Dexpanthenol GEL forming solution and method of preparation thereof

Abstract

The present invention provides a gel forming solution composition comprising dexpanthenol or its pharmaceutically acceptable salt, gel forming agent and one or more pharmaceutically acceptable excipients, wherein the composition forms gel on contact with lacrimal fluid. The present invention provides a gel forming solution composition for the treatment of dry eye disease or corneal epithelial damage. The invention further provides a process for preparation of such gel forming solution composition to treat dry eye disease or corneal epithelial damage.

Description

[0001] “DEXPANTHENOL GEL FORMING SOLUTION AND METHOD OF PREPARATION THEREOF”

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to an ophthalmic solution composition comprising dexpanthenol or its pharmaceutically acceptable salt, gel forming agent and one or more pharmaceutically acceptable excipients for the treatment of dry eye disease, conjunctival and corneal epithelial damage. The present invention relates to an ophthalmic solution composition wherein ophthalmic solution composition converts into gel composition after contacting the lacrimal fluid. The invention further relates to a process for the preparation of an ophthalmic solution composition.

[0004] BACKGROUND OF THE INVENTION

[0005] In the ophthalmology field, dexpanthenol plays an important role in healing of the conjunctival and corneal epithelial damage and to treat dry eye disease. Due to its hygroscopic nature, it prevents epithelial dryness and maintains the ocular surface integrity. There are number of products available in market containing dexpanthenol in the form of solutions, gels, ointments etc.

[0006] US2005164979 discloses ophthalmic solution composition comprising Panthenol and / or pantothenic acid and hyaluronic acid and / or hyaluronate, citric acid, sodium citrate for the treatment of ophthalmological malfunctions.

[0007] EA202092583 discloses ophthalmic solution composition comprising hyaluronic acid, ectoine, panthenol.

[0008] RU2778503 discloses ophthalmic gel composition comprising sodium hyaluronate, silver glycinate or natural calendula flower water, dexpanthenol.

[0009] US2011230424 discloses ophthalmic gel composition comprising dexpanthenol, hyaluronic acid, carnosine.

[0010] RU2 669 768 discloses gel drops for the treatment of inflammatory eye diseases, contain boric acid, sodium hyaluronate and water.

[0011] RU2679319 discloses gel-like composition comprising sodium salt of hyaluronic acid, dexpanthenol, boric acid, sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dodecahydrate, sodium chloride, potassium chloride and water. However, all these compositions mentioned in the prior arts are either in the form of solution or gel. Ophthalmic solution dosage forms pose problems e.g. absorption of drug after administration is limited due to the distinctive anatomy and eye’s protective mechanisms, leading to rapid drug elimination, contributing to short lived therapeutic effects and thus necessitating frequent and high-concentration applications causing both ocular and systemic side effects. Hence, further increases cost of the treatment and non-compliance in patient.

[0012] Therefore, in order to prolong ocular contact time and to slow down the elimination, gels were prepared. However, gels are also associated with problems such as it is difficult to administer gels as compared to eye drops. Also, due to high viscosity, gels may cause temporary blurring of vision after application. Further, these semi-solid dosage forms are also associated with disadvantages like staining, deterioration due to temperature fluctuation and transportation issues. Moreover, incomplete product removal from pack of semi-solid dosage form e.g. extracting last portion of gel from tube is another problem.

[0013] Therefore, all the existing prior art products are present either in the form of gel or as eye drops and cause certain problems as mentioned above. Hence, there exists an unmet need to develop a composition which solves the problems associated with the prior art products such as absorption of drug after administration, rapid drug elimination, short lived therapeutic effects, high cost of the treatment, low bioavailability, and patient non-compliance associated with existing products.

[0014] Technical Solution

[0015] The inventors of the present invention have surprisingly invented an ophthalmic solution composition which can overcome the existing problems. They have developed a composition which is in the form of solution while administration and can conveniently forms gel on contact with lacrimal fluid. It combines the benefits of both liquid dosage form and gel dosage form. It provides the ease of administration associated with liquid solutions while exhibiting prolonged contact time and enhanced bioavailability like gels. The composition of the present invention provides better bioavailability, ease of administration and prolonged ocular retention time than conventional ophthalmic compositions available as gels or solutions. SUMMARY OF THE INVENTION

[0016] The present invention provides an ophthalmic composition which is in the form of solution, and it gels upon contact with tear fluid and is useful to treat dry eye disease, conjunctival and corneal epithelial damage.

[0017] According to one aspect, the present invention provides an ophthalmic solution composition comprising: dexpanthenol or its pharmaceutically acceptable salt, gel forming agent; and one or more pharmaceutically acceptable excipients, wherein ophthalmic solution composition converts into gel composition after contacting the lacrimal fluid.

[0018] According to one aspect, the present invention provides an ophthalmic gel forming solution composition which comprises dexpanthenol or its pharmaceutically acceptable salt in an amount ranging from 0.5 w / v% to 10 w / v% of the composition.

[0019] According to one aspect, the present invention provides an ophthalmic gel forming solution composition which comprises dexpanthenol or its pharmaceutically acceptable salt in an amount ranging from 1 w / v% to 5 w / v% of the composition.

[0020] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has pH in the range of 4.0-7.5

[0021] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has pH in the range of 6.0-7.5

[0022] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has viscosity in the range of 1-50 cps.

[0023] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has osmolarity in the range of 300 to 450 msOs / kg.

[0024] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has less than 2.5% total impurities when stored for 1 month at 40 ±2°C & not more than 25% relative humidity. According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has less than 5% total impurities when stored for 12 months at 25 ±2°C & not more than 40% relative humidity.

[0025] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which has less than 2% total impurities when stored for 12 months at 2-8°C.

[0026] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which comprises gel forming agent wherein said gel forming agent is selected from the group comprising of gellan gum, xanthan gum, guar gum, cellulose derivative, carbopol, alginic acid, polyacrylic acid, xyloglucan, pectin, chitosan, poly(DL-lactic acid), poly(DL-lactide-co-glycolide) and poly-caprolactone and / or mixtures thereof.

[0027] According to another preferred aspect, the present invention provides an ophthalmic gel forming solution composition wherein gel forming agent is gellan gum.

[0028] According to another aspect, the present invention provides an ophthalmic gel forming solution composition wherein gel forming agent is present in an amount of 0.1 w / v% to 1 w / v% of the composition.

[0029] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which forms gel in the time period of 5 seconds to 2 minutes.

[0030] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, which forms in-situ gel, wherein said in-situ gel has strength of 1-5 g.

[0031] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition is free from boric acid or its derivatives.

[0032] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition is free from surfactant.

[0033] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition is free from antioxidant.

[0034] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises one or more pharmaceutically acceptable excipients which are selected from the group comprising of preservative, chelating agent, buffering agent, pH adjusting agent, lubricant and / or mixtures thereof. According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises preservative which is selected from the group comprising of cetrimide, benzalkonium chloride, benzothonium chloride, benzyldodecinium bromide, chlorobutanol, sodium perborate, chlorhexidine, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid, polyquaternium ammonium chloride, cetyltrimethylammonium chloride / cetrimonium chloride, cetyl pyridinium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl mercuric acetate, hydrogen peroxide, sodium benzoate, sodium propionate and / or mixtures thereof.

[0035] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises chelating agent, which is selected from the group comprising of edetate sodium, edetate disodium, ethylene diamine tetraacetic acid, edetate trisodium, edetate calcium disodium, edetate dipotassium, and / or mixtures thereof.

[0036] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises buffering agent, which is selected from the group comprising of, borax, tromethamine, citrates, acetates, tartrates, phosphates, dibasic sodium phosphate dodecahydrate, monobasic sodium phosphate dihydrate and / or mixtures thereof.

[0037] According to another preferred aspect, the buffering agent is di sodium phosphate dodecahydrate and monosodium dihydrogen phosphate dihydrate.

[0038] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises gel forming agent and buffering agent in a ratio of 1 :5 to 1 : 0.1.

[0039] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises gel forming agent and buffering agent in a ratio of 1 :3 to 1 :0.5.

[0040] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein said composition comprises lubricant which is selected from the group comprising of hyaluronic acid or its pharmaceutically acceptable salt, polyethylene glycol, cellulose derivatives such as carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and methylcellulose. According to another aspect, the present invention provides an ophthalmic gel forming solution composition which gels upon contact with the tear fluid, wherein said composition comprises dexpanthenol or its pharmaceutically acceptable salt thereof, gel forming agent and one or more pharmaceutically acceptable excipients, wherein said composition is useful to treat dry eye disease, conjunctival and corneal epithelial damage.

[0041] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein the composition is used in the treatment of dry eye disease, conjunctival and corneal epithelial damage.

[0042] According to another aspect, the present invention provides an ophthalmic gel forming solution composition, wherein ophthalmic solution composition converts into gel composition in-situ.

[0043] According to another aspect, the present invention provides an ophthalmic gel forming solution composition which is prepared by the process comprising the following steps: a. preparing an aqueous slurry comprising of preservative, at least one gel forming agent and water; b. sterilizing the slurry of step a) to form gel forming phase; c. preparing drug excipient phase by dissolving drug and one or more pharmaceutically acceptable excipients selected from the group comprising chelating agent, buffering agent, surfactant, lubricant; d. filtering the drug excipient phase of step c) e. adding the filtered drug excipient phase obtained in step d) to gel forming phase obtained in step b) and mixing well; f. adjusting the pH of the solution and making the final volume upto 100% using water.

[0044] DESCRIPTION OF THE INVENTION

[0045] At the very outset of the detailed description, it can be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is an only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is understood as an exemplary embodiment and teaching of invention and is not intended to be taken restrictively.

[0046] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by person of ordinary skill in the art to which this invention belongs. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.

[0047] It is to be understood that the present disclosure is not limited in its application to the details of the method set forth in the following description. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0048] Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to a person skilled in the art that various modifications and variations can be made to the methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Therefore, it is intended that the present invention includes such modifications and variations and their equivalents. Other objects, features, and aspects of the present disclosure are disclosed in or are obvious from, the following detailed description. It is to be understood by a person skilled in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

[0049] The present invention relates to an ophthalmic solution composition comprising: dexpanthenol or its pharmaceutically acceptable salt, gel forming agent; and one or more pharmaceutically acceptable excipients, wherein ophthalmic solution composition converts into gel composition after contacting the lacrimal fluid.

[0050] The stable ophthalmic gel forming solution composition provides longer contact time for drug at site of absorption by transforming into gel.

[0051] The composition is a clear solution, which is in the form of a liquid before instillation into the eye and it undergoes phase transition from liquid phase to gel phase when comes into contact with lacrimal fluid. This action is brought by the ionic strength of the lacrimal fluid.

[0052] Dexpanthenol (also referred as D-panthenol, bepanthen or panthenol) is the alcohol analog of the dextrorotatory isomer of pantothenic acid (vitamin B5) i.e. D-pantothenic acid and belongs to the group of water-soluble vitamins. Dexpanthenol plays an important role in healing the conjunctival and corneal epithelial damage. Due to its hygroscopic nature, it prevents epithelial dryness and maintains the ocular surface integrity.

[0053] The ophthalmic pharmaceutical solution composition of the present invention comprises dexpanthenol or its pharmaceutically acceptable salt in an amount ranging from 0.1 w / v% to 10 w / v%, preferably from 1 w / v% to 10 w / v%, and more preferably 1 w / v% to 5 w / v%, but not limited thereto.

[0054] The present invention may comprise single or combination of drugs suitable for ophthalmic delivery and which are used to treat dry eye such as, but not limited to, cyclosporin, lifitegrast, loteprednol, diquafosol, dexamethasone phosphate, bromfenac or their pharmaceutically acceptable salts or combinations thereof.

[0055] Gel forming agents are used in this invention which trigger solution to gel conversion of composition after administration to eye. Suitable gel forming agent is selected form the group comprising of gellan gum, xanthan gum, guar gum, cellulose derivative (hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, ethyl methyl cellulose), carbopol, alginic acid, polyacrylic acid, xyloglucan, pectin, chitosan, poly(DL-lactic acid), poly(DL- lactide-co-glycolide) and poly-caprolactone and / or mixtures thereof. Gel forming agent converts solution to gel form due to change in temperature, pH, ionic content and tear fluid. Preferably, gel forming agent is gellan gum. Gellan gum converts into gel on contact with lacrimal fluid, by virtue of change in pH.

[0056] The amount of the gel forming agent contained in the present composition is not particularly limited but is preferably 0.1 w / v% to 15.0 w / v%, more preferably 1 w / v% to 10 w / v%, and most preferably 0.1 w / v% to 1 w / v% of the composition.

[0057] The composition of the present invention forms gel in the time period of 5 seconds to 2 minutes.

[0058] The composition, wherein in-situ gel formed has strength in the range of 1-5 g. Preferably, gel formed has strength of 1.6 g.

[0059] The present invention comprises pharmaceutically acceptable excipients which are selected from the group comprising of preservative, surfactant, chelating agent, buffering agent, pH adjusting agent, tonicity adjusting agent, lubricant and / or combinations thereof. Preservative prevents growth of microbes and maintains sterility of the dosage form. Suitable preservative is selected from the group comprising of cetrimide, benzalkonium chloride, benzothonium chloride, benzyldodecinium bromide, chlorobutanol, sodium perborate, chlorhexidine, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid, polyquaternium ammonium chloride, cetyltrimethylammonium chloride / cetrimonium chloride, cetyl pyridinium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl mercuric acetate, hydrogen peroxide, sodium benzoate, sodium propionate and / or mixtures thereof. The amount of the preservative contained in the present composition is not particularly limited but is preferably 0.0001 w / v% to 5.0% w / v%, more preferably 0.001 w / v% to 1 w / v%, and most preferably 0.001 w / v% to 0.1 w / v% of the composition.

[0060] Surfactants used in the present invention is selected from the group comprising of polysorbate, tyloxapol, tromethamine, triton, poloxamer, ethoxylated alcohol, propoxylated alcohol and / or combinations thereof. The amount of the surfactant contained in the present composition is not particularly limited but is preferably 0.0001 w / v% to 10.0 w / v%, more preferably 0.001 w / v% to 5 w / v% of the composition.

[0061] The chelating agent is a compound that is capable of complexing a metal. Chelating agents are used in ophthalmic compositions to enhance preservative effectiveness. Some useful chelating agents for the purposes of this invention are edetate salts like edetate sodium, edetate disodium, ethylene diamine tetraacetic acid, edetate trisodium, edetate calcium disodium, edetate dipotassium, and / or mixtures thereof. The amount of the chelating agent contained in the present composition is not particularly limited but is preferably 0.0001 w / v% to 10.0 w / v%, more preferably 0.001 w / v% to 5.0 w / v%, most preferably 0.01 w / v% to 1.0 w / v% of the composition.

[0062] A buffering agent is an agent which stabilizes the pH of the solution. The buffering agent is selected from the group comprising borax, tromethamine, citrates, acetates, tartrates, phosphates, dibasic sodium phosphate dodecahydrate, monobasic sodium phosphate dihydrate and / or mixtures thereof. The amount of the buffering agent contained in the present composition is not particularly limited but is preferably 0.01 w / v% to 5.0 w / v% of the composition. In some embodiments, the buffering agent is selected from the group comprising of borax, tromethamine, citrate acid, phosphate acid, tartaric acid, acetate acid and / or mixtures thereof. Lubricants are used to moisten, soothe and lubricate the surface of your eye, making it feel more comfortable. Suitable lubricants are selected from the group comprising hyaluronic acid or its pharmaceutically acceptable salt, polyethylene glycol, cellulose derivatives such as carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and methylcellulose. In the present invention, lubricant is present in an amount ranging from 0.01 w / v% to 5 w / v%, preferably 0.05 w / v% to 1.0 w / v%, more preferably 0.1 w / v% to 0.5 w / v% of the composition.

[0063] The present invention preferably uses hyaluronic acid as a lubricant, having an average molecular weight of 500,000 to 3,900,000, more preferably hyaluronic acid having an average molecular weight of 500,000 to 1,200,000. Salts of hyaluronic acid which can be used are, for example, potassium hyaluronates, sodium hyaluronates, calcium hyaluronates and / or magnesium hyaluronates. Particularly, sodium salts are preferred.

[0064] Tonicity adjusting agents are used to adjust the concentration of dissolved material to the desired isotonic range. Tonicity agent is selected from the group comprising glycerin / glycerol, mannitol, sorbitol, dextrose, potassium chloride, sodium chloride, sodium chloride, sodium borate, propylene glycol, polyethylene glycol and / or mixtures thereof.

[0065] In order to prevent oxidation of drug, antioxidants are used such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium sulfite, sodium sulfate, ascorbyl palmitate, citric acid, ascorbic acid or salts thereof, and / or mixtures thereof. According to one embodiment of the present invention, the pharmaceutical composition is free from antioxidants and still maintains the drug assay value.

[0066] Small amounts of pH adjusting agents are also used in the composition to achieve the desired pH range. The pH-adjusting agents are selected from the group comprising hydrochloric acid, sodium hydroxide, sodium hydrogen carbonate, potassium hydroxide, phosphates and the like.

[0067] The present composition has pH in the range of 4-7.5. Preferably, in the range of 6.0-7.5.

[0068] The present composition has viscosity in the range of 1-100 cps. Preferably, in the range of 1- 50 cps.

[0069] The present composition has osmolarity in the range of 200 to 450 msOs / kg. Preferably, in the range of 300 to 450 msOs / kg. In the present composition, gel forming agent and buffering agent are present in a ratio of 1 : 5 to 1 : 0.1.

[0070] In the present composition, gel forming agent and buffering agent are present in a ratio of 1 :3 to 1 :0.5.

[0071] The present invention provides an ophthalmic gel forming solution composition which has less than 2% total impurities when stored for 12 months at 2-8°C.

[0072] The present invention provides an ophthalmic gel forming solution composition which has less than 5% total impurities when stored for 12 months at 25 ±2°C & not more than 40% relative humidity.

[0073] The composition of the present invention is used in the treatment of dry eye disease, conjunctival and corneal epithelial damage.

[0074] The process for preparing the present composition, comprises the following steps: a. preparing an aqueous slurry comprising of preservative and at least one gel forming agent and water; b. sterilizing the slurry of step a) to form gel forming phase; c. preparing drug excipient phase by dissolving drug and one or more pharmaceutically acceptable excipients selected from the group comprising chelating agent, buffering agent, surfactant, lubricant; d. filtering the drug excipient phase of step c); e. adding and mixing the filtered drug excipient phase obtained in step d) to gel forming phase obtained in step b); f. adjusting the pH of the solution and making the final volume upto 100% using water.

[0075] A process for preparing the present composition comprises the following steps: a. preparing an aqueous slurry comprising of cetrimide and gellan gum and water; b. sterilizing the slurry of step a) to form gel forming phase; c. preparing Dexpanthenol excipient phase by dissolving Dexpanthenol, hyaluronic acid, di sodium edetate, di sodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate; d. filtering the Dexpanthenol excipient phase of step c); e. adding and mixing the filtered Dexpanthenol excipient phase obtained in step d) to gel forming phase obtained in step b); f. adjusting the pH of the solution and making the final volume upto 100% using water.

[0076] The sterilization may be conducted by dry heat sterilization, gas sterilization, filtration, irradiation, moist heat sterilization. Autoclaving is a preferred method of sterilization of the aqueous solution of the present invention. Typically, the autoclaving can be conducted at a temperature of about 115°C to about 125°C for about 10 to 30 minutes.

[0077] The present invention is useful for treating dry eye disease, conjunctival and corneal epithelial damage. Dry eye syndrome, also called dry eye disease (DED), is a condition in which the eyes do not make enough tears. The present composition is used as supportive treatment to heal corneal and mucous membrane lesions of the eye in cases of so-called “dry eye” conditions (conjunctivitis sicca and / or keratoconjunctivitis sicca). Unless otherwise prescribed and depending on the severity and intensity of complaints, instill one drop into the conjunctival sac 3 to 5 times a day or more frequently. It is also used for the symptomatic treatment of drying out of the cornea and conjunctiva.

[0078] The present composition may be supplied as single dose or multi-dose product with or without preservative.

[0079] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0080] The invention is further exemplified with the following example and is not intended to limit the scope of the invention.

[0081] EXAMPLES

[0082] Example 1

[0083] Manufacturing process:

[0084] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0085] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0086] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and polysorbate were dissolved in water to form drug excipient phase.

[0087] 4) The drug excipient phase obtained in step 3 was filtered.

[0088] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0089] 6) pH was checked and adjusted to 6.9

[0090] 7) The final volume was made upto 100% using water.

[0091] Example 2 Manufacturing process:

[0092] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0093] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0094] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and polysorbate were dissolved in water to form drug excipient phase.

[0095] 4) The drug excipient phase obtained in step 3 was filtered.

[0096] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0097] 6) pH was checked and adjusted to 6.9

[0098] 7) The final volume was made upto 100% using water.

[0099] Example 3

[0100] Manufacturing process:

[0101] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0102] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0103] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0104] 4) The drug excipient phase obtained in step 3 was filtered. 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0105] 6) pH was checked and adjusted to 6.9

[0106] 7) The final volume was made upto 100% using water.

[0107] Example 4

[0108] Manufacturing process:

[0109] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0110] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0111] 3) Dexpanthenol, disodium edetate, disodium phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0112] 4) The drug excipient phase obtained in step 3 was filtered.

[0113] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0114] 6) pH was checked and adjusted to 6.9

[0115] 7) The final volume was made upto 100% using water.

[0116] Example 5

[0117]

[0118] Manufacturing process:

[0119] 1) An aqueous slurry was prepared by dissolving BKC and gellan gum in water.

[0120] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0121] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0122] 4) The drug excipient phase obtained in step 3 was filtered.

[0123] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0124] 6) pH was checked and adjusted to 6.9

[0125] 7) The final volume was made upto 100% using water.

[0126] Example 6 Manufacturing process:

[0127] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0128] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0129] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0130] 4) The drug excipient phase obtained in step 3 was filtered.

[0131] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0132] 6) pH was checked and adjusted to 6.5

[0133] 7) The final volume was made upto 100% using water.

[0134] Example 7

[0135] Manufacturing process:

[0136] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0137] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0138] 3) Dexpanthenol, disodium edetate, disodium phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0139] 4) The drug excipient phase obtained in step 3 was filtered.

[0140] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0141] 6) pH was checked and adjusted to 6.5 7) The final volume was made upto 100% using water.

[0142] Example 8

[0143] Manufacturing process:

[0144] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0145] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0146] 3) Dexpanthenol, hyaluronic acid, tromethamine, boric acid, polysorbate were dissolved in water to form drug excipient phase.

[0147] 4) The drug excipient phase obtained in step 3 was filtered.

[0148] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0149] 6) pH was checked and adjusted to 6.9

[0150] 7) The final volume was made upto 100% using water.

[0151] Stability Studies

[0152] The compositions prepared according to example 1, 2, 3, 4, 6, 7, 8 were subjected to stability studies at 25 ±2°C & 40% ±5% RH and 40 ±2°C & NMT 25% RH for 1 month. The results are mentioned in Table 1 below:

[0153]

[0154]

[0155] NP: Not performed

[0156] ND: Not detected

[0157] BDL; Below detected limit

[0158] Conclusion: From the above data it is clear that addition of boric acid leads to an increase in amount of total impurities when stored for 1 M at 40 ±2°C & NMT 25% RH. Therefore, use of boric acid is not recommended in the present composition. However, the compositions without boric acid contain total impurities less than 2.5% when measured at 40 ±2°C & NMT 25% RH.

[0159] Example 9

[0160] Manufacturing process:

[0161] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0162] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0163] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, sodium metabisulfite were dissolved in water to form drug excipient phase.

[0164] 4) The drug excipient phase obtained in step 3 was filtered.

[0165] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0166] 6) pH was checked and adjusted to 6.25

[0167] 7) The final volume was made upto 100% using water.

[0168] Example 10 Manufacturing process:

[0169] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0170] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0171] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0172] 4) The drug excipient phase obtained in step 3 was filtered.

[0173] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0174] 6) pH was checked and adjusted to 6.5

[0175] 7) The final volume was made upto 100% using water.

[0176] Stress Studies

[0177] The compositions prepared according to Example 9 (with antioxidant) and Example 10 (without antioxidant) were subjected to stress studies at room temperature for 30 days. The results are mentioned in Table 2 below:

[0178] Table 2

[0179] Conclusion: From the above data, the inventors have found that the addition of antioxidant leads to an increase in amount of total impurities when the composition was stored for 30 days at room temperature. Example 11

[0180] Manufacturing process:

[0181] 1) An aqueous slurry was prepared by dissolving cetrimide and gellan gum in water.

[0182] 2) The slurry of step 1 was autoclaved for 30 min at 121.5°C to form gel forming phase.

[0183] 3) Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate were dissolved in water to form drug excipient phase.

[0184] 4) The drug excipient phase obtained in step 3 was filtered.

[0185] 5) The filtered drug excipient phase obtained in step 4 was added to gel forming phase obtained in step 2 and mixed well.

[0186] 6) The final volume was made upto 100% using water.

[0187] 7) pH was checked and found to be 6.7.

Claims

WE CLAIM1. An ophthalmic solution composition comprising:- dexpanthenol or its pharmaceutically acceptable salt;- gel forming agent; and- one or more pharmaceutically acceptable excipients, wherein ophthalmic solution composition converts into gel composition after contacting the lacrimal fluid.

2. The composition as claimed in claim 1, wherein composition comprises dexpanthenol or its pharmaceutically acceptable salt in an amount ranging from 0.5 w / v% to 10 w / v%, preferably 1.0 w / v% to 5.0 w / v% of the composition.

3. The composition as claimed in claim 1, wherein composition has pH in the range of 4.0- 7.5, preferably 6.0-7.5.

4. The composition as claimed in claim 1, wherein composition has viscosity in the range of 1-50 cps.

5. The composition as claimed in claim 1, wherein composition has osmolarity in the range of 300 to 450 msOs / kg.

6. The composition as claimed in claim 1, wherein gel formed has strength is in the range of 1-5 g.

7. The composition as claimed in claim 1, wherein composition has less than 2.5% total impurities when stored for 1 month at 40 ±2°C and not more than 25% relative humidity.

8. The composition as claimed in claim 1, wherein gel forming agent is selected from the group comprising of gellan gum, xanthan gum, guar gum, cellulose derivative, carbopol, alginic acid, polyacrylic acid, xyloglucan, pectin, chitosan, poly(DL-lactic acid), poly(DL-lactide-co-glycolide) and poly-caprolactone and / or mixtures thereof.

9. The composition as claimed in claim 8, wherein gel forming agent is gellan gum.

10. The composition as claimed in claim 1, wherein gel forming agent is present in an amount 0.1 w / v% to 1 w / v% of the composition.

11. The composition as claimed in claim 1, wherein composition forms gel in the time period of 5 seconds to 2 minutes.

12. The composition as claimed in claim 1, wherein composition is free from boric acid and antioxidant.

13. The composition as claimed in claim 1, wherein pharmaceutically acceptable excipients are selected from the group comprising of preservative, chelating agent, buffering agent, pH adjusting agent, lubricant and / or mixtures thereof.

14. The composition as claimed in claim 13, wherein the pH adjusting agent is optional.

15. The composition as claimed in claim 13, wherein preservative is selected from the group comprising of cetrimide, benzalkonium chloride, benzothonium chloride, benzyldodecinium bromide, chlorobutanol, sodium perborate, chlorhexidine, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid, polyquaternium ammonium chloride, cetyltrimethylammonium chloride / cetrimonium chloride, cetyl pyridinium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl mercuric acetate, hydrogen peroxide, sodium benzoate, sodium propionate and / or mixtures thereof.

16. The composition as claimed in claim 13, wherein chelating agent is selected from the group comprising of edetate sodium, edetate disodium, ethylene diamine tetraacetic acid, edetate trisodium, edetate calcium disodium, edetate dipotassium, and / or mixtures thereof.

17. The composition as claimed in claim 13, wherein buffering agent is selected from the group comprising of borax, tromethamine, citrate acid, phosphate acid, tartaric acid, acetate acid and / or mixtures thereof.

18. The composition as claimed in claim 17, wherein buffering agent is disodium phosphate dodecahydrate and monosodium dihydrogen phosphate dihydrate.

19. The composition as claimed in claims 1 and 13, wherein gel forming agent and buffering agent are present in a ratio of 1 : 5 to 1 : 0.1, preferably 1 :3 to 1 :0.5.

20. The composition as claimed in claim 13, wherein lubricant is hyaluronic acid or its pharmaceutically acceptable salt.

21. The composition as claimed in any of the proceeding claim, wherein the composition is used in the treatment of dry eye disease, conjunctival and corneal epithelial damage.

22. The composition as claimed in claim 1, wherein ophthalmic solution composition converts into gel composition in-situ.

23. A process for preparing the ophthalmic solution composition comprises the following steps: a. preparing an aqueous slurry comprising of preservative and at least one gel forming agent and water; b. sterilizing the slurry of step a) to form gel forming phase; c. preparing drug excipient phase by dissolving drug and one or more pharmaceutically acceptable excipients selected from the group comprising chelating agent, buffering agent, surfactant, lubricant; d. filtering the drug excipient phase of step c); e. adding and mixing the filtered drug excipient phase obtained in step d) to gel forming phase obtained in step b); f. adjusting the pH of the solution and making the final volume upto 100% using water.

24. A process for preparing the ophthalmic solution composition comprises the following steps: a. preparing an aqueous slurry comprising of cetrimide and gellan gum and water; b. sterilizing the slurry of step a) to form gel forming phase; c. preparing Dexpanthenol excipient phase by dissolving Dexpanthenol, hyaluronic acid, disodium edetate, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate; d. filtering the Dexpanthenol excipient phase of step c);e. adding and mixing the filtered Dexpanthenol excipient phase obtained in step d) to gel forming phase obtained in step b); f. adjusting the pH of the solution and making the final volume upto 100% using water.

25. The composition as claimed in any one of claims 1 to 22, for use in treating disease or condition such as dry eye disease, conjunctival and corneal epithelial damage.

26. A method of treating disease or condition such as dry eye disease, conjunctival and corneal epithelial damage, comprising the administrating to a subject in need thereof an effective amount of the ophthalmic solution composition as claimed in any one of claims 1 to 22. 1

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