WO2008027341A2 - Formulations ophtalmiques locales - Google Patents

Formulations ophtalmiques locales Download PDF

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Publication number
WO2008027341A2
WO2008027341A2 PCT/US2007/018851 US2007018851W WO2008027341A2 WO 2008027341 A2 WO2008027341 A2 WO 2008027341A2 US 2007018851 W US2007018851 W US 2007018851W WO 2008027341 A2 WO2008027341 A2 WO 2008027341A2
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alkyl
heterocyclyl
oil
aryl
agent
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WO2008027341A3 (fr
Inventor
Miller Ogidigben
Yu Ren
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Merck and Co Inc
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Merck and Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • 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.
  • 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.
  • 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:
  • R represents hydrogen, or C] -6 alkyl
  • X represents -(CHR.7) p -, -(CHR7) p CO-;
  • 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, NO 2 , CN or -C(O)N(R) 2 ;
  • R2 represents hydrogen, Ci- 10 alkyl, OH, C2-6 alkenyl, Cl -6 alkylSR, -(CH2) n O(CH2)mOR, - (CH2) n Cl-6 alkoxy, -(CH2) n C3-8 cycloalkyl, -(CH2) n C3-10 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 -i ⁇ alkyl, -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, - (CH 2 )nCOOR, -(CH 2 ) n C 6 -10 aryl, -(CH 2 ) n NHR8, -(CH 2 ) n N(R)2, -(CH 2 ) n N(R8)2, - (CH2)nNHCOOR, -(CH2) n N(R8)C ⁇ 2R, -(CH2) n N(R8)COR, -(CH2) n NHCOR, - (CH 2 )nCONH(R8), aryl, -(CH 2 ) n Cl-6 alkoxy, CF 3 , -(CH 2 ) n S ⁇ 2R, -(CH 2 )nS ⁇ 2N(R)2, -
  • R6 represents hydrogen, Ci-io alkyl, -(CH2)nC6-10 aryl, NR 0 Rd. -NR(CH2)nC6-10 aryl, - N((CH2)nC6-10 aryl) 2 , -(CH2) n C3-10 heterocyclyl, -NR(CH2) n C3-10 heterocyclyl, - N((CH2) n C3-10 heterocyclyl)2 (C6-10 aryl)O-, -(CH2) n C3-8 cycloalkyl, -COOR, -C(O)CO 2 R, 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) m OR, -(CH2)nCl-6 alkoxy, or -(CH2) n C3-8 cycloalkyl;
  • 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) n COOR or -(CH2) n N(R)2,
  • Rs represents -(CH2)nC3-8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Ci -6 alkoxy or -(CH 2 ) n C5- 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, CF 3 , N(R) 2 , NO 2 , CN, -O-, -COR8, -CONHRs, -CON(Rs) 2 , - O(CH 2 ) n COOR, -NH(CH2) n OR, -COOR, -OCF3, CF 2 CH 2 OR, -NHCOR, -SO 2 R, -SO 2 NR 2 , - SR, (C 1 -C 6 alkyl)O-, -(CH 2 ) n O(CH 2 ) m OR, -(CH 2 ) n Ci_ 6 alkoxy, (aryl)O-, -(CH 2 ) n OH, (C 1 - C 6 alkyl)S(O) m -, H 2 N-C(NH)-, (C 1 -C 6 alkyl)C(O)-, (C 1 -C 6 alkyl)OC(O)NH-,
  • 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
  • Potassium channel blockers may be used for the treatment of ocular hypertension.
  • 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
  • complexation agents including but not limited to different derivatized ⁇ -cyclodextrin
  • 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®).
  • 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
  • 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.
  • the emulsion may optionally contain:
  • 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.
  • 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.
  • any variable e.g. aryl, heterocycle, R*, R ⁇ etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • R a 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.
  • a nitrogen e.g., nitrogen atom on a pyridyl group
  • sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • 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.
  • 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.
  • heterocyclyl or heterocyclic 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.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • 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, morpholin
  • 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.
  • heteroatom means O, S or N, selected on an independent basis.
  • 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.
  • 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, quinazolin
  • 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 ⁇ -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 01/722), an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140
  • hypotensive lipid (the carboxylic acid group on the ⁇ -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 OCH 3 (PGF 2a 1-OCH 3 ), 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
  • 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.
  • 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.
  • 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.
  • 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.N 1 - 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.
  • basic ion exchange resins such as argin
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • 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.
  • 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.
  • a compound used in this invention 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.
  • a non-toxic pharmaceutical organic carrier or with a non-toxic pharmaceutical inorganic carrier.
  • 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.
  • auxiliary substances such as e
  • 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 malian eye will be about once or twice daily, preferably once daily.
  • 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.
  • 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.
  • 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)-3 5 3- dimethylbutan-2-one.
  • the emulsion using Miglyol 812 showed similar drug loading as the emulsion with castor oil.
  • carbopol® polyacrylic acid
  • different sufactants, polysorbate 80 and Cremophor® EL Polyoxyl 35 castor oil
  • 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.
  • 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.
  • 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 ⁇ g/mL (the top potency due to the solubility limit) ophthalmic solution formulation (0.49 nM).

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Abstract

La présente invention concerne des formulations pharmaceutiques ophtalmiques en émulsion qui augmentent fortement l'exposition oculaire d'agents pharmaceutiques actifs hautement insolubles, présentent une stabilité physique suffisante et permettent une redispersion aisée de particules de médicament insolubles, de manière à obtenir une plus grande uniformité de dose de médicament. La présente invention concerne en outre une formulation ophtalmique en émulsion dans laquelle l'agent pharmaceutique actif est un inhibiteur de canal Maxi-K à faible solubilité et comprend une huile, un tensioactif et un agent de tonicité.
PCT/US2007/018851 2006-08-30 2007-08-24 Formulations ophtalmiques locales Ceased WO2008027341A2 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
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WO2010141648A3 (fr) * 2009-06-05 2011-03-10 Allergan, Inc. Larmes artificielles et utilisations thérapeutiques
WO2013000909A1 (fr) 2011-06-28 2013-01-03 Bayer Intellectual Property Gmbh Composition pharmaceutique topique ophtalmologique contenant du sorafénib
WO2013000917A1 (fr) 2011-06-28 2013-01-03 Bayer Intellectual Property Gmbh Composition pharmaceutique topique ophtalmologique contenant du régorafénib
WO2013115844A1 (fr) * 2012-02-02 2013-08-08 Alpha Synergy Development, Inc. Compositions et méthodes destinées à traiter le glaucome
WO2013188283A1 (fr) 2012-06-12 2013-12-19 Bayer Healthcare Llc Composition pharmaceutique ophtalmique topique contenant du sunitinib
WO2014100797A1 (fr) 2012-12-21 2014-06-26 Bayer Healthcare Llc Composition pharmaceutique ophtalmologique topique contenant régorafénib
US9907826B2 (en) 2011-12-07 2018-03-06 Allergan, Inc. Efficient lipid delivery to human tear film using a salt-sensitive emulsion system
US10105386B2 (en) 2011-10-06 2018-10-23 Allergan, Inc. Compositions for the treatment of dry eye
US10279005B2 (en) 2014-11-25 2019-05-07 Allergan, Inc. Stabilized omega-3 ophthalmic compositions
US11084789B2 (en) 2016-01-14 2021-08-10 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
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US11045515B2 (en) 2009-06-05 2021-06-29 Allergan, Inc. Artificial tears and therapeutic uses
US8679554B2 (en) 2009-06-05 2014-03-25 Allergan, Inc. Artificial tears and therapeutic uses
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US9821020B2 (en) 2009-06-05 2017-11-21 Allergan, Inc. Artificial tears and therapeutic uses
WO2013000909A1 (fr) 2011-06-28 2013-01-03 Bayer Intellectual Property Gmbh Composition pharmaceutique topique ophtalmologique contenant du sorafénib
WO2013000917A1 (fr) 2011-06-28 2013-01-03 Bayer Intellectual Property Gmbh Composition pharmaceutique topique ophtalmologique contenant du régorafénib
US10105386B2 (en) 2011-10-06 2018-10-23 Allergan, Inc. Compositions for the treatment of dry eye
US10888598B2 (en) 2011-12-07 2021-01-12 Allergan, Inc. Efficient lipid delivery to human tear film using a salt-sensitive emulsion system
US9907826B2 (en) 2011-12-07 2018-03-06 Allergan, Inc. Efficient lipid delivery to human tear film using a salt-sensitive emulsion system
WO2013115844A1 (fr) * 2012-02-02 2013-08-08 Alpha Synergy Development, Inc. Compositions et méthodes destinées à traiter le glaucome
WO2013188283A1 (fr) 2012-06-12 2013-12-19 Bayer Healthcare Llc Composition pharmaceutique ophtalmique topique contenant du sunitinib
WO2014100797A1 (fr) 2012-12-21 2014-06-26 Bayer Healthcare Llc Composition pharmaceutique ophtalmologique topique contenant régorafénib
US10279005B2 (en) 2014-11-25 2019-05-07 Allergan, Inc. Stabilized omega-3 ophthalmic compositions
US11084789B2 (en) 2016-01-14 2021-08-10 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
WO2023039213A1 (fr) * 2021-09-09 2023-03-16 Biora Therapeutics, Inc. Formulations aqueuses de tofacitinib et de sels de tofacitinib
US12564572B2 (en) 2022-11-04 2026-03-03 Qlaris Bio, Inc. Topical ocular delivery of cromakalim
US12564573B2 (en) 2022-11-04 2026-03-03 Qlaris Bio, Inc. Topical ocular delivery of cromakalim

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