COMPOSITIONS, METHODS AND USES THEREOF

TECHNICAL FIELD OF THE INVENTION

[0001] The present disclosure generally relates to compounds and compositions for the treatment of eye disorders. More particularly, the present disclosure relates to ophthalmic composition comprising of pilocarpine, its pharmaceutically acceptable salt forms or physical mixture of pilocarpine salt forms with dithiol agents concomitantly combined with nonsteroidal anti-inflammatory drug or its pharmaceutically acceptable salts. Further, related to method of preparing and using the ophthalmic composition for treating ocular disease conditions with a pharmaceutically acceptable dose.

BACKGROUND OF THE INVENTION

[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0003] Pilocarpine is a well-known parasympathomimetic drug used to reduce pressure inside the eye and treat dry mouth. It is used in the treating various eye disorders. Pilocarpine is a cholinergic receptor agonist agent and has been used to treat glaucoma for long time. It is on the World Health Organization's List of Essential Medicines. It is also known to be used in eye surgeries, ocular hypertension, to open and narrow angle glaucoma, constrict the dilated pupil, angle closure glaucoma etc.

[0004] Commonly reported side effects of the pilocarpine include miosis, accommodative spasm, frontal headaches, twitching lids, blurry vision, irritation, allergic reactions and retinal detachment, increased permeability of the blood aqueous barrier, anterior chamber narrowing, increased sweating, nausea, and vomiting . [0005] Pilocarpine works by activating cholinergic receptors of the muscarinic type which cause the trabecular meshwork to open and the aqueous humor to drain from the eye. Hence not suitable for long term management.

[0006] Presbyopia is a condition associated with the aging that results in progressive loss of ability to see things clearly up close. There is no way to stop or reverse the normal aging process leading to presbyopia. However, it can be corrected with eyeglasses, contact lenses or surgery.

[0007] Use of pilocarpine alone or in combination with other drug has been described in many patent and patent applications for the treatment of presbyopia. US20190321337A1 describes compositions for the treatment of ocular conditions and for the improvement of vision using pharmaceutically acceptable ophthalmic pilocarpine hydrochloride formulations. Another US20160008278A1 discloses compositions of the invention contain pilocarpine and tropicamide for treating presbyopia.

[0008] The most common forms of vision impairment are errors of refraction resulting from aging others include Age-related Macular Degeneration (AMD), cataract, diabetic retinopathy, glaucoma, and presbyopia. Glaucoma is a progressive condition that causes damage to optic nerve due to buildup of pressure inside the eye. Presbyopia is an age- related condition due to gradual thickening and loss of flexibility of the natural lens inside your eye. Age related disorder is the major reasons for the increase in blindness in elderly/aging populations.

[0009] Major treatment options for the correction of vision and related problems include various use of ocular therapeutics and surgeries. Challenges faced in the formulation of therapeutics include attainment of an optimal concentration at the target site, ocular barriers, reduced bioavailability, faster clearance, and drug associated adverse effects.

[0010] The composition having pilocarpine and dapiprazole produced headache, light sensitivity, redness and itching and burning. While composition comprising pilocarpine and brimonidine produced blurred vision, burning sensation of eyes, drowsiness, eye pruritus, and follicular conjunctivitis. THE OBJECTS AND SUMMARY OF THE INVENTION

[0011] In an embodiment, the present invention discloses an ophthalmic composition for age related vision problems. In particular it discloses a composition comprising at least two actives acting concomitantly and an ophthalmological acceptable carrier/vehicle for treatment of age related eye disorder such as glaucoma and presbyopia. [0012] In another embodiment, the ophthalmic composition comprises muscarinic cholinergic receptor agonist such as pilocarpine or its pharmaceutical acceptable salt forms, physical mixture, or a combination thereof. The pilocarpine salt form is selected from pilocarpine nitrate, pilocarpine hydrochloride, pilocarpine alpha lipoate, pilocarpine-R- lipoate, or pilocarpine mononitrate thereof.

[0013] In an embodiments, ophthalmic composition comprises physical mixtures containing muscarinic cholinergic receptor agonist or its salt forms and an antioxidant ingredient.

[0014] In some embodiments, ophthalmic composition comprises physical mixtures containing pilocarpine or its salt forms and an antioxidant ingredient.

[0015] In another embodiments, ophthalmic composition comprises physical mixtures containing muscarinic cholinergic receptor agonist or the salt forms and lipoic acid. The lipoic acid can be R-lipoic acid or alpha lipoic acid.

[0016] In an embodiment, the physical mixtures/combination is selected from physical mixtures of pilocarpine nitrate and alpha lipoic acid, or physical mixtures of pilocarpine nitrate and R-lipoic acid or physical mixtures of pilocarpine mononitrate and alpha lipoic acid or physical mixtures of pilocarpine mononitrate and R lipoic acid or physical mixtures of pilocarpine hydrochloride and R-lipoic acid or physical mixtures of pilocarpine hydrochloride and alpha lipoic acid thereof. In an embodiment, the present invention discloses an ophthalmic composition may further comprise one or more nonsteroidal anti-inflammatory drug (NSAID) to reduce intraocular inflammation. The NS AID are selected from but not limiting to ketorolac, diclofenac, bromfenac, nepafenac, indomethacin, flurbiprofen or other known NSAIDs suitable for ophthalmic applications or their pharmaceutical acceptable salt forms such as diclofenac sodium, diclofenac potassium, ketorolac tromethamine, bromfenac sodium and/or other known pharmaceutical acceptable salt forms of NSAIDs or is a combination thereof.

[0017] In some embodiment the ophthalmic composition comprises: muscarinic cholinergic agonist or a salt or a physical mixture of muscarinic cholinergic agonist and lipoic acid thereof; in combination with a NSAID.

[0018] In an embodiments, the concentration of pilocarpine salt forms or physical mixture of pilocarpine salt and alpha lipoic acid or R-lipoic acid in the ophthalmic composition is about 0.001% (w/w or w/v) to 20 % (w/w or w/v).

[0019] In certain embodiments, said ophthalmic composition further comprises NSAIDs or a pharmaceutically acceptable salt forms. The concentration of NSAIDs can range from 0.001% (w/w or w/v) to 20 % (w/w or w/v).

[0020] In an embodiment, the concentration of physical mixture of pilocarpine salt and lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[0021] In some aspect the ophthalmic composition may comprises of NSAID alone. [0022] In certain embodiment, said ophthalmic composition comprises NSAID in combination with salts of alpha lipoic or R-lipoic acid. In a preferred embodiment the salt of lipoic acid is sodium salt of R- lipoic acid.

[0023] In an embodiment, the ophthalmic composition is an ophthalmic topical solution.

[0024] In an embodiment, the ophthalmic composition is formulated into powder phase and solvent phase. Wherein the pilocarpine salt or lipoic acid salt or physical mixture of pilocarpine salt and alpha lipoic or R-lipoic acid with one or more excipients is formulated into a powder phase; and the NSAID or its salt form with one or excipients is formulated into solvent phase.

[0025] In certain embodiments, said ophthalmic composition further comprises one or more other agents referred as vehicle or carrier or excipients collectively known as ophthalmological acceptable pharmaceutical ingredients or agents. Ophthalmological acceptable pharmaceutical ingredients or agents are known agents in the art of ophthalmic formulation. In some embodiments, one or more such ingredients are used in the ophthalmic composition to control or modulate the pH, tonicity, stability, sterility, solubility, viscosity and other properties of the composition. Non-limiting examples of such agents in general include diluents, isotonic agents, thickening agent or viscosity modifier or agent, wetting agent, preservative, chelating agent, solvents, buffers and or solubilizer. In some embodiments, ophthalmological acceptable pharmaceutical ingredients or agents which improve viscosity and the contact time of the drug with the cornea and improve bioavailability of the drug. Non-limiting examples of excipients include hyaluronic acid or one of its salts, and particularly of sodium hyaluronate, povidone (PVP), polyvinyl alcohol, carboxymethylcellulose, Gelrite®, Methocel™, boric acid, trisodium citrate anhydrous, EDTA, Kolliphor®, BKC, SOC, sterile water, polysorbate 80, and other known in art and combination thereof. The composition further comprises use of excipients such as salts, sugar, lubricants etc.

[0026] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, alpha lipoic acid, diclofenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0027] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, R- lipoic acid, diclofenac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0028] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, alpha lipoic acid, diclofenac or its pharmaceutically acceptable salt forms and ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0029] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, R- lipoic acid, diclofenac or its pharmaceutically acceptable salts, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0030] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride, alpha lipoic acid, diclofenac or its pharmaceutically acceptable salt forms and one or more ophthalmologic al acceptable pharmaceutical ingredients/agents and preparation of the ophthalmic composition.

[0031] In some embodiments, the ophthalmic composition comprises, physical mixture of pilocarpine hydrochloride, R- lipoic acid, diclofenac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0032] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, ketorolac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0033] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, R- lipoic acid, ketorolac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation the ophthalmic composition.

[0034] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, alpha lipoic acid, ketorolac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation the ophthalmic composition.

[0035] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, R- lipoic acid, ketorolac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0036] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride, alpha lipoic acid, ketorolac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0037] In some embodiments, the ophthalmic composition comprises, physical mixture of pilocarpine hydrochloride and R- lipoic acid, ketorolac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0038] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, alpha lipoic acid, bromfenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0039] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, R- lipoic acid, bromfenac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0040] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, alpha lipoic acid, bromfenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0041] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, R- lipoic acid, bromfenac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0042] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride, alpha lipoic acid, bromfenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0043] In some embodiments, the ophthalmic composition comprises, physical mixture of pilocarpine hydrochloride, R- lipoic acid, bromfenac or its pharmaceutically acceptable salts, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0044] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, alpha lipoic acid, nepafenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0045] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate, R- lipoic acid, nepafenac or its pharmaceutically acceptable salt forms, and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0046] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, alpha lipoic acid, nepafenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0047] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate, R- lipoic acid, nepafenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0048] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride, alpha lipoic acid, nepafenac or its pharmaceutically acceptable salt forms and one or more ophthalmologic al acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0049] In some embodiments, the ophthalmic composition comprises, physical mixture of pilocarpine hydrochloride, R- lipoic acid, nepafenac or its pharmaceutically acceptable salt forms and one or more ophthalmological acceptable pharmaceutical ingredients or agents and preparation of the ophthalmic composition.

[0050] In some embodiments, the ophthalmic composition comprises pilocarpine-R- lipoate, NSAID or its pharmaceutical acceptable salt forms of NSAIDs and one or more ophthalmological acceptable pharmaceutical ingredients or agents. Wherein, the NSAIDs is selected from ketorolac, diclofenac, bromfenac, nepafenac, indomethacin or flurbiprofen or its salts forms.

[0051] In some embodiments, the ophthalmic composition comprises pilocarpine alpha lipoate, NSAID or its pharmaceutical acceptable salt forms of the NSAIDs and one or more ophthalmological acceptable pharmaceutical ingredients or agents. Wherein, the NSAID is selected from ketorolac, diclofenac, bromfenac, nepafenac, indomethacin or flurbiprofen or its salts forms.

[0052] In an embodiment, the ophthalmic composition comprises: diclofenac sodium with one or more excipients, wherein, the excipients are viscosity agent, surfactant, buffering agent, chelating agent, solubilizer, preservative and solvent.

[0053] In an embodiment, the ophthalmic composition comprises: diclofenac sodium, methocel E4M, di- sodium phosphate dihydrate, sodium phosphate monohydrate, EDTA, polysorbate 80, BKC and purified water.

[0054] In an embodiment, the ophthalmic composition comprises diclofenac sodium, boric acid, trisodium citrate, EDTA, kolliphor ELP, BKC and purified water.

[0055] In another embodiment, the ophthalmic composition comprises: diclofenac sodium, di- sodium phosphate dihydrate, sodium phosphate monohydrate, EDTA, kolliphor ELP, BKC and purified water.

[0056] In an embodiment, the ophthalmic composition comprises: a powder phase and a solvent/buffer phase. In an embodiment the powder phase comprises of the first active agent along with one or more excipient; and the solvent or buffer phase comprises of second active agent with one or more excipient. In another embodiment first active agent and the second active agent can be present in powder phase with one or more excipient.

[0057] In an embodiment, the first active agent is a muscarinic cholinergic agonist or its salt form, or a physical mixture of muscarinic cholinergic agonist or its salt form with R-lipoic acid or alpha lipoic acid, or salt of lipoic acid.

[0058] In another embodiment, the second active agent is nonsteroidal antiinflammatory drug. [0059] In an embodiment, the ophthalmic composition comprises: powder phase consisting of pilocarpine R- lipoate and a diluent, wherein the diluent is mannitol. The solvent phase comprises of NSAID and one or more excipients, wherein, the excipients are viscosity agent, surfactant, buffering agent, chelating agent, solubilizer, preservative and solvent.

[0060] In an embodiment, the ophthalmic composition comprises: a powder phase and a solvent or buffer phase. The powder phase consists of pilocarpine R- lipoate and mannitol; and the solvent phase comprises of diclofenac sodium, methocel E4M, boric acid, trisodium citrate anhydrous, EDTA, kolliphor ELP, BKC and purified water.

[0061] In some embodiment, the ophthalmic composition comprises: a powder phase and a solvent or buffer phase. The powder phase consists of sodium R- lipoate and mannitol; and the solvent phase comprises of diclofenac sodium, boric acid, trisodium citrate anhydrous, EDTA, kolliphor ELP, BKC and purified water.

[0062] In other embodiments, the pH of the ophthalmic composition is maintained between 3.3-7.4., (for e.g., 3.3, 3.5, 3.7, 3.9, 4.0, 4.2, 4.5, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4,) or any ranges based on these specified numeric values. In one embodiment, the pH is near physiological pH of tear (pH 7). Non-limiting examples include phosphate buffers (e.g., sodium 420 phosphate monobasic monohydrate, ascorbic acid, sodium phosphate dibasic anhydrous), acetate buffer, citrate buffer, borate buffers, and HBSS (Hank's Balanced Salt Solution).

[0063] In other embodiments, the tonicity agent is added to the ophthalmic composition to maintain the osmolality of the solution with that of the tears to avoid irradiation. Non-limiting examples include sodium chloride, potassium chloride and other alkali and alkaline earth metals.

[0064] In other embodiments, stability of the composition is maintained by using proper storage container and using stabilizing antioxidant to minimize the deterioration of the drug in the ophthalmic composition. [0065] In other embodiments, the microbial contamination of the ophthalmic composition is prevent by using bactericidal or bacteriostatic preservative.

[0066] In other embodiments, ophthalmic composition may further comprises a pharmaceutical acceptable diluent and/or a solvent.

[0067] In an embodiment, the ophthalmic composition is formulated into solution, emulsion, suspension, micro-emulsions, micro-suspension, nanoemulsion, nanosuspension, ointments, gel form, preformed and in situ gels, hydrogels, implants or inserts, eye drop, spray, colloidal systems such as liposomes, nanoparticles and niosomes. Furthermore the ophthalmic composition is formulated for controlled and sustained release composition.

[0068] In another embodiment, ophthalmic composition is administrated by topical, local (ie, subconjunctival, intravitreal, retrobulbar, intracameral), and systemic to the subject.

[0069] In an embodiment, the ophthalmic composition is packaged into a single use or a multi-use dropper bottles or container. In certain embodiments, the ophthalmic composition is packaged into a single container having provisions of two separate chambers for holding the powder and solvent phase separately. The two chambers are separated by semipermeable polymer membrane. This membrane prevent interaction of the powder and solvent phase.

[0070] In another embodiment the semipermeable polymeric membrane can be raptured using slight external pressure or other means known in the art. Once the membrane is raptured the two phase are allowed to mix and form the clear ready to use ophthalmic solution.

[0071] In another embodiment the dropper bottle used for the packaging of the ophthalmic composition can be selected from low density polyethylene (LDPE) dropper bottles, high density polyethylene (HDPE) dropper bottles, polypropylene (PP) dropper bottles, polyester dropper bottles, ethylene vinyl alcohol copolymer dropper bottles.

[0072] In another embodiment, ophthalmic composition is for reducing the pressure and associated inflammation in glaucoma subjects. A method of treating subjects with glaucoma comprises: administering therapeutically effective amount of ophthalmic composition at selected time. The ophthalmic composition is administrated to the subject topically or by surgically intervention

[0073] In some embodiments, ophthalmic composition is used for correcting presbyopia. A method of correcting presbyopia comprises: administrating therapeutically effective amount of an ophthalmic composition at selected time without affecting the visual acuity. The ophthalmic composition is administrated to the subject topically or by surgically intervention.

DETAILED DESCRIPTION OF THE INVENTION

[0074] The following is a detailed description of embodiments of the disclosure depicted in the accompanying drawings. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

[0075] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the “invention” may in some cases refer to certain specific embodiments only. In other cases it will be recognized that references to the “invention” will refer to subject matter recited in one or more, but not necessarily all, of the claims.

[0076] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.

[0077] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. [0078] The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0079] The various terms as used herein and not defined should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

[0080] The term “ophthalmological acceptable pharmaceutical ingredients/agents” is a collective term used for or vehicle or carrier or excipient used in the ophthalmic composition. The ophthalmological acceptable ingredients/agents are non-active ingredients/agents used with the actives or drug(s) to prepare/formulate the ophthalmic composition. The ophthalmological acceptable pharmaceutical ingredients/agents are employed to control the pH, tonicity, stability, viscosity, solubility, sterility and other properties of the ophthalmic composition. The ophthalmological acceptable pharmaceutical ingredients/agents which as used in here includes solvents, media for suspension and emulsions, diluents, isotonic agents, buffers, wetting agents, thickening agents/viscosity enhancer, lubricating agents, emulsifying agents, preservatives, and/or solubilizers. The ophthalmological acceptable pharmaceutical ingredients/agents are well known in the art (Remimgton: The Science and Practice of Pharmacy by Allen, Lody V., Jr, Pharmaceutical Press is incorporated herein by reference in its entirety).

[0081] The term “pharmaceutical acceptable salts/salts forms” refers to ionisable compounds used in present composition that has been combined with a counter-ion to form a neutral complex. Using different chemical species to neutralize the compounds used in present composition can produce a diverse series of compounds. Non-limiting examples of pharmaceutically acceptable salts include salts of amines, carboxylic acids, metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts, include gluconate, acetate, citrate, nitrate, potassium, tartrate adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bitartrate, bromide, bisulfate, borate, butyrate, carbonate, chloride, dodecylsulfate, ethanesulfonate, edetate, edisylate, estolate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glycerophosphate, hemisulfate, hydrobromide, hydrovhloride, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, mandelate, methyl bromide, methyl sulfate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, diphosphate, picrate, pivalate, propionate, stearate, succinate, salicylate, disalicylate, sulfate, thiocyanate, ptoluenesulfonate, triethiodide, undecanoate, and valerate salts. Examples of alkali or alkaline earth metal salts or cationic salts include sodium, lithium, potassium, calcium, and magnesium, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. For example in some embodiment, ophthalmic composition comprises pilocarpine nitrate or pilocarpine hydrochloride or pilocarpine mononitrate or pilocarpine-R-lipoate, pilocarpine-alpha lipoate, sodium R lipoate or a mixture thereof. Furthermore, in some embodiment, ophthalmic composition comprises diclofenac sodium or diclofenac potassium or ketorolac tromethamine or bromfenac sodium or bromfenac potassium.

[0082] The embodiments described in this application relate to an ophthalmic composition preparation as defined in the appended paragraph and claims.

[0083] In an embodiment, the ophthalmic composition comprises of muscarinic cholinergic receptor agonist such as pilocarpine salt, or a physical mixture of muscarinic cholinergic receptor agonist and R-lipoic acid or alpha lipoic acid thereof; nonsteroidal anti-inflammatory drug or a pharmaceutically acceptable salt(s) thereof and one or more ophthalmological acceptable ingredients/agents. Alternatively ophthalmic composition may not comprise a NSAIDs or salts of NSAIDs, or may comprises of NSAIDs alone.

[0084] In some embodiments, the pilocarpine salts is selected from a group comprising of pilocarpine nitrate, pilocarpine-alpha lipoate, pilocarpine-R- lipoate, or pilocarpine mononitrate or pilocarpine hydrochloride. Preferably physical mixtures containing pilocarpine or its salt forms and an antioxidant ingredient. The physical mixture is selected from group of pilocarpine nitrate and R-lipoic acid, pilocarpine nitrate and alpha lipoic acid, pilocarpine mononitrate and R-lipoic acid, pilocarpine mononitrate and alpha lipoic acid, pilocarpine hydrochloride and R-lipoic acid, pilocarpine hydrochloride and alpha lipoic acid or a combination/mixture thereof.

[0085] In an embodiment, the present invention discloses an ophthalmic composition may further comprise one or more nonsteroidal anti-inflammatory drug (NSAID) to reduce intraocular inflammation. The NSAID are selected from but not limiting to ketorolac, diclofenac, bromfenac, nepafenac, indomethacin, flurbiprofen or other known NSAIDs suitable for ophthalmic applications or their pharmaceutical acceptable salt forms such as diclofenac sodium, diclofenac potassium, ketorolac tromethamine, bromfenac sodium and/or other known pharmaceutical acceptable salt forms of NSAIDs or is a combination thereof.

[0086] In some embodiments, the concentration of pilocarpine or the pharmaceutical acceptable salt(s) of pilocarpine R-lipoate in the composition may be present in the amount of about 0.001% to 20%(w/w or w/v).

[0087] In some embodiments, the concentration of physical mixture of pilocarpine salt(s) and R-lipoic acid; or pilocarpine salts and alpha lipoic acid may be present individually as separate ionic moieties in the amount of about 0.001% to 20% (w/w or w/v). In all the embodiments, the percentile numbers is determined by weigh (w/w) or alternatively determined by volume (w/v).

[0088] In certain embodiments, said ophthalmic composition further comprises NSAIDs or a pharmaceutically acceptable salt forms. The concentration of NSAIDs can range from 0.001% (w/w or w/v) to 20 % (w/w or w/v). In some aspect the ophthalmic composition may comprises of NSAID alone.

[0089] In certain embodiments, said ophthalmic composition comprises NSAID in combination with salts of alpha lipoic or R-lipoic acid. In a preferred embodiment, the salt of lipoic acid is sodium salt of R- lipoic acid or sodium R-Lipoate.

[0090] In an embodiment, the ophthalmic composition is solution.

[0091] In an embodiment, the ophthalmic composition is formulated into powder phase and solvent phase. Wherein the pilocarpine salt or lipoic acid salt or physical mixture of pilocarpine salt and alpha lipoic or R-lipoic acid with one or more excipient is formulated into a powder phase; and the NSAID or its salt form with one or excipient is formulated into solvent phase.

[0092] In an embodiment, the ophthalmic composition comprising diclofenac sodium with one or more excipients, wherein, the excipients are viscosity agent, surfactant, buffering agent, chelating agent, solubilizer, preservative and solvent.

[0093] In an embodiment, the ophthalmic composition comprising diclofenac sodium, methocel E4M, di- sodium phosphate dihydrate, sodium phosphate monohydrate, EDTA, polysorbate 80, BKC and purified water.

[0094] In an embodiment, the ophthalmic composition comprising diclofenac sodium, boric acid, trisodium citrate, EDTA, kolliphor ELP, BKC and purified water.

[0095] In an embodiment, the ophthalmic composition comprising diclofenac sodium, di- sodium phosphate dihydrate, sodium phosphate monohydrate, EDTA, kolliphor ELP, BKC and purified water.

[0096] In an embodiment, the ophthalmic composition powder phase and solvent phase. The powder phase consists of pilocarpine R-lipoate and a diluent, wherein the diluent is mannitol. The solvent phase comprises of NSAID and one or excipients, wherein, the excipients are viscosity agent, surfactant, buffering agent, chelating agent, solubilizer, preservative and solvent.

[0097] In an embodiment, the ophthalmic solution powder phase and solvent phase. The powder phase consists of pilocarpine R-lipoate and mannitol; and the solvent phase comprises of diclofenac sodium, methocel E4M, boric acid, trisodium citrate anhydrous, EDTA, kolliphor ELP, BKC and purified water.

[0098] In an embodiment, the ophthalmic solution powder phase and solvent phase. The powder phase consists of sodium R-lipoate and mannitol; and the solvent phase comprises of diclofenac sodium, boric acid, trisodium citrate anhydrous, EDTA, kolliphor ELP, BKC and purified water.

[0099] In an embodiment, the ophthalmic solution comprising powder and solvent phase are stored separately in a container having two separate chambers, separated by semipermeable polymeric membrane for storing the powder and solvent phase separately or any commercially available dual chamber container for longer shelf life of the composition. Such packing is targeted to increase the stability and shelf-life of pilocarpine-R-lipoate.

[00100] In some embodiments, the ophthalmic composition may further comprise a nonsteroidal anti-inflammatory drug (NSAID) or a pharmaceutical acceptable salt forms thereof. The NSAID is used to reduce the inflammation in ocular tissues. In some embodiments, NSAIDs is selected from group comprising ketorolac, diclofenac, bromfenac, nepafenac, aminophenazone, ampyrone, azapropazone, clofezone, difenamizole, famprofazone, feprazone, kebuzone, metamizole, mofebutazone, morazone, oxyphenbutazone, phenazone, phenylbutazone, propyphenazone, sulfinpyrazone, suxibuzone, aceclofenac, acemetacin, alclofenac, amfenac, bendazac, indomethacin, indometacin farnesyl, isoxepac, lonazolac, oxametacin, proglumetacin, sulindac, tiopinac or a pharmaceutical acceptable salt forms thereof. The non-limiting examples of pharmaceutical acceptable salts of a NSAID include diclofenac sodium, diclofenac potassium, ketorolac tromethamine, bromfenac sodium and other known salts of NSAID.

[00101] In some embodiments, the concentration of NSAIDs or the pharmaceutical acceptable salt(s) of NSAIDs in the composition may be present in the amount of about 0.001% to 20%(w/w or w/v). [00102] In some embodiments, the ophthalmologic al acceptable ingredients/agents includes solvents, diluents, isotonic agents, buffers, wetting agents, thickening agents/viscosity enhancer, lubricating agents, preservatives, and/or solubilizers,

[00103] In another embodiment, ophthalmological acceptable agents include inert (non-active) agents to dissolve or improve the solubility of the drug and control the viscosity of the drug. Viscosity enhancer/thickening agent increases the contact time of the drug with the cornea and improve bioavailability of the drug. Non-limiting examples include hyaluronic acid or one of its salts, (e.g., sodium hyaluronate), povidone (PVP), polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), methyl cellulose, cellulose, dextran, polyol, glycerin, PEG 300, PEG 400, polysorbate, carboxymethylcellulose Gelrite®, Methocel™ or a mixture thereof. The composition further comprises use of excipients such as salts, sugar, lubricants or other compounds to improve the formulation of ophthalmic composition. Alternatively, ophthalmic composition may not comprise a Viscosity enhancer/thickening agent. In some embodiments the composition includes additional wetting agent, solubilizers or dispensing agents. The non-limiting examples of wetting agents, include carboxymethylcellulose, HPMC, glycerin, mannitol. PVA or hydroxyethylcellulose and other known in art. The non- limiting examples of solubilizers include polysorbate, polyethylene glycol or propylene glycol, Kolliphor RH40 and others known in art. The non- limiting examples of dispensing agent include poly(ethylene- glycol), alcohol and others known in art. Examples of chelating agent is ETDA.

[00104] In another embodiments, the pH of the ophthalmic composition is maintained between 3.3-7.4., (for e.g., 3.3, 3.5, 3.7, 3.9, 4.0, 4.2, 4.5, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4,) or any ranges based on these specified numeric values. In one embodiment, the pH is near physiological pH of tear (pH 7). Non-limiting examples include phosphate buffers (e.g., sodium 420 phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous), acetate buffer, citrate buffer, borate buffers, and HBSS (Hank's Balanced Salt Solution). Suitable amount of a buffer agent can be readily calculated based on a desired pH. In any of the embodiments described herein, the buffer agent is in an amount that is ophthalmological acceptable. However, in some embodiments, the ophthalmic composition does not include a buffer agent. In some embodiments, the pH of the aqueous solution or the final ophthalmic composition is adjusted with an acid (e.g., hydrochloride acid) or a base (e.g., sodium hydroxide) to the desired pH range (e.g., as described herein).

[00105] In other embodiments, the tonicity agent is added to the ophthalmic composition to maintain the osmolality of the solution with that of the tears to avoid irradiation. Non-limiting examples include sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. Suitable amount of tonicity agent in the ophthalmic composition is any amount that can achieve a tolerable osmolality. In some embodiments, the ophthalmic composition is an isotonic composition. In some embodiments, the ophthalmic composition is a hypertonic composition if water is to be drawn out of eye as in corneal edema and angle closure glaucoma.

[00106] In some embodiments, the composition may additional include surface active agents (SAAs). Depending on their physicochemical properties, SAAs can perform a variety of roles ranging from wetting agents, emulsifiers, stabilizers, charge inducers, solubilizer, antimicrobial agents, corneal permeation enhancers, and gelling agents.

[00107] In other embodiments, stability of the ophthalmic composition is maintained by using proper storage container and also using antioxidant to minimize the deterioration/degradation of the drug in the ophthalmic composition due to environmental conditions. The drug in the ophthalmic composition when exposed to direct light, heat, and humidity can undergo degradation. Once opened and exposed to the atmosphere oxidative degradation can also take place. In order to preserve the drug in its active and potent form storage under proper conditions are required along with use of antioxidants such as alpha lipoic acid or R-lipoic acid sodium bisulfate, ethylene diaminetetra acetic acid, tocopherols, sodium metabisulfite, thiourea, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate hydrates or solvates, and mixtures thereof. Examples of buffering agent or buffer components include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, boric acid, di-sodium phosphate dehydrate, sodium phosphate monohydrate, trisodium citrate and sorbic acid, and mixtures thereof.

[00108] In other embodiments, the microbial contamination of the ophthalmic composition is prevent by using bactericidal or bacteriostatic preservative. Non-limiting examples of preservatives include benzalkonium chloride, stabilized oxychloro complex (SOC), chlorobutanol, thimerosal, methyl and propylparaben, phenyl ethanol, chlorhexidine, polyaminopropyl biguanide, sodium perborate, propylparabens, methylparaben, chlorbutol, sorbitrate, pxychloride compounds, quaternary ammonium and other known in the art. Preferably benzalkonium chloride, stabilized oxychloro complex (SOC).

[00109] In an embodiment, the ophthalmic composition discloses herein are useful in treating age related eye disorders such as glaucoma, presbyopia or symptoms thereof. The ophthalmic composition may reduce or eliminate the symptoms of presbyopia while maintaining the accommodative function of the eyes, and allow patients suffering from presbyopia the ability to focus both far and near. In some embodiments, ophthalmic composition is used to reduce the elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension, in management of acute angle-closure glaucoma and prevention of postoperative elevated IOP associated with laser surgery.

[00110] In an embodiment, the ophthalmic composition is formulated into solution, emulsion or suspension. Ophthalmic suspensions are aqueous formulations that contain solid particles. The particle size is kept to a minimum to prevent irritation of the eye. Suspensions, in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures thereof.

[00111] In an embodiment, the ophthalmic composition is formulated into solution, emulsion, suspension, micro-emulsions, micro-suspension, nano-emulsion, nanosuspension, ointments, gel form, preformed and in situ gels, hydrogels, eye implants, eye inserts, and colloidal systems such as liposomes, nanoparticles and niosomes. Furthermore the ophthalmic composition is formulated for controlled and sustained release composition.

[00112] In another embodiment, ophthalmic composition is administrated to the subjects/patients in need, by topical, local (i.e., subconjunctival, intravitreal, retrobulbar, intracameral) and systemic administration.

[00113] Method of Preparing the pilocarpine salt:

Example A:

[00114] Another aspect of the present disclosure provides a method of synthesis of pilocarpine-(R)-lipoate, the method comprising: contacting pilocarpine with (R)-lipoic acid at a suitable temperature to obtain pilocarpine(R)-lipoate. In an embodiment, the method comprises contacting pilocarpine HC1 with a base to obtain pilocarpine. In an embodiment, the method comprises treating pilocarpine HC1 in a solvent with a base to obtain pilocarpine. In an embodiment, the method comprises treating pilocarpine HC1 in acetone with sodium hydrogen carbonate for about 18h at room temperature to obtain pilocarpine. In an embodiment, the method effects yield of about 100%. However, a person skilled in the pertinent art would appreciate that any other method of synthesis of pilocarpine-(R)-lipoate, as known to or appreciated by a person skilled in the art, can be suitably employed to sub-serve its intended purpose without departing from the scope and spirit of the present disclosure.

[00115] In an embodiment, the method further comprises a step of effecting recrystallization of the pilocarpine-(R)-lipoate. In an embodiment, the step of effecting recrystallization comprises effecting recrystallization of pilocarpine(R)-lipoate with ethyl acetate (5 volumes) at 50-55°C to obtain crystalline pilocarpine-(R)-lipoate with yield of about 80%. However, it should be appreciated that recrystallization of the pilocarpine-(R)-lipoate can be effected employing any other method as known to or appreciated by a person skilled in the pertinent art without departing from the scope and spirit of the present invention.

[00116] In an embodiment the ophthalmic composition is packed into a single use or a multi-use dropper bottles, or a container or a dropper bottle having multiple chamber such as dual chamber wherein the dropper bottles are selected from a group of low density polyethylene dropper bottle, high density polyethylene dropper bottle, polypropylene dropper bottle, polyester dropper bottle or ethylene vinyl alcohol copolymer dropper bottle.

[00117] Although several embodiments of the present disclosure describes the method of preparation and recrystallization of pilocarpine-(R)-lipoate, it should be appreciated by a person skilled in the art, the substantially same or similar method can be used for synthesis of pilocarpine-(R, S)-lipoate and/or pilocarpine(S)-lipoate and the same has not been described in detail for the sake of brevity.

[00118] The ophthalmic composition of this invention may be prepared as follows: The formulations of the present invention are prepared as solutions incorporating the ingredients listed in the table within the approximate ranges. The following examples are intended to illustrate the present invention and its advantages. They must in no case be considered as limiting the scope of the present invention.

[00119] Table A:

[00120] Table B [00121] Table C

[00122] Table D

[00123] In some embodiments, the ophthalmic composition comprises a physical mixture or combination or blending of one ingredient selected from each table A, B,D or combining the ingredient from table C and D or combining ingredient from table B and D in combination with one or more ophthalmological acceptable pharmaceutical ingredients/agents. It is to be understood that the various embodiments and the examples presented is not limiting the scope if present invention. The other variations and combinations/modifications are intended to be within the scope of the present invention.

[00124] Examples of Ophthalmic Compositions:

Composition 1

[00125] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, NS AID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00126] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine nitrate and R lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00127] Example 1:

[00128] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, diclofenac or its pharmaceutical acceptable salts and one or more ophthalmological acceptable pharmaceutical ingredients/agents. Wherein the pharmaceutical acceptable salt of diclofenac is diclofenac sodium or diclofenac potassium. The concentration of physical mixture of pilocarpine nitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00129] Example 2:

[00130] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and R-lipoic acid, diclofenac or its pharmaceutical acceptable salts and one or more ophthalmological acceptable pharmaceutical ingredients/agents. Wherein the pharmaceutical acceptable salt of diclofenac is diclofenac sodium or diclofenac potassium. Further, the concentration of physical mixture of pilocarpine nitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00131] Example 3:

[00132] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, diclofenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine nitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00133] Example 4:

[00134] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and R-lipoic acid, diclofenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine nitrate and R-lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00135] Example 5:

[00136] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine nitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00137] Example 6:

[00138] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and R-lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine nitrate and R-lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00139] Example 7: [00140] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and alpha lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine nitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or W/V) to 20 %(w/w or w/v).

[00141] Example 8:

[00142] The ophthalmic composition comprises physical mixture of pilocarpine nitrate and R lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine nitrate and R-lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00143] Composition 2:

[00144] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and alpha lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00145] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and R-lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00146] Example 1:

[00147] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and alpha lipoic acid, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual ionic moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein, the pharmaceutical acceptable salt forms of diclofenac are diclofenac sodium or diclofenac potassium.

[00148] Example 2

[00149] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and R- lipoic acid, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein, the pharmaceutical acceptable salt forms of diclofenac are diclofenac sodium or diclofenac potassium.

[00150] Example 3

[00151] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and alpha lipoic acid, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00152] Example 4

[00153] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine mononitrate and R-lipoic acid, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 1 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00154] Example 5:

[00155] The ophthalmic composition comprises physical mixture of pilocarpine mononitrate and alpha lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00156] Example 6:

[00157] The ophthalmic composition comprises physical mixture of pilocarpine mononitrate and R lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine mononitrate & R-lipoic acid, in the composition is as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00158] Example 7:

[00159] The ophthalmic composition comprises physical mixture of pilocarpine mononitrate and alpha lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine mononitrate and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00160] Example 8:

[00161] The ophthalmic composition comprises physical mixture of pilocarpine mononitrate and R-lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine mononitrate and R-lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00162] Composition 3:

[00163] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and alpha lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00164] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and R-lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents .

[00165] Example 1:

[00166] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and alpha lipoic acid, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein, the pharmaceutical acceptable salts of diclofenac is diclofenac sodium or diclofenac potassium.

[00167] Example 2

[00168] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and R lipoic acid, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein, the pharmaceutical acceptable salts of diclofenac is diclofenac sodium or diclofenac potassium.

[00169] Example 3

[00170] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and alpha lipoic acid, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00171] Example 4

[00172] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and R-lipoic acid, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00173] Example 5:

[00174] The ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and alpha lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). [00175] Example 6:

[00176] The ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and R-lipoic acid, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine hydrochloride and R-lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00177] Example 7:

[00178] The ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and alpha lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine hydrochloride and alpha lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00179] Example 8:

[00180] The ophthalmic composition comprises physical mixture of pilocarpine hydrochloride and R-lipoic acid, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine hydrochloride and R-lipoic acid, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00181] Composition 4:

[00182] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine alpha lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents . [00183] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine R- lipoic acid, NSAID or pharmaceutical acceptable salts selected from table D, and ophthalmological acceptable pharmaceutical ingredients/agents.

[00184] Example 1:

[00185] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine alpha lipoate, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration pilocarpine alpha lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein the pharmaceutical acceptable salts of diclofenac is diclofenac sodium or diclofenac potassium.

[00186] Example 2

[00187] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine-R-lipoate, diclofenac or its pharmaceutical acceptable salts, and ophthalmological acceptable ingredients. Further, the concentration pilocarpine -R- lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac or its pharmaceutical acceptable salts in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v). Wherein the pharmaceutical acceptable salts of diclofenac is diclofenac sodium or diclofenac potassium.

[00188] Example 3

[00189] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine alpha lipoate, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine alpha lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00190] Example 4 [00191] In some embodiments, the ophthalmic composition comprises physical mixture of pilocarpine R lipoate, diclofenac sodium and ophthalmological acceptable pharmaceutical ingredients/agents. Further, the concentration of physical mixture of pilocarpine R lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of diclofenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00192] Example 5:

[00193] The ophthalmic composition comprises physical mixture of pilocarpine alpha lipoate, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein the concentration of physical mixture of pilocarpine alpha lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00194] Example 6:

[00195] The ophthalmic composition comprises physical mixture of pilocarpine R lipoate, ketorolac tromethamine and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein, the concentration of physical mixture of pilocarpine R lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of ketorolac tromethamine in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00196] Example 7:

[00197] The ophthalmic composition comprises physical mixture of pilocarpine alpha lipoate, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents wherein, the concentration of physical mixture of pilocarpine alpha lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

[00198] Example 8: [00199] The ophthalmic composition comprises physical mixture of pilocarpine R lipoate, bromfenac sodium and one or more ophthalmological acceptable pharmaceutical ingredients/agents, wherein the concentration of physical mixture of pilocarpine R lipoate, in the composition as individual moieties is within the range of 0.001% (w/w or w/v) to 20 %(w/w or w/v) and the concentration of bromfenac sodium in the composition is 0.001% (w/w or w/v) to 20 %(w/w or w/v).

Composition 5:

[00200] In an embodiment, the ophthalmic composition is a solution formulation.

[00201] In an embodiment the ophthalmic composition comprises of two separate phase: powder and solvent or buffer phase. The powder phase consists of first active agent selected from table A or B or C and one or more excipients and the solvent phase includes second active agent selected from table D and one or more excipients.

Example 1:

[00202] In an embodiment, the ophthalmic composition comprises of powder phase and solvent phase. The powder phase consists of first active agent the pilocarpine salt such as pilocarpine R-lipoate and a diluent such as mannitol; and the solvent phase comprises of second active agent- a NSAIDs such as diclofenac sodium along with methocel E4M, boric acid, trisodium citrate anhydrous, EDTA, kolliphor ELP, BKC and purified water.

[00203] In an embodiment the concertation of the pilocarpine -R-lipoate, in the ophthalmic solution range from 0.01 mg/mL to 20 mg/mL.

[00204] In an embodiment the concertation of the sodium-R-lipoate, in the ophthalmic solution range from 0.01 mg/mL to 10 mg/mL.

[00205] In an embodiment the concertation of the diclofenac sodium, in the ophthalmic solution range from 0.01 mg/mL to 5 mg/mL.

[00206] In an embodiment the ophthalmic composition comprising powder phase and solvent phase is stored in the commercially available dual chamber container for longer shelf life of the product for more than 24 months. [00207] In another embodiment, the commercially available sterile, gas impermeable, dual chambers or containers are used for storing or packing the ophthalmic composition of the present invention. In certain aspects, any commercially available dual chamber container or bottles having two separate chambers or units suitable for filling or storing each component of the composition, separately without mixing until reconstitution and use is preferred. Mostly, the commercially available dual chambers will include a bottom container or a chamber or reservoir or a bottle suitable for holding the solvent which constitute the solvent phase, and a reservoir or a chamber for storing the powder phase, which can be proximally fitted over the bottle holding the solvent phase. The chambers/units holding the solvent and powder phase are separated using a thin membrane or seal, which can be tom, punctured using light pressure by the individual before reconstitution and mixing of the two components. A perforator extending throughout the length of the reservoir with a tapering end at one end for puncturing/breaking the membrane/seal is provided. When the seal is broken the powder from the reservoir flow through into the solvent, which is mixed by shaking and thus reconstituted ophthalmic solution is ready for administration/use. Examples of such dual chamber containers are disclosed in following patent documents US 9,193,517, US 5,647,481, US 2019/0177057, US 3802604, US 5409141 and US 10703532.

[00208] The ophthalmic solution stored in the dual chamber containers can be reconstituted before use by removing the tamper seal and applying slight pressure on the top of the cap. Pressing down ward on the cap helps in punching or piercing the membrane/seal separating the powder phase from solvent phase, thus dispensing the powder phase into the solvent phase, mix the solution by shaking before administration. The solution once reconstituted should be used within 21 to 60 days.

[00209] In some embodiments, the ophthalmic composition is formulated for controlled and sustained release composition.

[00210] In an embodiment, the ophthalmic composition discloses herein are useful in treating age related eye disorders such as glaucoma, presbyopia, cataract, AMD, retinal diseases or symptoms thereof. The ophthalmic composition may reduce or eliminate the symptoms of presbyopia while maintaining the accommodative function of the eyes, and allow patients suffering from presbyopia the ability to focus both far and near.

[00211] The R-lipoic acid is a highly unstable substance having a thiol and therefore is sensitive to temperature, pH, humidity, light and moisture. Ikuta et al. (International Journal of Molecular Sciences (2013) 14, 3639-3655) teaches that R-(+)-lipoic acid is not stable when exposed to low PH or heat and is therefore difficult to use as a pharmaceutical. The lipoic acid forms a stable ionic salt with pilocarpine as disclosed in WO2019/097318.

[00212] In an embodiment, the ophthalmic solution comprising pilocarpine or its salt form (a muscarinic agonists), alpha lipoic acid or R-lipoic acid and diclofenac or its salts forms are useful for correcting vision in case of presbyopia. The pilocarpine provides both miosis and ciliary body contraction, thus stimulating accommodation and potentially improving tear production by stimulating tear gland secretion, while, sodium diclofenac a NSAID reduced inflammation. The pilocarpine, lipoic acid and NSAID combination decreases inflammation and restored near vision without causing blurred far and half-distance vision or inflammatory reactions. The NSAIDs combined with muscarinic agents and antioxidant, prolongs the effects of the parasympathomimetic agent through the inhibition of prostaglandin synthesis in the anterior uvea. The lipoic acid an antioxidant helps to reduce the stiffens of the lens by breaking down the disulfide bonds caused due to oxidation proteins in the lens, thus increasing the dynamic lens refractive power. In some embodiment, ophthalmic composition is for reducing the intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension, management of acute angle-closure glaucoma and prevention of postoperative elevated IOP associated with laser surgery and associated inflammation. A method of treating subjects/patients with glaucoma conditions described above comprises administering therapeutically effective amount of ophthalmic composition at selected time. The ophthalmic composition is administrated to the subject topically or by surgically intervention. [00213] In some embodiments, ophthalmic composition is used for correcting presbyopia conditions. A method of correcting presbyopia comprises administrating therapeutically effective amount of an ophthalmic composition at selected time without affecting the visual acuity. The ophthalmic composition is administrated to the subject topically or by surgically intervention.

[00214] The ophthalmic composition may be packaged for administration by any means known in the art including, but not limited to, individual dose units or multi-dose units, e.g., dropper bottles. Multi-dose units may include, for example, about 1 mL to about 100 mL, about 1 mL to about 50 mL, about 1 mL to about 10 mL, about 2 mL to about 7 mL, or about 5 mL. An individual dose may be, e.g., 1-10 drops, 1-5 drops, or 2- 3 drops, wherein each drop is about 5 to about 50 pl, about 10 to about 30 pl, or about 20 pl. Depending on the active agent concentration and the condition of the patient, doses may be administered.

[00215] In another embodiment the packing device system is a single container or bag or unit made of suitable material having two separate chamber or units namely chamber one and chamber two. The chamber one and chamber two are separated by semipermeable polymer to avoid mixing of the stored components of the composition. The powder blend prepared according to the above method is filled into chamber one and the solvent obtained according to the process of preparing the solvent is filled into chamber two. Alternatively, the powder and solvent phase of the composition can be packed into commercially available dual chamber container or packing system. Such packing is targeted to increase the stability and shelf-life of pilocarpine-R-lipoate.

[00216] The composition is reconstituted before use by removing the tamper evidence seal/TE-ring and applying slight pressure on the cap. Pressing downward on the cap helps in tearing or piercing the membrane separating the powder phase from solvent phase thereafter dispensing and the powder into the solvent or buffer and mixing, by shaking the container for minimum 3 minutes before administration.

[00217] Methods of preparing the ophthalmic composition: [00218] Method 1. Dispense all the raw material as per weight. Take 80% batch quantity of sterile water for injection (WFI) in a container- 1 and add viscosity agent, stir to obtain a clear solution; to this solution, add buffers component and stir to until the clear solution is obtained; to this add chelating agent stir to obtain clear solution, next add surfactant stir to obtain clear solution. In a separate container-2 take required batch quantity of preservative and add 10% batch quantity of sterile WFI, mix for 15 minutes to obtain uniform clear solution which is add to the solution in container 1 and add WFI make up the volume of the solution final add the batch quantity of NSAID stir to obtain clear solution and filled to suitable container.

[00219] Method 2: Method of preparing the powder and buffer or solvent phase ophthalmic composition comprises of: preparing the powder blend for powder phase comprises of weighing and dispensing required batch quantity of first active agent and diluent, sifting first active agent and diluent through #40 ASTM sieve, and transfer to a blender for blending the mixture for 10 minutes at 15 RPM, the blending mixture is resifted using a #40 ASTM sieve and again added to a blender for blended for 10 minutes at 15 RPM this final mixture of filled into the reservoir of the commercially available dual chamber container. The solvent preparation for the solvent phase comprises of weighing and dispensing viscosity agent, buffer component, chelating agent, solubilizer into a container -1, containing 80% batch quantity of sterile WFI and mixing well to obtain a solution; in a separate container-2 take required batch quantity of preservative and add 10% batch quantity of sterile WFI, mix for 15 minutes to obtain uniform clear solution which is add to the solution in container 1 and add WFI make up the volume of the solution, final step add the batch quantity of NSAID, stir to obtain clear solution and fill the solvent to bottle of the commercially available dual chamber container.

[00220] The exemplified methods disclosed in the preparation of ophthalmic solutions is widely applicable to manufacture the formulation compositions of diclofenac and other NSAID combinations with pilocarpine R-lipoic acid.

[00221] Examples of Ophthalmic Solution

Table 1: Ophthalmic Solution comprising Diclofenac sodium

[00222] Manufacturing Procedure:

1. Dispense all the required raw materials using a calibrated weighing balance.

2. Take 80% of batch quantity of WFI in a suitable glass beaker and add Methocel E4M to it. Stir till clear solution is obtained.

3. Add batch quantity of Di-Sodium Hydrogen Phosphate dihydrate and stir till clear solution is obtained

4. Add batch quantity of Sodium phosphate monohydrate and stir till clear solution is obtained.

5. Add batch quantity of EDTA and stir till clear solution. Add batch quantity of Polysorbate 80 and stir till clear solution. Take the batch quantity of Benzalkonium Chloride into glass vial and add 10% of batch quantity of Sterile Water for Injection (WFI) to it and mix for 15 minutes till uniform solution is obtained. Add the Benzalkonium Chloride solution to the above solution and stir till clear solution is obtained. Rinse the vial used for stirring Benzalkonium Chloride solution with WFI and transfer to the above solution. Make up the volume of solution to the batch quantity using sterile Water for Injection. Add batch quantity of Diclofenac Sodium to the above solution and stir till clear solution is obtained. Filling: Fill the solution into container as applicable at 10 mL per each bottle.

Table 2: Ophthalmic Solution comprising Diclofenac sodium

[00223] Manufacturing Procedure:

1. Dispense all the required raw materials using a calibrated weighing balance.

2. Take 80% of batch quantity of WFI in a suitable glass beaker and add Boric Acid to it. Stir till clear solution is obtained.

3. Add batch quantity of trisodium citrate anhydrous and stir till clear solution is obtained.

4. Add batch quantity of EDTA and stir till clear solution.

5. Add batch quantity of Kolliphor ELP and stir till clear solution.

6. Take the batch quantity of benzalkonium chloride into glass vial and add 10% of batch quantity of Sterile Water for Injection (WFI) to it and mix for 15 minutes till uniform solution is obtained. Add the benzalkonium chloride solution to the above solution and stir till clear solution is obtained.

7. Rinse the vial used for stirring benzalkonium chloride solution with WFI and transfer to the above solution.

8. Make up the volume of solution to the batch quantity using sterile Water for Injection.

9. Add batch quantity of Diclofenac sodium to the above solution and stir till clear solution is obtained.

10. Filling: Fill the solution into container as applicable at 10 mF per each bottle.

Table 3: Ophthalmic Solution comprising Diclofenac sodium

[00224] Manufacturing Procedure:

1. Dispense all the required raw materials using a calibrated weighing balance.

2. Take 80% of batch quantity of WFI in a suitable glass beaker and add di-sodium hydrogen phosphate dihydrate to it. Stir till clear solution is obtained.

3. Add batch quantity of sodium phosphate monohydrate and stir till clear solution is obtained.

4. Add batch quantity of EDTA and stir till clear solution.

5. Add batch quantity of Kolliphor ELP and stir till clear solution.

6. Take the batch quantity of benzalkonium chloride into glass vial and add 10% of batch quantity of Sterile Water for Injection (WFI) to it and mix for 15 minutes till uniform solution is obtained. Add the benzalkonium chloride solution to the above solution and stir till clear solution is obtained.

7. Rinse the vial used for stirring benzalkonium chloride solution with WFI and transfer to the above solution. 8. Make up the volume of solution to the batch quantity using sterile Water for Injection.

9. Add batch quantity of diclofenac sodium to the above solution and stir till clear solution is obtained.

10. Filling: Fill the solution into container as applicable at 10 mL per each bottle.

Table 4: Ophthalmic Solution comprising Pilocarpine RLA and Diclofenac Sodium:

[00225] Manufacturing Procedure:

Step - 1: Powder Blend preparation

1. Dispensing: Dispense all the required raw materials using a calibrated weighing balance.

2. Sifting: Sift the batch quantities of Pilocarpine (R)-Lipoate and Mannitol through #40 ASTM sieve. 3. Blending: Transfer the sifted raw materials into suitable blender and mix for 10 minutes at 15 RPM.

4. Resifting: Resift the mixed materials through #40 ASTM sieve.

5. Blending: Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM.

6. Filling: Fill the mixed material into commercially available dual chamber pack.

Step - 2: Solvent Preparation:

12. Dispensing: Dispense all the required raw materials using a calibrated weighing balance.

13. Mixing: Dispense 80% of batch quantity of WFI in a suitable glass beaker and add batch quantities of Methocel E4M, Boric Acid, trisodium citrate, Kolliphor RH40 and EDTA.

14. Dispense batch quantity of benzalkonium chloride using calibrated weighing balance into glass vial and add Sterile Water for Injection (WFI) to it. Mix for 15 minutes and add to step - 2 solution.

15. Rinse the vial used for stirring the benzalkonium chloride solution with WFI and transfer to step - 2 solution.

16. Make up the volume to required batch quantity using sterile WFI.

17. Add batch quantity of diclofenac sodium stirred till clear solution observed.

18. Filling: Fill the solvent into respective chamber of commercially available dual chamber pack and label the container.

Step - 3: Reconstitution of solution is done prior to administration

Table 5: Ophthalmic Solution comprising Sodium RLA and Diclofenac Sodium Ophthalmic Solution

Manufacturing Procedure:

Step - 1: Powder Blend preparation

7. Dispensing: Dispense all the required raw materials using a calibrated weighing balance.

8. Sifting: Sift the batch quantities of Sodium R-Lipoic acid and Mannitol through #40 ASTM sieve.

9. Blending: Transfer the sifted raw materials into suitable blender and mix for 10 minutes at 15 RPM.

10. Resifting: Resift the mixed materials through #40 ASTM sieve.

11. Blending: Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM.

12. Filling: Fill the mixed material into commercially available dual Chamber pack.

Step - 2: Solvent Preparation:

19. Dispensing: Dispense all the required raw materials using a calibrated weighing balance.

20. Mixing: Dispense 80% of batch quantity of WFI in a suitable glass beaker and add batch quantities of Boric Acid, Trisodium Citrate, Kolliphor RH40 and EDTA.

21. Dispense batch quantity of Benzalkonium Chloride using calibrated weighing balance into glass vial and add Sterile Water for Injection (WFI) to it. Mix for 15 minutes and add to step - 2 solution. 22. Rinse the Vial used for stirring the Benzalkonium Chloride solution with WFI and transfer to step - 2 solution.

23. Make up the Volume to required batch quantity using sterile WFI.

24. Add batch quantity of Diclofenac Sodium stirred till clear Solution observed.

25. Filling: Fill the solvent into respective chamber of commercially available dual Chamber Pack and label the container.

[00226] Step - 3: Reconstitution of Solution is done prior to administration

EQUIVALENTS

[00227] The present disclosure provides among other things compositions and methods for treating eye diseases and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE

[00228] All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.