of aqueous carriers include, but are not limited to, aqueous solutions or suspensions, such as saline, plasma, bone marrow aspirate, buffers such as Hank's Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringer's buffer, ProVisc™, diluted ProVisc™, ProVisc™ diluted in PBS, Krebs buffer, Dulbecco's PBS, standard PBS, sodium hyaluronate solution (HA, 5 mg / mL in PBS), simulated aqueous humor, simulated tear fluid, platelet-rich plasma and tissue culture medium, or aqueous solutions or suspensions containing organic solvents. Pharmaceutical formulations for ocular administration are preferably in the form of a sterile aqueous solution. Acceptable solutions include, for example, water, Ringer's solution, phosphate buffered saline (PBS), citrate buffered saline, and isotonic sodium chloride solution. The formulation may also be a sterile solution, suspension, or emulsion in a non-toxic diluent or solvent, such as 1,3-butanediol. In one embodiment, the carrier is PBS. In one embodiment, the carrier is a citrate buffer, including citrate buffered saline. Further examples of buffers that may be used in pharma- ceutically acceptable ophthalmic formulations for appropriate indications are described above.

[0329] Suitable non-aqueous pharma- ceutically acceptable carriers include, but are not limited to, oleoyl polyethylene glycol glyceride, linoleoyl polyethylene glycol glyceride, lauroyl polyethylene glycol glyceride, liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin (petrolatum), hard paraffin, vegetable fatty oils such as castor oil, arachis oil, or sesame oil, medium chain triglycerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acids), synthetic fatty oils such as isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glyceride, wool alcohols such as cetylstearyl alcohol, wool fat, glycerol, propylene glycol, propylene glycol diesters of caprylic / capric acid, polyethylene glycol (PEG), semifluorinated alkanes (e.g. as described in WO 2011 / 113855), or mixtures thereof. Preferably, the non-aqueous pharma- ceutically acceptable vehicle used in the solution is hydrophobic.

[0330] Pharmaceutically acceptable excipients used in topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, stabilizers, surfactants, polymer-based carriers such as gelling agents, organic co-solvents, pH active ingredients, osmotically active ingredients, and preservatives.

[0331] Surfactants for use in the topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, lipids such as phospholipids, phosphatidylcholines, lecithins, cardiolipins, fatty acids, phosphatidylethanolamines, phosphatides, tyloxapol, polyethylene glycols and derivatives such as PEG 400, PEG 1500, PEG 2000, poloxamer 407, poloxamer 188, polysorbate 80, polysorbate 20, sorbitan laurate, sorbitan stearate, sorbitan palmitate, or mixtures thereof, preferably polysorbate 80. Suitable polymer-based carriers such as gelling agents for use in the topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase and derivatives, amylopectin and derivatives, dextran and derivatives, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and acrylic polymers such as HEMA, polyacrylic acid or polymethacrylic acid derivatives such as carbopol, and derivatives of the above, or mixtures thereof.

[0332] Suitable pH active ingredients, such as buffers or pH adjusters, for use in pharmaceutical compositions according to the invention include, but are not limited to, acetate buffers, borate buffers, carbonate buffers, citrate buffers, and phosphate buffers, including disodium phosphate, monosodium phosphate, boric acid, sodium borate, sodium citrate, hydrochloric acid, sodium hydroxide. The pH active ingredients are selected based on the target pH for the composition, which is generally in the range of pH 4 to 9. In certain embodiments, the sustained release formulations comprising a compound of Formula I-III or a pharma- ceutically acceptable salt thereof have a pH of approximately between 5 and 8, between 5.5 and 7.4, between 6 and 7.5, or between 6.5 and 7. In one embodiment, the formulation comprises a citrate buffer at a pH of approximately 6.5 to 7. In another embodiment, the formulation comprises a phosphate buffer at a pH of approximately 6.5 to 7. Suitable osmotically active ingredients for use in pharmaceutical compositions according to the invention include, but are not limited to, sodium chloride, mannitol, and glycerol.

[0333] Organic co-solvents for use in the pharmaceutical compositions according to the present invention include, but are not limited to, ethylene glycol, propylene glycol, N-methylpyrrolidone, 2-pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, dimethyl glycol monomethyl ether, diethylene glycol monomethyl ether, solketal, glycerol, polyethylene glycol, polypropylene glycol.

[0334] Preservatives used in pharmaceutical compositions according to the present invention include, but are not limited to, benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propylparaben, chlorhexidine digluconate, EDTA, or mixtures thereof.

[0335] If desired, a viscosity agent can be added to the pharmaceutical composition to increase the viscosity of the composition.Examples of useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamides, polyvinyl alcohols (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof, and mixtures thereof.In one embodiment, the viscosity agent is hyaluronic acid, and the hyaluronic acid is crosslinked.In one embodiment, the viscosity agent is hyaluronic acid, and the hyaluronic acid is linear.

[0336] The topical dosage form can be administered, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), once every two days (Q2d), once every three days (Q3d), or any dosing schedule that results in the treatment of the disorders described herein, as needed. Alternatively, the sustained release formulation can be prepared for extended delivery, such as every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks or more, or every month, every two months, every three months, every four months, every five months, or every six months or more or less.

[0337] In certain non-limiting embodiments, the pharmaceutical composition is in an ophthalmic dosage form comprising a sustained release formulation of a compound of Formula I-III or a pharma- ceutical acceptable salt thereof comprising about 0.005 mg to about 5 mg, about 0.003 mg to about 3 mg, about 0.001 mg to about 1 mg, about 0.05 mg to about 0.5 mg, about 0.03 mg to about 0.3 mg, or about 0.01 mg to about 0.1 mg, or about 0.01 mg to about 0.05 mg of levcromakalim.

[0338] In certain embodiments, the ophthalmic solution contains approximately 0.1% to 5.0% of the sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, measured in mg / mL. In certain embodiments, the ophthalmic solution contains approximately 5% to 30% of the compound of Formula I-III, measured in mg / mL. In certain embodiments, the solution contains approximately 0.2% to 4.5%, 0.3% to 3.0%, 0.4% to 2.0%, or 0.5% to 1.5% of the compound of Formula I-III, measured in mg / mL. In certain embodiments, the solution contains at least 10%, at least 8%, at least 5%, at least 4%, at least 3%, at least 2%, at least 1%, at least 0.9%, at least 0.7%, at least 0.5%, at least 0.3%, or at least 0.1% of the sustained release formulation of a compound of Formula I-III. In other embodiments, the solution comprises at least 30%, at least 25%, at least 20%, or at least 15% of a compound of Formula I-III. In certain embodiments, the solution comprises a sustained release formulation of a compound of Formula I-III or a salt thereof comprising approximately 0.2%, 0.4%, or 0.8% levcromakalim. In certain embodiments, the solution comprises at least approximately 0.5%, 1%, or 2% of a sustained release formulation of a compound of Formula I-III or a salt thereof.

[0339] In alternative embodiments, the ophthalmic solution comprises a sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, comprising approximately 0.01%-5.0% levcromakalim, measured in mg / mL. In certain embodiments, the solution comprises approximately 0.01%-3%, 0.01%-1.0%, 0.01%-0.5%, 0.01%-0.1%, 0.01%-0.08%, or 0.01%-0.05% of a compound of Formula I-III, measured in mg / mL.

[0340] In other embodiments, the liquid formulation has a concentration of the sustained release formulation of the compound of Formula I-III or a pharma- ceutically acceptable salt thereof, including levcromakalim, in the range of about 2.5 mM to 500 mM. In certain embodiments, the concentration is no more than about 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 50 mM, 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, 20 mM, 15 mM, 10 mM, 8 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2.5 mM, 2.0 mM, 1.5 mM, or 1.0 mM.

[0341] In alternative embodiments, the solution has a concentration of the sustained release formulation of a compound of Formula I-III or a pharma- ceutically acceptable salt thereof, including levcromakalim, in the range of about 0.1 mM to 2.5 mM. In certain embodiments, the concentration does not exceed about 1.0 mM, 0.9 mM, 0.8 mM, 0.7 mM, 0.6 mM, 0.5 mM, 0.4 mM, 0.3 mM, 0.2 mM, or 0.1 mM.

[0342] In certain embodiments, the concentration of the sustained release formulation of the compound of Formula I-III or a pharma- ceutically acceptable salt thereof, including levcromakalim, is in the range of about 0.2% to 2% (corresponding to a 5 mM to 52 mM solution). In certain embodiments, the concentration is at least 0.2% (corresponding to 5 M), at least 0.4% (corresponding to 10 mM), at least 0.5% (corresponding to 12.5 mM), at least 0.8% (corresponding to 20 mM), at least 1% (corresponding to approximately 25 mM), or at least 2% (corresponding to approximately 50 mM).

[0343] In alternative embodiments, the concentration of the sustained release formulation of the compound of Formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, ranges from about 0.02% to 0.2%. In one embodiment, the concentration is at least 0.02%, at least 0.04%, at least 0.05%, at least 0.08%, at least 0.1%, or at least 0.2%.

[0344] The sustained release formulation of the compound of formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, may also be used in ophthalmic therapy using alternative routes, i.e., intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, periocular, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, posterior juxtascleral, pericornal, or lacrimal injection, or through a mucus, mucin, or mucosal barrier, in an immediate or controlled release manner, or via an ophthalmic device, or injection. In one embodiment, the ophthalmic device is a contact lens that releases the sustained release formulation of the compound of formula I-III, including levcromakalim, or a pharma-ceutically acceptable salt thereof.

[0345] In one embodiment, the sustained release formulation of the compound of Formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, is administered via suprachoroidal injection.Suprachoroidal delivery is described in U.S. Pat. No. 9,636,332, U.S. Pat. No. 9,539,139, U.S. Pat. No. 10,188,550, U.S. Pat. No. 9,956,114, U.S. Pat. No. 8,197,435, U.S. Pat. No. 7,918,814, and WO 2012 / 051575, WO 2015 / 095772, WO 2018 / 031913, WO 2017 / 192565, WO 2017 / 190142, WO 2017 / 120601, and WO 2017 / 120600.

[0346] A device for minimally invasive delivery of drugs to the suprachoroidal space may include a needle that directly injects drugs or drug-containing materials into the suprachoroidal space. The device may also include an element that advances the needle through the conjunctiva and scleral tissue into the suprachoroidal space or immediately adjacent to the suprachoroidal space without puncturing or trauma to the inner choroidal layer. The location of the tip of the delivery device may be confirmed by non-invasive imaging such as ultrasound or optical coherence tomography, external depth markers or stops on the tissue contacting portion of the device, depth or position sensors built into the device, or a combination of such sensors. For example, the delivery device may include a sensor at the tip, such as a light guide or ultrasound sensor, that measures choroidal depth and position, or a pressure transducer that measures the change in local fluid pressure due to entry into the suprachoroidal space. In certain embodiments, the suprachoroidal injection is performed using a 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge thin-walled or regular-walled needle. In alternative embodiments, the suprachoroidal injection is performed using a 31 gauge, 32 gauge, or 33 gauge thin or regular walled needle. In further alternative embodiments, the suprachoroidal injection is performed using a 34 gauge or smaller thin or regular walled needle.

[0347] Additional non-limiting examples of methods of delivering active compounds are described in WO 2015 / 085251 (Envisia Therapeutics, Inc.), entitled "Intracameral Implant for Treatment of an Ocular Condition"; WO 2011 / 008737 (Engineered Aerosol Particles, and Associated Methods), entitled "Engineered Aerosol Particles, and Associated Methods," WO 2013 / 082111 (Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses), and WO 2014 / 082112 (Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting molds). WO 2009 / 132265 entitled "Interventional drug delivery systems and associated methods," WO 2010 / 099321 entitled "Interventional drug delivery systems and associated methods," WO 2008 / 100304 entitled "Polymer particle composite having high fidelity order, size, and shape particles," WO 2007 / 024323 entitled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc.and the University of North Carolina at Chapel Hill; WO 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" and WO 2009 / 132206 entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo", WO 2007 / 133808 entitled "Nano-particles for cosmetic applications", WO 2007 / 056561 entitled "Medical device, materials, and methods" and WO 2007 / 056561 entitled "Method for producing patterned materials" These techniques are presented in WO 2010 / 065748 entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.) and WO 2007 / 081876 entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0348] In one embodiment, the sustained release formulation of the compound of Formula I-III is stored as a depot in the tissue and then slowly released over time, where it is converted to levcromakalim to induce an IOP lowering effect. In one embodiment, the sustained release formulation of the compound of Formula I-III is stored in the trabecular meshwork and then slowly released into the proximal-distal outflow pathway. In one embodiment, the return to baseline IOP following administration of the sustained release formulation of the compound of Formula I-III in a host in need thereof, including a human, is at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, or at least about 72 hours.

[0349] Local or transdermal delivery Administration of the sustained release formulations of the compounds of Formula I-III, including levcromakalim, or pharma- ceutically acceptable salts, can also include topical or transdermal administration. Pharmaceutical compositions suitable for topical application to the skin can take the form of gels, ointments, creams, lotions, pastes, sprays, aerosols, or oils, and can optionally include petroleum jelly, lanolin, polyethylene glycol, alcohol, or combinations thereof.

[0350] Pharmaceutical compositions suitable for transdermal administration may be provided as separate patches adapted to remain in close contact with the epidermis of the recipient for extended periods of time. Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), typically taking the form of an optionally buffered aqueous solution of active compound. In one embodiment, a microneedle patch or device is provided for drug delivery across or into biological tissue, particularly the skin. The microneedle patch or device allows drug delivery across or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0351] Advantageously, the composition may contain, but is not limited to, conditioning agents, skin protectants, other antioxidants, UV absorbers, sunscreen actives, cleansing agents, viscosity modifiers, film formers, emollients, surfactants, solubilizers, preservatives, fragrances, chelating agents, foaming or defoaming agents, opacifiers, stabilizers, pH adjusters, absorbents, anti-caking agents, slip improvers, various solvents, solubilizers, denaturants, abrasives, weighting agents, emulsion stabilizers, suspending agents, colorants, binders, conditioning agents-emollients, surfactant emulsifiers, biological materials, anti-acne actives, anti-wrinkle and anti-skin atrophy actives, skin barrier repair aids, cosmetic soothing ... A wide variety of skin care actives and inactive ingredients may be combined with the compounds according to the present invention, including topical anesthetics, artificial tanning agents and accelerators, skin lightening actives, antimicrobial and antifungal actives, sebum stimulators, sebum inhibitors, moisturizers, and / or combinations thereof.

[0352] In general, conditioning agents can be used to improve the appearance and / or feel of the skin through moisturizing, hydrating, plasticizing, lubricating, and occlusive, or combinations thereof, during and after topical application. Non-limiting examples of conditioning ingredients include, but are not limited to, mineral oil, petrolatum, C7-C 40 Branched chain hydrocarbons, C1-C 30 Carboxylic Acid C1-C 30 Alcohol esters, C2-C 30 Dicarboxylic acids C1-C 30 Alcohol esters, C1-C 30 Monoglycerides of carboxylic acids, C1-C 30 Diglycerides of carboxylic acids, C1-C 30 Triglycerides of carboxylic acids, C1-C 30 Ethylene glycol monoesters of carboxylic acids, C1-C 30 Ethylene glycol diesters of carboxylic acids, C1-C 30 Propylene glycol monoesters of carboxylic acids, C1-C 30 Propylene glycol diesters of carboxylic acids, C1-C sugars 30Carboxylic acid monoesters and polyesters, polydialkylsiloxanes, polydiarylsiloxanes, polyalkarylsiloxanes, cyclomethicones with 3 to 9 silicon atoms, vegetable oils, hydrogenated vegetable oils, polypropylene glycols C4 to C 20 Alkyl ether, diC8~C 30 Non-limiting examples of linear and branched chain hydrocarbons having from about 7 to about 40 carbon atoms include, but are not limited to, dodecane, isododecane, squalane, cholesterol, hydrogenated polyisobutylene, docosane, hexadecane, isohexadecane, C7-C8 alkyl ethers, and mixtures thereof. 40 Isoparaffin, C1-C 30 Monoglycerides of carboxylic acids, C1-C 30 Diglycerides of carboxylic acids, C1-C 30 Triglycerides of carboxylic acids, C1-C 30 Ethylene glycol monoesters of carboxylic acids, C1-C 30 Ethylene glycol diesters of carboxylic acids, C1-C 30 Propylene glycol monoesters of carboxylic acids, and C1-C 30 Included are propylene glycol diesters of carboxylic acids, including linear, branched, and aryl carboxylic acids, as well as the propoxylated and ethoxylated derivatives of these materials.

[0353] Non-limiting examples of sugars include sucrose, mannitol, trehalose, glucose, arabinose, fucose, mannose, rhamnose, xylose, D-xylose, glucose, fructose, ribose, D-ribose, galactose, dextrose, dextran, lactose, maltodextrin, maltose, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, aspartame, saccharin, stevia, sucralose, acesulfame potassium, advantame, alitame, neotame, and sucralose.

[0354] Non-limiting examples of sunscreens useful in the composition include 4-N,N-(2-ethylhexyl)methylaminobenzoic acid esters of 2,4-dihydroxybenzophenone, 4-N,N-(2-ethylhexyl)methylaminobenzoic acid esters with 4-hydroxydibenzoylmethane, 4-N,N-(2-ethylhexyl)-methylaminobenzoic acid esters of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone, 4-N,N-(2-ethylhexyl)-methylaminobenzoic acid esters of 4-(2-hydroxyethoxy)dibenzoylmethane, acid esters, 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p-aminobenzoate, p-aminobenzoic acid, 2-phenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone, homomenthyl salicylate, octyl salicylate, 4,4'-methoxy-t-butyldibenzoylmethane, 4-isopropyldibenzoylmethane, 3-benzylidene camphor, 3-(4-methylbenzylidene) camphor, titanium dioxide, zinc oxide, silica, iron oxide, and mixtures thereof. Other useful sunscreens include 4-aminobenzoic acid (PABA), benzylidene camphor, butyl methoxydibenzoylmethane, diethanolamine p-methoxycinnamate, 5 dioxybenzone, ethyl dihydroxypropyl PABA, glyceryl aminobenzoate, homomenthyl salicylate, isopropyl dibenzoylmethane, lawsone and dihydroxyacetone, menthyl anthranilate, methyl anthranilate, methyl benzylidene camphor, octocrylene, octyl dimethyl PABA, octyl methoxycinnamate, oxybenzone, 2-phenylbenzimidazole-5-sulfonic acid, red petrolatum, sulisobenzone, titanium dioxide, triethanolamine salicylate, zinc oxide, and mixtures thereof.

[0355] The exact amount of sunscreen that can be used will vary depending on the sunscreen chosen and the sun protection factor (SPF) desired to be achieved.

[0356] If desired, viscosity agents can be added to topical formulations to increase the viscosity of the composition.Examples of useful viscosity agents include, but are not limited to, water-soluble polyacrylic resins and hydrophobically modified polyacrylic resins such as Carbopol and Pemulen, starches such as corn starch, potato starch, and tapioca, gums such as guar gum and gum arabic, and cellulose ethers such as hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose.

[0357] A wide variety of emulsifiers are also useful, including, but not limited to, sorbitan esters, glyceryl esters, polyglyceryl esters, methyl glucose esters, sucrose esters, ethoxylated fatty alcohols, hydrogenated castor oil ethoxylates, sorbitan ester ethoxylates, polymeric emulsifiers, silicone emulsifiers, glyceryl monoesters, preferably C 16 ~C 22 Glyceryl monoesters of saturated, unsaturated, and branched chain fatty acids, such as glyceryl oleate, glyceryl monostearate, glyceryl monopalmitate, glyceryl monobehenate, and mixtures thereof; 16 ~C 22 Polyglyceryl esters of saturated, unsaturated and branched fatty acids, such as polyglyceryl-4 isostearate, polyglyceryl-3 oleate, diglycerol monooleate, tetraglycerol monooleate and mixtures thereof, methyl glucose esters, preferably C 16 ~C 22 Methyl glucose esters of saturated, unsaturated and branched fatty acids, such as methyl glucose dioleate, methyl glucose sesquiisostearate and mixtures thereof, sucrose fatty acid esters, preferably C 12 ~C 22 Sucrose esters of saturated, unsaturated, and branched fatty acids, such as sucrose stearate, sucrose laurate, sucrose distearate (e.g., CRODESTA® F10), and mixtures thereof; 12 ~C 22Ethoxylated fatty 5 alcohols such as oleth-2, oleth-3, steareth-2, and mixtures thereof, hydrogenated castor oil ethoxylates such as PEG-7 hydrogenated castor oil, sorbitan ester ethoxylates such as PEG-40 sorbitan peroleate, polysorbate-80, and mixtures thereof, polymeric emulsifiers such as ethoxylated dodecyl glycol copolymers, and silicone emulsifiers such as lauryl methicone copolyol, cetyl dimethicone, dimethicone copolyol, and mixtures thereof.

[0358] systemic delivery In another embodiment, the sustained release formulation of the compounds of formula I-III, including levcromakalim, or their pharma- ceutically acceptable salts, is administered via any systemic route that achieves the desired effect in an effective amount. Examples are enteral or parenteral administration, including oral, buccal, sublingual, intravenous, subcutaneous, intramuscular, intrathecal, or intranasal delivery, including solutions, suspensions, emulsions, or lyophilized powders. In some cases, the composition is dispensed or packaged in liquid form. Alternatively, the formulation may be packaged as a solid, for example obtained by lyophilization of a suitable liquid formulation. The solid may be reconstituted with a suitable carrier or diluent prior to administration. In one embodiment, the compound is administered vaginally via a suppository, cream, gel, lotion, or ointment.

[0359] Other modes of administration include oral, rectal, sublingual, sublabial, or buccal, and typical dosage forms for these routes include pills, tablets, capsules, solutions, suspensions, emulsions, or suppositories.

[0360] In one embodiment, the sustained release formulation of the compounds of Formula I-III, including levcromakalim, or their pharma- ceutically acceptable salts, is administered via the inhalation pulmonary route.Dosage forms for pulmonary drug delivery include propellants, non-aqueous inhalers, dry powder inhalers, and jet or ultrasonic nebulizers.

[0361] Oral Delivery In one aspect, the sustained release formulation of the compounds of Formula I-III, including levcromakalim, or a pharma- ceutically acceptable salt thereof, is administered orally. The sustained release formulation may be formulated using any desired technique, including formulating the sustained release formulation as a solvent-free chemical (e.g., powder, amorphous, non-crystalline form, or oil) or mixing the sustained release formulation with a pharma- ceutically acceptable excipient. The resulting pharma- ceutically acceptable composition for oral delivery comprises an effective amount of the sustained release formulation or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0362] Excipients A pharma-ceutically acceptable excipient should have a high enough purity and low enough toxicity to make it suitable for administration to the patient being treated. The excipient may be inert or may have its own pharmaceutical benefit. The amount of excipient used in combination with the compound is sufficient to provide a practical amount of material administered per unit dose of the compound. Classes of excipients include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavorings, glidants, lubricants, pH adjusters, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Exemplary pharma-ceutically acceptable excipients include sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, starch, gum, and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and buffers generally including mixtures of acids and salts of the acids. Optionally, other active agents may be included in the pharmaceutical composition as long as they do not substantially interfere with the activity of the compound of the present invention.

[0363] In certain embodiments, the excipient is selected from the group consisting of phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleylphosphatidylethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexanedecanol; fatty alcohols; polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate (Span™ 85); glycocholate; sorbitan monolaurate (Span™ 20); polysorbate 20 (Tween™ 20); polysorbate 60 (Tween™ 60); polysorbate 65 (Tween™ 65); polysorbate 20 (Tween™ 20); polysorbate 60 (Tween™ 60); polysorbate 65 (Tween™ 65); polysorbate 20 (Tween™ 20); polysorbate 2 ...20); polysorbate 60 (Tween™ 60); polysorbate 65 (Tween™ 65); poly Polysorbate 80 (Tween 80); Polysorbate 85 (Tween 85); Polyoxyethylene monostearate; Surfactin; Poloxamer; Sorbitan fatty acid esters such as sorbitan trioleate; Lecithin; Lysolecithin; Phosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiolipin; Phosphatidic acid; Cerebroside; Dicetyl phosphate; Dipalmitoyl phosphatase Phatidylglycerol;stearylamine;dodecylamine;hexadecylamine;acetyl palmitate;glycerol ricinoleate;hexadecyl stearate;isopropyl myristate;tyloxapol;poly(ethylene glycol) 5000-phosphatidylethanolamine;poly(ethylene glycol) 400-monostearate;phospholipids;synthetic and / or natural detergents with high surface active properties;deoxycholate;cyclodextrins;chaotropic salts;ion pairing agents;Glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid;Pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextrin, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pustulan, heparin, hyaluronic acid, curdlan and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, Pluronic® polymers, polyethylene, polycarbonates (e.g., poly(1,3-dioxane-2 -one), polyanhydrides (e.g. poly(sebacic anhydride)), polypropyl fumarate, polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters (e.g. polylactides, polyglycolides, polylactide-co-glycolides, polycaprolactones, polyhydroxy acids (e.g. poly(β-hydroxyalkanoates)), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes and polyamines, polylysine, polylysine-PEG copolymers and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monocaprylocaprate, propylene glycol, vitamin E selected from TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS);

[0364] Oral dosage form Typical dosage forms for oral administration include pills, tablets, capsules, gel capsules, liquids, suspensions, or emulsions. Dosage forms may also feature compartmentalization. For example, when the dosage form is a pill, tablet, or capsule, it may have layers of different materials with different excipients or excipients at different concentrations. For example, enteric-coated oral tablets may be used to enhance the bioavailability of the compound for oral administration routes. The enteric coating will be a layer of excipients that allows the tablet to withstand gastric acid. The most effective dosage form will depend on the bioavailability / pharmacokinetics of the particular agent selected, as well as the severity of the disease in the patient. Oral dosage forms are particularly preferred due to their ease of administration and the potential for favorable patient compliance.

[0365] In certain embodiments, the oral dosage form comprises one or more additional active agents described herein. In certain embodiments, the second active agent is administered separately from the compound of the invention.

[0366] In another embodiment, one dosage form can be converted into another dosage form to advantageously improve properties. For example, a suitable liquid formulation can be lyophilized to produce a solid pharma- ceutically acceptable composition. A solid can be reconstituted with a suitable carrier or diluent prior to administration.

[0367] Oral pharmaceutical compositions may contain any amount of active compound that achieves the desired result, e.g., from 0.1% to 99% by weight of the compound, usually at least about 5% by weight of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25% to about 50% by weight, or about 5% to about 75% by weight of the compound.

[0368] Oral dosage forms can be administered, for example, as needed, once daily (qd), twice daily (bid), three times daily (tid), four times daily (qid), once every two days (Q2d), once every three days (Q3d), or any dosing schedule that results in treatment of the disorders described herein.

[0369] General Synthesis of Compounds of the Invention and Their Pharmaceutically Acceptable Salts The described pharma- ceutically acceptable salts of the invention can be prepared according to known methods.

[0370] [ka]

[0371] The reaction of 4-cyanophenol (4-hydroxybenzonitrile) with 2-hydroxy-2-methyl-3-butyne under phase transfer catalysis almost certainly proceeds with the initial formation of a propargyl carbocation. This then attacks the aromatic ring, after which the resulting allylic cation can capture the adjacent phenolic oxygen, leading to the formation of the observed product (3), which can be predicted by assuming that it is possible. Treatment of the product with aqueous N-bromosuccinimide results in the addition of an element of hypobromous acid to form the bromohydrin (4) as a mixture of trans enantiomers. This cyclizes in the presence of sodium hydroxide to the epoxide 5 (5). Ring-opening of the oxirane with ammonia gives a mixture of trans amino alcohols (6). These are almost certainly resolved at this stage, with the 3S,4R-enantiomer being used in the next step. The isomer is then acylated with 4-chlorobutyl chloride to give the chloroamide (7). The anion resulting from reaction of this amide with sodium hydride then displaces the chlorine at the end of the chain to form a pyrrolidine ring, thus giving levcromakalim (8).

[0372] Pharmaceutically acceptable salts Salts of the compounds of formula I, formula II, or formula III described herein can be prepared by many known methods. These methods include, but are not limited to, reacting the compounds with alkali metal hydroxides or alkali metal alkoxides, such as NaOH, KOH, or NaOCH3, in various solvents that can be selected from, for example, low molecular weight ketones (e.g., acetone, methyl ethyl ketone, etc.), tetrahydrofuran (THF), dimethylformamide (DMF), and n-methylpyrrolidinone, etc. In one embodiment, the solvent is water. In another embodiment, the solvent is THF.

[0373] The compounds described herein can also form salts with organic cations that contain at least one tertiary amine or ammonium cation. The organic cation compounds can have a charge of +1, +2, +3, or +4 per molecule by including one, two, three, or four tertiary amine or ammonium ions, respectively, in the compound. When a multi-charge compound is used, the tertiary amine or quaternary ammonium moieties are preferably separated by a chain of at least four atoms, more preferably by a chain of at least six atoms, such as, for example, hexamethylhexamethylenediammonium dihydroxide, where the quaternary ammonium moieties are separated by -(CH2)6-.

[0374] Salts of the compounds described herein can be prepared by reacting the compounds with compounds containing at least one tertiary amine or quaternary ammonium ion (e.g., choline hydroxide, hexamethylhexamethylenediammonium dihydroxide) in a solvent selected from low molecular weight ketones (e.g., acetone, methyl ethyl ketone), tetrahydrofuran, dimethylformamide, and n-methylpyrrolidinone.Similar to the preparation of salts from alkali metal hydroxides, amine-containing and ammonium-containing compounds typically do not form salts when the solvent is alcohol.

[0375] Typically, basic addition salts of the compounds described herein may include those containing hexamethylhexamethylenediammonium, choline, sodium, potassium, methyldiethylamine, triethylamine, diethylaminoethanol, hydroxyethylpyrrolidine, tetrapropylammonium, and tetrabutylphosphonium ions.

[0376] Typically, the basic addition salts of the compounds described herein can be prepared using any suitable reagent, such as hexamethylhexamethylenediammonium dihydroxide, choline hydroxide, sodium hydroxide, sodium methoxide, potassium hydroxide, potassium methoxide, ammonium hydroxide, tetrapropylammonium hydroxide, or tetrabutylphosphonium hydroxide. The basic addition salts can be divided into inorganic salts (e.g., sodium, potassium, etc.) and organic salts (e.g., choline, hexamethylhexamethylenediammonium hydroxide, etc.).

[0377] Salts of the compounds described herein may contain organic or inorganic counterions, including, but not limited to, calcium, dimeglumine, dipotassium, disodium, meglumine, polystirex, or tromethamine. Suitable organic cations include compounds with tertiary amine or quaternary ammonium groups.

[0378] Pharmaceutically acceptable salts of the compounds described herein may also include basic addition salts, such as salts containing chloroprocaine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, and alkylamines. See, e.g., Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, Pa., Vol. 2, p. 1457, 1995.

[0379] Salts of the compounds described herein can be prepared, for example, by dissolving the free base form of the compound in an appropriate solvent, such as an aqueous or aqueous alcoholic solution containing the appropriate acid, and then isolating by evaporating the solution. In another example, a salt is prepared by reacting the free base and an acid in an organic solvent.

[0380] Solvents useful for preparing pharma- ceutically acceptable salts of the compounds described herein include organic solvents such as, for example, acetonitrile, acetone, alcohols (e.g., methanol, ethanol, and isopropanol), tetrahydrofuran, methyl ethyl ketone (MEK), ethers (e.g., diethyl ether), benzene, toluene, xylene, dimethylformamide (DMF), and N-methylpyrrolidinone (NMP), etc. In one embodiment, the solvent is selected from acetonitrile and MEK.

[0381] In certain embodiments, the salts described herein can be formed via ion exchange chromatography. When ion exchange chromatography is used, the resulting cations are those that were present in the ion exchange wash solution.

[0382] For example, sodium or potassium salts (shown below) can be produced by obtaining the salt using NaHCO3, or K2CO3, KHCO3, or KOH.

[0383] [ka]

[0384] For example, ammonium salts can be generated by using (NH4)2CO3 or NH4OH to obtain the salt.

[0385] [ka]

[0386] For example, calcium salts can be produced by using CaCO3 or Ca(OH)2 to obtain the salt.

[0387] [ka]

[0388] For example, the calcium salt can be produced by substituting 1M NaHCO3 with 1M Li2CO3 or LiOH to give the salt.

[0389] [ka]

[0390] Other column materials, salt washes, and concentrations can be utilized if desired.

[0391] Synthetic Salt Formation In certain embodiments, the phosphate esters described herein can be formed by direct chemical reaction instead of ion exchange. For example, to produce the sodium salt of the compounds described herein, the acid form of the compound can be reacted in a reaction vessel with an aqueous or base solution such as NaOH, NaHCO3, Na2CO3, or sodium acetate. In certain embodiments, other aqueous solutions can be used, such as potassium hydride, lithium hydride, calcium hydride, acetates, sulfates, phosphates, and the like.

[0392] In certain embodiments, chemical reactions can occur when the equivalent ratio is the same, for example, 1:1 ratio, or when the equivalent ratio is different, for example, 1:10, 1:5, 1:3, 1:2, or 1:1.5 ratio of CKLP1 to cation source. The concentration of salt in the solution can vary. For example, chemical reactions can occur when the sample is washed with 1M NaHCO3 aqueous solution, but also when the sample is washed with less than 1M or more than 1M NaHCO3 aqueous solution, if desired. This change in equivalent can also be applied to chemical reactions involving other salts or base solutions, if desired, to obtain the salt of the present invention.

[0393] Alternatively, other salts can be prepared from: (a) metal hydroxides, such as any alkali metal hydroxide (e.g., NaOH and KOH), divalent metals (magnesium, calcium, etc.), and (b) organic hydroxides, such as organic compounds containing at least one tertiary amine, ammonium group, or at least one quaternary ammonium ion (e.g., diethylaminoethanol, triethylamine, hydroxyethylpyrrolidine, choline, and hexamethylhexamethylenediammonium, etc.).

[0394] This specification has been described with reference to embodiments of the present invention. However, those skilled in the art will appreciate that various variations and modifications can be made without departing from the scope of the invention described herein. Thus, this specification should be regarded as illustrative rather than restrictive, and such variations are intended to be included within the scope of the present invention.

Claims

1. Cromakalim of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. The sustained-release pharmaceutical composition of claim 1, wherein the cromakalim is substantially in a levorotatory configuration.

3. The sustained-release pharmaceutical composition of claim 1, wherein the cromakalim is a mixture of levorotatory and dextrorotatory configurations.

4. A sustained-release pharmaceutical composition as described in claim 3, wherein the mixture of levorotatory cromakalim and dextrorotatory cromakalim is racemic.

5. The sustained release pharmaceutical composition of claim 1, wherein the compound is formulated in biodegradable microparticles.

6. The sustained-release pharmaceutical composition of claim 5, wherein the biodegradable microparticles have an average diameter of about 0.5 μm to about 100 μm.

7. The sustained-release pharmaceutical composition of claim 6, wherein the biodegradable microparticles have an average diameter of about 0.5 μm to about 10 μm.

8. The sustained-release pharmaceutical composition of claim 6, wherein the biodegradable microparticles have an average diameter of about 10 μm to about 30 μm.

9. The sustained-release pharmaceutical composition of claim 6, wherein the biodegradable microparticles have an average diameter of about 30 μm to about 70 μm.

10. The sustained-release pharmaceutical composition of claim 6, wherein the biodegradable microparticles have an average diameter of about 10 μm to about 50 μm.

11. The sustained release pharmaceutical composition of claim 1, wherein the compound is formulated in biodegradable nanoparticles.

12. The sustained-release pharmaceutical composition of claim 11, wherein the biodegradable nanoparticles have an average diameter of about 0.5 nm to about 100 nm.

13. The sustained release pharmaceutical composition of claim 12, wherein the biodegradable nanoparticles have an average diameter of about 0.5 nm to about 10 nm.

14. The sustained-release pharmaceutical composition of claim 12, wherein the biodegradable nanoparticles have an average diameter of about 10 nm to about 30 nm.

15. The sustained-release pharmaceutical composition of claim 12, wherein the biodegradable nanoparticles have an average diameter of about 30 nm to about 70 nm.

16. The sustained-release pharmaceutical composition of claim 12, wherein the biodegradable nanoparticles have an average diameter of about 10 nm to about 50 nm.

17. Formula I includes Formula IA, Formula IB, and Formula IC: 【Chemistry 2】 (In the formula, X ＋ and M ２＋ is a pharmaceutically acceptable cation, and Z ＋ is X ＋ (a mixed salt cation of The sustained release pharmaceutical composition of claim 1, wherein the sustained release pharmaceutical composition is selected from the group consisting of:

18. X ＋ Cations include sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, cesium, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanolamine, triethylamine, and the formula: 【Chemistry 3】 and an ammonium ion of the formula: 【Chemistry 4】 (In the formula, R １ is C １ ~C ６ selected from alkyl and aryl 18. The sustained release pharmaceutical composition of claim 17, wherein the ammonium ion is selected from the group consisting of:

19. M ２＋ 18. The sustained release pharmaceutical composition of claim 17, wherein is selected from alkaline earth metal cations, metal cations, and ammonium ions.

20. The sustained-release pharmaceutical composition of claim 1, wherein the microparticle or nanoparticle formulation is formed using solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, or low-temperature casting.

21. A sustained release pharmaceutical composition for treating an eye disorder, comprising the sustained release pharmaceutical composition described in any one of claims 1 to 20.

22. The sustained-release pharmaceutical composition of claim 21, wherein the ocular disorder is selected from Graves' ophthalmopathy, cavernous sinus thrombosis, orbital venous vasculitis, carotid-cavernous sinus fistula, orbital varicose veins, central retinal vein occlusion, branch retinal vein occlusion, and non-arteritic anterior ischemic optic neuropathy.

23. The sustained-release pharmaceutical composition of claim 21, wherein the eye disorder is glaucoma.

24. The sustained-release pharmaceutical composition of claim 23, wherein the glaucoma is associated with elevated intraocular pressure.

25. The sustained-release pharmaceutical composition of claim 23, wherein the glaucoma is primary open-angle glaucoma.

26. The sustained-release pharmaceutical composition described in claim 23, wherein the glaucoma is normal-tension glaucoma.

27. The sustained-release pharmaceutical composition of claim 23, wherein the glaucoma is primary angle-closure glaucoma.

28. The sustained-release pharmaceutical composition described in claim 23, wherein the glaucoma is uveitic glaucoma.

29. The sustained-release pharmaceutical composition of claim 21, wherein the eye disorder is Sturge-Weber syndrome.

30. A sustained-release pharmaceutical composition as described in claim 21, which does not cause significant hyperemia.

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