Ophthalmic composition of dexamethasone

Abstract

The present invention discloses an ophthalmic composition comprising dexamethasone or its pharmaceutically acceptable salt thereof and that is used to treat cataract surgery pain and diabetic macular edema. The present invention relates to use of a topically administrate ophthalmic suspension composition of dexamethasone, or it pharmaceutically acceptable salt thereof suspended in pharmaceutically acceptable vehicle, wherein the pharmaceutical acceptable vehicle comprises at least one excipient selected from suspending agent, tonicity agent, antimicrobial agent, buffering agent, chelating agent, antioxidant, surface active agent, and pH adjusting agent.

Description

[0001] “OPHTHALMIC COMPOSITION OF DEXAMETHASONE”

[0002] FIELD OF INVENTION

[0003] The present invention relates to ophthalmic compositions, more particularly ophthalmic suspension comprising dexamethasone or its pharmaceutically acceptable salt thereof. The invention also relates to the process of making ophthalmic compositions. In particular, the present invention relates to use of a topically administrable ophthalmic composition of dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle for the treatment of cataract surgery pain and diabetic macular edema.

[0004] BACKGROUND OF INVENTION

[0005] Corticosteroids are implicated in a wide range of physiological processes, including stress response, regulation of immune responses and inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. In particular, glucocorticoids control carbohydrate, fat, and protein metabolism, have anti-inflammatory effects, prevent the release of phospholipids, reduce eosinophil activity, and many other mechanisms.

[0006] Dexamethasone, a potent corticosteroid, specifically a glucocorticoid, exhibits remarkable anti-inflammatory and immunosuppressant properties. Introduced to the field of ophthalmology in 1958, glucocorticoids have become widely utilized as efficacious and potent anti-inflammatory agent. Their mechanism of action involves preventing the progression of the inflammatory response, effectively mitigating redness, swelling, and tenderness. Additionally, they inhibit capillary dilation and phagocytosis, while also demonstrating an ability to impede hypersensitivity reactions resulting from antigen-antibody interactions. However, due to its hydrophilic nature, dexamethasone exhibits limited absorption through the intact comeal epithelium. Absorption primarily occurs via the ocular and nasal mucosa. DEXTENZA® by Ocular Therapeutix Inc, was approved as dexamethasone ophthalmic insert in a form of fluorescent yellow, 3 mm cylindrical-shaped insert containing 0.4 mg drug. It was approved for the treatment of ocular inflammation and pain following ophthalmic surgery and for the treatment of ocular itching associated with allergic conjunctivitis. The major drawback of ophthalmic insert is their movement around the eye, in rare instances, the simple removal is made more difficult by unwanted migration of the insert to the upper fornix, interference with vision and difficulty in placement of the inserts.

[0007] MAXIDEX® by Harrow Eye LLC, was approved as dexamethasone ophthalmic suspension of 0.1% concentration administered topically in conjunctival sac. In severe diseases, drops may be used hourly, being tapered to discontinuation as the inflammation subsides. In mild disease, drops may be used up to four to six times daily.

[0008] Potential challenges associated with successful topical treatment include spillage and drug dilution due to tearing and blinking, administration difficulties for certain patients, tear film turnover, inadequate absorption, and low bioavailability of the active ingredient. Additionally, patients may experience confusion due to varying dosing schedules, with some preparations requiring twice daily (BID) administration, others four times daily (QID), and still others only once daily. This may lead to poor compliance if patients require more than one medication or have difficulty adhering to complex tapering schedules or short dosing intervals. Thus, there is a clear need for preparations with simpler and less frequent dosing.

[0009] Administering a topical steroid once daily would likely enhance compliance, reduce instillation challenges, and eliminate confusion resulting from intricate tapering schedules. In addition, reduced frequency of medication could improve the health of the ocular surface.

[0010] Thus, the present invention is being developed to address these unmet needs by reducing dosing frequency, improving bioavailability, and consequent short contact time, and penetration into the eye tissues.

[0011] OBJECT OF THE INVENTION An object of the invention is to provide an ophthalmic composition comprising dexamethasone or its pharmaceutically acceptable salts thereof.

[0012] Another object of the invention is to provide an ophthalmic composition comprising dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle, wherein the pharmaceutically acceptable vehicle comprises at least one excipient selected from suspending agent, tonicity agent, antimicrobial agent, buffering agent, chelating agent, antioxidant, surface active agent, pH adjusting agent.

[0013] Another object of the invention is to provide a process for preparing ophthalmic composition comprising dexamethasone or its pharmaceutically acceptable salts thereof.

[0014] One another object of the present invention is to provide safe and efficacious ophthalmic composition of comprising dexamethasone or its pharmaceutically acceptable salts thereof.

[0015] Another object of the present invention is used to treat cataract surgery pain and diabetic macular edema by topically administering ophthalmic composition comprising dexamethasone or its pharmaceutically acceptable salts thereof.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention relates to an ophthalmic composition comprising dexamethasone, or its pharmaceutically acceptable salt thereof. The invention also relates to an ophthalmic composition of dexamethasone suspended in a pharmaceutically acceptable vehicle, wherein the pharmaceutically acceptable vehicle comprises at least one excipient selected from suspending agent, tonicity agent, antimicrobial agent, buffering agent, chelating agent, antioxidant, surface active agent, pH adjusting agent. The present invention further relates to use of a topically administrable ophthalmic composition of dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle for the treatment of cataract surgery pain and diabetic macular edema. In an embodiment of the present invention, the ophthalmic composition comprises dexamethasone or its pharmaceutically acceptable salt thereof in concentration range of about 0. l%w / v to about 2.0% w / v.

[0018] In another embodiment, the ophthalmic composition of the present invention comprises at least one or more suspending agent selected from Carbomer Copolymer Type A, Carbomer Copolymer Type B, Carbomer Homopolymer Type B, Carbomer Homopolymer Type C, Hydroxyethyl Cellulose, Polycarbophil, Carboxymethylcellulose Sodium, Guar Gum, Sodium Hyaluronate, Xanthan Gum, Hydroxy Propyl Guar Gum, Alginate, Hydroxypropyl Methyl Cellulose (HPMC).

[0019] In one embodiment, the ophthalmic composition of the present invention comprises at least one or more tonicity agent selected from Mannitol, boric acid, sodium chloride, glycerine, propylene glycol, sorbitol, trehalose, erythritol and polyethylene glycol.

[0020] In further embodiment, the ophthalmic composition of the present invention comprises at least one or more antimicrobial agent selected from benzalkonium chloride, stabilized oxycholoro complex (SOC), polyquatemium, sodium perborate, benzododecinium chloride, benzododecinium bromide.

[0021] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more buffering agent selected from boric acid, citric acid, sodium citrate, sodium phosphate monobasic, sodium phosphate dibasic, tromethamine and sodium acetate.

[0022] In another embodiment, the ophthalmic composition of the present invention comprises at least one or more chelating agent selected from disodium EDTA, citric acid and tartaric acid.

[0023] In further embodiment, the ophthalmic composition of the present invention comprises at least one or more antioxidant selected from sodium thiosulfate, sodium metabisulfite, monothioglycerol, formaldehyde sodium bisulphite, potassium metabisulfite.

[0024] In aspect of the present invention, the ophthalmic composition of the present invention comprises at least one or more surface active agent selected from tyloxapol, poloxamer 407, polysorbate-80, span-80. In one aspect of the present invention, the ophthalmic composition of the present invention comprises at least one or more pH adjusting agent selected from hydrochloric acid, sulphuric acid, sodium hydroxide, tromethamine.

[0025] DETAILED DESCRIPTION OF THE INVENTION:

[0026] The present invention relates to an ophthalmic composition comprising dexamethasone or its pharmaceutically acceptable salt, isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, and mixtures thereof. The invention particularly relates to ophthalmic composition comprising dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle.

[0027] As used in the present specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0028] As used herein, the term "about" may be used to specify a value of a quantity or parameter (e.g. the length of an element) to within a continuous range of values in the neighborhood of (and including) a given (stated) value. For example, “about 100” means any value between 90 and 110, including 90 and 110 such as 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, and / or 110 and fractions in-between.

[0029] As used herein and unless otherwise stated, the term “concentration” refers to the weight percent concentration. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.

[0030] The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and refers to a pharmaceutical composition which is suitable for administration to a patient or subject. The subject can be an animal, preferably a mammal, more preferably a human.

[0031] The terms “comprise”, "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such process or method. Similarly, one or more devices or sub-systems or elements or structures or components proceeded by "comprises...a" does not, without more constraints, preclude the existence of other devices or other sub-systems or other elements or other structures or other components or additional devices or additional subsystems or additional elements or additional structures or additional components.

[0032] The "topical administration" herein means a pharmaceutical composition aimed to be administered locally. The topical administration preferably includes topical eye preparations (e.g., eye drops), topical ear preparations (e.g., ear drops), topical nose preparations (e.g., nose drops) and topical lung preparations (e.g., inhalers). These topical preparations can be used to treat or prevent inflammatory or infectious diseases of the eye, ear, nose, or lung. The preparation form also includes eye drops, ear drops, nose drops and inhalers. The topical preparations may preferably be topical eye preparations (including eye drops) for treating or preventing ocular inflammatory or infectious diseases, topical ear preparations (including ear drops) for treating or preventing otogenic inflammatory or infectious diseases, topical nose preparations (including nose drops) for treating or preventing nasal inflammatory or infectious diseases or topical lung preparations (including inhalers) for treating or preventing pulmonary inflammatory or infectious diseases.

[0033] The "ophthalmic suspension" herein means a liquid of dexamethasone compound is suspended. The ophthalmic suspension herein may constitute a pharmaceutical composition which can be administered as a pharmaceutical drug by itself or may constitute a pharmaceutical composition by adding other components or a pharmaceutically acceptable excipient or may not be used for a pharmaceutical drug.

[0034] The present invention discloses an ophthalmic suspension comprising dexamethasone or its pharmaceutically acceptable salt thereof. Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is designated chemically as 9-fluoro-l ip, 17, 21 -trihydroxy- 16a- methylpregna-1, 4-diene, 3, 20-dione. Dexamethasone, as used herein i.e., mitomycin, or its pharmaceutically acceptable salts, isomers, racemates, enantiomers, tautomer, hydrates, solvates, metabolites, prodrug polymorphs, complexes, and mixtures thereof, in the form of ophthalmic suspension. Dexamethasone is a corticosteroid indicated for allergic states, ophthalmic diseases, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematologic disorders, neoplastic diseases, nervous system, renal diseases, respiratory diseases, and rheumatic disorders.

[0035] In an embodiment, the ophthalmic composition comprises dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle.

[0036] In another embodiment of the present invention, the ophthalmic composition comprises dexamethasone or its pharmaceutically acceptable salt thereof in concentration range of about 0. l%w / v to about 2.0% w / v.

[0037] In another embodiment of the present invention, the ophthalmic composition comprises pharmaceutically acceptable vehicle further comprising at least one excipient selected from suspending agent, tonicity agent, antimicrobial agent, buffering agent, chelating agent, antioxidant, surface active agent, pH adjusting agent.

[0038] The purpose of the suspending agent is to maintain the suspension of the ophthalmic active ingredient within the formulation vehicle. In an embodiment, the ophthalmic composition of dexamethasone of the present invention comprises at least one or more suspending agent in the range of about 0.0I%w / v to about 3.00%w / v, about 0.05%w / v to about I.50%w / v, or preferably about 0.0I%w / v to about I.00%w / v.

[0039] In another embodiment, the ophthalmic composition of the present invention comprises at least one or more suspending agent selected from Carbomer Copolymer Type A, Carbomer Copolymer Type B, Carbomer Homopolymer Type B, Carbomer Homopolymer Type C, Hydroxyethyl Cellulose, Polycarbophil, Carboxymethylcellulose Sodium, Guar Gum, Sodium Hyaluronate, Xanthan Gum, Hydroxy Propyl Guar Gum, Alginate, Hydroxypropyl Methyl Cellulose (HPMC). In a preferred embodiment of the present invention, the ophthalmic composition comprises Carbomer Homopolymer Type B and Hydroxyethyl cellulose as a suspending agent. In an embodiment, the ophthalmic composition of the present invention comprises at least one or more tonicity agent of about 0.01%w / v to about 10.0%w / v, about 0.01%w / v to about 7.50%w / v or about 0.01%w / v to about 3.00%w / v or about 0.01% w / v to about 2.00%w / v or preferably about 0.01 %w / v to about 1.50 %w / v or more preferably 0.01 %w / v to about 1.00 %w / v. The concentration of the tonicity agent will vary based on the specific agent used.

[0040] The tonicity of the formulation can be adjusted by using different tonicity agents. In one embodiment, the ophthalmic composition of the present invention comprises at least one or more tonicity agent selected from mannitol, boric acid, sodium chloride, glycerine, propylene glycol, sorbitol, trehalose, erythritol and polyethylene glycol. In a preferred embodiment of the present invention, the ophthalmic composition comprises sodium chloride, mannitol, zinc chloride, propylene glycol and glycerin as a tonicity agent.

[0041] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more antimicrobial agent in the range of about 0.0001%w / v to about 0.20%w / v.

[0042] Since topical ophthalmic composition is often packed in multiple dose forms, preservatives are usually needed to avoid microbial contamination while the product is being used. In further embodiment, the ophthalmic composition of the present invention comprises at least one or more antimicrobial agent selected from benzalkonium chloride, stabilized oxycholoro complex (SOC), polyquatemium, sodium perborate, benzododecinium chloride, benzododecinium bromide. In a preferred embodiment of the present invention, the ophthalmic composition comprises benzalkonium chloride, stabilized oxycholoro complex (SOC), and sodium perborate as antimicrobial agent.

[0043] In order to reduce pH drift during storage, the composition may include a suitable buffering agent. The present invention of the present invention comprises at least one or more buffering agent in the range of about 0.0I%w / v to about 5.00%w / v, or about 0.05%w / v to about 3.50%w / v, or preferably about 0. l%w / v to about 2.00%w / v, or more preferably about 0.I%w / v to about I.00%w / v. The particular concentration of the buffer will vary, depending on the specific agent employed.

[0044] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more buffering agent selected from boric acid, citric acid, sodium citrate, sodium phosphate monobasic, sodium phosphate dibasic, tromethamine and sodium acetate. Preferably, the ophthalmic composition of the present invention comprises sodium citrate, citric acid, and boric acid.

[0045] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more chelating agent in the range of about 0.0I%w / v to about 1.00% w / v.

[0046] A chelating agent may be included to enhance the efficacy of the antimicrobial agent. In another embodiment, the ophthalmic composition of the present invention comprises at least one or more chelating agent selected from disodium EDTA, citric acid and tartaric acid. Preferably, the present invention of an ophthalmic composition comprises disodium EDTA as chelating agent.

[0047] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more antioxidant in the range of about 0.01%w / vto about 2.00%w / v, about 0.001%w / v to about 1 %w / v.

[0048] In further embodiment, the ophthalmic composition of the present invention comprises at least one or more antioxidant selected from sodium thiosulfate, sodium metabisulfite, monothioglycerol, formaldehyde sodium bisulphite, potassium metabisulfite.

[0049] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more surface active agent in the range of about 0.01 %w / v to about 5.00 %w / v, or about 0.01%w / v to about 2.50%w / v or preferably about 0.01%w / v to about 2.00%w / v, or more preferably about 0.01 %w / v - 1.00 %w / v.

[0050] The concentration of the surface -active agent may be limited only to neutralize the bactericidal effect of the accompanying preservatives, if present, or by concentration which may cause eye irritation. Surface active agent that are acceptable for ophthalmic application is selected from tyloxapol, poloxamer 407, polysorbate-80, span-80. In a preferred embodiment of the present invention, the ophthalmic composition comprises poloxamer 407 and tyloxapol as surface active agent.

[0051] In an embodiment, the ophthalmic composition of the present invention comprises at least one or more pH adjusting agent selected from hydrochloric acid, sulphuric acid, sodium hydroxide, tromethamine. In a preferred embodiment of the present invention, the ophthalmic composition comprises sodium hydroxide and hydrochloric acid.

[0052] In one embodiment, the ophthalmic composition of the present invention is aqueous.

[0053] In another embodiment, the ophthalmic composition of the present invention is non-aqueous.

[0054] In one more embodiment, the ophthalmic composition of dexamethasone is free of cyclodextrin.

[0055] In one embodiment, the ophthalmic composition of the present invention comprises water for injection.

[0056] In a preferred embodiment, the ophthalmic composition of the present invention comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.01%w / v stabilized oxycholoro complex (SOC), about 0.001%w / v to about 1.00 % w / v sodium thiosulfate, about 0.01 %w / v to about 1 % w / v disodium EDTA, about 0.1%w / v to about 1% w / v sodium chloride, about 0.1%w / v to about 1.0% w / v sodium phosphate dibasic, about 0.1%w / v to 5.0%w / v propylene glycol, about 0.01%w / vto 1.00% w / v tyloxapol, about 0.1%w / v to about 1% w / v Carbopol 974P or Carbomer Copolymer Type B, and water for injection.

[0057] In a preferred embodiment, the ophthalmic composition of the present invention comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.0001%w / v to about 0.10% w / v stabilized oxycholoro complex (SOC), about 0.01%w / v to about 0.20% w / v disodium EDTA, about 0.01%w / v to about 1.50% w / v sodium chloride, about 0.01%w / v to 7.50%w / v mannitol, about 0.01%w / v to 0.50% w / v tyloxapol, about 0.01 %w / v to about 1.0% w / v Carbomer Homopolymer Type B, and water for injection. In a preferred embodiment, the ophthalmic composition of the present invention comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.0001%w / v to about 0.20% w / v sodium perborate, about 0.01%w / v to about 2.00% w / v boric acid, about 0.0001%w / v to about 0. 10% w / v zinc chloride, about 0.01%w / v to 3.00%w / v propylene glycol, about 0.01%w / v to 1.50% w / v poloxamer407, about 0.01%w / v to about 3.0% w / v hydroxyethyl cellulose, and water for injection.

[0058] In a preferred embodiment, the ophthalmic composition of the present invention comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.001%w / v to about 0.20% w / v benzalkonium chloride, about 0.01%w / v to about 0.20% w / v disodium EDTA, about 0.01%w / vto about 10.00% w / v glycerine, about 0.01%w / v to 1.50%w / v sodium citrate, about 0.01%w / v to 1.50% w / v poloxamer407, and water for injection.

[0059] Examples

[0060] The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.

[0061] Example 1

[0062] Example 2

[0063] Manufacturing Process: 1. Collected the Water for Injection and Sparged the nitrogen gas till dissolved oxygen level reaches below 24 % DO saturation.

[0064] Polymer Phase:

[0065] 2. Collected the WFI and heat up to 70 °C to 90 °C.

[0066] 3. Dry mix the dispensed quantity of Carbomer Homopolymer Type B, manually.

[0067] 4. Transferred the dry mix slowly from Step 3 to WFI in Step 2 with continuous stirring, at 70 °C to 90 °C.

[0068] 5. Stirred the bulk solution of Step 4 until a lump free slurry was obtained. 6. Transferred the bulk solution to the suitable container and closed it tightly.

[0069] 7. For sterilization of bulk solution, autoclave the tightly closed container containing the bulk solution from Step 6 at 121 °C for 30 min.

[0070] 8. After the sterilization of bulk solution, cool the container to room temperature.

[0071] Buffer Phase:

[0072] 9. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0073] 10. Added and dissolved the Stabilized Oxychloro Complex (SOC) in WFI from Step 9 and stirred until a clear solution was obtained.

[0074] 11. Added and dissolved the disodium EDTA in bulk solution from Step 10 and stirred until a clear solution was obtained.

[0075] 12. Added and dissolved the sodium chloride in bulk solution from Step 11 and stirred until a clear solution was obtained.

[0076] 13. Added and dissolved the mannitol in bulk solution from Step 12 and stirred until a clear solution was obtained.

[0077] 14. Adjusted the pH of bulk solution up to 6.00, using the sodium hydroxide solution or hydrochloric acid solution, under stirring.

[0078] 15. The bulk solution was stirred from Step 14, until it was completely mixed.

[0079] 16. For sterilization of bulk solution, fdtered the bulk solution of Step 15 through the sterile 0.22 micron Poly Ethyl Sulfone (PES) fdters.

[0080] 17. Aseptically transferred the sterile bulk solution from Step 16 to the sterilized bulk solution of Step 8, under continuous stirring until a clear solution was obtained.

[0081] Drug Slurry Phase:

[0082] 18. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0083] 19. Added and dissolved the tyloxapol in WFI from Step 18 and stirred until a clear solution was obtained.

[0084] 20. Transferred the bulk solution from Step 19 to autoclavable glass bottle and closed the bottle tightly.

[0085] 21. Autoclaved the bulk solution from Step 20, at 121 °C for 30 min, using the autoclave. 22. After the autoclaved, cool bulk solution to 20 °C to 25 °C.

[0086] 23. Added the sterile dexamethasone to bulk solution of Step 22, under stirring. Stirred bulk solution until a uniform drug slurry was obtained.

[0087] 24. Homogenized the bulk solution from Step 23, for predetermined times.

[0088] 25. Aseptically transferred the sterile bulk solution from Step 23 to the sterilized bulk solution of Step 17, under stirring until a clear solution was obtained.

[0089] 26. Adjusted the volume of bulk solution using the WFI from Step 1. Stirred the bulk solution until a clear solution was obtained.

[0090] Stability data of example 2: It is evident from the above data that the composition of the present invention demonstrates acceptable stability.

[0091] Example 3 :

[0092] Manufacturing Process:

[0093] 1. Collected the Water for Injection and sparged the nitrogen gas till dissolved oxygen level reaches below 24 % DO Saturation.

[0094] Polymer Phase:

[0095] 2. Collected the WFI and heat up to 70 °C to 90 °C.

[0096] 3. Dry mix the dispensed quantity of Hydroxy ethyl Cellulose, manually.

[0097] 4. Transferred the dry mix slowly from Step 3 to WFI in Step 2, with continuous stirring, at 70 °C to 90 °C.

[0098] 5. Stirred the bulk solution of Step 4 until a lump free slurry was obtained

[0099] 6. Transferred the bulk solution to the suitable container and closed it tightly.

[0100] 7. For sterilization of bulk solution, autoclaved the tightly closed container containing the bulk solution from Step 6 at 121 °C for 30 min.

[0101] 8. After the sterilization of bulk solution, cool the container to room temperature. Buffer Phase:

[0102] 9. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0103] 10. Added and dissolved the sodium perborate in WFI from Step 9 and stirred until a clear solution was obtained.

[0104] 11. Added and dissolved the boric acid in bulk solution from Step 10 and stirred until a clear solution was obtained.

[0105] 12. Added and dissolved the zinc chloride in bulk solution from Step 11 and stirred until a clear solution was obtained.

[0106] 13. Added and dissolved the propylene glycol in bulk solution from Step 12 and stirred until a clear solution was obtained.

[0107] 14. Adjusted the pH of bulk solution up to 6.00, using the sodium hydroxide solution or hydrochloric acid solution, under stirring.

[0108] 15. The bulk solution was stirred from Step 14, until it was completely mixed.

[0109] 16. For sterilization of bulk solution, fdtered the bulk solution of Step 15 through the sterile 0.22 micron Poly Ethyl Sulfone (PES) fdters.

[0110] 17. Aseptically transferred sterile bulk solution from Step 16 to the sterilized bulk solution of Step 8, under continuous stirring until a clear solution was obtained.

[0111] Drug Slurry Phase:

[0112] 18. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0113] 19. Added and dissolved the poloxamer 407 in WFI from Step 18 and stirred until a clear solution was obtained.

[0114] 20. Transferred the bulk solution from Step 19 to autoclavable glass bottle and closed the bottle tightly.

[0115] 21. Autoclaved the bulk solution from Step 20, at 121 °C for 30 min, using the autoclave.

[0116] 22. After the autoclaved, cool bulk solution to 20 °C to 25 °C.

[0117] 23. Added sterile dexamethasone to bulk solution of Step 22, under stirring. Stirred bulk solution until a uniform drug slurry was obtained.

[0118] 24. Homogenized the Bulk Solution from Step 23, for predetermined times.

[0119] 25. Aseptically transferred sterile bulk solution from Step 23 to the sterilized bulk solution of Step 17, under stirring until a clear solution was obtained. 26. Adjusted the volume of bulk solution using the WFI from Step 1. Stirred the bulk solution until a clear solution was obtained.

[0120] Example 4

[0121] Manufacturing Process:

[0122] 1. Collected the Water for Injection and sparged the nitrogen gas till dissolved oxygen level reaches below 24 % DO Saturation.

[0123] Buffer Phase:

[0124] 2. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0125] 3. Added and dissolved the benzalkonium chloride in WFI from Step 2 and stirred until a clear solution was obtained.

[0126] 4. Added and dissolved the disodium EDTA in bulk solution from Step 3 and stirred until a clear solution was obtained.

[0127] 5. Added and dissolved the glycerin in bulk solution from Step 4 and stirred until a clear solution was obtained.

[0128] 6. Added and dissolved the sodium citrate in bulk solution from Step 5 and stirred until a clear solution was obtained. 7. Added and dissolved the citric acid in bulk solution from Step 6 and stirred until a clear solution was obtained.

[0129] 8. Adjusted the pH of Bulk Solution up to 6.00, using the sodium hydroxide solution or hydrochloric acid solution, under stirring.

[0130] 9. The bulk solution was stirred from Step 8, until it was completely mixed.

[0131] 10. For sterilization of bulk solution, filtered the bulk solution of Step 9 through the sterile 0.22 micron Poly Ethyl Sulfone (PES) filters.

[0132] 11. Aseptically transferred sterile bulk solution from Step 10 to the sterilized bulk solution of Step 8, under continuous stirring until a clear solution was obtained.

[0133] Drug Slurry Phase:

[0134] 12. In another vessel, collected the WFI and cool up to 20 °C to 25 °C.

[0135] 13. Added and dissolved the poloxamer 407 in WFI of Step 12 and stirred until a clear solution was obtained.

[0136] 14. Transferred the bulk solution from Step 13 to autoclavable glass bottle and closed the bottle tightly.

[0137] 15. Autoclaved the bulk solution from Step 14, at 121 °C for 30 min, using the autoclave.

[0138] 16. After the autoclaved, cool bulk solution to 20 °C to 25 °C.

[0139] 17. Added sterile dexamethasone to bulk solution of Step 16, under stirring. Stirred bulk solution until a uniform drug slurry was obtained.

[0140] 18. Homogenized the bulk solution of Step 17, for predetermined times.

[0141] 19. Aseptically transferred sterile bulk solution from Step 18 to the sterilized bulk solution of Step 11, under stirring until a clear solution was obtained.

[0142] 20. Adjusted the volume of bulk solution using the WFI from Step 1. Stirred the bulk solution, until a clear solution was obtained.

[0143] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

Claims

We claim,1. An ophthalmic composition comprising dexamethasone, or its pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable vehicle, wherein the pharmaceutically acceptable vehicle comprises at least one excipient selected from suspending agent, tonicity agent, antimicrobial agent, buffering agent, chelating agent, antioxidant, surface active agent, pH adjusting agent.

2. The composition according to claim 1, wherein the dexamethasone or its pharmaceutically acceptable salt thereof is present in a concentration of about 0. l%w / v to about 2.0% w / v.

3. The composition according to claim 1, wherein the suspending agents are selected from Carbomer Copolymer Type A, Carbopol 974P, Carbomer Copolymer Type B, Carbomer Homopolymer Type B, Carbomer Homopolymer Type C, Hydroxyethyl Cellulose, Polycarbophil, Carboxymethylcellulose Sodium, Guar Gum, Sodium Hyaluronate, Xanthan Gum, Hydroxy Propyl Guar Gum, Alginate, Hydroxypropyl Methyl Cellulose (HPMC), in concentration of about 0.01%w / v to about 3.00%w / v.

4. The composition according to claim 1, wherein the tonicity agents are selected from mannitol, boric acid, sodium chloride, glycerine, propylene glycol, sorbitol, trehalose, erythritol and polyethylene glycol, in concentration of about 0.01%w / v to about 10.0%w / v.

5. The composition according to claim 1, wherein the antimicrobial agents are selected from benzalkonium chloride, stabilized oxycholoro complex (SOC), polyquatemium, sodium perborate, benzododecinium chloride, benzododecinium bromide, in concentration of about 0.0001%w / v to about 0.2%w / v.

6. The composition according to claim 1, wherein the buffering agents are selected from boric acid, citric acid, sodium citrate, sodium phosphate monobasic, sodium phosphate dibasic, tromethamine and sodium acetate, in concentration of about 0.01%w / v to about 5.00%w / v.

7. The composition according to claim 1, wherein the chelating agents are selected from disodium EDTA, citric acid and tartaric acid, in concentration of about 0.01%w / v to about 1.00% w / v.

8. The composition according to claim 1, wherein the antioxidant agents are selected from sodium thiosulfate, sodium metabisulfite, monothioglycerol, formaldehyde sodium bisulphite, potassium metabisulfite, in concentration of about 0.01%w / v to about 2.00%w / v.

9. The composition according to claim 1, wherein the surface-active agents are selected from tyloxapol, poloxamer 407, polysorbate-80, span-80, in concentration of about 0.01 %w / v to about 5.00 %w / v.

10. The composition according to claim 1, wherein the pH adjusting agent are selected from hydrochloric acid, sulphuric acid, sodium hydroxide, tromethamine.

11. The composition according to claim 1, wherein the composition comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.01%w / v stabilized oxycholoro complex (SOC), about 0.001%w / v to about 1.00 % w / v sodium thiosulfate, about 0.01%w / v to about 1% w / v disodium EDTA, about 0. l%w / v to about 1% w / v sodium chloride, about 0.1%w / v to about 1.0% w / v sodium phosphate dibasic, about 0.1%w / v to 5.0%w / v propylene glycol, about 0.01%w / v to 1.00% w / v tyloxapol, about 0. l%w / v to about 1% w / v Carbopol 974P or Carbomer Copolymer Type B, and water for injection.

12. The composition according to claim 1, wherein the composition comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.000 l%w / v to about 0.10% w / v stabilized oxycholoro complex (SOC), about 0.01%w / v to about 0.20% w / v disodium EDTA, about 0.01%w / v to about 1.50% w / v sodium chloride, about 0.01%w / v to 7.50%w / v mannitol, about 0.01%w / v to 0.50% w / v tyloxapol, about 0.01%w / v to about 1.0% w / v Carbomer Homopolymer Type B and water for injection.

13. The composition according to claim 1, wherein the composition comprises about 0.1%w / v to about 2.0% w / v dexamethasone, about 0.000 l%w / v to about 0.20% w / v sodium perborate, about 0.01%w / v to about 2.00% w / v boric acid,about 0.0001%w / v to about 0.10% w / v zinc chloride, about 0.01%w / v to 3.00%w / v propylene glycol, about 0.01%w / v to 1.50% w / v poloxamer407, about 0.01%w / v to about 3.0% w / v hydroxyethyl cellulose, and water for injection.

14. The composition according to claim 1, wherein the composition comprises about 0. l%w / v to about 2.0% w / v dexamethasone, about 0.001%w / v to about 0.20% w / v benzalkonium chloride, about 0.01%w / v to about 0.20% w / v disodium EDTA, about 0.01%w / v to about 10.00% w / v glycerine, about 0.01%w / v to 1.50%w / v sodium citrate, about 0.01%w / v to 1.50% w / v poloxamer 407, and water for injection.

15. The composition according to claim 1, wherein the composition is free of cyclodextrin.

16. The composition according to claim 1, for use in the treatment of cataract surgery pain and diabetic macular edema.

Images