WO2008027341A2 - Topical ophthalmic formulations - Google Patents

Abstract

This invention relates to ophthalmic pharmaceutical emulsion formulations that drastically increases the ocular exposure of highly insoluble active drug agents, exhibit sufficient physical stability and permit easy re-dispersion of insoluble drug particles, thus yielding greater uniformity of drug dosing. This invention further relates to ophthalmic emulsion formulation wherein the active drug agent is a low-solubility Maxi-K channel blocker and includes an oil, surfactant and tonicity agent.

Description

TITLE OF THE INVENTION

TOPICAL OPHTHALMIC FORMULATIONS

BACKGROUND OF THE INVENTION Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.

There are several therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal. Recently potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see US Patent Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719). In general, a simple ophthalmic solution pharmaceutical composition is preferred.

However, in the case of highly insoluble compounds (i.e., solubility in water is only several micrograms per mL or less), such as the Maxi-K channel blockers described herein, solution formulations are severely limited by the low solubility of these compounds. Emulsion compositions may therefore be a chosen method of formulation. This invention provides for ophthalmic emulsion formulations which can increase the ocular exposure of compounds with low aqueous solubility.

SUMMARY OF THE INVENTION

This invention relates to ophthalmic emulsion formulations that increase the ocular exposure of the active drug agent, and exhibit sufficient physical stability, thus yielding greater uniformity of drug dosing. This invention further relates to ophthalmic emulsion formulation wherein an active drug agent is a low-solubility Maxi-K channel blocker. More particularly this invention relates to ophthalmic emulsion formulations comprising a Maxi-K channel blocker having the structural formula I:

Fo a I or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof: wherein,

R represents hydrogen, or C] -6 alkyl;

X represents -(CHR.7)_p-, -(CHR7)_pCO-;

Y represents -CO(CH2)rr, CH2, or -CH(OR)-;

Q represents CRY; Ry represents H, or C i -6 alkyl;

R_w represents H, C\-6 alkyl, -C(O)Ci_6 alkyl, -C(O)OCi_6 alkyl, -SO2N(R)2, -SO2C1-6 alkyl, -SO2C6-IO aryl, NO₂, CN or -C(O)N(R)₂;

R2 represents hydrogen, Ci- 10 alkyl, OH, C2-6 alkenyl, Cl -6 alkylSR, -(CH2)_nO(CH2)mOR, - (CH2)_nCl-6 alkoxy, -(CH2)_nC3-8 cycloalkyl, -(CH2)_nC3-10 heterocyclyl, -N(R)2, -COOR, or - (CH2)nC6-10 aryl. said alkyl, heterocyclyl, or aryl optionally substituted with 1-3 groups selected from R^a;

R3 represents hydrogen, Cl -iθ alkyl, -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, - (CH₂)nCOOR, -(CH₂)_nC₆-10 aryl, -(CH₂)_nNHR8, -(CH₂)_nN(R)2, -(CH₂)_nN(R8)2, - (CH2)nNHCOOR, -(CH2)_nN(R8)Cθ2R, -(CH2)_nN(R8)COR, -(CH2)_nNHCOR, - (CH₂)nCONH(R8), aryl, -(CH₂)_nCl-6 alkoxy, CF₃, -(CH₂)_nSθ2R, -(CH₂)nSθ2N(R)2, -

(CH2)_nCON(R)2, -(CH2)_nCONHC(R)3, -(CH2)_nCONHC(R)2Cθ2R, -(CH2)_nCOR8, nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-3 groups of Ra; or R2 and R3 taken together with the intervening Q form a 3-10 membered carbocyclic or heterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra; or R2 and R3 taken together with the intervening Q represent OR; R4 and R5 independently represent hydrogen, Cl -6 alkoxy, OH, Ci_6 alkyl, COOR, SOqCi_-6 alkyl, COCi-6 alkyl, SO3H, -O(CH2)_nN(R)2, -O(CH₂)_nCO₂R, -OPO(OH)₂, CF3, OCF3 - N(R)₂, nitro, cyano, Ci_6 alkylamino, or halogen; and

R6 represents hydrogen, Ci-io alkyl, -(CH2)nC6-10 aryl, NR₀Rd. -NR(CH2)nC6-10 aryl, - N((CH2)nC6-10 aryl)₂, -(CH2)_nC3-10 heterocyclyl, -NR(CH2)_nC3-10 heterocyclyl, - N((CH2)_nC3-10 heterocyclyl)2 (C6-10 aryl)O-, -(CH2)_nC3-8 cycloalkyl, -COOR, -C(O)CO₂R, said aryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from R^a, wherein the Ra(s) can be attached to any carbon atom or heteroatom selected from N and S;

Rc and Rd independently represent H, C 1-6 alkyl, C2-6 alkenyl, Cl -6 alkylSR, - (CH2)nO(CH2)_mOR, -(CH2)nCl-6 alkoxy, or -(CH2)_nC3-8 cycloalkyl;

or Rc and Rd taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra;

R7 represents hydrogen, Cl -6 alkyl, -(CH2)_nCOOR or -(CH2)_nN(R)2,

Rs represents -(CH2)nC3-8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Ci -6 alkoxy or -(CH₂)_nC5- 10 heteroaryl, -(CH2)nC6-10 aryl said heterocyclyl, aryl or heteroaryl optionally substituted with 1 -3 groups selected from Ra;

Ra represents F, Cl, Br, I, CF₃, N(R)₂, NO₂, CN, -O-, -COR8, -CONHRs, -CON(Rs)₂, - O(CH₂)_nCOOR, -NH(CH2)_nOR, -COOR, -OCF3, CF₂CH₂OR, -NHCOR, -SO₂R, -SO₂NR₂, - SR, (C₁-C₆ alkyl)O-, -(CH₂)_nO(CH₂)_mOR, -(CH₂)_nCi_₆ alkoxy, (aryl)O-, -(CH₂)_nOH, (C₁- C₆ alkyl)S(O)_m-, H₂N-C(NH)-, (C₁-C₆ alkyl)C(O)-, (C₁-C₆ alkyl)OC(O)NH-, -(C₁-C₆ alkyl)NR_w(CH₂)_nC3-iθ heterocyclyl-R_w, -(C₁-C₆ alkyl)O(CH₂)_nC3-l0 heterocyclyl-R_w, -(C₁- C₆ alkyl)S(CH2)_nC3-10 heterocyclyl-R_w, -(C₁-C₆ alkyl)-C3-io heterocyclyl-R_w, -(CH₂)_n-Zl- C(=Z2)N(R)₂, -(C₂-6 alkenyl)NR_w(CH₂)_nC3-l O heterocyclyl-R_w, -(C₂-6 alkenyl)O(CH₂)_nC3- 10 heterocyclyl-R_w, -(C₂-6 alkenyl)S(CH₂)_nC3-i0 heterocyclyl-R_w, -(C₂-6 alkenyl)-C3_io heterocyclyl-R_w, -(C₂_6 alkenyl)-Zl-C(=Z2)N(R)₂, -(CH2)_nSO₂R, -(CH₂)_nSθ3H, - (CH₂)_nPO(OR)2, Cs-iocycloalkyl, C6-10 aryl, C3-10 heterocyclyl, C₂-6 alkenyl, and C₁-C₁₀ alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C₁-C₆ alkyl, halogen, (CH2)_nOH, CN, NO2, CON(R)2 and COOR;

Zl and Z2 independently represents NR_W, O, CH2, or S; m is 0-3; n is 0-3; p is 0-3 and q is 0-2

and a vehicle. This and other aspects of the invention will be realized upon inspection of the invention as a whole.

DETAILED DESCRIPTION OF THE INVENTION

Potassium channel blockers may be used for the treatment of ocular hypertension. However, certain potassium channel blockers such as those described herein are practically insoluble (sub microgram per mL) in water across the entire pH range. This presents a significant challenge to formulate these compounds in a pharmaceutically acceptable ophthalmic preparation and deliver the compound to the site of action. Various surfactants (including but not limited to poloxamer 407, polysorbate 80, and Cremophor EL), co-solvents (including but not limited to PEG400, propylene glycol, and glycerol), and complexation agents (including but not limited to different derivatized β-cyclodextrin), were investigated to improve the aqueous solubility with limited success. Much effort was focused to significantly enhance the ocular exposure (the active concentration in aqueous humor). It was discovered that emulsion formulations were able to drastically increase the ocular exposure of the Maxi-K channel blocker by up to about 30 fold or more over clinical solution formulations containing the same compound..

For purposes of this invention, highly insoluble compounds are those that exhibit, solubility in water typically about one microgram per mL. Low solubility and highly insoluble are terms used interchangeably herein. The instant emulsion formulations are also applicable with compounds that have solubility of several milligrams/mL. The emulsion formulations disclosed herein comprise using active pharmaceutical ingredients such as the compounds of formula I.

The vehicle components of the emulsion formulation contain oils, such as long- chain triglycerides ( including but not limited to castor oil, soybean oil, corn oil, flaxseed oil, cottonseed oil, coconut oil, canola oil, argan oil, palm oil, peanut oil, and other vegetable oils), and/or medium-chain triglycerides (including but not limited to caprylic/capric triglycerides (e.g. Miglyol 812®), and/or mono- and di-glycerides (including but not limited to caprylic/capric mono- and di- glycerides, e.g. Imwitor 742®). In addition, one or more surfactants, including but not limited to polysorbate 80, lecithin, poloxamers, Cremophor EL, and other poly(ethylene glycol)-based surfactants are also used in the formulation to effectively emulsify the system. The formulations may also contain tonicity agents (including but not limited to glycerol, mannitol and sodium chloride) to adjust the formulation osmolality; buffers (including but not limited to phosphate, citrate, and tromethamine buffers); and preservatives, including but not limited to benzalkonium chlorides, benzododecinium bromide, and chlorobutanol. Polymeric emulsion stabilizers such as polyacrylic acid polymers (e.g. Carbopol®) can also be added to improve the formulation stability.

The oil content can vary from about 0.5% to about 5% relative to the total volume of the formulation.

Table 1 below provides examples of non-limiting excipients and amount (percentage = w/v% of the total formulation; l%=10mg/mL of the active drug agent) the emulsion may optionally contain:

tromethamine (tris) buffer 0.09%-0.94% tyloxapo! solubilizer 0.05%-0.1%

The excipients listed in Table 1 can be utilized in combinations to arrive at a emulsion formulation which yields increased ocular exposure of the active drug agent up to about 30 fold or more over solution formulations.

Phosphate (~0.2 - 1% (w/v)) and citrate buffers (~0.2 - 2.2% (w/v)) such as sodium phosphate, potassium phosphate sodium phosphate monobasic dehydrate, sodium phosphate dibasic and the like, and sodium citrate, potassium citrate, and the like can be used in the formulation to adjust the microsuspension formulation to about neutral. Water is added (qs) to a desired volume or weight as one skilled in the art can readily appreciate.

Examples of compounds to be used in this invention are found in Tables 2 and 3

Tables 2 and 3:

Table 3

wherein R₁ is

or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof.

The invention is described herein in detail using the terms defined below unless otherwise specified.

The compounds used in this invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S.H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190) When any variable (e.g. aryl, heterocycle, R*, R^ etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds. When R^a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which are fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkenyl is C2-C6 alkenyl.

Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like. Halogen (halo) refers to chlorine, fluorine, iodine or bromine.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Examples of aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl. The term heterocyclyl or heterocyclic, as used herein, represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamoφholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. Preferably, heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

The term "heteroatom" means O, S or N, selected on an independent basis. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof with a emulsion formulation containing a compound, of formula I in combination with a β -adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol, a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140 and WO 01/72268), a prostaglandin such as latanoprost, travaprost, unoprostone, rescula, S1033 (compounds set forth in US Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151 ,444); a hypotensive lipid such as lumigan and the compounds set forth in US Patent No. 5,352,708; a neuroprotectant disclosed in US Patent No. 4,690,931, particularly eliprodil and R-eliprodil as set forth in WO 94/13275, including memantine; or an agonist of 5-HT2 receptors as set forth in PCT/USOO/31247, particularly l-(2-aminopropyl)-3-methyl-lH-irndazol-6-ol fumarate and 2-(3- chloro-6-methoxy-indazol- 1 -yl)- 1 -methyl-ethylamine. An example of a hypotensive lipid (the carboxylic acid group on the α-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a C_{1 -6} alkoxy group such as OCH₃ (PGF_2a 1-OCH₃), or a hydroxy group (PGF_2a 1-OH).

Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.

The present invention is based upon the finding that maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower

IOP. This finding suggests that maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the emulstions of this invention are useful for treating macular edema and/or macular degeneration. It is believed that maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering IOP, which when coupled together benefits optic nerve health. As a result, this invention further relates to use of the emulsions of this invention for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof. For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compounds used in the present invention are acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts, more preferred are monosodium and disodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N.N¹- dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanoI, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

When the compounds used in the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al. , "Pharmaceutical Salts," J. Pharm. ScI, 1977:66:1-19.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts. When a compound used in this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms. The maxi-K channel blockers used can be administered in a therapeutically effective amount intravaneously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art.

Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of an emulsion. Ophthalmic formulations of this compound may contain from 0.01 ppm to 0.1% and especially 0.1 ppm to 0.02% of medicament. For a single dose, from between 0.01 to 10,000 ng, preferably 1 to 10,000 ng, and especially 100 to 10,000 ng of the compound can be applied to the human eye.

The pharmaceutical emulsion preparation which contains the active pharmaceutical compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. As indicated throughout typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, polyalkylene glycols, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like.

Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.

The surfactants and Carbopol® disclosed in this invention may also be used as physical stabilizers to stabilize the emulsion formulation by keeping the oil droplets from aggregating. Chemical stabilizers such as sodium bisulfite, sodium mtabisulfate and sodium thiosulfate may also be used in the formulation to stabilize the molecule by preventing or minimizing chemical degradation.

Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.

The ophthalmic emulsion may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the mamalian eye will be about once or twice daily, preferably once daily.

For topical ocular administration the novel formulations of this invention will take the form of an emulsion formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.

The compounds used in this invention can be made in accordance with WO2004/043932 incorporated herein by reference in its entirety Example 1

Step 1

Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ml) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 5°C in ice water bath. Charged 3 eq of isopropylmagnesium chloride (6 ml of a 2M solution) in THF and stired for 0.5 hr at room temp. Carefully charged IN HCl (240 ml) and stired for 1 h. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product.

LCMS [M+H] = 219

Step 2

Indazole (0.60 mmoles from Step 1) starting material obtained as above was dissolved in DMF

(3 mL) followed by the addition of sodium hydride (0.88 mmoles) . The reaction was stirred at room temperature for 15 min, followed by the addition of 1 -bromo-pinacolone (0.669 mmoles).

The reaction was stirred at room temperature for 30 min. TLC and LC-MS analysis indicated complete consumption of starting material concurrent with the formation of a new product spot.

The reaction mixture was quenched by the addition of water. Standard aqueous work-up followed by purification of crude by SGC gave the desired product as white solid.

IH NMR in CDCL: 8.22 (IH, d, J = 9 Hz); 6.97 (IH, dd, J = 2 and 9 Hz); 6.5 (IH₅ d J = 2 Hz);

5.4 ( 2H, s); 3.94 ( 3H₅ s); 2.8 (IH, m); 1.38 (9H, s); 1.27 (6H₅ d₅ J = 6.5 Hz).

LCMS = [M+H] = 317

Examples 2 through 5

The invention is illustrated by the following non-limiting examples. The percentages in Table 4 are express by weight/volume% relative to the total volume of the formulation.

The active in Table 4 refers to l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3₅3- dimethylbutan-2-one. The emulsion using Miglyol 812 showed similar drug loading as the emulsion with castor oil. The addition of carbopol® (polyacrylic acid) significantly improved the emulsion physical stability. Also, different sufactants, polysorbate 80 and Cremophor® EL (Polyoxyl 35 castor oil), were tested.

A small batch of emulsion formulation example 5 was prepared as follows: In a glass container, 80 milligrams of (l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3,3- dimethylbutan-2-one ) and 212 milligrams of carbopol® (polyacrylic acid) were added into 5 grams of castor oil. The suspension in oil was mixed vigorously. Separately, in another glass container, 10 grams of Cremophor EL (Polyoxyl 35 castor oil), 4.5 grams of glycerol, and 51 milligrams of 50% concentrated Benzalkonium chlorides were added. The solution pH was adjusted to pH7.0 using NaOH/HCl. And the total volume was brought to 20OmL with the addition of purified water. A solution was obtained. Finally, 0.4 gram of the oil suspension with the active and carbopol® (polyacrylic acid) was vigorously mixed with 32 mL of the solution with 5% Cremophor EL (Polyoxyl 35 castor oil), 2.25% glycerol, and 0.01% Benzalkonium chlorides at pH7, and an emulsion was obtained. Using a similar procedure, a matching placebo containing all the aforementioned components except the active was also prepared.

Rabbit Ocular PK Study

Example 4 was tested in the rabbit ocular PK study. Dutch Belted rabbits were dosed topical bilaterally with 25 ul volume of the oil emulsion or vehicle. After 0.5, 1, 2 and 3 hours, each animal eye was washed with physiological saline and aqueous humor was removed by paracentesis. In this study, the 0.2 mg/mL oil emulsion formulation provided a maximum aqueous humor concentration of (l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3,3- dimethylbutan-2-one) (15.4 nM) which was 30-fold higher than the maximum aqueous humor concentration of (l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3,3-dimethylbutan-2-one) from an 2.5 μg/mL (the top potency due to the solubility limit) ophthalmic solution formulation (0.49 nM).

Claims

WHAT IS CLAIMED IS:

1. An emulsion formulation comprising an active pharmaceutical agent with a solubility in aqueous solution of about one microgram per mL, an oil, surfactant, and tonicity agent, said emulsion formulation increasing the ocular exposure of the active agent up to about 30 fold or more over solution formulations.

2. The formulation according to claim 1 wherein the active pharmaceutical agent is a Maxi-K channel blocker agent.

3. The formulation according to claim 2 having about 0.001% to about 20% of the Maxi-K channel blocker, about 0.5% to about 5 % (w/v) of oil selected from the group consisting of castor oil, soybean oil, corn oil, flaxseed oil, cottonseed oil, coconut oil, canola oil, argan oil, palm oil, peanut oil, and other vegetable oils; about 0.1% to about 10 % (w/v) of surfactant selected from the group consisting of poloxamer 407, polyoxyl 35 castor oil, lecithin, polysorbate 80 and poly (ethylene glycol)-based surfactants, and about 0.01% to about 5% of tonicity agent selected from the group consisting of glycerol, mannitol and sodium chloride.

4. The formulation according to claim 3 which further contains about 0.01% to about 0.1% of an emulsion stabilizer, Carbopol®.

5. The formulaton according to claim 4, wherein the pH is adjusted to neutral using a buffer selected from the group consisting of sodium phosphate, potassium phosphate, sodium phosphate monobasic dihydrate; sodium citrate, potassium citrate and tromethamine.

6. The formulation according to claim 5 wherein the Maxi-K channel blocker is a compound of structural formula I:

Formula I or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof: wherein, R represents hydrogen, or C l -6 alkyl; X represents -(CHR.7)p-, -(CHR7)_pCO-; Y represents -CO(CH2)rr_> CH2, or -CH(OR)-;

Q represents CRY;

Ry represents H, or C 1-6 alkyl; R_w represents H, C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -Sθ2N(R)2, -SO2C1-6 alkyl, -SO2C6.IO aryl, NO₂, CN or -C(O)N(R)2;

R2 represents hydrogen, Ci-IO alkyl, OH, C2-6 alkenyl, Cl -6 alkylSR, -(CH2)_nO(CH2)mOR, - (CH2)_nCl-6 alkoxy, -(CH2)_nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, -N(R)2, -COOR, or - (CH2)nC6-10 aryl, said alkyl, heterocyclyl, or aryl optionally substituted with 1-3 groups selected from R^a;

R3 represents hydrogen, Ci-io alkyl, -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, - (CH₂)_nCOOR, -(CH₂)nC6-10 aryl, -(CH₂)_nNHR₈, -(CH₂)_nN(R)2, -(CH₂)nN(R8)2, - (CH2)_nNHCOOR, -(CH2)_nN(R8)Cθ2R, -(CH2)nN(Rg)COR, -(CH2)_nNHCOR, - (CH₂)nCONH(R₈), aryl, -(CH₂)_nCl-6 alkoxy, CF₃, -(CH₂)_nSO₂R, -(CH₂)_nSO₂N(R)2, - (CH2)_nCON(R)2, -(CH2)_nCONHC(R)3, -(CH2)_nCONHC(R)2Cθ2R, -(CH2)_nCOR8, nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-3 groups of Ra; or R2 and R3 taken together with the intervening Q form a 3-10 membered carbocyclic or heterocyclic carbon ring optionally interrupted by 1 -2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from R^a; or R2 and R3 taken together with the intervening Q represent OR;

R4 and R5 independently represent hydrogen, Cl -6 alkoxy, OH, Ci-6 alkyl, COOR, SO_qCi-₆ alkyl, COC 1-6 alkyl, SO3H, -O(CH2)_nN(R)2, -O(CH2)_nCθ2R, -OPO(OH)₂, CF3, OCF3 - N(R)2, nitro, cyano, C 1-6 alkylamino, or halogen; and

R6 represents hydrogen, Ci- 10 alkyl, -(CH2)_nC6-10 aryl, NR₀Rd, -NR(CH2)_nC6-10 aryl, - N((CH2)_nC6-10 aryl)2, -(CH2)_nC3-10 heterocyclyl, -NR(CH2)_nC3-10 heterocyclyl, - N((CH2)_nC3-10 heterocyclyl)2 (C6-10 aryl)O-, -(CH2)_nC3-8 cycloalkyl, -COOR, -C(O)CO2R, said aryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from Ra, wherein the Ra(s) can be attached to any carbon atom or heteroatom selected from N and S; Rc and R<J independently represent H, Cl -6 alkyl, C2-6 alkenyl, C 1-6 alkylSR, - (CH2)nO(CH2)_mOR, -(CH2)_nCl-6 alkoxy, or -(CH₂)_nC3-8 cycloalkyl;

or Rc and Rtf taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1-2 atoms of O₅ S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra;

R7 represents hydrogen, C 1-6 alkyl, -(CH2)_nCOOR or -(CH2)_nN(R)2,

R8 represents -(CH2)nC3-8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Cl -6 alkoxy or -(CH2)_nC5- 10 heteroaryl, -(CH2)nC6-10 aryl said heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;

Ra represents F, Cl, Br, I, CF₃, N(R)₂, NO₂, CN, -O-, -COR8, -CONHRg, -CON(Rs)2, -

O(CH2)_nCOOR, -NH(CH₂)_nOR, -COOR, -OCF3, CF₂CH₂OR, -NHCOR, -SO₂R, -SO₂NR₂, - SR, (C₁-C₆ alkyl)O-, -(CH₂)_nO(CH₂)mOR, -(CH₂)_nCi-₆ alkoxy, (aryl)O-, -(CH₂)_nOH, (C₁- C₆ alkyl)S(O)_m-, H₂N-C(NH)-, (C₁-C₆ alkyl)C(O)-, (C₁-C₆ alkyl)OC(O)NH-, -(C₁-C₆ alkyl)NR_w(CH₂)nC3-i0 heterocyclyl-R_w, -(C₁-C₆ alkyl)O(CH2)_nC3-10 heterocyclyl-R_w, -(C₁ - C₆ alkyl)S(CH₂)_nC3- 10 heterocyclyl-R_w, -(C ₁ -C₆ alkyl)-C3_ 10 heterocyclyl-R_w, -(CH2)_n-Z¹ - C(=Z2)N(R)₂, -(C2-6 alkenyl)NR_w(CH₂)_nC3-10 heterocyclyl-R_w, -(C₂-6 alkenyl)O(CH2)_nC3- 10 heterocyclyl-R_w, -(C₂-6 alkenyl)S(CH₂)_nC3-io heterocyclyl-R_w, -(C₂.₆ alkenyl)-C3_io heterocyclyl-R_w, -(C₂-O alkenyl)-Zl-C(=Z2)N(R)₂, -(CH₂)nSθ2R, -(CH₂)_nSθ3H, - (CH2)_nPO(OR)2, Cs-iocycloalkyl, C6-10 aryl C3.10 heterocyclyl, C2-6 alkenyl, and C₁-C₁₀ alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C₁-C₆ alkyl, halogen, (CH2)_nOH, CN, NO2, CON(R)₂ and COOR;

Zλ and Z2 independently represents NR_W, O, CH2, or S; m is 0-3; n is 0-3; p is 0-3 and q is 0-2.

7. The formulation of claim 6 wherein the Maxi-K channel blocker is a compound as recited in Tables 2 or 3:

wherein R₁ is

or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof.

8. The formulation according to claim 7 wherein the active pharmaceutical agent is:(l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl) -3,3-dimethylbutan-2-one ); or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof.

9. A pharmaceutical emulsion formulation comprising from about 0.001% to about 5% of (l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3,3-dimethylbutan-2-one ); or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof with a solubility in aqueous solution less than a microgram per mL; about 0.5% to about 5 % (w/v) of oil selected from the group consisting of castor oil, soybean oil, corn oil, flaxseed oil, cottonseed oil, coconut oil, canola oil, argan oil, palm oil, peanut oil, and other vegetable oils; about 0.1% to about 10 % (w/v) of surfactant selected from the group consisting of poloxamer 407, polyoxyl 35 castor oil, lecithin, polysorbate 80 and poly (ethylene glycol)- based surfactants, and about 0.01 % to about 5% of tonicity agent selected from the group consisting of glycerol, mannitol and sodium chloride.said emulsion formulation increasing the ocular exposure of the active agent by up to 30 fold over solution formulations.

10. The formulation according to claim 9 which further contains about 0.01% to about 0.1% of an emulsion stabilizer, Carbopol®;; and wherein the pH is adjust to neutral using a buffer selected from the group consisting of sodium phosphate, potassium phosphate, sodium phosphate monobasic dehydrate, sodium phosphate dibasic, sodium citrate, potassium citrate and tromethamine.

11. The formulation according to claim 10 comprising about 0.001 % to about

5% of (l-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-3,3-dimethylbutan-2-one ) or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof; about 0.01% to about 0.1% of carbopol® (polyacrylic acid), about 0.5 to about 5% castor oil; about 0.5% to about 5% of Cremophor EL (Polyoxyl 35 castor oil); about 0.5% to about 3% glycerol; about 0.001% to about 0.025% of Benzalkonium chlorides, and sodium phosphate buffer to adjust to neutral pH.

12. A method for treating ocular hypertension, glaucoma, macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administering the formulation of claim 1.

13. A method for treating ocular hypertension, glaucoma, macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administering the formulation of claim 11.

14. The formulation according to claim 11 wherein an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof, hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist is optionally added.

15. The formulation according to claim 14 wherein the β-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathomimetic agent is epinephrine, brimonidine, iopidine, clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S 1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is l-(2-arninopropyl)-3-methyl-lH-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-l-yl)-l-methyl-ethylamine.