Classifications

• • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • 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
• • 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
  • A61K9/08—Solutions

Definitions

• the present invention relates to ophthalmic formulations; more particularly to ophthalmic formulations of methotrexate; most particularly eye drops of methotrexate used for the treatment of anterior uveitis.
• the anterior uveitis preferably is auto immune mediated and non-infectious acute anterior uveitis.
• Methotrexate is structurally represented as
• Methotrexate based medicaments have been known in the art for years, and have been shown to possess anti-neoplastic, anti-angiogenic, anti-fibroblastic, and/or immunosuppressive activities. While administering methotrexate based medicaments have been identified as a promising remedy to treat many of the above-identified irregularities, delivering methotrexate based medicaments to an affected area of a living subject's eye has remained heretofore largely problematic.
• methotrexate based medicaments for example, delivering methotrexate based medicaments to an affected, local area of a living subject's eye using a systemic delivery method is problematic because of the many severe, sometimes life threatening, side effects associated with systemic delivery of methotrexate based medicaments, such as, for examples, hepatitis, liver fibrosis, cirrhosis, leukopenia (bone marrow suppression), mucositis, ulcerative stomatitis, skin rash, nausea, abdominal distress, malaise, fatigue, chills and fever, diarrhea, gastrointestinal ulceration or perforation, pancreatitis, pericarditis, hypotension, deep venous thrombosis, thrombophlebitis, interstitial pneumonitis, headaches, drowsiness, cognitive dysfunction, reduced immunity, rash, photosensitivity, nephropathy, hematuria, alopecia, defective oogenesis, oligospermia, infertility
• PCT Patent Publication No. W02016019165 discloses the method of treating or reducing the risk of proliferative vitreoretinopathy (PVR) or epiretinal membranes (ERM) in a subject with intravitreal injections of methotrexate.
• PVR proliferative vitreoretinopathy
• ELM epiretinal membranes
• the present invention relates to a topical ophthalmic composition formulated for application to the eye, said composition comprising a therapeutically effective amount of methotrexate for the treatment of anterior uveitis.
• anterior uveitis is auto immune mediated and non-infectious.
• the present invention relates to a method of treating anterior uveitis of the mammalian eye, said method comprising administering to the mammal in eye about 5pg to about 200pg of methotrexate.
• the present invention relates to a method of treating anterior uveitis of the mammalian eye, said method comprising administering to the mammal in eye about 5pg to about 200pg of methotrexate, wherein methotrexate is administered as an ophthalmic solution once a day, twice a day or thrice a day in each affected eye.
• the present invention relates to a topical ophthalmic composition formulated for application to the eye, said composition comprising a therapeutically effective amount of methotrexate, solubilizers, viscosifying agents, buffering agents, osmotic agents, antioxidants, pH adjusting agents, optionally preservatives and water for injection.
• the present invention relates to a topical ophthalmic composition formulated for application to the eye, said composition comprising a therapeutically effective amount of methotrexate, tromethamine, xanthan gum, trisodium citrate, sodium chloride, disodium EDTA and pH adjusting agents, wherein the composition has the pH of about 6.8 to about 8.5.
• Figure 1 discloses effect of methotrexate formulations of examples 1 , 2 and 3 for treatment of anterior uveitis in rabbit’s eye after 24 hours of intra-vitreal BSA injection.
• Figure 2 discloses effect of methotrexate formulations of examples 5, 6, 7, 8 and 9 for treatment of anterior uveitis in rabbit’s eye after 24 hours of intra-vitreal BSA injection.
• Figure 3 discloses effect of methotrexate formulations of examples 5, 6, 7, 8 and 9 for treatment of anterior uveitis in rabbit’s eye after 48 hours of intra-vitreai BSA injection.
• Figure 4 discloses effect of methotrexate formulations of examples 5, 6, 7, 8 and 9 for treatment of anterior uveitis in rabbit’s eye after 72 hours of intra-vitreai BSA injection.
• the term“Uveitis” swelling of the middle layer of the eye which is called the uvea. It may occur from both infectious and non-infectious causes.
• the uvea supplies blood to the retina.
• the retina is the light-sensitive part of the eye that focuses the images you see and sends them to the brain. It’s normally red due to its blood supply from the uvea.
• Anterior uveitis is an inflammation of the middle layer of the eye. This layer includes the iris (colored part of the eye) and the adjacent tissue, known as the ciliary body. If untreated, it can cause permanent damage and loss of vision from the development of glaucoma, cataract or retinal edema.
• the term“ophthalmic solution” a sterile solution that is free from foreign particles and is compounded and dispensed for eye drops.
• the terms“about” mean +/- 10% of the indicated value, including the indicated value.
• the term“therapeutically effective amount of methotrexate” means about 5pg to about 200pg of methotrexate administered into the mammal’s each eye once, twice, thrice or four times a day.
• the present invention generally provides topical ophthalmic composition formulated for application to the eye, said composition comprising a therapeutically effective amount of methotrexate for the treatment of anterior uveitis.
• anterior uveitis is auto immune mediated and non-infectious.
• the present invention generally provides topical ophthalmic composition, preferably in the form of solution, suspensions or emulsions for application to the eye, said composition comprising a therapeutically effective amount of methotrexate for the treatment of anterior uveitis.
• the present invention provides a method of treating anterior uveitis of the mammalian eye, said method comprising administering to the mammal in eye about 5pg to about 200pg of methotrexate.
• the present invention provides a method of treating anterior uveitis of the mammalian eye, said method comprising administering to the mammal in eye about 5pg to about 200pg of methotrexate, wherein methotrexate is administered as an ophthalmic solution once a day, twice a day or thrice a day in each affected eye.
• methotrexate is administered to the mammalian eye in the dosages of about 5pg, 7.5 pg, l Opg, l2.5pg, l5pg, 17.5pg, 20.0pg, 22.5pg, 25.0pg, 27.5pg, 30.0pg, 32.5pg, 35.0pg, 37.5pg, 40.0pg, 42.5pg, 45.0pg, 47.5pg, 50 pg, 52.5pg, 55pg, 57.5pg, 60pg, 62.5pg, 65pg, 67.5pg, 70pg, 72.5pg, 75 pg, 77.5pg, 80pg, 82.5pg, 85pg, 87.5pg, 90pg, 92.5pg, 95pg, 97.5pg, l OOpg, 102.5pg, 105pg, 107.5pg, 105pg, 107.5pg, H Opg, 1 12.5pg, 1 15pg, 1 17.5
• the present invention provides a topical ophthalmic composition formulated for application to the eye, said composition comprising a therapeutically effective amount of methotrexate, solubilizers, viscosifying agents, buffering agents, osmotic agents, antioxidants, pH adjusting agents, optionally preservatives and purified water.
• the present invention provides a method of treating anterior uveitis of the mammalian eye, said method comprising administering to the mammal in eye a methotrexate topical ophthalmic composition comprising therapeutically effective amount of methotrexate, solubilizers, viscosifying agents, buffering agents, osmotic agents, antioxidants, pH adjusting agents, optionally preservatives and purified water.
• the composition preferably comprises about 0.01% w/v to about 0.5% w/v methotrexate; more preferably 0.01% w/v to about 0.1 % w/v methotrexate; even more preferably 0.01 % w/v, 0.015% w/v, 0.02% w/v, 0.025% w/v, 0.03% w/v, 0.035% w/v, 0.04% w/v, 0.045% w/v, 0.05% w/v, 0.055% w/v, 0.06% w/v, 0.065% w/v, 0.07% w/v, 0.075% w/v, 0.08% w/v, 0.085% w/v, 0.095% w/v, 0.1% w/v methotrexate, and most preferably 0.025% w/v of methotrexate.
• the composition comprises solubilizers selected from the group consisting of tromethamine, pluronics, polyethylene glycol, polysorbate 20, polysorbate 80, lecithin, hydroxypropyl b-cyclodextrin, cholesterol and tyloxapol.
• solubilizers selected from the group consisting of tromethamine, pluronics, polyethylene glycol, polysorbate 20, polysorbate 80, lecithin, hydroxypropyl b-cyclodextrin, cholesterol and tyloxapol.
• Most preferred solubilizer used in the present invention is tromethamine.
• the amount of solubilizers ranges from about 0.1 % w/v to about
• the amount of tromethamine present in the composition ranges from about 0.1% w/v to about 1.0% w/v, more preferably 0.2% w/v to about 0.8% w/v and most preferably 0.4% w/v.
• compositions comprising of about 0.2% w/v to about 0.8% w/v has total impurities less than 2.0% and individual impurity less than 1.0% after storage of composition for six months at 2-8°C.
• An impurity level of the methotrexate ophthalmic solution is determined by use of high performance liquid chromatography-mass spectrometry (HPLC-MS or LC- MS).
• HPLC-MS high performance liquid chromatography-mass spectrometry
• the methotrexate ophthalmic compositions are typically stored under a refrigerated condition (2 to 8° C) with very low humidity.
• methotrexate total degradation impurities in the final product are less than about 2.0% under the refrigerated storage condition for six months and the individual impurity is less than 1.0%.
• the composition comprises viscosifying agents selected from the group consisting of polyvinyl alcohol and derivatives, polyvinylpyrrolidone and derivatives, hydroxypropylmethylcellulose and derivatives, carboxymethylcellulose and its derivatives, tamarind seed polysaccharide (xyloglucan), polyacrylic acids, xanthan gum and its derivatives, beta glucan and its derivatives.
• the most preferred viscosifying agent is xanthan gum.
• the amount of viscosifying agent ranges from about 0.1 % w/v to about 1.0% w/v, more preferably in the range from about 0.2% w/v to about 0.8% w/v and most preferably 0.6% w/v.
• the amount of xanthan gum present in the composition ranges from about 0.1% w/v to about 1.0% w/v, more preferably 0.2% w/v to about 0.8% w/v and most preferably 0.6% w/v.
• Other preferred percentages of xanthan gum include 0.1 % w/v, 0.15% w/v, 0.2% w/v, 0.25% w/v, 0.3% w/v, 0.35% w/v, 0.4% w/v, 0.45% w/v, 0.5% w/v, 0.55% w/v, 0.6% w/v, 0.65% w/v, G.7%w/v, 0.75% w/v, 0.8% w/v, 0.85% w/v and 0.9% w/v.
• the composition comprises buffering agents selected from the group consisting of one or more citrate salt(s) and/or the free acid thereof (for example citric acid, citric acid monohydrate, trisodium citrate dihydrate, tripotassium citrate monohydrate), acetate salt(s) and/or the free acid thereof (for example acetic acid, sodium acetate, sodium acetate trihydrate) or L- histidine and/or an acid-addition salt thereof, such as, for example, L-histidine monohydrochloride monohydrate.
• buffering agent selected is trisodium citrate dihydrate.
• the amount of buffering agent in the present composition ranges from about 0.05% w/v to about 0.5% w/v and most preferably from about 0.1 % w/v to about 0.3% w/v.
• the composition comprises osmotic agents selected from the group consisting of trehalose, mannitol, sorbitol, lactulose, sodium chloride, and propylene glycol.
• osmotic agent selected is sodium chloride.
• the amount of osmotic agent in the present composition ranges from about 0.1% w/v to about 1 % w/v and most preferably from about 0.3% w/v to about 0.8% w/v.
• the composition comprises antioxidants selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycerol, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite sodium, cystein/cysteinate HC1, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gal late, sulfite sodium, to
• antioxidant selected is disodium EDTA.
• the amount of antioxidant in the present composition ranges from about 0.005% w/v to about 0.5% w/v and most preferably from about 0.01 % w/v to about 0.05% w/v.
• the composition comprises pH adjusting agents selected from the group consisting of consisting of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium carbonate, calcium carbonate, amino acid derivatives, alkali metal carbonate (such as sodium glycine carbonate) hydrochloric acid, nicotinic acid, acetylsalicylic acid, adipic acid or mixtures thereof.
• the pH adjusting agents are selected from sodium hydroxide and hydrochloride acid. pH adjusting agents are used in the present composition to adjust the pH from about 6.8 to about 8.5.
• ophthalmic composition of methotrexate are stable to form a clear solution in the pH range from about 6.8 to about 8.5; below the pH range of about 6.8, and above pH range of about 8.5, the present inventors have observed that the composition is turbid and does not form a clear solution that is administrable into the eye.
• the composition comprises preservative selected from the group consisting of benzalkonium chloride (BAK), butyl paraben and propyl paraben. Most preferred preservative used in the present invention is BAK.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition comprises about 0.01% w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of solubilizers, about 0.1 % w/v to about 1.0% w/v of viscosifying agents and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting essentially of about 0.01 % w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of solubilizers, about 0.1 % w/v to about 1 .0% w/v of viscosifying agents, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting of about 0.01 % w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of solubilizers, about 0.1% w/v to about 1.0% w/v of viscosifying agents, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition comprises about 0.01% w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1% w/v to about 1.0% w/v of xanthan gum and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting essentially of about 0.01 % w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1% w/v to about 1.0% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting of about 0.01 % w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1 % w/v to about 1.0% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition comprises about 0.025% w/v of methotrexate, about 0.4% w/v of tromethamine, about 0.6% w/v of xanthan gum and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting essentially of about 0.025% w/v of methotrexate, about 0.4% w/v of tromethamine, about 0.6% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting of about 0.025% w/v of methotrexate, about 0.4% w/v of tromethamine, about 0.6% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition comprises about 0.01 % w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1% w/v to about 1.0% w/v of xanthan gum and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting essentially of about 0.01% w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1 % w/v to about 1.0% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1 .0% and total amount of impurities present in the said composition is less than 2.0%.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting of about 0.01% w/v to about 0.05% w/v of methotrexate, about 0.2% w/v to about 0.8% w/v of tromethamine, about 0.1% w/v to about ] .0% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition comprises about 0.025% w/v of methotrexate, about 0.4% w/v of tromethamine, about 0.6% w/v of xanthan gum and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting essentially of about 0.025% w/v of methotrexate, about 0.4% w/v of trometh a ine, about 0.6% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.
• the present invention provides the topical ophthalmic composition formulated for application to the eye, said composition consisting of about 0.025% w/v of methotrexate, about 0.4% w/v of tromethamine, about 0.6% w/v of xanthan gum, buffering agents, osmotic agents, antioxidants, preservatives and pH adjusting agents; wherein the composition has the pH of about 6.8 to about 8.5 and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.
• the following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below.
• step 1.1.9 Under stirring, add dispensed quantity of Disodium EDTA to step 1.1.9 purified water, ensure complete solubilisation.
• step 2.3.1 Under stirring to the Carbomer slurry in step 2.2.2, vehicle concentrate from step 2.1.2 was added and stirred.
• step 2.3.1 pH of step 2.3.1 slurry was adjusted to 5.5, using 1 N Sodium hydroxide
• step 3.3 Volume of step 3.3 was made up to 40% using purified water from step 1.
• API phase was added to step 2.3.3 polymer phase and stirred for 30 min to form the suspension of methotrexate.
• Example 4 Therapeutic use of methotrexate ophthalmic compositions of
• the Rabbits were divided into six groups with 5 animals in each group as normal control, induction group, reference group ( a Folitrax-50mg/2ml), Example 1 formulation, Example 2 formulation and Example 3 formulation were subjected for treatment accordingly.
• the rabbits were subjected to topical ophthalmic drop for the test formulations for a period of 12 days [50m1 of methotrexate solution of example 1 (50 g of methotrexate), 50m1 of methotrexate solution of example 2 (250pg of methotrexate) and 50m1 of methotrexate solution of example 3 (250pg of methotrexate)] once a day in each eye, whereas reference group was treated subcutaneously on commencement of study (I st day).
• the rabbits were observed for any abnormal inflammation for a period of 1 to 2 hours post intra-vitreal injection. Later, the rabbits were monitored and scored for the induction of flare and accumulation of inflammatory cells, causing opacity of cornea.
• the scores of the individual animals are averaged and subjected to the One Way ANOVA followed by Dunnett’s post hoc test for significance in the induction and recovery.
• the Induction group produced a significant (pO.OOOl) induction of Anterior Uveitis as compared to the Normal Control group.
• the ophthalmic example 1 formulation with the dosage of 50pg methotrexate once daily in Rabbit produced significant (pO.OOl ) prevention of anterior uveitis as compared to the induction group, whereas, example 2 formulation and example 3 formulation didn’t produce any significant prevention of anterior uveitis.
• the Reference group when treated subcutaneously produced significant (pO.OOOl) prevention of Anterior Uveitis development as compared to induction group.
• Rabbits for treatment of anterior uveitis in Rabbits Rabbits for treatment of anterior uveitis in Rabbits.
• the Rabbits were divided into nine groups with 5 animals in each group as normal control, induction group, reference group (Durezol®), Example 5 formulation, Example 6 formulation, Example 7 formulation, Example 8 formulation, Example 9 formulation and Placebo formulation were subjected to treatment accordingly.
• 50m1 of methotrexate solution of example 5 (5pg of methotrexate), 50m1 of methotrexate solution of example 6 (12.5pg of methotrexate), 50m1 of methotrexate solution of example 7 (25 g of methotrexate), 50m1 of methotrexate solution of example 8 (50pg of methotrexate), 50m1 of methotrexate solution of example 9 (125pg of methotrexate) once a day in each eye; placebo group was administered with 50m1 of placebo formulation once a day each eye, whereas reference group was treated with 50m1 of Durezol® ophthalmic emulsion (Difluprednate 0.05% ophthalmic emulsion) once a day in each eye for a period of 12 days.
• Durezol® ophthalmic emulsion Durezol® ophthalmic emulsion
• the rabbits were observed for any abnormal inflammation for a period of 1 to 2 hours post intra-vitreal injection. Later, the rabbits were monitored and scored for the induction of flare and accumulation of inflammatory cells, causing opacity of cornea.
• the Induction group produced a significant (pO.OOOl ) induction of Anterior
• the ophthalmic example 6 formulation with the dosage of 12.5pg methotrexate administered once daily in each eye of Rabbit produced significant (p ⁇ Q.00l ) prevention of Anterior Uveitis at 24 hours and 48 hours.
• Examples 11 to 14 Ophthalmic Solutions of Methotrexate
• Process for Preparation The process for preparation is similar to examples 6 with the changes in the percentages of the tromethamine in the ophthalmic solution.
• compositions prepared as in examples 6, 1 1, 12, 13 and 14 are stored at 2°C - 8°C and was tested for impurities at specific intervals.
• the results of examples 6, 1 1, 12, 13 and 14 are as tabulated in tables 3 to 7 respectively.

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