WO2013171764A2

WO2013171764A2 - Ophthalmic formulations

Info

Publication number: WO2013171764A2
Application number: PCT/IN2013/000283
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi
Original assignee: Rubicon Research Private Limited
Priority date: 2012-04-30
Filing date: 2013-04-29
Publication date: 2013-11-21
Also published as: WO2013171764A3

Abstract

The present invention relates to ophthalmic formulations comprising fenugreek fiber based excipient. Particularly the present invention relates to ophthalmic formulations suitable for drug delivery and placebo ocular formulations comprising fenugreek fiber based excipient.

Description

OPHTHALMIC FORMULATIONS

Field of the Invention

The present invention relates to ophthalmic formulations comprising fenugreek fiber based excipient. Particularly the present invention relates to ophthalmic formulations suitable for drug delivery and placebo ocular formulations comprising fenugreek fiber based excipient. The present invention also provides processes for preparing such compositions and methods of using such compositions.

Background of the Invention

Amongst the various routes of drug delivery, ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical researchers. The usefulness of this route of drug administration can be easily appreciated because the drug enters the systemic circulation circumventing the hepatic first pass effect. However the anatomy, physiology and biochemistry of the eye render this organ, exquisitely impervious to foreign substances. The challenge to the formulator is therefore to circumvent the protective barriers of the eye without causing permanent tissue damage to design beneficial ophthalmic formulations.

Ocular conditions are treated by administration of therapeutic or beneficial agents by topical, intraocular, periocular or systemic modes of administration. Topical administration to the tissues around the ocular cavity has traditionally been one of the commonest routes of treatment for patients with ophthalmic conditions. Conventional ophthalmic drug delivery systems include solutions, suspensions, gels, ointments, and the like. Drug absorption occurs through corneal and non-corneal pathways. Most non- corneal absorption occurs via the nasolacrimal duct and leads to non-productive systemic uptake, while most of the drug transported through the cornea is taken up by the targeted intraocular tissue. Further in addition to nasolacrimal drainage a major fraction of the drug following topical administration is lost by lacrimation, tear dilution and tear turnover. Such precorneal losses need to be considered while designing an ophthalmic delivery system. Various approaches have been made towards optimization of conventional ocular delivery systems such as improving ocular contact time, enhancing corneal permeability and enhancing site specificity. More efficient ophthalmic systems have also been developed in recent years that enhance drug bioavailability either by providing prolonged/sustained delivery to the eye or by facilitating transcorneal penetration. Such advanced ophthalmic delivery systems include in-situ gelling systems, mucoadhesive formulations, colloidal delivery systems, non-erodible ocular inserts and erodible inserts.

In order to improve the performance of formulations for ophthalmic delivery, the formulations comprise excipients that modify the viscosity of the ophthalmic formulations, and/or gel in an aqueous environment, and/or have bioadhesive properties. In order to prolong the precorneal residence time and/or to improve drug absorption and bioavailability, generally an increase in viscosity of ophthalmic formulations is attempted. Viscosity enhancers such as sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, or polysaccharide gums such as xanthan gum or guar gum are found to be commonly used in ophthalmic formulations. Gel formation through viscosity enhancement is also employed for drug delivery or for achieving other beneficial effects. Further bioadhesive polymers that adhere to the mucin coat covering the conjunctiva and the corneal surfaces of the eye are employed in ophthalmic formulations. Bioadhesive polymers that are commonly used for this purpose include polyacrylic acid, chitosan, xanthan gum or carrageenan.

The above excipients are useful in both placebo ophthalmic compositions such as artificial tear products that are used to treat conditions like dry eye syndrome or keratoconjunctivitis sicca, as well as in ocular formulations for delivery of active agents for treatment of ocular conditions and disorders such as conjunctivitis, glaucoma, keratitis, iritis and the like and many ophthalmic formulations have been developed for the same. U.S. Patent 5888493 discloses an ophthalmic aqueous gel formulation comprising a pharmaceutically active substance in a therapeutically effective amount for those in need thereof, purified water, and an amount of gelling agent effective to form an aqueous gel, wherein said gelling agent consists essentially of cellulose or water soluble cellulose derivative such as sodium carboxymethylcellulose, hydroxyl propyl methylcellulose, hydroxyl ethylcellulose and the like and said gel has a Brookfield LV viscosity of from about 75,000 to about 3,000,000 cps at a temperature of from 22° to 30°C. U.S. Patent 5075104 discloses an ophthalmic gel composition for use as artificial tears for treatment of dry eye syndrome comprising, a carboxy vinyl polymer (carbomer) having a molecular weight in the range of 400,000 to 6,000,000 (i.e., Carbopol 934 and 940) at 0.25% to 8% by weight and water. The carboxy vinyl polymer used in the composition of the present invention thickens the composition to provide a gel. U.S. Patent 7947295 discloses an aqueous composition suitable for ophthalmic administration comprising a viscosity enhancing amount of combination of two polymers having a synergistic effect on the composition's viscosity, wherein the combination of two polymers is selected from the group consisting of hydroxypropyl methylcellulose and guar gum; a carboxyvinyl polymer and guar gum; and hyaluronic acid and guar gum, wherein the viscosity of the composition is greater than 150% of the simple sum of two respective single polymer solutions containing only one of the two polymers. This patent discusses that a mixed polymer system containing more than one polymer can significantly enhance the viscosity and lubrication property of a composition while minimizing total polymer concentration. U.S. Patent 7128928 discloses a pharmaceutical composition suitable for topical administration to an eye, comprising active agent and a set of at least two ophthalmically compatible polymers selected from the group consisting of konjac and sodium alginate; konjac and hydroxyl propyl guar, konjac and propylene glycol alginate; konjac and Carbopol 971 ; hydroxyl propyl guar and agarose; propylene glycol alginate and agarose; and propylene glycol alginate and scleroglucan. This patent discusses that the set of at least two ophthalmically compatible polymers reduces rate of removal of the composition from the eye by lacrimation, such that the concentration of the active agent in lacrimal fluid of the eye is maintained above the minimum inhibitory concentration for at least about 2 hours following topical application to the eye.

However most of the ophthalmic formulations developed by researchers require combination of polymers that provide the desired viscosity to the formulation and/or use viscosity enhancing and/or gelling polymers that are either expensive or exhibit variable viscosity building or gelling properties resulting in undesirable changes in the ocular formulations or interact with the active agents or other excipients in the ophthalmic formulations. Certain gelling polymers or systems also have rehydration and cloud point instability problems associated with autoclaving.

Further in the case of certain ophthalmic formulations such as solutions, dispersions, colloidal solutions and the like, for viscosity enhancers to confer advantageous features to a composition, it is not sufficient that said viscosity enhancers generically increase the viscosity of the ophthalmic product and increase the residence time of the drug/product in the eye, but it is necessary that the viscosity enhancers impart a non-newtonian pseudoplastic Theological behavior to the ophthalmic formulations. Such a pseudoplastic behavior is similar to the Theological behavior of natural tears and results in minimized interference with blinking.

A need therefore exists to employ an excipient in ophthalmic formulations that is biocompatible, has excellent viscosity enhancement and gelling reproducibility and is compatible with active agents and other excipients commonly employed in the ophthalmic formulations. Moreover such an excipient must exhibit pseudoplastic and mucoadhesive behavior.

The present inventors after thorough research provide ophthalmic formulations comprising fenugreek fiber based excipient obtained from fenugreek seeds. The fenugreek fiber based excipient employed is a simple, economical excipient obtained from a natural source. Rigorous experimental studies have shown that the fenugreek fiber based excipient has viscosity, hydrating and gelling properties desirable for use in ophthalmic formulations. Moreover the fenugreek fiber based excipient exhibits a pseudoplastic rheological behavior and has bioadhesive properties desirable for ophthalmic formulations. Further the fenugreek fiber based excipient is stable and compatible with active agents and other ophthalmically acceptable excipients employed in ocular formulations. The fenugreek fiber based excipient has ocular tolerance. Such a use of any excipient derived from fenugreek seeds in ophthalmic formulations has not been reported or disclosed before. Fenugreek fiber based excipient comprising fenugreek dietary fibers, such as, but not limited to, soluble dietary fibers, insoluble dietary fibers or combinations thereof can be employed in ophthalmic formulations in accordance with the present invention. Exemplary fenugreek fiber based excipient comprising fenugreek fibers with soluble and insoluble dietary fibers and processes for preparation thereof have been described in European Patent 1697050B1 and PCT Publication WO2011/124973A1 , entire contents of which have been incorporated herein by reference. Summary of the Invention

Detailed Description of the Invention

The present invention provides an ophthalmic formulation comprising fenugreek fiber based excipient and an ophthalmically acceptable excipient.

In one embodiment the ophthalmic formulations of the present invention are suitable for drug or active agent delivery. In another embodiment, the ophthalmic formulations of the present invention are placebo ocular formulations such as artificial tears or lubricating compositions comprising fenugreek fiber based excipient.

In a further embodiment, the ophthalmic formulation of the present invention can be employed to deliver one or more active agent/s. Active agents useful for treating or preventing ocular conditions or disorders such as, but not limited to, wet and dry age- related macular degeneration, glaucoma, cataracts, dry eye syndrome or keratoconjunctivitis sicca, ocular melanogenesis, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, increased intraocular pressure, conjunctival hyperemia and/or hemorrhage, corneal edema, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; and the like can be delivered using the ophthalmic formulations of the present invention. Active agents that may be incorporated include but are not limited to, anti-hypertensive, anti- glaucoma, neuro-protective, anti-allergy, muco-secretagogue, angiostatic, anti-microbial, pain relieving, anti-inflammatory agents and the like or combinations thereof. Active agents that may be incorporated include but are not limited to, hydrocortisone, prednisone, fluorometholone acetate, dexamethasone sodium phosphate, dexamethasone, suprofen, fluorometholone, medrysone, proparacaine hydrochloride, betaxolol hydrochloride, cyclopentolate hydrochloride, ciprofloxacin, tobramycin, naproxen, phenylephrine hydrochloride, epinephrine, apraclonidine hydrochloride, atropine sulfate, carbachol, pilocarpine hydrochloride, sulfacetamide sodium, homatropine hydrobromide, scopolamine hydrobromide, tetrahydrocortisol, tropicamide, naphazolinehydrochloride, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, ketorolac tromethamine, levobunolol hydrochloride, acyclovir, levofloxacin, idoxuridine, trimethoprim, dipivefrin hydrochloride, metipranolol, trifluridine, diclofenac sodium, zinc isoflurophate, demecarium bromide, timolol maleate, carteolol hydrochloride, dorzolamide hydrochloride, vidrabine, amoxicillin, ampicillin, cefaclor, clarithromycin, ceftriaxone, cefprozil, gentamicin sulfate and/or vancomycin and the like or combinations thereof. Active agents in the form of free acid or free base or pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof can be employed in the ophthalmic formulations of the present invention. In one embodiment one or more active agents within any dose range can be delivered with the ophthalmic formulations of the present invention comprising fenugreek fiber based excipient. In a further embodiment one or more active agents within any water solubility range can be delivered with the ophthalmic formulations of the present invention comprising fenugreek fiber based excipient.

Fenugreek fiber based excipient isolated from seeds of Fenugreek or Trigonella foenum- graceum is employed in ophthalmic formulations of the present invention. Fenugreek or Trigonella foenum-graceum is an herbaceous plant of the leguminous family and is one of the oldest cultivated plants and through the ages has found wide applications as a food, a food additive and as a traditional medicine in every region where it has been cultivated.

The term "fenugreek fiber based excipient" as used in the present invention refers to an excipient obtained from fenugreek or Trigonella foenum-graceum seeds comprising fenugreek dietary fibers such as either soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In a further embodiment "fenugreek fiber based excipient" as used in the present invention refers to an excipient obtained from fenugreek or Trigonella foenum-graceum seeds comprising at least about 30% by weight of fenugreek dietary fibers such as either soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. The soluble fenugreek dietary fiber that may be present in the fenugreek fiber based excipient includes, but is not limited to, fenugreek galactomannans. The insoluble fenugreek dietary fibers that may be present in the fenugreek fiber based excipient includes, but is not limited to, cellulose, hemicellulose, lignin and the like or any combinations thereof.

In one embodiment the fenugreek fiber based excipient employed in the composition of the present invention has a viscosity of at least 10,000 cps at 2%w/v at 25°C. In a further embodiment the fenugreek fiber based excipient employed in the composition of the present invention has a viscosity of at least 50,000 cps at 2%w/v at 25°C. In another embodiment the fenugreek fiber based excipient employed in the composition of the present invention has a protein content of not more than about 10% by weight of the fiber based excipient. In a further embodiment the fenugreek fiber based excipient employed in the composition of the present invention is substantially free of 4-hydroxyisoleucine, saponins and alkaloids. The term "substantially free" as used herein means the fenugreek fiber based excipient employed in the compositions of the present invention contain not more than 1% by weight, preferably not more than 0.4% of 4- hydroxyisoleucine, not more than 5%, preferably not more than 1%, more preferably not more than 0.5% of alkaloids such as trigonelline and not more than 5%, preferably not more than 1%, more preferably not more than 0.5% of saponins such as diosgenin.

The fenugreek fiber based excipient may be present in the compositions of the present invention in an amount of about 0.01% to about 99% by weight of the ophthalmic formulation of the present invention.

In one embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulations of the present invention comprises soluble dietary fibers and insoluble dietary fibers. In a further embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulations of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers including soluble and insoluble dietary fibers are present in an amount of about at least 30% by weight of the fenugreek fiber based excipient. In another embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulation of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of about at least 50% by weight of the fenugreek fiber based excipient. In another embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulation of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of about at least 75% by weight of the fenugreek fiber based excipient. In another embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulation of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of about at least 85% by weight of the fenugreek fiber based excipient. In another embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulation of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of about at least 90% by weight of the fenugreek fiber based excipient. In another embodiment, the fenugreek fiber based excipient employed in the ophthalmic formulation of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of about at least 95% by weight of the fenugreek fiber based excipient.

In one embodiment of the present invention, the fenugreek fiber based excipient when comprising soluble and insoluble dietary fibers the ratio of insoluble dietary fiber to soluble dietary fiber in the fenugreek fiber based excipient is about 0.05 to about 5. In another embodiment of the present invention, this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.1 to about 4. In further embodiment of the present invention; this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.5 to about 4. In another embodiment of the present invention, this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.8 to 3. In yet another embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 1 to about 3. In a further embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.05 to about 1. In another embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.075 to about 0.8. In a further embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.1 to about 0.6. In a further embodiment, fenugreek fibers can be incorporated in the compositions of the present invention in any suitable form not restricted to powder and granules. Without being bound by any theory it is believed that the fenugreek fiber based excipient employed in the present invention provides desired viscosity to the ophthalmic formulations. The fenugreek fiber based excipient has bioadhesive properties and exhibits pseudoplastic rheological behavior whereby the excipient helps provide ophthalmic formulations with desired ocular performance. The fenugreek fiber based excipient also has gelling and hydrating ability making it suitable for use in different ophthalmic formulations. The fenugreek fiber based excipient also has some film forming ability, which can also provide desirable ophthalmic formulations. The ophthalmic formulations further comprise at least one ophthaimically acceptable excipient such as, but not limited to, demulcent, tonicity adjusting agent, preservative, buffering agent, pH adjusting agent, solubilizing agent, surfactant, chelating agent, penetration enhancer, emulsifying agent, suspending agent, stabilizing agent, antioxidant, carrier, plasticizer, release modifying or controlling excipients, ion exchange resins and the like. Suitable demulcents include, but are not limited to, glycerin, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol (PEG) such as but not limited to PEG 400, PEG 300 and the like or combinations thereof; propylene glycol, sorbitol and polyacrylic acid and the like or combinations thereof. Tonicity adjusting agents useful in the compositions of the present invention may include, but are not limited to, salts such as, but not limited to, sodium chloride, potassium chloride and calcium chloride, non- ionic tonicity agents may include, but are not limited to, propylene glycol, glycerol, mannitol, dextran and the like or combinations thereof.

Suitable chelating agents may include, but are not limited to, EDTA and its salts. Solubilizing agents, that may be employed include, but are not limited to, Cremophor EL^®, tween 80, cyclodextrin and the like or combinations thereof. Suitable cyclodextrins may be employed, such as, but not limited to, alpha. -cyclodextrin, beta.- cyclodextrin.gamma.-cyclodextrin, hydroxypropyl-. beta. -cyclodextrin, hydroxypropyl- .gamma.-cyclodextrin, dimethyl-. beta.-cyclodextrin and dimethyl-. gamma. -cyclodextrin, and the like or combinations thereof. pH adjusting agents may include sodium hydroxide, hydrochloric acid, boric acid, Tris, triethanolamine and sodium hydroxide. Suitable buffering agents include, but are not limited to, phosphates, acetates and the like, and amino alcohols such as 2-amino-2-methyl-1-propanol (AMP), ascorbates, borates, hydrogen carbonate/carbonates, citrates, gluconates, lactates, propionates and TRIS (tromethamine) buffers, and the like or combinations thereof. Suitable preservatives include, but are not limited to, benzalkonium chloride, polyquatemium-1 , p- hydroxybenzoic acid ester, sodium perborate, sodium chlorite, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, sorbic acid, and the like or combinations thereof. Suitable penetration enhancers that may optionally be employed include, but are not limited to, polyoxyethylene glycol lauryl ether, polyoxyethylene glycol stearyl ether, polyoxyethylene glycol oleyl ether, sodium taurocholate, saponins, Cremophor EL, and the like or combinations thereof.

Suitable surfactants that may be employed include, but are not limited to, ionic and nonionic surfactants, and the like or combinations thereof. Suitable nonionic surfactants include, but are not limited to, poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture of two or more thereof. Suitable pharmaceutical carriers include sterile water; electrolytes such as sodium chloride; dextrose; dextrose in water or saline; lower alkanols, ointment bases such as but not limited to, natural wax e.g. white bees wax, camauba wax, wool wax (wool fat), purified lanolin, anhydrous lanolin; petroleum wax e.g. solid paraffin, microcrystalline wax; hydrocarbons e.g. liquid paraffin, white petrolatum (e.g. white Protopet®), yellow petrolatum, and the like or combinations thereof. Suitable emulsifying agent may be included such as, but not limited to, mono- or di-glyceride of a fatty acid, phosphatide, e.g., lecithin, polysorbates, macrogols, poloxamers, tyloxapol, polyethylene glycol derivatives, polyvinyl alcohol and the like, and mixtures thereof. Suitable stabilizing agent such as, but not limited to, polyethylene glycol hydroxystearate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate, monothioglycerol and the like, or combinations thereof may be employed. Antioxidants such as, but not limited to, ascorbic acid, acetylcysteine, cysteine, sodium hydrogen sulfite, butylated hydroxyanisole, butylated hydroxytoluene or alpha-tocopherol acetate may be employed. Plasticizers, such as, but not limited to, glycerol, and the like may be employed.

Release modifying or controlling excipients, such as but not limited to, polymeric release modifying or controlling excipients, non-polymeric release modifying or controlling excipients or combinations thereof may be included in the compositions of the present invention. Exemplary release modifying or controlling excipients include glyceryl behenate, chitosan, carrageenan, cellulose derivatives such as ethylcellulose, acrylic acid and methacrylic acid polymers or copolymers and the like, or derivatives or combinations thereof. The ophthalmic formulations of the present invention may optionally include additional viscosity enhancing agents such as, but not limited to, cellulose and cellulose derivatives, such as, but not limited to, methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, cellulose acetophthalate, and the like or combinations thereof; alginic acid, sodium alginate, propylene glycol alginate, polyvinylpyrrolidone, carboxyvinyl polymers or carbomers (Carbopol®), polyvinyl alcohol, glycerin, polyethylene glycol, triblock copolymers of polyoxypropylene and polyoxyethylene, polyethoxylated sorbitan, polysorbate 80, chondroitin sulfate, dimethicone, perfluorononyl dimethicone, cyclomethicone, dextrans, proteoglycans, natural polysaccharides, such as, but not limited to, hyaluronic acid and salts thereof, guar gum, karaya, xyloglucan gum, chitosan, gellan gum, pectin, collagen, modified collagen and like or combinations thereof.

The ophthalmic formulations of the present invention may optionally include additional gelling agents such as, but not limited to, polysaccharide gums such as, but not limited to, gellan gum, tamarind gum, tragacanth, locust bean gum, agarose, carageenans, guar gum, hydroxypropyl guar gum, hyaluronic acid, chitosan, konjac, acacia, pectin, arabic, curdlan, glucan gum, scleroglucan and sulfated glucan sulfate and the like or combinations thereof; cellulose and its derivatives such as, but not limited to, methyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, methyl hydroxypropyl cellulose, hydroxypropyl methyl cellulose^ cellulose acetate, ethyl cellulose, methyl hydroxyethyl cellulose, hydroxyethyl cellulose, cellulose gum, and the like or combinations thereof; cross-linked acrylic polymers or carbomer (Carbopol™), aloe vera gel, polyvinyl alcohol, polyacrylamide, poloxamer, polymethylvinylether-maleic anhydride, swellable water-insoluble polymers such as, but not limited to, hydrogel and the like or combinations thereof. Ion exchange resins such as, but not limited to, inorganic zeolites or synthetically produced organic resins may be employed in the compositions of the present invention. The ophthalmic formulations of the present invention may optionally include additional mucodhesive agents such as, but not limited to, polyacrylic acid, hyaluronans, chitosan, pullulan, cellulose derivatives such as, but not limited to, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, poly (galacturonic) acid, sodium alginate, pectin, xyloglucan, xanthan gum, carbomers (Carbopol™), polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, poloxamer, and the like or combinations thereof.

The above listing of examples is given for illustrative purposes and is not intended to be exhaustive. Examples of other agents useful for the foregoing purposes are well known in ophthalmic formulation and are contemplated by the present invention. It is also contemplated that the concentrations of the excipients in the formulations of the present invention can vary. The ophthalmic formulations of the present invention can be in the form of eye drops, eye lotions, suspensions, dispersions, gels, ointments, emulsions, colloidal solutions, ocular inserts, ocular hydrogels, films, minitablets, nanoemulsions, and particulate systems such as but not limited to, liposomes, microparticles, nanoparticles, and the like. In one embodiment, the ophthalmic formulation of the present invention is in the form of an in-situ gelling system. In another embodiment, the in-situ type gelling composition of the present invention may comprise one or more cross-linking agent, such as but not limited to borate, and the like. In another embodiment, the in-situ type gelling composition of the present invention does not comprise one or more cross-linking agent.

In a further embodiment, the ophthalmic formulation of the present invention in the form of ocular insert is a bioerodible ocular insert. In another embodiment, the ophthalmic formulation of the present invention in the form of ocular insert is a non-bioerodible ocular insert.

The ophthalmic formulations of the present invention may be in the form of liquid, solid or semisolid dosage form. Further, in one embodiment, the ophthalmic formulations of the present invention are formulated so as to have a pH and osmolality that are compatible with the eye. The ophthalmic formulations of the present invention may comprise depending on the final dosage form suitable ophthalmically acceptable excipients. In one embodiment, the ophthalmic formulations are formulated to maintain a physiologically tolerable pH range. In one embodiment, the pH range of the ophthalmic formulation is in the range of from 5 to 9. In another embodiment, pH range of the ophthalmic formulation is in the range of from 6 to 8.

In a further embodiment, the ophthalmic formulations of the present invention are for topical administration to the eye. In another embodiment, the ophthalmic formulations of the present invention are for intraocular or periocular administration. In a further embodiment, the ophthalmic formulations of the present invention are for immediate release of active agent in the ocular cavity.

In another embodiment, the ophthalmic formulations of the present invention are for sustained or controlled release in the ocular cavity. In a further embodiment, the ophthalmic formulations of the present invention are for at once-a-day administration. In one embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 24 hours. In another embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 12 hours. In a further embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 10 hours. In yet another embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 8 hours. In one embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 6 hours. In a further embodiment, the sustained or controlled release delivery of the active agent from the ophthalmic formulation is for a sustained period of time of about 4 hours to about 24 hours.

Depending on the dosage form of the ophthalmic formulations of the present invention, appropriate method of preparation is employed. Various methods for preparation of ophthalmic formulations known in the art may be employed. Further depending on the dosage form, the ophthalmic formulations or excipients and/or active agents employed therein are suitably sterilized by one or more methods known to a person skilled in the art. In one embodiment, the ophthalmic formulations of the present invention in the form of ocular insert, is prepared by molding or extrusion procedures well known in the art. In another embodiment, the ophthalmic formulation of the present invention in the form of ophthalmic solution is prepared by either by dissolving or suspending prescribed amount of a drug in a prescribed volume of a carrier solvent along with fenugreek fiber based excipient and other ophthalmically acceptable excipient. Particle size of certain ophthalmic formulations of the present invention is within ophthalmically acceptable limits known to a person skilled in the art.

The compositions of the present invention are useful for the treatment of humans or animals.

In yet another embodiment, the present invention discloses use of fenugreek fiber based excipient for the manufacture of a medicament that delivers one or more active agent to the ocular cavity. In a further embodiment, the present invention discloses use of fenugreek fiber based excipient for the manufacture of a medicament that treats or prevents one or more ocular conditions or disorders. Still another embodiment of the present invention discloses a method of using compositions of the present invention employing fenugreek fiber based excipient comprising ophthalmically administering to a subject in need thereof an effective amount of the composition depending on the active agent used. In one embodiment the present invention discloses a method of preparing ophthalmic formulations incorporating fenugreek fiber based excipient in the compositions along with optionally one or more active agents and at least one ophthalmically acceptable excipient. According to a further aspect of the invention there is provided a method of treatment or prophylaxis of an ocular disease or condition comprising administration to the subject in need thereof ophthalmic formulation comprising one or more active agent effective against said disease or disorder, fenugreek fiber based excipient and at least one ophthalmically acceptable excipient.

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

The invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way. EXAMPLES

Example 1 : Artificial tears

Table 1 : Composition of artificial tears

Procedure: The fenugreek fiber was first dispersed in PEG-400 and autoclaved. The other ingredients were dissolved in about 90% of the volume of water and sterile filtered. The autoclaved fenugreek dispersion obtained was then added under vigorous stirring to the sterile filtered solution of other ingredients. The pH was then adjusted aseptically and the final volume was made. This final composition was then aseptically filtered to remove particulates, if any.

Example 2: Ophthalmic gel of timolol maleate

Table 2: Composition of timolol ophthalmic gel formulation

Ingredients Amount (%w/w)

Timolol maleate equivalent to 0.5% timolol base 0.684

Fenugreek fiber based excipient 2

Polyethylene glycol (PEG 400) 5

Sodium chloride 0.165

Benzalkonium chloride 0.01

Sodium hydroxide/hydrochloric acid q.s. to pH 7

Water for injection q.s. to 100 Procedure: The fenugreek fiber based excipient was first dispersed in PEG-400 and autoclaved. Timolol maleate and other ingredients were dissolved in about 80% of the water for injection and sterile filtered through 0.2 micron nylon filter. To this solution, the autoclaved dispersion of fenugreek fiber based excipient was added under vigorous stirring to form a viscous gel. The pH of the gel was then adjusted aseptically and the final weight was adjusted to 100g using water for injection.

Claims

We claim:

1) An ophthalmic formulation comprising fenugreek fiber based excipient and an ophthalmically acceptable excipient.

2) The formulation of claim 1 wherein the fenugreek fiber based excipient comprises fenugreek dietary fibers. 3) The formulation of claim 2 wherein the fenugreek dietary fibers are soluble fenugreek dietary fibers, insoluble dietary fibers or any combinations thereof.

4) The formulation of claim 3 wherein the fenugreek dietary fibers are a combination of insoluble and soluble dietary fibers.

5) The formulation of claim 4 wherein the insoluble and soluble dietary fibers are present in a ratio of insoluble dietary fibers to soluble dietary fibers of about 0.05 to about 5. 6) The formulation of claim 1 wherein the fenugreek fiber based excipient is substantially free of 4-hydroxyisoleucine, saponins and alkaloids.

7) The formulation of claim 1 wherein the fenugreek fiber based excipient has protein content of not more than about 10% by weight of the fiber based excipient.

8) The formulation of claim 1 wherein the ophthalmically acceptable excipient is a demulcent, a tonicity adjusting agent, a preservative, a buffering agent, a pH adjusting agent, a solubilizing agent, a surfactant, a chelating agent, a penetration enhancer, an emulsifying agent, a suspending agent, a stabilizing agent, an antioxidant, a carrier, a plasticizer, a release modifying excipient, an ion exchange resin or any combination thereof. 9) The formulation of claim 1 wherein the formulation further comprises viscosity enhancing agent, gelling agent, mucoadhesive agent or any combination thereof.

10) The formulation of claim 1 wherein the formulation is a placebo formulation or a formulation comprising at least one drug or active agent.

11) The formulation of claim 10 wherein the drug or active agent is an agent useful for treating or preventing ocular conditions or disorders. 12) The formulation of claim 1 1 wherein the drug or active agent is an antihypertensive, anti-glaucoma, neuro-protective, anti-allergy, muco-secretagogue, angiostatic, anti-microbial, pain relieving, anti-inflammatory agent or any combination thereof. 13) The formulation of claim 1 wherein the formulation is in the form of a liquid, solid or semisolid dosage form.

14) The formulation of claim 1 wherein the formulation is in the form of eye drops, eye lotions, suspensions, dispersions, gels, ointments, emulsions, colloidal solutions, ocular inserts, ocular hydrogels, films, minitablets, nanoemulsions, or particulate systems.

15) The formulation of claim 1 wherein the formulation is in the form of in-situ gelling system.

16) The formulation of claim 1 wherein the formulation is for topical, intraocular or periocular administration to the eye.

17) The formulation of claim 1 wherein the formulation is for immediate release of active agent in the ocular cavity.

18) The formulation of claim 1 wherein the formulation is for sustained or controlled release in the ocular cavity. 19) Use of fenugreek fiber based excipient for the manufacture of a medicament to deliver one or more active agents to the ocular cavity.

20) A method of treatment or prophylaxis of an ocular disease or condition comprising administration to the subject in need thereof ophthalmic formulation comprising one or more active agents effective against said disease or disorder, fenugreek fiber based excipient and at least one ophthaimicaliy acceptable excipient.