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WO2025169089A1 - Compositions ophtalmiques d'inhibiteurs de tyrosine kinase et leurs utilisations - Google Patents

Compositions ophtalmiques d'inhibiteurs de tyrosine kinase et leurs utilisations

Info

Publication number
WO2025169089A1
WO2025169089A1 PCT/IB2025/051225 IB2025051225W WO2025169089A1 WO 2025169089 A1 WO2025169089 A1 WO 2025169089A1 IB 2025051225 W IB2025051225 W IB 2025051225W WO 2025169089 A1 WO2025169089 A1 WO 2025169089A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
acid
axitinib
combination
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/051225
Other languages
English (en)
Inventor
Ajay Jaysingh Khopade
Arindam Halder
Vivek Patel
Raghavendra MUNDARGI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharmaceutical Industries Ltd
Original Assignee
Sun Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2025169089A1 publication Critical patent/WO2025169089A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to topical pharmaceutical compositions of tyrosine kinase inhibitors.
  • the invention also relates to the use of said topical pharmaceutical compositions for preventing or treating ophthalmological disorders such as age-related macular degeneration (AMD), diabetic macular edema, and/or diabetic retinopathy.
  • ophthalmological disorders such as age-related macular degeneration (AMD), diabetic macular edema, and/or diabetic retinopathy.
  • the invention relates to topical pharmaceutical compositions comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof and a solubility enhancer and its use for treating ophthalmological disorders such as age-related macular degeneration (AMD), diabetic macular edema, and/or diabetic retinopathy.
  • Age-related macular degeneration, diabetic macular edema, and diabetic retinopathy are the leading cause of blindness worldwide.
  • the AMD is characterized by progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a specialized area in the center of the retina and is recognized as dry and wet AMD, while macular ischemia is a major cause of irreversible vision acuity loss and decreased contrast sensitivity in patients with diabetic retinopathy.
  • tyrosine kinase inhibitors such as axitinib, lenvatinib, pazopanib, and sorafenib
  • Various literature disclosed topical use of tyrosine kinase inhibitors in the treatment of AMD and diabetic retinopathy.
  • Cornea (2012) 3 1 (8), 907 the entire disclosures of which are incorporated by reference herein.
  • an active pharmaceutical ingredient e.g. a tyrosine kinase inhibitor
  • an active pharmaceutical ingredient e.g. a tyrosine kinase inhibitor
  • the topical pharmaceutical composition for ophthalmic administration is administered.
  • the present invention provides a topical pharmaceutical composition to deliver a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the present invention provides a topical pharmaceutical composition to deliver a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 50 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, and a solubility enhancer.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising:
  • the present invention provides an ophthalmic solution composition
  • an ophthalmic solution composition comprising:
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and a solubility enhancer.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and one or more solubility enhancer.
  • the present invention provides an ophthalmic solution composition
  • an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition
  • an ophthalmic solution composition comprising:
  • the invention provides use of compositions for use in treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
  • AMD age-related macular degeneration
  • mCNV Myopic Choroidal Neovascularization
  • CTLF Corrected Total Lesion Fluorescence
  • the active pharmaceutical ingredient may be referred to as a "drug".
  • the active pharmaceutical ingredient is an ophthalmic drug, i.e. a compound that exhibits a therapeutic effect when administered in a sufficient amount to a patient suffering from an ocular condition.
  • the active pharmaceutical ingredient is a "protein kinase inhibitor" (PKI) that specifically blocks the action of one or more protein kinases.
  • PKIs include, but are not limited, to protein kinase inhibitors and tyrosine kinase inhibitors, such as axitinib, afatinib, bosutinib, crizotinib, cediranib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, lestaurtinib, motesanib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, semaxanib, sunitinib, tandunitib, tipifarnib, vandetanib, and vemurafenib; or their isomers
  • tyrosine kinase inhibitors suitable for use with the invention include, but are not limited to, axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib or any combination thereof, their pharmaceutically acceptable prodrugs, isomers, hydrates, or salts thereof.
  • the tyrosine kinase inhibitors are axitinib, sunitinib, lenvatinib, pazopanib, and more preferably axitinib.
  • salt means those salts of a compound of interest that are safe and effective for the administration to a mammal.
  • salts see Berge et al., J. Pharm. Sci. (1977) 66, 1 - 19, incorporated herein by reference.
  • Suitable salts for the purpose of the present invention include, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, mesylate, tosylate, besylate, esylate, etc.
  • compositions may comprise the active pharmaceutical ingredient in free base form or salt form, i.e. as its inorganic or organic salt selected from the group consisting of propionate, acetate, 2,5-dihydroxybenzoate, citrate, malonate, sulfate, bisulfate, benzoate, maleate, tosylate, fumarate, succinate, tartrate, lactate, glycolate, phosphate, pyrophosphate, benzene sulfonate, ascorbate, chloride, bromate, malate, propionate, oxalate, isobutyrate, sulfonate, mesylate, esylate and pyroglutamate, as well as their isomers.
  • inorganic or organic salt selected from the group consisting of propionate, acetate, 2,5-dihydroxybenzoate, citrate, malonate, sulfate, bisulfate, benzoate, maleate, tosylate, fumarate, succinate,
  • the salts are preferably selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate.
  • the salts of axitinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate.
  • the salts of lenvatinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate.
  • isomers refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • the present invention encompasses all structural and geometrical isomers including cis, trans, E, and Z isomers, independently at each occurrence.
  • the invention includes enantiomers, diastereomers, or racemates of the compound. Any combinations of the above features are also contemplated.
  • the active pharmaceutical ingredient is present in an amount from about 0.01% to about 10% w/v.
  • the active pharmaceutical ingredient is axitinib, present in an amount from about 0.001% to about 10% w/v.
  • the active pharmaceutical ingredient is axitinib, present in an amount from about 0.01% to about 2% w/v.
  • the percentage(s) or % expressed herein are based on the final volume of the topical pharmaceutical composition.
  • the term "about” as used herein refers to as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. As used herein, the term “about” means ⁇ approximately 10% of the indicated value.
  • mixing refers to the addition of different compounds in a solid, semisolid, solution, or suspension state, irrespective of the sequence of addition to form a “mixture”.
  • mixture can be a solid mixture, a clear solution, a hazy solution, or a suspension.
  • undissolved particles refer to any particle of active drug and/or any excipient which is visible or having a particle size of D 90 more than 1 micron, 0.5 micron, 0.2 micron, 0.1 micron or 0.001 micron.
  • Preferred posterior eye diseases include age-related macular degeneration (AMD) like dry AMD, wet AMD or choroidal neovascularization (CNV), diabetic macular edema, macular edema following retinal vein occlusion, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
  • AMD age-related macular degeneration
  • AMD choroidal neovascularization
  • subject refers to a warm-blooded animal such as a mammal, guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, rabbits, and humans are examples of mammals within the scope of the meaning of the term, preferably a human or a human child, which is afflicted with, or has the potential to be affected with one or more disease and condition described herein.
  • Cyclodextrins refers to cyclic oligosaccharides containing 6 ( ⁇ -cyclodextrin), 7 ( ⁇ -cyclodextrin), and 8 ( ⁇ -cyclodextrin) glucopyranose monomers linked via ⁇ -1,4-glycoside bonds.
  • SBE ⁇ CD refers to sulfobutyl ether ⁇ -cyclodextrin.
  • SBE ⁇ CD refers to sulfobutyl ether ⁇ -cyclodextrin.
  • the amount of cyclodextrin in the ophthalmic composition of the disclosure typically may be from about 0.001% w/v to 50% w/v. Preferably, from about 0.001% w/v to 40% w/v. More preferably, from about 0.001% w/v to 30% w/v.
  • the phrase 'preservative efficacy test' (PET) or ‘Antimicrobial Effectiveness Test’ (AET) refers to a test laid down by regulatory authorities to validate the preservative efficacy of pharmaceutical preparations containing a preservative.
  • preservatives are added in sterile pharmaceutical preparations that are meant to be used multiple times and not for single use.
  • Such preparations are generally ophthalmic preparations, subcutaneous or intramuscular injections stored in multiple-dose containers.
  • an antimicrobial agent or preservative is included to inhibit the growth of the micro-organisms.
  • the Pharmacopoeias of various countries provide procedures and criteria to check whether the preparations pass the preservative efficacy test. For instance, according to United States Pharmacopoeia, the requirements for antimicrobial effectiveness are met if:
  • the preservative system used in the composition has sufficient antimicrobial activity to allow the composition to satisfy USP General Chpater ⁇ 51 ⁇ antimicrobial effectiveness testing requirements.
  • composition according to the present invention comprises tyrosine kinase inhibitor as a sole therapeutically active ingredient. It is present in an amount ranging from about 0.001% to 10% w/v, such as 0.001%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.125%, 0.2%, 0.3% w/v.
  • concentration (% w/v or % weight by volume) of tyrosine kinase inhibitor (axitinib, sunitinib, lenvatinib, pazopanib) as expressed herein refers to the concentration of base form.
  • the present invention provides a topical pharmaceutical composition of an active pharmaceutical ingredient for the prevention or treatment of a posterior eye disease.
  • the present invention provides a topical pharmaceutical composition to deliver a high concentration of an active pharmaceutical ingredient in the posterior segment of the eye.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 8000 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 6000 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 4000 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 3000 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 2500 times higher than the IC 50 value of the active pharmaceutical ingredient.
  • the present invention provides a topical pharmaceutical composition of tyrosine kinase inhibitor.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, and one or more solubility enhancer.
  • topical pharmaceutical composition further comprises one or more precipitation inhibitor.
  • the present invention provides a topical pharmaceutical composition comprising:
  • composition further comprises:
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, and one or more pH adjusting agent.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, one or more pH adjusting agent and one or more penetration enhancer.
  • the composition is for ophthalmic administration, wherein the composition is a suspension, an emulsion, a solution, or a gel.
  • the present invention provides a topical pharmaceutical composition comprising:
  • the present invention provides a topical pharmaceutical composition comprising:
  • the topical pharmaceutical composition is an ophthalmic solution.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the composition further comprises water as a vehicle.
  • the composition does not comprise any non-aqueous vehicle.
  • the present invention provides an ophthalmic solution composition comprising:
  • the tyrosine kinase inhibitor is selected from the group consisting of axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib, their isomers or salts thereof.
  • one or more solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.
  • the precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.
  • the organic acid is alkyl sulfonic acid.
  • the alkyl sulfonic acid is selected from the group consisting of methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof.
  • the alkyl sulfonic acid is methane sulfonic acid.
  • the mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or a combination thereof.
  • cyclic polymer is selected from the group consisting of cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.
  • cyclic oligosaccharide is cyclosophoran, cycloamylose, cyclotetraglucose, cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD), 2-hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, carboxymethyl ⁇ -cyclodextrin, or a combination thereof.
  • the composition is free of ⁇ -cyclodextrin. According to any one of the embodiments described herein, the composition is free of 2-hydroxypropyl- ⁇ -cyclodextrin.
  • cyclic polysaccharide is cyclic ⁇ -1,2-glucan.
  • cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly( ⁇ -caprolactone) (PCL), cyclo poly(ethylene oxide) (PEO), or a combination thereof.
  • the linear polymer is selected from the group consisting of linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.
  • the linear oligosaccharide is selected from the group consisting of maltodextrin, raffinose, stachyose, fructo-oligosaccharide, or a combination thereof.
  • the linear polysaccharide is selected from the group consisting of starch and its derivatives, amylose, amylopectin, modified starch, carboxymethyl starch, glycogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.
  • the linear polymer is a carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.
  • the composition further comprises a penetration enhancer.
  • the composition further comprises preservative, pH adjusting agent, or a combination thereof.
  • the preservative is present in an amount of about 0.001% to about 4% w/v and selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes, or a combination thereof.
  • the preservative is a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalkylene diamine biguanide or their water-soluble salt; 1,1'-hexamethylene-bis- ⁇ 5-(4-chlorophenyl)-biguanide ⁇ ; 1,1'-hexamethylene-bis- ⁇ 5-(2-ethylhexyl) biguanide ⁇ , 1,1 '-hexamethylene-bis- ⁇ 5-(4-fluoro phenyl)-biguanide ⁇ ; (N,N"-bis(2-ethyl hexyl)-3, 12-diimino-2,4, 11, 13-tetraazatetra decanediimidamine, chlorhexidine or their salts, or a combination thereof.
  • a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalky
  • the salts of biguanide compounds include but are not limited to hydrochloride, gluconate, digluconate, borate, acetate, sulphonate, tartrate, and citrate.
  • the preservative is polyhexamethylene biguanide or its salt.
  • the preservative is polyhexamethylene biguanide hydrochloride.
  • the composition comprises benzalkonium chloride, N-lauroyl sarcosine sodium, polyhexamethylene biguanide hydrochloride, or a combination thereof.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof and the solubility enhancer ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:40.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:20.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:10.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:35.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:3 to about 1:30.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:16.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:30.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:40.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:20.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:10.
  • the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:10.
  • the composition has one or more following characteristics:
  • the composition is useful to deliver a high concentration of a tyrosine kinase inhibitor in the posterior segment of the eye.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to about 5000 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to about 2500 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 50 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 100 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 200 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 300 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 500 times higher than the IC 50 value of the tyrosine kinase inhibitor.
  • the composition delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 0.1 to about 1000 ng/gm.
  • the composition delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.
  • the posterior segment of the eye may include sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), neural retina, and vitreous humor.
  • RPE retinal pigment epithelium
  • the posterior segment of eye may include retina, vitreous humor, sclera, RPE-Choroid, aqueous humor, and Iris-ciliary body.
  • the present invention provides an ophthalmic solution composition for use in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
  • AMD age-related macular degeneration
  • mCNV Myopic Choroidal Neovascularization
  • the present invention provides use of a medicament prepared according to the present invention in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity by administering via ophthalmic route in mammals.
  • AMD age-related macular degeneration
  • macular edema following retinal vein occlusion diabetic macular edema
  • diabetic retinopathy diabetic retinopathy
  • mCNV Myopic Choroidal Neovascularization
  • retinopathy of prematurity by administering via ophthalmic route in mammals.
  • the salts of tyrosine kinase inhibitors, or their isomers are selected from mesylate, tosylate, besylate, or esylate.
  • the present invention provides a topical pharmaceutical composition of axitinib.
  • the present invention provides a topical pharmaceutical composition of axitinib for the prevention or treatment of a posterior eye disease.
  • the present invention provides a topical pharmaceutical composition to deliver a high concentration of axitinib in the posterior segment of the eye.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 8000 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 6000 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 4000 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 3000 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 2500 times higher than the IC 50 value of the axitinib.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and a solubility enhancer.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and one or more solubility enhancer.
  • composition further comprises one or more precipitation inhibitor.
  • the present invention provides a topical pharmaceutical composition comprising:
  • composition further comprises:
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, one or more pH adjusting agent and one or more penetration enhancer.
  • the composition is for ophthalmic administration, wherein the composition is a suspension, an emulsion, a solution, or a gel.
  • the present invention provides a topical pharmaceutical composition of axitinib, its isomer, or a salt thereof comprising:
  • the present invention provides a topical pharmaceutical composition comprising:
  • the present invention provides a topical pharmaceutical composition comprising:
  • the topical pharmaceutical composition is an ophthalmic solution.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the composition further comprises water as a vehicle.
  • the composition does not comprise any non-aqueous vehicle.
  • the present invention provides an ophthalmic solution composition comprising:
  • one or more solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.
  • the precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.
  • the present invention provides an ophthalmic solution composition comprising:
  • the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.
  • the organic acid is alkyl sulfonic acid.
  • the alkyl sulfonic acid is selected from the group consisting of methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof.
  • the alkyl sulfonic acid is methane sulfonic acid.
  • the mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or a combination thereof.
  • cyclic polymer is selected from the group consisting of cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.
  • the composition is free of ⁇ -cyclodextrin. According to any one of the embodiments described herein, the composition is free of 2-hydroxypropyl- ⁇ -cyclodextrin.
  • cyclic polysaccharide is cyclic ⁇ -1,2-glucan.
  • cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly( ⁇ -caprolactone) (PCL), cyclo poly(ethylene oxide) (PEO), or a combination thereof.
  • the linear polymer is selected from the group consisting of linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.
  • the linear oligosaccharide is selected from the group consisting of maltodextrin, raffinose, stachyose, fructo-oligosaccharide, or a combination thereof.
  • the linear polysaccharide is selected from the group consisting of starch and its derivatives, amylose, amylopectin, modified starch, carboxymethyl starch, glycogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.
  • the linear polymer is a carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.
  • the precipitation inhibitor is sulfobutyl ether ⁇ -cyclodextrin and hydroxypropyl methyl cellulose
  • the solubilizing agent is methane sulfonic acid
  • the composition further comprises a penetration enhancer.
  • the penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA, and sodium glycocholate, or a combination thereof.
  • benzalkonium chloride protamine sulfate
  • synthetic N-acylated amino acid (SNAC) / salcaprozate sodium perifosine
  • N-Dodecyl-Beta-D-Maltoside (DDM) N-Dodecyl-Beta-D-Maltoside (DDM)
  • Palmitoyl tripeptide Quil A, DMSO, EDTA, and sodium glycocholate, or a combination thereof.
  • the composition further comprises preservative, pH adjusting agent, or a combination thereof.
  • the preservative is present in an amount of about 0.001% to about 4% w/v and selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes, or a combination thereof.
  • the preservative is a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalkylene diamine biguanide or their water-soluble salt; 1,1'-hexamethylene-bis- ⁇ 5-(4-chlorophenyl)-biguanide ⁇ ; 1,1'-hexamethylene-bis- ⁇ 5-(2-ethylhexyl) biguanide ⁇ , 1,1 '-hexamethylene-bis- ⁇ 5-(4-fluoro phenyl)-biguanide ⁇ ; (N,N"-bis(2-ethyl hexyl)-3, 12-diimino-2,4, 11, 13-tetraazatetra decanediimidamine, chlorhexidine or their salts, or a combination thereof.
  • a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalky
  • the salts of biguanide compounds include but are not limited to hydrochloride, gluconate, digluconate, borate, acetate, sulphonate, tartrate, and citrate.
  • the preservative is acylated amino acid selected from a group consisting of acyl sarcosines or sarcosinates, acyl glutamates, acyl glycinates, acyl aspartates, acyl taurates, acyl malonates or acyl amino-malonates, their salts, or a combination thereof.
  • the composition comprises benzalkonium chloride, N-lauroyl sarcosine sodium, polyhexamethylene biguanide hydrochloride, or a combination thereof.
  • one or more pH-adjusting agent is an acid, an alkali metal salt, or a combination thereof.
  • the pH-adjusting agent is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:10.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:35.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:3 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:16.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.
  • the molar ratio between the axitinib, its isomer, or a salt thereof and the precipitation inhibitor ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:20.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:10.
  • the molar ratio between the axitinib and the methane sulfonic acid ranges from about 1:0.5 to about 1:3.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:2 to about 1:4.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:10.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:1 to about 1:30.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether ⁇ -cyclodextrin ranges from about 1:0.5 to about 1:50.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether ⁇ -cyclodextrin ranges from about 1:0.5 to about 1:40.
  • the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether ⁇ -cyclodextrin ranges from about 1:1 to about 1:30.
  • the composition has one or more following characteristics:
  • the composition has one or more following characteristics:
  • the composition has one or more following characteristics:
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising:
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v ⁇ -cyclodextrin derivatives such as SBE ⁇ CD and about 0.1% to about 2% w/v HPMC.
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v ⁇ -cyclodextrin derivatives such as SBE ⁇ CD and about 0.1% to about 2% w/v HPMC, and about 0.05% to about 15%w/v polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v ⁇ -cyclodextrin derivatives such as SBE ⁇ CD and about 0.1% to about 2% w/v HPMC, and about 0.1% to about 4% w/v boric acid.
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v ⁇ -cyclodextrin derivatives such as SBE ⁇ CD and about 0.1% to about 2% w/v HPMC, and about 0.5% to about 5% w/v tromethamine.
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v ⁇ -cyclodextrin derivatives such as SBE ⁇ CD and about 0.1% to about 2% w/v HPMC and about 0.01% to 5% w/v protamine sulfate.
  • the present invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising:
  • the composition has a pH in the range of about 4.5 to 8.5.
  • the composition has a pH in the range of about 6.0 to 7.1.
  • the composition has an osmolality in the range of about 150 to 450 mOsml/kg.
  • the viscosity of the composition according to the present invention ranges from about 2 cps to 1000 cps.
  • the viscosity of the composition according to the present invention ranges from about 5 cps to 75 cps, more preferably from 5 cps to 30 cps such as for example 6, 7, 8, 9, 10, ii, 12, 13, 14, 15, 16, 17, 18, 19, 20, 60 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 cps or intermediate values thereof.
  • the viscosity is measured at 25° C with a Rheometer-type viscometer at a shear rate of 100 s -1 .
  • the present invention provides an ophthalmic solution composition comprising:
  • the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.
  • the organic acid is alkyl sulfonic acid.
  • the alkyl sulfonic acid is methane sulfonic acid.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • one or more excipient is selected from the group consisting of benzalkonium chloride, tromethamine, N-lauroyl sarcosine sodiums, boric acid, polyhexamethylene biguanide hydrochloride, Quil A, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), and Palmitoyl tripeptide.
  • benzalkonium chloride tromethamine
  • N-lauroyl sarcosine sodiums boric acid
  • polyhexamethylene biguanide hydrochloride polyhexamethylene biguanide hydrochloride
  • Quil A synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), and Palmitoyl tripeptide.
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the present invention provides an ophthalmic solution composition comprising:
  • the ophthalmic solution compositions are stable.
  • the term “stable” refers to preparation as per the present invention having sufficient stability to allow storage at a convenient temperature and relative humidity such as 25°C and 60% R.H., 40°C and 75% and/or 2-8°C for a pharmaceutically acceptable duration of time.
  • the ophthalmic solution compositions are stable for at least one day.
  • the ophthalmic solution compositions are stable for at least about one week.
  • the ophthalmic solution compositions are stable for one month.
  • the ophthalmic solution compositions are stable for six months.
  • the ophthalmic solution compositions are stable for about one month to about two years.
  • the composition does not comprise any non-aqueous vehicle.
  • the composition is not a suspension.
  • the composition is not an emulsion.
  • the composition is a single-phase solution.
  • the composition is a single-phase aqueous solution.
  • the composition is not a biphasic solution.
  • the composition is not for administered as injection composition.
  • the composition is not injected into the suprachoroidal space (SCS) or subretinal space of an eye.
  • SCS suprachoroidal space
  • the composition is free from surfactant.
  • the composition is free from poloxamer.
  • the composition is free from sorbitan monolaurate, poloxamer, and/or polysorbate.
  • the composition is free from poloxamer and/or polysorbate.
  • the composition is free of any chelating agent.
  • the composition is free of any chelating agent selected from the group consisting of edetate disodium, ethylenediamine tetraacetic acid (EDTA), edetic acid, disodium edetate dihydrate, and diethylenetriamine pentaacetic.
  • EDTA ethylenediamine tetraacetic acid
  • edetic acid edetic acid
  • disodium edetate dihydrate edetic acid
  • diethylenetriamine pentaacetic edetic acid
  • the composition is free of ethylenediamine tetraacetic acid (EDTA).
  • EDTA ethylenediamine tetraacetic acid
  • the composition comprises less than about 40% w/v of one or more solubility enhancer.
  • the composition comprises less than about 40% w/v of cyclodextrin derivatives.
  • the composition comprises less than about 40% w/v of cyclodextrin derivatives selected from the group consisting of 2-hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD) and 2-hydroxypropyl- ⁇ -cyclodextrin, or a combination thereof.
  • cyclodextrin derivatives selected from the group consisting of 2-hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD) and 2-hydroxypropyl- ⁇ -cyclodextrin, or a combination thereof.
  • the composition comprises less than about 40% w/v of sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD).
  • the composition is free of any stabilizer selected from the group consisting of adenine, guanine, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, uric acid, any combination thereof, etc.
  • the composition is free of caffeine.
  • the composition is useful to deliver a high concentration of axitinib in the posterior segment of the eye.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC 50 value of axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to about 5000 times higher than the IC 50 value of the axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to about 2500 times higher than the IC 50 value of axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 50 times higher than the IC 50 value of axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 100 times higher than the IC 50 value of axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 300 times higher than the IC 50 value of axitinib.
  • the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 500 times higher than the IC 50 value of axitinib.
  • the composition delivers axitinib in the posterior segment of the eye at a concentration of about 0.1 to about 1000 ng/gm.
  • the composition delivers axitinib in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.
  • the composition delivers axitinib in the posterior segment of the eye at a concentration of about 190 ng/gm.
  • the posterior segment of the eye may include sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), neural retina, and vitreous humor.
  • RPE retinal pigment epithelium
  • the posterior segment of eye may include retina, vitreous humor, sclera, RPE-Choroid, aqueous humor, and Iris-ciliary body.
  • the present invention provides an ophthalmic solution composition for use in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
  • AMD age-related macular degeneration
  • mCNV Myopic Choroidal Neovascularization
  • the present invention provides use of a medicament prepared according to the present invention in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity by administering via ophthalmic route in mammals.
  • AMD age-related macular degeneration
  • macular edema following retinal vein occlusion diabetic macular edema
  • diabetic retinopathy diabetic retinopathy
  • mCNV Myopic Choroidal Neovascularization
  • retinopathy of prematurity by administering via ophthalmic route in mammals.
  • the salts of axitinib or their isomers are selected from mesylate, tosylate, besylate, or esylate.
  • the composition contains axitinib as the sole active ingredient.
  • axitinib is present in the free base form.
  • the process for the preparation of a pharmaceutical composition comprising:
  • the process for the preparation of a pharmaceutical composition comprising:
  • the process for the preparation of a pharmaceutical composition comprising:
  • the process for the preparation of a pharmaceutical composition comprising:
  • the process for the preparation of a pharmaceutical composition comprising:
  • the process for the preparation of a pharmaceutical composition comprising:
  • Cyclic polysaccharide includes cyclic ⁇ -1,2-glucan (C ⁇ G).
  • Cyclic non-oligosaccharide is macromolecule with ring like architecture formed repeating units of moieties other than monosaccharides. Cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly( ⁇ -caprolactone) (PCL), cyclo poly(ethylene oxide) (PEO), or a combination thereof.
  • Linear polymer includes macromolecular chain in which all structural units or monomers exist in a single line with no branches or intramolecular bridges.
  • Linear polymer includes, but not limited to, linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.
  • Linear oligosaccharide is an oligosaccharide with a straight chain of (3-10) monosaccharides without any branching.
  • Linear oligosaccharide include maltodextrin, raffinose, stachyose, fructo-oligosaccharide, galacto-oligosaccharide, or a combination thereof.
  • Raffinose is a trisaccharide having formula C 18 H 32 O 16 formed with three sugar units, fructose, glucose, and galactose.
  • Fructo-oligosaccharides are short chains of fructose residues.
  • Galacto-oligosaccharides are made up of galactose molecules.
  • Linear polysaccharide include macromolecules with a straight chain of more than 10 monosaccharides without any branching.
  • Linear polysaccharide include starch and its derivatives, amylose, amylopectin, modified starch (esterified starch, carboxymethyl starch, pregelatinized starch, acetylated starch, etc.), carboxymethyl starch, glycogen, galactogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.
  • Hydrocolloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. Hydrocolloids describe certain chemicals (mostly polysaccharides and proteins) that are colloidally dispersible in water.
  • One or more hydrocolloid may include polyvinyl pyrrolidones, starch, polysaccharides, cellulose and cellulose derivatives, and mixtures thereof.
  • the polysaccharide may include one or more of alginic acid, sodium alginate, and calcium alginate.
  • Linear cellulosic polymer includes cellulose which is an organic compound with the formula (C 6 H 10 O 5 )n, a polysaccharide consisting of a linear chain of several hundred to many thousands of ⁇ (1 ⁇ 4) linked D-glucose units.
  • linear polymer include carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.
  • the precipitation inhibitors can also act as viscosity-regulating agent.
  • the precipitation inhibitor is a polymer.
  • the precipitation inhibitor is sulfobutyl ether ⁇ -cyclodextrin and hydroxypropyl methyl cellulose.
  • the composition may include any other pharmaceutically acceptable compounds or excipients capable of inhibiting the precipitation.
  • One or more precipitation inhibitor are present in an amount from about 0.001% to about 50% w/v, preferably from about 0.001% to about 40% w/v. In one embodiment, one or more precipitation inhibitor is present in an amount from about 0.05% to about 30% w/v. For example, about 0.44%, about 5.525%, about 4.9%, about 10%, about 15%, about 20%, about 25%, or about 30% w/v.
  • the preservative is benzalkonium chloride, boric acid, or a combination thereof.
  • one or more preservative is selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes or a combination thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the preservative efficacy.
  • the preservatives are present in an amount from about 0.001% to about 10% w/v, preferably about 5% w/v. For example, about 0.
  • One or more pH adjusting agent is selected from pharmaceutically acceptable buffer systems such as citrate buffer, tartrate buffer, phosphate buffer, acetate buffer, lactate buffer, glycine buffer, or a mixture thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the pH.
  • pharmaceutically acceptable buffer systems such as citrate buffer, tartrate buffer, phosphate buffer, acetate buffer, lactate buffer, glycine buffer, or a mixture thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the pH.
  • buffers containing any of the commonly used compounds or a combination of compounds such as citric acid, ascorbic acid, gluconic acid, carbonic acid, succinic acid, sodium citrate, potassium citrate, tartaric acid, sodium tartrate, phosphoric acid, methane sulfonic acid, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, acetic acid, phthalic acid, sodium acetate, lactic acid, sodium lactate, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, disodium succinate hexahydrate, Tris, and tromethamine.
  • the pH-adjusting agent is tromethamine.
  • one or more preservative is selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine and potassium phosphate or a combination thereof.
  • One or more pH adjusting agent is present in an amount from about 0.001% to about 10% w/v, preferably about 5% w/v. For example, about 0.5%, about 0.1%, about 1%, about 2%, about 3%, about 4%, about 5% w/v.
  • the osmotic/tonicity adjusting agents may be selected from propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, sucrose, mannose and the like and mixtures thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the tonicity.
  • compositions as per the present invention have osmolality in the range of about 150 to 450 mOsml/kg, preferably from about 250 to 375 mOsml/kg, preferably 270-350 mOsml/kg, such as for example 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340 or 345 mOsml/kg.
  • Suitable pharmaceutically acceptable vehicles include but are not limited to oleoyl polyethyleneglycol gylcerides, linoleoyl polyethyleneglycol gylcerides, lauroyl polyethyleneglycol gylcerides, hydrocarbon vehicles like liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin (vaseline), hard paraffin, vegetable fatty oils like castor oil, peanut oil or sesame oil, synthetic fatty oils like middle chain triglycerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid), isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glycerides, wool alcohols like cetylstearylalcohols, wool fat, glycerol, propylene glycol, propy
  • the ophthalmic composition comprises water.
  • the composition comprises at least 99% by weight of water, at least 90% by weight of water, at least 95% by weight of water, or at least 98% by weight of water based on the total weight or volume of the composition.
  • the aqueous medium includes purified water, water for injection, sterile distilled water, and so on.
  • the suitable vehicles/diluents include water, water for injection, purified water, Ringer's solution, and normal saline solution.
  • the term water is interchangeable with water for injection (WFI) and/or purified water and/or sterile water.
  • the term water means Water for Injection (WFI).
  • the pharmaceutical composition is suitable for administration to an animal or human.
  • the aim of this study was to determine whether topical ophthalmic administration (eye drops) of tyrosine kinase inhibitors of the present invention result in Corneal permeability, distribution, and safety pharmacology of active ingredient in the posterior segment of the eye.
  • the rabbits were restrained and were allowed to stabilize for 5-10 min before dosing. After that, they were administered axitinib (1.25 mg/ml) four times at approximately 3-4 hours intervals daily.
  • axitinib was well-distributed in target tissue choroid-retina with a concentration of 287.9 ng/gm of tissue and thus it is ⁇ 3700 fold higher than IC 50 of axitinib (0.077 ng/mL).
  • the concentration of sunitinib, lenvatinib, and pazopanib in choroid-retina was at least 100 times higher than the IC 50 of the respective drug.
  • SBE ⁇ CD was dissolved in water for injection. Weighed quantity of the axitinib was transferred to the vial containing SBE ⁇ CD solution and axitinib was solubilized by sonication and addition of methane sulfonic acid. Methane sulfonic acid was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.
  • Example 1b composition delivers axitinib in the posterior segment of the eye at a concentration of about 190 ng/gm in Choroid-Retina.
  • concentration of Axitinib ng/gm
  • Choroid-Retina 190.25 111.0289 Cornea 649.1 186.0317 Iris 89.6 14.22252 Lens 61.45 6.69384
  • axitinib was well-distributed in target tissue choroid-retina with concentration of 190 ng/gm of tissue and thus it is ⁇ 2400 fold higher than IC 50 of Axitinib (0.077 ng/mL).
  • Example 11-13 Ingredients 11 12 13 Quantity (% w/v) Axitinib 0.2 0.2 0.2 SBE ⁇ CD 8 8 8 Methane sulfonic acid 0.16 0.16 0.16 Hydroxypropyl methylcellulose 0.3 0.3 0.3 Benzalkonium chloride 0.01 0.01 0.01 Sodium N-lauroyl sarcosinate 0.06 0.06 0.06 Boric acid 0.45 0.45 0.45 Polyhexamethylene biguanide hydrochloride 0.02 0.02 0.02 0.02 Quil A 0.05 - - Salcaprozate sodium (SNAC) - 0.05 - Perifosine - - 0.05 Tromethamine 0.22 - 0.23 Water for Injection (WFI) q.s. q.s. q.s.
  • Example 18-20 18 19 20 Ingredients Quantity (% w/v) Axitinib 0.3 0.1 0.1 SBE ⁇ CD 9.2 5 7 Methane sulfonic acid 0.23 0.08 0.08 Hydroxypropyl methylcellulose 0.3 0.3 0.3 Benzalkonium chloride 0.01 0.01 0.01 0.01 Polyhexamethylene biguanide hydrochloride HCl - 0.02 0.02 Sodium N-lauroyl sarcosinate 0.06 - - Boric acid 0.05 0.9 0.5 Potassium sorbate 0.1 - Tromethamine 0.25 0.20 0.20 Water for Injection (WFI) q.s. q.s. q.s.
  • WFI Water for Injection
  • Polymer phase The required quantity of water for injection was taken in a vessel. Hydroxypropyl methylcellulose was added slowly into the vortex of vigorously agitated water for injection maintained at a suitable temperature of about 70-90°C using an overhead stirrer. Stirring was continued to obtain a homogeneous dispersion. The temperature was maintained throughout the preparation. Once homogeneous dispersion was formed, the temperature was decreased to room temperature and stirring was continued. The total volume was made up to the mark with water for injection and the phase was autoclaved to make it sterile.
  • Vehicle phase Required quantity of water for injection was taken in a vessel or glass vial. Required excipients (boric acid, benzalkonium chloride, Polyhexamethylene biguanide hydrochloride, Sodium N-lauroyl sarcosinate, or tromethamine) were added. The solution was stirred after the addition of each excipient and was dissolved till a clear solution was formed.
  • Drug phase Filtered water for injection was taken in a vessel or glass bottle and methane sulfonic acid was added to this and stirred. The drug was added followed by the addition of water for injection. This was heated to a suitable temperature of about 40-50 °C and was stirred. SBE ⁇ CD was added to the above solution and was kept under stirring at a suitable temperature of about 40-50°C, till it became a clear solution.
  • Drug phase solution was added to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). The solution was stirred to ensure sufficient mixing. The volume was made to the desired batch size. The bulk solution was filtered through a suitable filter (40 ⁇ micron polishing filter).
  • the filtered solution was aseptically filled in a suitable bottle with nitrogen purging, plugged, and capped with a tamper-proof closure.
  • the objective was to evaluate the efficacy of compositions prepared in examples 16 and 17, in a model of laser-induced choroidal neovascularization (CNV) in domestic swine.
  • CNV laser-induced choroidal neovascularization
  • OEs ocular examinations
  • FA fluorescein angiography
  • F fundus imaging.

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Abstract

La présente invention concerne une composition pharmaceutique topique d'inhibiteurs de tyrosine kinase pour la prévention ou le traitement d'une maladie oculaire postérieure. La composition pharmaceutique topique de la présente invention est utile pour administrer une concentration élevée d'un ingrédient pharmaceutique actif tel que l'inhibiteur de tyrosine kinase dans le segment postérieur de l'oeil par exemple à une concentration jusqu'à 10000 fois supérieure à la valeur IC50 de l'ingrédient pharmaceutique actif.
PCT/IB2025/051225 2024-02-05 2025-02-05 Compositions ophtalmiques d'inhibiteurs de tyrosine kinase et leurs utilisations Pending WO2025169089A1 (fr)

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