WO2024042550A1 - Ophthalmic combination composition - Google Patents
Ophthalmic combination composition Download PDFInfo
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- WO2024042550A1 WO2024042550A1 PCT/IN2023/050801 IN2023050801W WO2024042550A1 WO 2024042550 A1 WO2024042550 A1 WO 2024042550A1 IN 2023050801 W IN2023050801 W IN 2023050801W WO 2024042550 A1 WO2024042550 A1 WO 2024042550A1
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- Prior art keywords
- composition
- acid
- sodium
- combinations
- group
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 124
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Definitions
- the present invention is related to an ophthalmic combination composition
- an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof.
- the said composition is useful for treatment of dry eye syndrome.
- Dry Eye Disease is a common condition that occurs when your tears are not able to provide adequate lubrication for your eyes.
- the medical term for this condition is keratoconjunctivitis sicca.
- Tear film has three layers: fatty oils, aqueous fluid, and mucus. This combination normally keeps the surface of eyes lubricated, smooth and clear. Problems with any of these layers can cause dry eyes. For example, dry eyes may occur if you do not produce enough tears or there is increased tear evaporation. This tear instability leads to inflammation and damage of the eye's surface. It is accompanied by increased osmolality of the tear film. Dry eye symptoms affect activities of daily living and can lead to despair, depression, decreased productivity, and adversely impact tasks such as driving and our daily routine works. If left untreated, the chronic nature of DED can progress to corneal scarring, ulcers and ultimately vision loss.
- Commonly prescribed drugs for dry eye includes immune-suppressing medication (XiidraTM, RestasisTM, CequaTM, IkervisTM) or corticosteroids (e.g., FluoromethoIone, FMLTM, FlarexTM) which can help relieve inflammation in the cornea.
- Corticosteroids are not ideal for long-term use due to possible side effects.
- RestasisTM (Cyclosporine) ophthalmic emulsion is administered twice a day in each eye approximately 12 hours apart. Cyclosporine works by reducing the inflammation in eyes and tear ducts. This action helps to improve body's natural ability to make tears, which moistens your eyes and reduces dry eye symptoms.
- XiidraTM (Lifitegrast) is also administered twice daily (approximately 12 hours apart) into each eye.
- Lifitegrast is a lymphocyte function-associated antigen- 1 (LFA-1) antagonist.
- LFA-1 is ubiquitously expressed on large granular lymphocytes, B lymphocytes, and T lymphocytes.
- Lifitegrast binds to LFA-1 and inhibits it from interacting with its ligand, intercellular adhesion molecule 1 (ICAM-1), an immunoglobulin superfamily cellular adhesion molecule.
- ICAM-1 is expressed by endothelial cells when inflammation or an infection is present but may be overexpressed in corneal and conjunctival tissues in individuals with DED.
- cytokine secretion e.g., interferon gamma, interleukin 4
- cell destruction e.g., cell destruction, and self-amplification of the inflammatory immune response that further aggravates symptoms of DED.
- RestasisTM and XiidraTM normally take a period of time to take effect. These medications are available as monotherapies.
- the inventors of the present invention have formulated the ophthalmic composition comprising combination of lifitegrast and cyclosporine, which has stability, safety, efficacy and leads to increased patient compliance.
- the present invention provides an ophthalmic composition comprising combination of lifitegrast and cyclosporine.
- the present invention provides an ophthalmic combination composition comprising of lifitegrast or a salt thereof and cyclosporine or a salt thereof.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains one or more pharmaceutically acceptable excipients.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution.
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of preservative.
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of antioxidant and/or preservative.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered twice daily.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
- the present invention provides a method of treating dry eye by administering a combination composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof.
- Lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid.
- the molecular formula of lifitegrast is C29H24CI2N2O7S and its molecular weight is 615.5 g/mol.
- the present invention contains lifitegrast in an amount of about 0.1% w/v to about 50% w/v of the composition. Preferably, about 1.0% w/v to about 10% w/v of the composition.
- Cyclosporine is a calcineurin inhibitor immunosuppressant with anti-inflammatory effects.
- Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)- 6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valylN-methyl-L-leucyl-L- alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl].
- the molecular formula of cyclosporine is C62H111N11O12 and its molecular weight is 1202.6 g/mol.
- the present invention contains cyclosporine in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- composition of the present invention may comprises the amorphous form of active ingredient or any of its crystalline form, or a combination thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast and cyclosporine, wherein the weight ratio of lifitegrast and cyclosporine is in the range of 1 :50 to 50: 1 by weight of the composition.
- the ophthalmic composition according to the present invention may also contain one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- Suitable buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2-hydroxymethyl- 1,3 -propanediol) and/or combinations thereof. Buffering agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
- Preservative is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (i.e., Tocopherols Such as a-tocopherol) derivatives of vitamin E (e.g., toco pheryl acetate), retinoids such as retinoic acid, retinol, trans retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A (e.g., retinyl acetate, retinal and retinyl palmitate, also known as tetinyl palmitate), sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycop
- Suitable chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
- Other acceptable chelating agents such as amino acids like glutamic and aspartic acids and borates may be used.
- Chelating agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
- Suitable tonicity adjusting agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- Tonicity agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers (Pluronics® / Poloxamers®), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol (e.g., Octoxynol-40), polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
- Surfactant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
- DMSO dimethylsulphoxide
- EDTA ethylenediaminetetraacetic acid
- the present invention contains penetration enhancer in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- Suitable thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
- the hydroxyalkylated cellulose may be hydroxypropylcellulose, hydroxymenthyl cellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose.
- the alkylated cellulose may be methylcellulose or ethylcellulose.
- the present invention contains thickening agent in an amount of about 0.1% w/v to about 50.0 % w/v of the composition.
- Suitable humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. Humectant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. Polyol is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable polymers include, but are not limited to, natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
- the present invention contains polymer in an amount of about 0.1% w/v to about 50.0 % w/v by weight of the composition.
- the ophthalmic composition according to the present invention may contain oils such as the medium chain triglycerides, mineral oil, vegetable oil such as castor oil.
- Suitable solvents may be selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- alcohols such as ethanol
- glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- composition as per the present invention is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- composition as per the present invention is in the form of solution or drops.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered once to thrice daily, more preferably twice daily or once daily.
- the pharmaceutical composition of the invention may be administered one to four drops per time, preferably one to two drops, more preferably one to two drops, and most preferably one drop per day.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of antioxidant and/or preservative.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative.
- the ophthalmic composition according to the present invention is provided/supplied in a single dose container or a multi-dose container.
- single-dose container refers to those containers which contain composition which is intended for a single use such as vials, ampoules, bottles, UNIMS, pre-filled syringes, cartridges, bags, BFS, etc.
- multi-dose container refers to those containers which are designed for removal of portions of composition multiple times such as multi-dose vials or bottles.
- the ophthalmic composition according to the present invention has pH in the range of about 5.0 to about 8.0, preferably in the range of about 6.5 to about 8.0.
- the ophthalmic composition according to the present invention is therapeutically as effective as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides synergistic effect as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides favourable safety profile as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention leads to reduced side effects as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention leads to increased patient compliance as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides reduction in total dose of active ingredients administered per day as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides early onset of action as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention is meant for topical ocular application.
- the pharmaceutical composition as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam).
- the pharmaceutical composition prepared according to present invention is stable when subject to stability testing conditions.
- composition according to present invention contains total impurities not more than 3.0% when stored at a temperature of about 40 °C for a period of at least 1 month.
- the particle size of the active ingredient i.e., D90 of cyclosporine in the present composition is in the range of about 1 pm to 30 pm.
- Milling/Size reduction of active ingredient can be performed using high pressure homogenizer, bead mill, ball mill etc.
- the ophthalmic composition of the present invention may be required to be isotonic with respect to the ophthalmic fluids present in the human eye.
- the composition of the present invention is having an osmolality of about 250 mOsm/kg to about 500 mOsm/kg.
- the ophthalmic composition according to the present invention has a viscosity between 5 and 100 cP.
- the present composition optionally further comprises one or more therapeutic agents.
- additional therapeutic agent for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an anti-inflammatory, analgesic or anaesthetic agent, steroid, antibiotic or the like.
- the present invention provides a pharmaceutical composition which is useful in treating any such conditions, preferably are ophthalmic or ocular conditions that is relating to or having to do with one or more parts of an eye of a human or animal. Included among such conditions are, without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis, uveitis, macular edema, vernal conjunctivitis, atopic keratoconjunctivitis, corneal graft rejection and the like conditions.
- the present invention is particularly effective in treating dry eye syndrome also known as keratoconjunctivitis sicca.
- composition of the present invention can also be provided as kit.
- the main embodiment of the present invention provides a composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients.
- lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition.
- cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- the ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50:1 by weight of the composition.
- the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
- phosphates sodium phosphate monobasic/dibasic
- bicarbonates acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
- the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
- benzalkonium chloride benzethonium chloride
- benzododecinium chloride chlorobutanol
- chlorhexidine parabens
- parabens stabilized oxy
- the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl
- the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
- the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
- the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- alkali metal chlorides and alkaline earth metal chlorides such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
- the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
- the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
- the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof.
- the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof.
- the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
- the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- alcohols such as ethanol
- glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- the pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition.
- the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- the composition is in the form of solution.
- the composition is free of preservative.
- the composition is free of antioxidant and/or preservative.
- the composition is administered once or twice daily, preferable once daily.
- the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
- the composition is used for treating dry eye syndrome.
- step 2 Slowly adding polyoxyl hydrogenated castor oil into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 3 Adding octoxynol-40 and polyvinylpyrrolidone into the above solution of step 2 to form clear solution. 4. Adding sodium chloride to the solution of step 3 under continuous stirring.
- step 5 Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 4 under continuous stirring till it dissolves completely.
- step 6 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 5 under continuous stirring to form clear solution.
- step 6 7. Adding cyclosporine to above solution of step 6 under continuous stirring till it dissolves completely.
- step 8 9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
- step 9 Checking the pH of solution of step 9 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 11 Filtering the solution of step 11 through 0.2 pm sterilizing grade filter.
- step 4 5. Adding sodium chloride to the water for injection of step 4 under continuous stirring.
- step 6 Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 5 under continuous stirring till it dissolves completely.
- step 7 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 6 under continuous stirring to form clear solution.
- step 8 9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
- step 11 Checking the pH of solution of step 10 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 13 Filtering the solution of step 12 through 0.2pm sterilizing grade filter.
- step 2 2. Adding Brij 35 into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 6 Adding EDTA dihydrate to the water for injection of step 5 under continuous stirring.
- step 7 Adding the dispensed quantity of glycerin to solution of step 6 under continuous stirring till it dissolves completely.
- step 10 Adding the dispensed quantity of lifitegrast to above solution of step 9 under continuous stirring to obtain clear solution.
- step 11 Checking the pH of solution of step 11 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 14 Filtering the solution of step 13 through 0.2 pm sterilizing grade filter.
- step 2 2. Adding EDTA dihydrate into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 3 Adding carbomer copolymer type A into the solution of step 2 under continuous stirring to get a clear solution.
- step 4 Adjusting the pH of step 4 solution with sodium hydroxide solution and making up the volume up to 50% of the actual batch size with water for injection.
- step 5 Autoclaving the step 5 solution at 121 °C for 30 minutes and cooling the solution.
- step 8 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to solution of step 8 under continuous stirring till it dissolves completely.
- step 11 Adding the dispensed quantity of lifitegrast to above solution of step 10 under continuous stirring to obtain clear solution. 12. Filtering the step 11 solution through 0.2pm sterilizing grade filter and adding cyclosporine into it under continuous stirring.
- step 12 Milling the step 12 cyclosporine slurry with high pressure homogenizer to get desired particle size.
- step 13 Transferring the step 13 homogenized slurry to step 6 solution under stirring to form suspension.
- step 14 Making up the volume of suspension obtained in step 14 up to 100% with water for injection.
- step 16 Filling the final suspension obtained in step 15 in suitable container.
- step 2 2. Adding carbomer copolymer type A into the water of injection of step 2 under continuous stirring to get a clear solution.
- step 6 Adding cyclosporine into step 5 mixture under stirring and maintaining the temperature up to 60°C until it dissolves completely. Taking 10% hot WFI in a separate container and adding glycerin into it under stirring. Adding step 6 solution into step 7 glycerin solution under high shear mixture for 60 minutes to achieve desire globule size. Adjusting the pH of the step 8 emulsion with sodium hydroxide solution. Filtering the step 9 emulsion through 0.2pm sterilizing grade filter and transferring it to step 3 solution under stirring to obtain emulsion. Taking 35 % WFI of the actual batch size in a container and adding sodium phosphate dibasic anhydrous into it under continuous stirring.
- step 11 Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 11 under continuous stirring to form clear solution. Adding the dispensed quantity of lifitegrast to above solution of step 12 under continuous stirring to obtain clear solution. Filtering the step 13 solution through 0.2pm sterilizing grade filter and adding it into emulsion of step 10 under stirring. Making up the volume of emulsion obtained in step 14 up to 100% with water for injection. Filling the final emulsion obtained in step 15 in suitable container.
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Abstract
The present invention provides an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof, along with one or more pharmaceutically acceptable excipients. It further provides the process of preparing such composition and its use for treatment of dry eye syndrome.
Description
“OPHTHALMIC COMBINATION COMPOSITION”
FIELD OF THE INVENTION
The present invention is related to an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof. The said composition is useful for treatment of dry eye syndrome.
BACKGROUND OF THE INVENTION
Dry Eye Disease (DED) is a common condition that occurs when your tears are not able to provide adequate lubrication for your eyes. The medical term for this condition is keratoconjunctivitis sicca. Tear film has three layers: fatty oils, aqueous fluid, and mucus. This combination normally keeps the surface of eyes lubricated, smooth and clear. Problems with any of these layers can cause dry eyes. For example, dry eyes may occur if you do not produce enough tears or there is increased tear evaporation. This tear instability leads to inflammation and damage of the eye's surface. It is accompanied by increased osmolality of the tear film. Dry eye symptoms affect activities of daily living and can lead to despair, depression, decreased productivity, and adversely impact tasks such as driving and our daily routine works. If left untreated, the chronic nature of DED can progress to corneal scarring, ulcers and ultimately vision loss.
Commonly prescribed drugs for dry eye includes immune-suppressing medication (Xiidra™, Restasis™, Cequa™, Ikervis™) or corticosteroids (e.g., FluoromethoIone, FML™, Flarex™) which can help relieve inflammation in the cornea. Corticosteroids are not ideal for long-term use due to possible side effects.
Restasis™ (Cyclosporine) ophthalmic emulsion is administered twice a day in each eye approximately 12 hours apart. Cyclosporine works by reducing the inflammation in eyes and tear ducts. This action helps to improve body's natural ability to make tears, which moistens your eyes and reduces dry eye symptoms.
Xiidra™ (Lifitegrast) is also administered twice daily (approximately 12 hours apart) into each eye. Lifitegrast is a lymphocyte function-associated antigen- 1 (LFA-1) antagonist. LFA-1 is ubiquitously expressed on large granular lymphocytes, B lymphocytes, and T lymphocytes. Lifitegrast binds to LFA-1 and inhibits it from interacting with its ligand, intercellular adhesion
molecule 1 (ICAM-1), an immunoglobulin superfamily cellular adhesion molecule. ICAM-1 is expressed by endothelial cells when inflammation or an infection is present but may be overexpressed in corneal and conjunctival tissues in individuals with DED. By competitively binding to the LFA-1, lifitegrast prevents the adhesion, activation, migration, and proliferation of lymphocytes, which ultimately lead to cytokine secretion (e.g., interferon gamma, interleukin 4), cell destruction, and self-amplification of the inflammatory immune response that further aggravates symptoms of DED. Restasis™ and Xiidra™ normally take a period of time to take effect. These medications are available as monotherapies.
However, to treat the large population of dry eye patients, physicians advise moving in a stepwise fashion, trying one method at a time and then supplementing with others in cases of unimproved symptoms by monotherapies or due to higher severity of disease. Further, there are concerns and expressed reservations in the ophthalmic community about patient compliance when the patient is required to administer separate medications to treat a single disease or condition such as dry eye. Therefore, there exists a long felt need for an effective and safe topical ophthalmic pharmaceutical composition which is capable of simultaneously treating more than one of the underlying DED pathologies and which could potentially improve the treatment efficacy. Unexpectedly, it has been discovered that cyclosporine in combination with lifitegrast meets these criteria.
The inventors of the present invention have formulated the ophthalmic composition comprising combination of lifitegrast and cyclosporine, which has stability, safety, efficacy and leads to increased patient compliance.
SUMMARY OF THE INVENTION
The present invention provides an ophthalmic composition comprising combination of lifitegrast and cyclosporine.
According to one aspect, the present invention provides an ophthalmic combination composition comprising of lifitegrast or a salt thereof and cyclosporine or a salt thereof.
According to one embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains one or more pharmaceutically acceptable excipients.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of preservative.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of antioxidant and/or preservative.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered twice daily.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
According to another aspect, the present invention provides a method of treating dry eye by administering a combination composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. For the values provided herein, the term “about” indicates a given number may vary by at least ±10%.
Lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid. The molecular formula of lifitegrast is C29H24CI2N2O7S and its molecular weight is 615.5 g/mol. The present invention contains lifitegrast in an amount of about 0.1% w/v to about 50% w/v of the composition. Preferably, about 1.0% w/v to about 10% w/v of the composition.
Cyclosporine is a calcineurin inhibitor immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)- 6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valylN-methyl-L-leucyl-L- alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]. The molecular formula of cyclosporine is C62H111N11O12 and its molecular weight is 1202.6 g/mol. The present invention contains cyclosporine in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
The composition of the present invention may comprises the amorphous form of active ingredient or any of its crystalline form, or a combination thereof.
The present invention provides an ophthalmic composition comprising lifitegrast and cyclosporine, wherein the weight ratio of lifitegrast and cyclosporine is in the range of 1 :50 to 50: 1 by weight of the composition.
The ophthalmic composition according to the present invention may also contain one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant,
penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
Suitable buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2-hydroxymethyl- 1,3 -propanediol) and/or combinations thereof. Buffering agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof. Preservative is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (i.e., Tocopherols Such as a-tocopherol) derivatives of vitamin E (e.g., toco pheryl acetate), retinoids such as retinoic acid, retinol, trans retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A (e.g., retinyl acetate, retinal and retinyl palmitate, also known as tetinyl palmitate), sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids (e.g., hesperitin, naringen, rutin and quercetin), superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof. The Antioxidant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof. Other acceptable chelating
agents such as amino acids like glutamic and aspartic acids and borates may be used. Chelating agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
Suitable tonicity adjusting agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof. Tonicity agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers (Pluronics® / Poloxamers®), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol (e.g., Octoxynol-40), polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof. Surfactant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof. The present invention contains penetration enhancer in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
Suitable thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof. The hydroxyalkylated cellulose may be hydroxypropylcellulose, hydroxymenthyl cellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose. The
alkylated cellulose may be methylcellulose or ethylcellulose. The present invention contains thickening agent in an amount of about 0.1% w/v to about 50.0 % w/v of the composition.
Suitable humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. Humectant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. Polyol is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable polymers, include, but are not limited to, natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof. The present invention contains polymer in an amount of about 0.1% w/v to about 50.0 % w/v by weight of the composition.
The ophthalmic composition according to the present invention may contain oils such as the medium chain triglycerides, mineral oil, vegetable oil such as castor oil.
Suitable solvents may be selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
The composition as per the present invention is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
The composition as per the present invention is in the form of solution or drops.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered once to thrice daily, more preferably twice daily or once daily. The pharmaceutical composition of the invention may
be administered one to four drops per time, preferably one to two drops, more preferably one to two drops, and most preferably one drop per day.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of antioxidant and/or preservative.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative.
The ophthalmic composition according to the present invention is provided/supplied in a single dose container or a multi-dose container.
The term “single-dose container” as used herein refers to those containers which contain composition which is intended for a single use such as vials, ampoules, bottles, UNIMS, pre-filled syringes, cartridges, bags, BFS, etc.
The term “multi-dose container” as used herein refers to those containers which are designed for removal of portions of composition multiple times such as multi-dose vials or bottles.
The ophthalmic composition according to the present invention has pH in the range of about 5.0 to about 8.0, preferably in the range of about 6.5 to about 8.0.
The ophthalmic composition according to the present invention is therapeutically as effective as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides synergistic effect as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides favourable safety profile as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention leads to reduced side effects as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention leads to increased patient compliance as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides reduction in total dose of active ingredients administered per day as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides early onset of action as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention is meant for topical ocular application.
The pharmaceutical composition as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam).
The pharmaceutical composition prepared according to present invention is stable when subject to stability testing conditions.
In another preferred embodiment the composition according to present invention contains total impurities not more than 3.0% when stored at a temperature of about 40 °C for a period of at least 1 month.
The particle size of the active ingredient i.e., D90 of cyclosporine in the present composition is in the range of about 1 pm to 30 pm.
Milling/Size reduction of active ingredient can be performed using high pressure homogenizer, bead mill, ball mill etc.
The ophthalmic composition of the present invention may be required to be isotonic with respect to the ophthalmic fluids present in the human eye. The composition of the present invention is having an osmolality of about 250 mOsm/kg to about 500 mOsm/kg.
The ophthalmic composition according to the present invention has a viscosity between 5 and 100 cP.
The present composition optionally further comprises one or more therapeutic agents. For example, additional therapeutic agent for conjoint administration or inclusion in a pharmaceutical
composition with a compound of this invention may be an anti-inflammatory, analgesic or anaesthetic agent, steroid, antibiotic or the like.
The present invention provides a pharmaceutical composition which is useful in treating any such conditions, preferably are ophthalmic or ocular conditions that is relating to or having to do with one or more parts of an eye of a human or animal. Included among such conditions are, without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis, uveitis, macular edema, vernal conjunctivitis, atopic keratoconjunctivitis, corneal graft rejection and the like conditions. The present invention is particularly effective in treating dry eye syndrome also known as keratoconjunctivitis sicca.
The composition of the present invention can also be provided as kit.
The main embodiment of the present invention provides a composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention, lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition.
In another embodiment of the present invention, cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
In another embodiment of the present invention, the ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50:1 by weight of the composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
In another embodiment of the present invention, the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
In another embodiment of the present invention, the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
In another embodiment of the present invention, the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof.
In another embodiment of the present invention, the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
In another embodiment of the present invention, the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium
hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
In another embodiment of the present invention, the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
In another embodiment of the present invention, the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
In another embodiment of the present invention, the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
In another embodiment of the present invention, the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
In another embodiment of the present invention, the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof.
In another embodiment of the present invention, the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof.
In another embodiment of the present invention, the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
In another embodiment of the present invention, the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
In another embodiment of the present invention, the pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition.
In another embodiment of the present invention, the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
In another embodiment of the present invention, the composition is in the form of solution.
In another embodiment of the present invention, the composition is free of preservative.
In another embodiment of the present invention, the composition is free of antioxidant and/or preservative.
In another embodiment of the present invention, the composition is administered once or twice daily, preferable once daily.
In another embodiment of the present invention, the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
In another embodiment of the present invention, the composition is used for treating dry eye syndrome.
EXAMPLES
While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.
Example 1:
Method of Preparation:
1. Taking 70 % (of actual batch size) of water for injection in a container.
2. Slowly adding polyoxyl hydrogenated castor oil into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding octoxynol-40 and polyvinylpyrrolidone into the above solution of step 2 to form clear solution.
4. Adding sodium chloride to the solution of step 3 under continuous stirring.
5. Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 4 under continuous stirring till it dissolves completely.
6. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 5 under continuous stirring to form clear solution.
7. Adding cyclosporine to above solution of step 6 under continuous stirring till it dissolves completely.
8. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
10. Checking the pH of solution of step 9 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
11. Making up the volume up to 100% with water for injection.
12. Filtering the solution of step 11 through 0.2 pm sterilizing grade filter.
13. Filling the final solution in suitable container.
Example 2:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Slowly adding Kolliphor Pl 88 into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding cyclosporine into the above solution of step 2 to form clear solution.
4. Taking 40 % (of actual batch size) of water for injection in a container.
5. Adding sodium chloride to the water for injection of step 4 under continuous stirring.
6. Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 5 under continuous stirring till it dissolves completely.
7. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 6 under continuous stirring to form clear solution.
8. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
10. Adding the solution of cyclosporine of step 3 into the solution of step 9 under continuous stirring.
11. Checking the pH of solution of step 10 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
12. Making up the volume up to 100% with water for injection.
13. Filtering the solution of step 12 through 0.2pm sterilizing grade filter.
14. Filling the final solution in suitable container.
Example 3:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Adding Brij 35 into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding polysorbate 80 into the solution of step 2 under continuous stirring to get a clear solution.
4. Adding cyclosporine into the above solution of step 3 to form clear solution.
5. Taking 40 % (of actual batch size) of water for injection in a container.
6. Adding EDTA dihydrate to the water for injection of step 5 under continuous stirring.
7. Adding the dispensed quantity of glycerin to solution of step 6 under continuous stirring till it dissolves completely.
8. Adding the dispensed quantity of boric acid to above solution of step 7 under continuous stirring to form clear solution.
9. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 8 under continuous stirring.
10. Adding the dispensed quantity of lifitegrast to above solution of step 9 under continuous stirring to obtain clear solution.
11. Adding the solution of cyclosporine of step 3 into the solution of step 10 under stirring.
12. Checking the pH of solution of step 11 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
13. Making up the volume up to 100% with water for injection.
14. Filtering the solution of step 13 through 0.2 pm sterilizing grade filter.
15. Filling the final solution in suitable container.
Example 4:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Adding EDTA dihydrate into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding carbomer copolymer type A into the solution of step 2 under continuous stirring to get a clear solution.
4. Adding sodium chloride into the above solution of step 3 to form clear solution.
5. Adjusting the pH of step 4 solution with sodium hydroxide solution and making up the volume up to 50% of the actual batch size with water for injection.
6. Autoclaving the step 5 solution at 121 °C for 30 minutes and cooling the solution.
7. Taking 40 % (of actual batch size) of water for injection in a container.
8. Adding polysorbate 80 to the solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to solution of step 8 under continuous stirring till it dissolves completely.
10. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 9 under continuous stirring to form clear solution.
11. Adding the dispensed quantity of lifitegrast to above solution of step 10 under continuous stirring to obtain clear solution.
12. Filtering the step 11 solution through 0.2pm sterilizing grade filter and adding cyclosporine into it under continuous stirring.
13. Milling the step 12 cyclosporine slurry with high pressure homogenizer to get desired particle size.
14. Transferring the step 13 homogenized slurry to step 6 solution under stirring to form suspension.
15. Making up the volume of suspension obtained in step 14 up to 100% with water for injection.
16. Filling the final suspension obtained in step 15 in suitable container.
Example 5:
Method of Preparation:
1. Taking 20 % (of actual batch size) of water for injection in a container.
2. Adding carbomer copolymer type A into the water of injection of step 2 under continuous stirring to get a clear solution.
3. Autoclaving the step 2 solution at 121 °C for 30 minutes and cooling the solution.
4. Taking castor oil in a container and heating it up to 70°C.
5. Adding polysorbate 80 half quantity into castor oil of step 4 while heating and mixing well.
6. Adding cyclosporine into step 5 mixture under stirring and maintaining the temperature up to 60°C until it dissolves completely.
Taking 10% hot WFI in a separate container and adding glycerin into it under stirring. Adding step 6 solution into step 7 glycerin solution under high shear mixture for 60 minutes to achieve desire globule size. Adjusting the pH of the step 8 emulsion with sodium hydroxide solution. Filtering the step 9 emulsion through 0.2pm sterilizing grade filter and transferring it to step 3 solution under stirring to obtain emulsion. Taking 35 % WFI of the actual batch size in a container and adding sodium phosphate dibasic anhydrous into it under continuous stirring. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 11 under continuous stirring to form clear solution. Adding the dispensed quantity of lifitegrast to above solution of step 12 under continuous stirring to obtain clear solution. Filtering the step 13 solution through 0.2pm sterilizing grade filter and adding it into emulsion of step 10 under stirring. Making up the volume of emulsion obtained in step 14 up to 100% with water for injection. Filling the final emulsion obtained in step 15 in suitable container.
Claims
THE CLAIMS: A composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients. The composition as claimed in claim 1 wherein lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition. The composition as claimed in claim 1 wherein cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition. The composition as claimed in claim 1 wherein ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50: 1 by weight of the composition. The composition as claimed in claim 1 wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof. The composition as claimed in claim 5 wherein the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof. The composition as claimed in claim 5 wherein the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol,
chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof. The composition as claimed in claim 5 wherein the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof. The composition as claimed in claim 5 wherein the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof. The composition as claimed in claim 5 wherein the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof. The composition as claimed in claim 5 wherein the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
The composition as claimed in claim 5 wherein the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-poly vinyl acetatepolyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof. The composition as claimed in claim 5 wherein the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof. The composition as claimed in claim 5 wherein the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof. The composition as claimed in claim 5 wherein the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. The composition as claimed in claim 5 wherein the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. The composition as claimed in claim 5 wherein the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
The composition as claimed in claim 5 wherein the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof. The composition as claimed in claim 5 wherein pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition. The composition as claimed in claim 1 wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof. The composition as claimed in claim 1 wherein the composition is in the form of solution. The composition as claimed in claim 1 wherein the composition is free of preservative. The composition as claimed in claim 1 wherein the composition is free of antioxidant and/or preservative. The composition as claimed in claim 1 wherein the composition is administered once or twice daily, preferable once daily. The composition as claimed in claim 1 wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month. The composition as claimed in claim 1 wherein the composition is used for treating dry eye syndrome.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202211048424 | 2022-08-25 | ||
| IN202211048424 | 2022-08-25 |
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| Publication Number | Publication Date |
|---|---|
| WO2024042550A1 true WO2024042550A1 (en) | 2024-02-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2023/050801 WO2024042550A1 (en) | 2022-08-25 | 2023-08-25 | Ophthalmic combination composition |
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| Country | Link |
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| WO (1) | WO2024042550A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180098937A1 (en) * | 2016-10-12 | 2018-04-12 | Ps Therapies Ltd | Artificial tear, contact lens and drug vehicle compositions and methods of use thereof |
| WO2019171260A1 (en) * | 2018-03-09 | 2019-09-12 | Mankind Pharma Ltd. | Pharmaceutical composition of lifitegrast |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
| US10918694B2 (en) * | 2016-02-29 | 2021-02-16 | Sun Pharma Global Fze | Topical cyclosporine-containing formulations and uses thereof |
-
2023
- 2023-08-25 WO PCT/IN2023/050801 patent/WO2024042550A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10918694B2 (en) * | 2016-02-29 | 2021-02-16 | Sun Pharma Global Fze | Topical cyclosporine-containing formulations and uses thereof |
| US20180098937A1 (en) * | 2016-10-12 | 2018-04-12 | Ps Therapies Ltd | Artificial tear, contact lens and drug vehicle compositions and methods of use thereof |
| WO2019171260A1 (en) * | 2018-03-09 | 2019-09-12 | Mankind Pharma Ltd. | Pharmaceutical composition of lifitegrast |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
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