Indian Patents. 259169:OPHTHALMIC COMPOSITION

Title of Invention	OPHTHALMIC COMPOSITION
Abstract	An ophthalmic composition comprising therapeutically effective amount of a beta-blocker and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003 PROVISIONAL SPECIFICATION {See section 10 and rule 13) OPHTHALMIC COMPOSITION SUN PHARMA ADVANCED RESEARCH COMPANY LTD. A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA, INDIA. The following specification describes the invention. The present invention provides a long-acting ophthalmic composition comprising therapeutically effective amount of a beta-blocker, suitable for therapy of glaucoma. BACKGROUND OF THE INVENTION Glaucoma is an ocular disease characterized by an elevated intra-ocular pressure, which, if untreated, may lead to optic nerve head damage, causing irreversible loss of visual field, and eventually blindness. Since elevated intraocular pressure is the major risk factor of glaucoma, lowering it by various drugs is the mainstay of glaucoma therapy. Currently five classes of drugs are available for use in patients with glaucoma, among which beta blockers are used predominantly. They lower the pressure in the eye by reducing the production of aqueous-humor. Timolol, a non-selective beta-blocker, first approved by FDA for ocular use in 1978, is available as topically administrable compositions for glaucoma therapy- the major composition being aqueous ophthalmic solutions. But the disadvantage associated with aqueous liquid formulations is that a large percentage of the drug administered to the eye is lost due to lachrymal drainage. As a result, only a small portion of the dose administered remains in contact with the cornea for a few minutes and an even smaller fraction penetrates to the eye. To overcome this disadvantage, a variety of gelling drug delivery systems comprising gel-forming polymers were developed, which systems undergo liquid-gel phase transition utilizing various mechanisms like increase in the ionic strength (U.S. Pat. No. 5,403,841 and 4861760), interaction with the enzyme-lysozyme present in tear fluids (US patent 6174524), change in pH (U.S. Pat. Nos. 4,136,173 and 4,136,177) or change in temperature (U.S. Pat. Nos. 4,474,751; 4,474,752; and 4,188,373). They are topically administered as a liquid drop, which gels upon contact with the physiological liquid of the eye, the transition occurring at the contact site. The active ingredients supplied in the form of gel forming solutions have their own advantages and disadvantages. There are a number of manufacturing, storage, dispensing and usage constraints associated with gel-forming eye drops. Moreover, the unpleasant feel in the eye is also a disadvantage. Further, some new compositions viz. gel formulations were developed which presents an improvement over gel-forming compositions. US patent 5397657 discloses one such ophthalmic composition that combines two polymers to obtain desired residual viscosity. The residual viscosity which develops upon instillation in the eye is the factor which ultimately determines the compatibility and the residence time of the gel. The formulations possess good film forming properties due to polyvinylalcohol component, and bioadhesion due to carbomer component. Though this gel formulation presents an improvement over the previously described gel-forming compositions, the residual viscosity attained is high enough to show adhesive effects, thereby leading to compatibility problem such as patients' complaint of the feeling of a foreign body presence. The US patent 6645963 discloses an eye drop that does not use a gel forming component, yet provides sustained release of the active medicament. The composition uses short chain fatty acids, such as sorbic acid, to increase penetration and improve retention time in the eye tissues. The ocular tissues thus act as a drug storage site that prolongs drug action. The composition utilizes high concentration of sorbic acid to achieve this effect. The long term effects of high tissue concentration may be adverse. Further, the demulcent effect and film forming properties of polymer solutions is lacking. US Patent no. 7147844, describes a system for stabilizing a lachrymal fluid layer over contact lenses, to remove dryness and unpleasantness in the eyes of contact lens wearers and provides a good, moist and instilling feel. The inventor found that polyvinylpyrrolidone is adsorbed on the ionic contact lens, which in turn enhances its water retention capacity, and further use of a viscosity increasing agent like hydroxypropyl methylcellulose sustains the above mentioned improvement effects in the eye of the wearers. The composition possessed a kinematic viscosity of 1-8 mm2/sec. The invention provides composition which ensures comfort to the eyes of contact lens bearers without involving therapeutic applicability. US Patent no. 7306802 ('802 patent), 7244440 ('440 patent) and 7329411 ('411 patent) relates to ophthalmic compositions containing a synergistic combination of three polymers. The '802 patent provides an aqueous composition suitable for topical ophthalmic administration comprising three polymeric ingredients having a synergistic effect on the viscosity of the composition, wherein the three polymeric ingredients include hydroxypropylmethylcellulose and a combination of two polymers selected from the group of combinations consisting of guar-gum and a carboxyvinyl polymer; guar gum and hydroxyethyl cellulose, guar gum and dextran, hydroxyethyl cellulose and a carbovinyl polymer and dextran and a carbovinyl polymer. The composition is suitable for use as artificial tears, or as a vehicle for ophthalmic drugs. The '440 patent and '411 patent provides a method of alleviating the symptoms of dry eye comprising topical administration to the eye an aqueous composition as described by the 802 patent. US Patent Application no.- 20070128156 and 20040253280 describe an aqueous ophthalmic composition suitable for use as artificial tears or as vehicles for ophthalmic drugs, comprising a viscosity enhancing amount of a combination of two polymers having a synergistic effect on the viscosity of the composition, and wherein the combination of two polymers is selected from the group consisting of - hydroxypropyl methylcellulose and guar gum; hydroxypropyl methylcellulose and a carboxyvinyl polymer; hydroxypropyl methylcellulose and hydroxyethylcellulose; hydroxypropyl methylcellulose and hyaluronic acid; hyaluronic acid and a carboxyvinyl polymer; hyaluronic acid and guar gum; or a carboxyvinyl polymer and guar gum. A formulation that eliminates above mentioned drawbacks of the eye drop formulations and combines the advantages of compatibility, improved penetration and ease of administration, with the beneficial properties of prolonged residence time, film-forming property and sustained release of the medicament in the eye, is the most preferred ophthalmic formulation for ocular therapy. The present invention provides such an ophthalmic composition. It is a surprising and interesting finding of the invention that when two polymers, hydroxypropylmethylcellulose and polyvinylpyrrolidone are combined in certain ratios, there occurs a synergistic increase in viscosity of the formulation, leading to good film-forming property and prolonged residence time, along with sustained release of the medicament and that such formulations are clear. Additional aspects and advantages of the present invention will become apparent to those skilled in the art upon reading the detailed description, wherein only the preferred embodiment of the invention is revealed and explained, in a simple manner along with illustration of the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details that are apparent, are capable of modifications in various respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. OBJECT OF THE INVENTION It is an object of the present invention to provide an ophthalmic composition comprising therapeutically effective amount of a beta-blocker, and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps. It is an object of the present invention to provide a long-acting, sustained-release ophthalmic composition suitable for once-a-day instillation. It is another object of the invention to provide a once-a-day ophthalmic composition for reducing and controlling elevated intraocular pressure (IOP), especially the elevated IOP associated with glaucoma. It is another object of the present invention to provide an ophthalmic composition which is a clear aqueous solution; is isotonic and compatible with the ocular fluids; has prolonged residence time; show good film-forming property; is non-irritating; possesses good antimicrobial properties; and has a pH of about 7.4. SUMMARY OF THE INVENTION The present invention may be summarized as follows: (A) An ophthalmic composition comprising therapeutically effective amount of a beta-blocker and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps. (B) An ophthalmic composition as defined in (A), wherein the beta-blocker is timolol maleate. (C) An ophthalmic composition comprising a therapeutically effective amount of a beta-blocker, hydroxypropylmethylcellulose whose 2 % w/v aqueous solution has a viscosity in the range of about 3500 cps to about 5600 cps at 20°C and polyvinylpyrrolidone whose 10 % w/v aqueous solution has a viscosity in the range of about 300 cps to about 700 cps at 20°C, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps. (D) An ophthalmic composition as defined in (A) or (C) wherein hydroxypropyl methylcellulose and polyvinylpyrrolidone are used in a weight by weight ratio ranging from about 95:5 to about 5:95. (E) An ophthalmic composition as defined in (A), wherein the polymer is present in a concentration of about 0.1 % to about 10.0 % by weight of the composition. (F) An ophthalmic composition as defined in (A), wherein hydroxypropyl methylcellulose is used in an amount ranging from about 0.05% to about 8.0% by weight of the composition and polyvinylpyrrolidone is used in an amount ranging from about 0.01% to about 10.0% by weight of the composition. (G) An ophthalmic composition as defined in (A) or (C), wherein the composition is suitable for once-a-day instillation. (H) An ophthalmic composition as defined in (C), wherein the concentration of hydroxypropyl methylcellulose is 0.5% and concentration of polyvinylpyrrolidone is 2.0% by weight of the composition. (I) An ophthalmic composition as defined in (A), wherein the percent transmission is greater than 95% and the viscosity is greater than 35 cps. BRIEF DESCRIPTION OF FIGURE FIGURE 1: It represents a comparative account of concentration-time profile of drug retained in aqueous humor, on topical application of the developed ophthalmic composition of the present invention (composition of Example 3 having timolol maleate in a concentration of 0.1% by weight of the composition) with that of marketed product NYOGEL composition (Novartis Pharmaceuticals Ltd.,) having timolol maleate in a concentration of 0.1% by weight of the composition. DETAILED DESCRIPTION OF THE INVENTION The present invention provides an ophthalmic composition comprising therapeutically effective amount of a beta-blocker, and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps. The ophthalmic compositions of the present invention are characterized as being clear aqueous solutions. These "clear aqueous solutions " as stated herein, are defined as those solutions which do not cause any visual disturbance and/or do not affect vision, upon topical instillation to the eye and when examined under suitable conditions of visibility, are practically clear and practically free from particles. Ophthalmic compositions which show a 'percent transmission' greater than 85 %, are 'clear aqueous solutions'. Such compositions may contain polymers as their ingredients. The term 'percent transmission' as used herein is defined below: When light is allowed to pass through the ophthalmic composition of the present invention, the percentage of incident light which is transmitted through the solution is referred to as "Percent Transmission". As mentioned, the property of "Percent Transmission" relates to the clarity of the aqueous solution or composition. The clarity of the composition is poor if percent transmission is less than 85%. Preferably the percent transmission is greater than 95%. The compositions of the present invention comprising pharmaceutically acceptable polymer are further characterized by possessing a viscosity greater than about 15 cps (centipoises per second); preferably the pharmaceutically acceptable polymer is used in an amount to provide synergistic viscosity. The term 'Synergistic viscosity' as used herein refers to the viscosity attained by the composition of the present invention (consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone) such that the viscosity attained (in cps) is more than the sum of viscosities of two aqueous compositions 'A' and 'B', wherein 'A' contains only hydroxypropylmethylcellulose and 'B' contains only polyvinylpyrrolidone. To achieve a target viscosity for a topically administrable ophthalmic composition, one approach could be to simply add a sufficient amount of one polymeric ingredient. This however may require use of large amount of that polymer, which can be undesirable. Instead, it is beneficiary and desirable to minimize the total amount of polymeric ingredients in topical ophthalmic compositions. So another approach comprising use of a mixed polymer system, containing two or more polymers that can interact in such a way so as to provide synergism in viscosity, can lead to attainment of the target viscosity at a comparatively very lower amount of the total polymer required, thus also reducing the cost of material. The present invention has developed ophthalmic compositions which consist of a combination of two specific polymers hydroxypropylmethylcellulose and polyvinylpyrrolidone in such grades, ratios and concentrations that provide a synergistic viscosity greater than about 15 cps, (besides being clear aqueous solutions). This synergistic viscosity of greater than about 15 cps, attained by the composition of the present invention, when the two polymers used, viz hydroxypropylmethylcellulose and polyvinylpyrrolidone, are combined in certain ratios, is useful in prolonging the retention (residence) time of the formulation at the surface of the eye, and sustaining release of the medicament from it, leading to prolonged action of the medicament, and thereby facilitating once-a-day administration. Thus, the present invention provides ophthalmic compositions which possess all the properties required to be present in an ophthalmic formulation. The ophthalmic composition of the present invention comprises therapeutically effective amount of a therapeutic agent useful for the treatment of glaucoma (anti-glaucoma agents).These include but are not limited to beta-blockers such as timolol, betaxolol, levobetaxolol, carteolol, their derivatives, salts and mixtures thereof. In one embodiment of the present invention, the therapeutic agent used is a salt of timolol. In preferred embodiment of the present invention, the therapeutic agent used is timolol maleate. Timolol, a non-selective beta-adrenergic blocker, having a molecular weight of 432.50, when applied topically as an ophthalmic solution, reduces the intraocular pressure in the eye. It is thus indicated in patients with ocular hypertension or open angle glaucoma. It also shows certain systemic effects which includes (1) Beta-adrenergic receptor blockade in the heart causing reduction in cardiac output in both healthy subjects and patients with heart disease and (2) Beta-adrenergic receptor blockade in the bronchi and bronchioles resulting in increased airway resistance from unopposed parasympathetic activity. Therefore, the drug must be used with caution in patients in whom beta-adrenergic blockade may be undesirable. Timolol for glaucoma therapy is thus contraindicated in patients with compromised pulmonary functions and in patients who cannot tolerate its systemic cardiovascular action. Timolol maleate is used in the compositions of the present invention in therapeutically effective amounts. Timolol maleate may be used in an amount ranging from about 0.01 % to about 2.0 % by weight of the composition, preferably from about 0.05 % to about 1.0 % by weight of the composition and most preferably from about 0.1 % to about 0.5 % by weight of the composition. The ophthalmic composition of the present invention further comprises pharmaceutically acceptable polymers such as hydroxypropylmethylcellulose and polyvinylpyrrolidone. Hydroxypropylmethylcellulose and polyvinylpyrrolidone are available in different viscosity grades and any such grade may be used in the compositions of the present invention. Hydroxypropylmethylcellulose and polyvinylpyrrolidone depending on the viscosity grades, may be used in the compositions of the present invention, in a weight by weight ratio ranging from about 95:5 to about 5:95, preferably 80:20 to about 20:80. The two polymers together may be present in the compositions of the present invention in an amount ranging from about 0.1 % to about 10.0 % by weight of the composition, preferably in an amount ranging from about 1.0 % to about 5.0 % by weight of the composition, more preferably in an amount ranging from about 1.0 % to about 3.0 % by weight of the composition; the amount being varying depending upon the grades of the polymer used. The hydroxypropyl methylcellulose (HPMC) used in the compositions of the present invention is a cellulose polymer, in particular, propylene glycol ether of methylcellulose. It functions to provide the desired level of viscosity via synergism with PVP and also shows demulcent activity. HPMC is available in a variety of grades under several trade names. The various grades differ in methoxy and hydroxypropyl content, as well as in terms of molecular weight and viscosity (of 2% solution in water at 20°C). The cellulose ether that can be used in the compositions of the present invention may be selected from any available grade of HPMC. Suitable material is sold by the 'The Dow Chemical Company' ("Dow") under the trademark METHOCEL. The HPMC grade which may be selected to be used in the compositions of the present invention include, but is not limited to: METHOCEL E, (USP grade 2910/ HYPROMELLOSE 2910) including (a)METHOCEL E3 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 2.4-3.6 cps (b) METHOCEL E5 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 4.0-6.0 cps. (c) METHOCEL E6 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 5.0-7.0 cps (d) METHOCEL El5 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 12.0-18.0 cps (e) METHOCEL E50 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 40.0-60.0 cps (f) METHOCEL E4M (Premium) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3000.0 - 5600.0 cps (g) METHOCEL E10M (Premium CR) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 7500.0- 14000.0 cps. METHOCEL F, (USP grade 2906/ HYPROMELLOSE 2906) including (a) METHOCEL F50 (Premium) having 27-30 weight percent methoxyl content and 4-7.5 weight percent hydroxypropyl content, (b) METHOCEL F4M (Premium LV). METHOCEL K, (USP grade 2208/HYPROMELLOSE 2208) including (a)METHOCEL K3 (Premium LV) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 2.4-3.6 cps (b) METHOCEL K100 (Premium LV) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 80.0-120.0 cps (c) METHOCEL K4M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3000.0-5600.0 cps (d) METHOCEL K15M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 11,250.0 - 21,000.0 cps (e) METHOCEL K100M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 80,000.0 - 120,000.0 cps. METHOCEL A15 (Premium LV); METHOCEL A4C (Premium); METHOCEL A15C (Premium); METHOCEL A4M (Premium), HPMC USP Grade 1828 having 16.5-20 weight percent methoxyl content, 23-32 weight percent hydroxypropyl content. Most preferred grade for use in the compositions of the present invention is METHOCEL E4M (USP 2910), characterized by having : 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3500-5600 cps (centipoises per second). It is to be understood, however, that the invention is not limited to any specific hydroxypropyl methylcellulose; and that any equivalent hydroxypropyl methylcellulose of pharmaceutical grade may be used to achieve equivalent results. The polymer HPMC may be used in the compositions of the present invention in an amount ranging from about 0.05% to about 8.0 % by weight of the composition, preferably in an amount ranging from about 0.1% to about 4.0 % by weight of the composition, more preferably in an amount ranging from about 0.5% to about 2.0 % by weight of the composition, the amount being varying depending upon the grades of the polymer used. The compositions of the present invention further comprise another pharmaceutically acceptable polymer, polyvinylpyrrolidone (PVP), a tertiary amide polymer. This is a linear polymer of 1- vinyl-2-pyrrolidone groups, in which the degree of polymerization results in polymers of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, which ranges from 10 to 120, constituting its various grades. The polyvinylpyrrolidone that can be used in the compositions of the present invention may be selected from any of the available grade of polyvinylpyrrolidone. Such materials are sold by ISP Technologies, Inc., under the trademark PLASDONE. The PVP grade which may be selected to be used in the compositions of the present invention include, but is not limited to: PVP K-l 1/14, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 1.3 cps to about 2.3 cps at 20°C, PVP K-l 6/18, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 1.5 cps to about 3.5 cps at 20°C, PVP K-24/27, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 3.5 cps to about 5.5 cps at 20°C, PVP K-28/32, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 5.5 cps to about 8.5 cps at 20°C, PVP K-85/95, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 300.0 cps to about 700.0 cps at 20°C, The preferred grades which can be used in the compositions of the present invention include PVP K-30, PVP K-60 and PVP K-90. The most preferred grade used in the compositions of the present invention is PVP K-90, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 300.0 cps to about 700.0 cps at 20°C, and has an approximate molecular weight of about 1,000,000. It is to be understood, however, that the invention is not limited to any specific polyvinylpyrrolidone; and that any equivalent polyvinylpyrrolidone of pharmaceutical grade, may be used to achieve equivalent results. Polyvinylpyrrolidone (PVP) is chosen because it is particularly useful as a wetting agent, besides acting as a viscosifying agent. PVP has a number of other characteristics that makes it useful in combination with the various well known components in ophthalmic solutions. Polyvinylpyrrolidone acts as a detoxicant, binding anti-toxins present in eye fluids and rendering them harmless. Additionally, PVP acts as a demulcent lubricant by means of a combination of adhesive and lubricating properties that aid in the spreading of the viscous solution over the eye. PVP provides tear film stability and wetting of the corneal surfaces, and also allows the use of benzalkonium chloride in effective preservative concentrations in the solution. PVP may be used in the compositions of the present invention in an amount ranging from about 0.01 % to about 10.0 % by weight of the composition, preferably in an amount ranging from about 0.1 % to about 8.0 % by weight of the composition, more preferably in an amount ranging from about 0.3 % to about 5.0 % by weight of the composition, the amount being varying depending upon the grades of the polymer used. In one embodiment of the present invention, a preferred combination of hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) that can be used in the compositions of the present invention is HPMC whose 2 % w/v aqueous solution has a viscosity in the range of about 3500 cps to about 5600 cps at 20°C (called HPMC E4M) and polyvinylpyrrolidone whose 10 % w/v aqueous solution has a viscosity in the range of about 300 cps to about 700 cps at 20°C (called PVP K90) . This combination may be used preferably in a weight by weight ratio (HPMC E4M:PVP K90) ranging from about 80:20 to about 10:90. In preferred embodiment of the present invention, the composition comprises HPMC E4M in an amount 0.5 % by weight of the composition and polyvinylpyrrolidone K-90 in an amount 2.0 % by weight of the composition. This combination may be used in a weight by weight ratio (HPMC E4M:PVP K90) ranging from about 80:20 to about 10:90, wherein the viscosity is greater than 25 cps, preferably greater than 35 cps and the percent transmission is greater than 85%, preferably greater than 95%. The present invention provides a long-acting, ophthalmic composition suitable for once-a-day instillation. The compositions of the present invention may further comprise pharmaceutically acceptable excipients conventional to the pharmaceutical art. Typical of such pharmaceutically acceptable excipients include osmotic/tonicity-adjusting agents, preservatives, one or more pharmaceutically acceptable buffering agents and pH-adjusting agents, solubilizing agents, vehicles and other agents conventional in art that may be used in formulating an ophthalmic composition. The ophthalmic compositions/solutions are required to be isotonic with respect to the ophthalmic fluids present in the human eye. These solutions are characterized by osmolalities of 250-375 mOsm/kg. Osmolality of the solutions is adjusted by addition of an osmotic/tonicity adjusting agent. Osmotic agents that may be used in the compositions of the present invention to make it isotonic with respect to the ophthalmic fluids present in the human eye, are selected from the group comprising sodium chloride, potassium chloride, calcium chloride, sodium bromide, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, and the like, and mixtures thereof. In preferred embodiments of the present invention, mannitol is used as the osmotic agent. Mannitol may be present in the compositions of the present invention in an amount ranging from about 2.0 % to about 6.0 % by weight of the composition, preferably from about 3.0 % to about 5.0 % by weight of the composition and most preferably in an amount of about 4.5 % by weight of the composition. Further, the ophthalmic compositions of the present invention comprise preservatives in antimicrobially effective amounts. Antimicrobial effective amounts of a preservative may be determined by performing preservative efficacy tests or antimicrobial effectiveness tests. These tests are inter alia described in chapter 51 of the United States Pharmacopoeia 29-National Formulary 24 (USP 29-NF 24). The preservatives may be used in an amount within the concentration ranges described in standard reference books like 'Remington's Pharmaceutical Sciences' and 'Handbook of Pharmaceutical Excipients'. The preservative may be selected from: Quaternary ammonium compounds such as benzalkonium chloride (BKC) and benzethonium chloride; Organic mercurials such as phenylmercuric acetate, phenylmercuric nitrate and thimerosal; Parabens such as methyl and propyl paraben; ethyl paraoxybenzoate or butyl paraoxybenzoate; Acids and their pharmaceutically acceptable salts such as sorbic acid, potassium sorbate, boric acid, borax, salicylic acid ; Substituted alcohols and phenols such as chlorobutanol, benzyl alcohol; phenyl ethanol; Amides such as acetamide; and the like, and combinations thereof. Preferably the ophthalmic compositions of the present invention comprise 'quaternary ammonium compound' as a preservative, particularly benzalkonium chloride. Benzalkonium chloride is characterized as a mixture of alkyldimethyl benzylammonium chlorides. It is employed in the compositions of the present in a preferable concentration of about 0.01 to about 0.02 % by weight of the composition. In order to achieve, and subsequently maintain, an optimum pH, the ophthalmic compositions essentially contain a pH adjusting agent and/or a buffering agent. The preferred range of pH for an ophthalmic formulation is about 6.8 to about 7.8, and the most preferred pH is about 7.4. The ophthalmic compositions of the present invention comprise a pharmaceutically acceptable pH adjusting agent that may be selected from the group comprising acetic acid or salts thereof, boric acid or salts thereof, phosphoric acid or salts thereof, citric acid or salts thereof, tartaric acid or salts thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, trometamol, and the like and mixtures thereof. Particularly, preferred pH adjusting agents that may be used in the composition of the present invention include acetic acid, sodium carbonate and sodium hydroxide. These agents are used in amounts necessary to produce a pH ranging from about 6.0 to about 8.0. Besides above mentioned ingredients, the formulation of the invention may include a number of additional components to provide various effects, as is well known in this field. For example, the composition may include edetate disodium, which may function as a co-preservative and chelating agent. The ophthalmic compositions of the present invention may be prepared by following a general method described below: Take WFI in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. Disperse the two polymers HPMC and PVP K-90 gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. Prepare a solution of the therapeutically active agent Timolol Maleate and the osmotic agent (mannitol, if present), in the WFI. Add this to the PVP K-90 dispersion under stirring. Mix homogeneously the HPMC phase with the PVP K-90 dispersion under stirring. With the stirring being continued, add the preservative (benzalkonium chloride) solution to this. Adjust the pH to about 7.4 with acetic acid or sodium hydroxide. Make up the volume to 100% with WFI. Autoclave the bulk solution for 20 min at 121°C, filter if required, and cool. This results in the desired ophthalmic composition of the present invention. The exact procedure varies slightly depending upon the ingredients used. The detailed description is included in the examples. The present invention provides a method of treatment of glaucoma, comprising once-a-day administration of the ophthalmic composition of the present invention comprising a therapeutic agent (beta-blocker), topically to the eye and attaining sustained release of the active agent, thereby reducing and controlling the elevated intraocular pressure, especially the elevated IOP associated with glaucoma. EXAMPLES While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto. EXAMPLE 1 An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 1. TABLE 1 S.No. Ingredients Concentration (% w/v) 1. Timolol Maleate (equivalent to Timolol) 0.5 2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5 3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0 4. Sodium carbonate 0.5 5. Benzalkonium chloride solution 0.02 6. Acetic acid q.s 7. Water for Injection (WFI) q.s. Procedure: WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, Sodium Carbonate was dissolved in required volume of WFI to get a preconcentrate (10%w/v) solution. To this, the drug Timolol Maleate was added and it is kept for lh to form an oily base of Timolol. The oily base so obtained was added to the PVP K-90 dispersion under stirring, the stirring being continued until the oily droplets dissolve. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion under stirring. Further, benzalkonium chloride solution (BKC solution) was added with stirring and the pH was adjusted to about 7.4 with acetic acid. Finally the volume was adjusted to 100% with WFI; the bulk solution was autoclaved for 20 min at 121°C and cooled to obtain the final formulation. EXAMPLE 2 An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 2. TABLE 2 S.No. Ingredients Concentration (% w/v) 1. Timolol Maleate (equivalent to Timolol) 0.5 2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5 3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0 4. Benzalkonium chloride solution 0.02 5. Acetic acid 0.05 6. Sodium Hydroxide q.s. 7. Water for Injection(WFI) q.s. Procedure: WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, the drug Timolol Maleate was dissolved in required quantity of WFI. The drug solution was added to the PVP K-90 dispersion under stirring followed by addition of required amount of acetic acid with stirring. The pH was adjusted to 7.0 with sodium hydroxide solution. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion, followed by addition of BKC solution under stirring. The pH was adjusted to 7.4 with sodium hydroxide or acetic acid solution. Finally the volume was adjusted to 100% with WFI; the bulk solution was autoclaved for 20 min at 121°C and cooled to obtain the final formulation. EXAMPLE 3 An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 3 TABLE 3 S.No. Ingredients Concentration (% w/v) 1. Timolol Maleate (equivalent to Timolol) 0.1 2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5 3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0 4. Benzalkonium chloride solution 0.02 5. Acetic acid 0.05 6. Sodium Hydroxide q.s. 7. Water for Injection(WFI) q.s. The ophthalmic composition of this example 3 was prepared by following the same method as described in example 2 above. EXAMPLE 4 An ophthalmic composition for once-a-day instillation, according to the present invention is shown in Table 4. TABLE 4 S.No. Ingredients Concentration (% w/v) 1. Timolol Maleate (equivalent to Timolol) 0.5 2. Hydroxypropylmethylcellulose E4M (HPMC E4M) 0.5 3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0 4. Mannitol 4.5 5. Benzalkonium chloride solution 0.02 6. Acetic acid 0.05 7. Sodium Hydroxide q.s. 8. Water for Injection(WFI) q.s. Procedure: WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, the drug Timolol Maleate and the osmotic agent Mannitol, was dissolved in required quantity of WFI. This solution was added to the PVP K-90 dispersion under stirring followed by addition of required amount of acetic acid with stirring. The pH was adjusted to 7.0 with sodium hydroxide solution. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion under stirring followed by addition of BKC solution with stirring. The pH was adjusted to 7.4 with sodium hydroxide or acetic acid solution. Finally the volume was adjusted to 100% with WFI; the bulk solution was filtered using 0.2um glass fiber; autoclaved for 20 min at 121 °C and cooled to obtain the final formulation. EXAMPLE 5 Studies were carried out by varying the ratio of HPMC-E4M and PVP K-90, (keeping the concentration of HPMC-E4M constant at 0.5%w/v), and their effects on the viscosity of the formulation, and on the percent transmission were determined. The percent transmission and viscosity of the formulation was determined by the methods given below. Determination of percent transmission: Optical Study. The optical study involving the determination of percent transmission of the formulation was carried out using the UV-1700 Spectrophotometer, Shimadzu, Japan. The result obtained for various formulations is shown in Table 5 and 6. Determination of Viscosity: Rheological Study. The rheological study involving the determination of viscosity of the formulation was carried out using the Brookfield dv-(iii) Ultra Programmable Rheometer (Spindle CPE 40, Entry Code: 40). Procedure- 0.5 g of formulation was taken in rheometer cup and a spindle was immersed in the test fluid through a calibrated spring which measures viscosity by sensing the torque required to rotate the spindle at constant speed while immersed in the sample fluid. The torque is proportional to the viscous drag on the immersed spindle, and thus to the viscosity of the fluid. The viscous drag of the fluid against the spindle was measured by the spring deflection. Spring deflection was measured with a rotary transducer. By rotating the spindle at several different speeds, shear dependent behavior of fluids can be also detected and analyzed. The Table 5 below describes the various compositions obtained by varying the ratio of HPMC-E4M:PVP K-90 from 100:0 to 0:100. It also includes the determined values of percent transmission and viscosity (in cps) for the corresponding compositions. TABLE 5 Ingredients Concentration (%w/v) HPMC E4M :PVP K90-100:0 HPMC E4M :PVP K90-80:20 HPMC E4M :PVP K90-60:40 HPMCE4M :PVP K90-50:50 HPMC E4M :PVP K90-40:60 HPMC E4M :PVP K90-20:80 HPMCE4M :PVP K90-15:85 HPMC E4M :PVP K90-10:90 HPMC E4M:PVP K90-0:100 Hydroxypropyl methylcellulose E4M 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0 Polyvinyl pyrrol i done K90 0 0.13 0.3 0.5 0.8 2.0 2.83 4.5 0.5 2.0 Water for Injection q.s q.s q.s q.s q.s q.s q.s q.s q.s % Transmission 99.8 99.5 99.6 99.5 99.4 97.5 90.1 85.1 100.0 100.0 Viscosity 20.14 23.28 24.33 24.85 28.25 42.38 57.03 60.95 1.57 7.59 The values indicate that the viscosity (in cps) of the composition increases by increasing percent PVP by weight of the total polymer or by increasing the weight by weight ratio of Hydroxypropyl methylcellulose (HPMC-E4M): Polyvinylpyrrolidone (PVP K90) from 100:0 to 0:100. At ratio from 80:20 to 10:90 ratio (HPMC-E4M: PVP K-90), synergistic viscosity was observed. Also the compositions were clear aqueous solutions having percent transmission greater than 85 %. EXAMPLE 6 Study regarding determination of concentration of the drug retained in the rabbit's aqueous humor on topical application of the developed ophthalmic composition of Example 3 above, to the rabbit eye, and comparison of the concentration-time profile so obtained with the instillation of the marketed product NYOGEL (Novartis Pharmaceuticals Ltd). The method followed is described below and the observation is represented in figure 1. Method: Two male NZ (Newzealand) rabbits weighing 1.5-3.0 Kg were taken. To both eyes of the first rabbit, a single dose of 70 ml of composition of Example 3 of the present invention, having timolol maleate in a concentration of 0.1% by weight of the composition, was instilled and to both eyes of the second rabbit, a single dose of 70 ml of the marketed product NYOGEL composition having timolol maleate in a concentration of 0.1% by weight of the composition, was instilled. At 15 min, 30 min, lh & 3hr post instillation of drug, animals were sacrificed by intravenous injection of thiopental sodium and aqueous humor was aspirated with insulin syringe (lml, BD Ultra fine) after puncturing the anterior chamber at the limbus and the samples were stored at -70°C till analysis. These aqueous humor samples were analyzed by HPLC and the data obtained for various compositions was compared (see figure 1). On analyzing the results obtained, as represented by figure 1, it is clear that composition of the present invention (Example 3- having timolol maleate in a concentration of 0.1% by weight of the composition) is able to provide comparatively much higher concentration of the drug; viz. a better Cmax and AUC; at the site of action, and the concentration is sustained for a much longer period of time in the desired therapeutic range, as compared to that provided by the marketed product NYOGEL (which is also a once-a-day preparation and having timolol maleate in a concentration of 0.1% by weight of the composition). Thus, the compositions of the present invention prove to be very effective ophthalmic compositions for once-a-day instillation, suitable for glaucoma therapy. Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof ABSTRACT An ophthalmic composition comprising therapeutically effective amount of a beta-blocker and a pharmaceutical^ acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps. To, The Controller of Patents, The Patent Office, Mumbai - 400 037

Full Text

FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
{See section 10 and rule 13)
OPHTHALMIC COMPOSITION
SUN PHARMA ADVANCED RESEARCH COMPANY LTD.
A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA, INDIA.
The following specification describes the invention.

The present invention provides a long-acting ophthalmic composition comprising therapeutically effective amount of a beta-blocker, suitable for therapy of glaucoma.
BACKGROUND OF THE INVENTION
Glaucoma is an ocular disease characterized by an elevated intra-ocular pressure, which, if untreated, may lead to optic nerve head damage, causing irreversible loss of visual field, and eventually blindness. Since elevated intraocular pressure is the major risk factor of glaucoma, lowering it by various drugs is the mainstay of glaucoma therapy.
Currently five classes of drugs are available for use in patients with glaucoma, among which beta blockers are used predominantly. They lower the pressure in the eye by reducing the production of aqueous-humor.
Timolol, a non-selective beta-blocker, first approved by FDA for ocular use in 1978, is available as topically administrable compositions for glaucoma therapy- the major composition being aqueous ophthalmic solutions. But the disadvantage associated with aqueous liquid formulations is that a large percentage of the drug administered to the eye is lost due to lachrymal drainage. As a result, only a small portion of the dose administered remains in contact with the cornea for a few minutes and an even smaller fraction penetrates to the eye.
To overcome this disadvantage, a variety of gelling drug delivery systems comprising gel-forming polymers were developed, which systems undergo liquid-gel phase transition utilizing various mechanisms like increase in the ionic strength (U.S. Pat. No. 5,403,841 and 4861760), interaction with the enzyme-lysozyme present in tear fluids (US patent 6174524), change in pH (U.S. Pat. Nos. 4,136,173 and 4,136,177) or change in temperature (U.S. Pat. Nos. 4,474,751; 4,474,752; and 4,188,373). They are topically administered as a liquid drop, which gels upon contact with the physiological liquid of the eye, the transition occurring at the contact site. The active ingredients supplied in the form of gel forming solutions have their own advantages and disadvantages. There are a number of manufacturing, storage, dispensing and usage constraints associated with gel-forming eye drops. Moreover, the unpleasant feel in the eye is also a disadvantage.
Further, some new compositions viz. gel formulations were developed which presents an improvement over gel-forming compositions. US patent 5397657 discloses one such ophthalmic composition that combines two polymers to obtain desired residual viscosity. The residual

viscosity which develops upon instillation in the eye is the factor which ultimately determines the compatibility and the residence time of the gel. The formulations possess good film forming properties due to polyvinylalcohol component, and bioadhesion due to carbomer component. Though this gel formulation presents an improvement over the previously described gel-forming compositions, the residual viscosity attained is high enough to show adhesive effects, thereby leading to compatibility problem such as patients' complaint of the feeling of a foreign body presence.
The US patent 6645963 discloses an eye drop that does not use a gel forming component, yet provides sustained release of the active medicament. The composition uses short chain fatty acids, such as sorbic acid, to increase penetration and improve retention time in the eye tissues. The ocular tissues thus act as a drug storage site that prolongs drug action. The composition utilizes high concentration of sorbic acid to achieve this effect. The long term effects of high tissue concentration may be adverse. Further, the demulcent effect and film forming properties of polymer solutions is lacking.
US Patent no. 7147844, describes a system for stabilizing a lachrymal fluid layer over contact lenses, to remove dryness and unpleasantness in the eyes of contact lens wearers and provides a good, moist and instilling feel. The inventor found that polyvinylpyrrolidone is adsorbed on the ionic contact lens, which in turn enhances its water retention capacity, and further use of a viscosity increasing agent like hydroxypropyl methylcellulose sustains the above mentioned improvement effects in the eye of the wearers. The composition possessed a kinematic viscosity of 1-8 mm2/sec. The invention provides composition which ensures comfort to the eyes of contact lens bearers without involving therapeutic applicability.
US Patent no. 7306802 ('802 patent), 7244440 ('440 patent) and 7329411 ('411 patent) relates to ophthalmic compositions containing a synergistic combination of three polymers. The '802 patent provides an aqueous composition suitable for topical ophthalmic administration comprising three polymeric ingredients having a synergistic effect on the viscosity of the composition, wherein the three polymeric ingredients include hydroxypropylmethylcellulose and a combination of two polymers selected from the group of combinations consisting of guar-gum and a carboxyvinyl polymer; guar gum and hydroxyethyl cellulose, guar gum and dextran, hydroxyethyl cellulose and a carbovinyl polymer and dextran and a carbovinyl polymer. The composition is suitable for use as artificial tears, or as a vehicle for ophthalmic drugs.

The '440 patent and '411 patent provides a method of alleviating the symptoms of dry eye comprising topical administration to the eye an aqueous composition as described by the 802 patent.
US Patent Application no.- 20070128156 and 20040253280 describe an aqueous ophthalmic composition suitable for use as artificial tears or as vehicles for ophthalmic drugs, comprising a viscosity enhancing amount of a combination of two polymers having a synergistic effect on the viscosity of the composition, and wherein the combination of two polymers is selected from the group consisting of - hydroxypropyl methylcellulose and guar gum; hydroxypropyl methylcellulose and a carboxyvinyl polymer; hydroxypropyl methylcellulose and hydroxyethylcellulose; hydroxypropyl methylcellulose and hyaluronic acid; hyaluronic acid and a carboxyvinyl polymer; hyaluronic acid and guar gum; or a carboxyvinyl polymer and guar gum.
A formulation that eliminates above mentioned drawbacks of the eye drop formulations and combines the advantages of compatibility, improved penetration and ease of administration, with the beneficial properties of prolonged residence time, film-forming property and sustained release of the medicament in the eye, is the most preferred ophthalmic formulation for ocular therapy. The present invention provides such an ophthalmic composition.
It is a surprising and interesting finding of the invention that when two polymers, hydroxypropylmethylcellulose and polyvinylpyrrolidone are combined in certain ratios, there occurs a synergistic increase in viscosity of the formulation, leading to good film-forming property and prolonged residence time, along with sustained release of the medicament and that such formulations are clear.
Additional aspects and advantages of the present invention will become apparent to those skilled in the art upon reading the detailed description, wherein only the preferred embodiment of the invention is revealed and explained, in a simple manner along with illustration of the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details that are apparent, are capable of modifications in various respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

OBJECT OF THE INVENTION
It is an object of the present invention to provide an ophthalmic composition comprising therapeutically effective amount of a beta-blocker, and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.
It is an object of the present invention to provide a long-acting, sustained-release ophthalmic composition suitable for once-a-day instillation.
It is another object of the invention to provide a once-a-day ophthalmic composition for reducing and controlling elevated intraocular pressure (IOP), especially the elevated IOP associated with glaucoma.
It is another object of the present invention to provide an ophthalmic composition which is a clear aqueous solution; is isotonic and compatible with the ocular fluids; has prolonged residence time; show good film-forming property; is non-irritating; possesses good antimicrobial properties; and has a pH of about 7.4.
SUMMARY OF THE INVENTION
The present invention may be summarized as follows:
(A) An ophthalmic composition comprising therapeutically effective amount of a beta-blocker and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.
(B) An ophthalmic composition as defined in (A), wherein the beta-blocker is timolol maleate.
(C) An ophthalmic composition comprising a therapeutically effective amount of a beta-blocker, hydroxypropylmethylcellulose whose 2 % w/v aqueous solution has a viscosity in the range of about 3500 cps to about 5600 cps at 20°C and polyvinylpyrrolidone whose 10 % w/v aqueous solution has a viscosity in the range of about 300 cps to about 700 cps at 20°C, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.

(D) An ophthalmic composition as defined in (A) or (C) wherein hydroxypropyl methylcellulose
and polyvinylpyrrolidone are used in a weight by weight ratio ranging from about 95:5 to about
5:95.
(E) An ophthalmic composition as defined in (A), wherein the polymer is present in a
concentration of about 0.1 % to about 10.0 % by weight of the composition.
(F) An ophthalmic composition as defined in (A), wherein hydroxypropyl methylcellulose is used
in an amount ranging from about 0.05% to about 8.0% by weight of the composition and
polyvinylpyrrolidone is used in an amount ranging from about 0.01% to about 10.0% by weight
of the composition.
(G) An ophthalmic composition as defined in (A) or (C), wherein the composition is suitable for
once-a-day instillation.
(H) An ophthalmic composition as defined in (C), wherein the concentration of hydroxypropyl methylcellulose is 0.5% and concentration of polyvinylpyrrolidone is 2.0% by weight of the composition.
(I) An ophthalmic composition as defined in (A), wherein the percent transmission is greater than 95% and the viscosity is greater than 35 cps.
BRIEF DESCRIPTION OF FIGURE
FIGURE 1: It represents a comparative account of concentration-time profile of drug retained in aqueous humor, on topical application of the developed ophthalmic composition of the present invention (composition of Example 3 having timolol maleate in a concentration of 0.1% by weight of the composition) with that of marketed product NYOGEL composition (Novartis Pharmaceuticals Ltd.,) having timolol maleate in a concentration of 0.1% by weight of the composition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an ophthalmic composition comprising therapeutically effective amount of a beta-blocker, and a pharmaceutically acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.

The ophthalmic compositions of the present invention are characterized as being clear aqueous solutions. These "clear aqueous solutions " as stated herein, are defined as those solutions which do not cause any visual disturbance and/or do not affect vision, upon topical instillation to the eye and when examined under suitable conditions of visibility, are practically clear and practically free from particles.
Ophthalmic compositions which show a 'percent transmission' greater than 85 %, are 'clear aqueous solutions'. Such compositions may contain polymers as their ingredients.
The term 'percent transmission' as used herein is defined below:
When light is allowed to pass through the ophthalmic composition of the present invention, the
percentage of incident light which is transmitted through the solution is referred to as "Percent
Transmission".
As mentioned, the property of "Percent Transmission" relates to the clarity of the aqueous
solution or composition. The clarity of the composition is poor if percent transmission is less than
85%. Preferably the percent transmission is greater than 95%.
The compositions of the present invention comprising pharmaceutically acceptable polymer are further characterized by possessing a viscosity greater than about 15 cps (centipoises per second); preferably the pharmaceutically acceptable polymer is used in an amount to provide synergistic viscosity.
The term 'Synergistic viscosity' as used herein refers to the viscosity attained by the composition of the present invention (consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone) such that the viscosity attained (in cps) is more than the sum of viscosities of two aqueous compositions 'A' and 'B', wherein 'A' contains only hydroxypropylmethylcellulose and 'B' contains only polyvinylpyrrolidone.
To achieve a target viscosity for a topically administrable ophthalmic composition, one approach could be to simply add a sufficient amount of one polymeric ingredient. This however may require use of large amount of that polymer, which can be undesirable. Instead, it is beneficiary and desirable to minimize the total amount of polymeric ingredients in topical ophthalmic compositions. So another approach comprising use of a mixed polymer system, containing two or more polymers that can interact in such a way so as to provide synergism in viscosity, can lead to attainment of the target viscosity at a comparatively very lower amount of the total polymer required, thus also reducing the cost of material.

The present invention has developed ophthalmic compositions which consist of a combination of two specific polymers hydroxypropylmethylcellulose and polyvinylpyrrolidone in such grades, ratios and concentrations that provide a synergistic viscosity greater than about 15 cps, (besides being clear aqueous solutions).
This synergistic viscosity of greater than about 15 cps, attained by the composition of the present invention, when the two polymers used, viz hydroxypropylmethylcellulose and polyvinylpyrrolidone, are combined in certain ratios, is useful in prolonging the retention (residence) time of the formulation at the surface of the eye, and sustaining release of the medicament from it, leading to prolonged action of the medicament, and thereby facilitating once-a-day administration.
Thus, the present invention provides ophthalmic compositions which possess all the properties required to be present in an ophthalmic formulation.
The ophthalmic composition of the present invention comprises therapeutically effective amount of a therapeutic agent useful for the treatment of glaucoma (anti-glaucoma agents).These include but are not limited to beta-blockers such as timolol, betaxolol, levobetaxolol, carteolol, their derivatives, salts and mixtures thereof. In one embodiment of the present invention, the therapeutic agent used is a salt of timolol. In preferred embodiment of the present invention, the therapeutic agent used is timolol maleate.
Timolol, a non-selective beta-adrenergic blocker, having a molecular weight of 432.50, when applied topically as an ophthalmic solution, reduces the intraocular pressure in the eye. It is thus indicated in patients with ocular hypertension or open angle glaucoma. It also shows certain systemic effects which includes (1) Beta-adrenergic receptor blockade in the heart causing reduction in cardiac output in both healthy subjects and patients with heart disease and (2) Beta-adrenergic receptor blockade in the bronchi and bronchioles resulting in increased airway resistance from unopposed parasympathetic activity. Therefore, the drug must be used with caution in patients in whom beta-adrenergic blockade may be undesirable. Timolol for glaucoma therapy is thus contraindicated in patients with compromised pulmonary functions and in patients who cannot tolerate its systemic cardiovascular action. Timolol maleate is used in the compositions of the present invention in therapeutically effective amounts. Timolol maleate may be used in an amount ranging from about 0.01 % to about 2.0 % by weight of the composition,

preferably from about 0.05 % to about 1.0 % by weight of the composition and most preferably from about 0.1 % to about 0.5 % by weight of the composition.
The ophthalmic composition of the present invention further comprises pharmaceutically acceptable polymers such as hydroxypropylmethylcellulose and polyvinylpyrrolidone. Hydroxypropylmethylcellulose and polyvinylpyrrolidone are available in different viscosity grades and any such grade may be used in the compositions of the present invention. Hydroxypropylmethylcellulose and polyvinylpyrrolidone depending on the viscosity grades, may be used in the compositions of the present invention, in a weight by weight ratio ranging from about 95:5 to about 5:95, preferably 80:20 to about 20:80.
The two polymers together may be present in the compositions of the present invention in an amount ranging from about 0.1 % to about 10.0 % by weight of the composition, preferably in an amount ranging from about 1.0 % to about 5.0 % by weight of the composition, more preferably in an amount ranging from about 1.0 % to about 3.0 % by weight of the composition; the amount being varying depending upon the grades of the polymer used.
The hydroxypropyl methylcellulose (HPMC) used in the compositions of the present invention is a cellulose polymer, in particular, propylene glycol ether of methylcellulose. It functions to provide the desired level of viscosity via synergism with PVP and also shows demulcent activity. HPMC is available in a variety of grades under several trade names. The various grades differ in methoxy and hydroxypropyl content, as well as in terms of molecular weight and viscosity (of 2% solution in water at 20°C). The cellulose ether that can be used in the compositions of the present invention may be selected from any available grade of HPMC. Suitable material is sold by the 'The Dow Chemical Company' ("Dow") under the trademark METHOCEL. The HPMC grade which may be selected to be used in the compositions of the present invention include, but is not limited to:
METHOCEL E, (USP grade 2910/ HYPROMELLOSE 2910) including (a)METHOCEL E3 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 2.4-3.6 cps (b) METHOCEL E5 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 4.0-6.0 cps. (c) METHOCEL E6 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 5.0-7.0 cps (d) METHOCEL El5 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent

hydroxypropyl content and viscosity of a 2% aqueous solution of 12.0-18.0 cps (e) METHOCEL E50 (Premium LV) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 40.0-60.0 cps (f) METHOCEL E4M (Premium) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3000.0 - 5600.0 cps (g) METHOCEL E10M (Premium CR) having 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 7500.0- 14000.0 cps.
METHOCEL F, (USP grade 2906/ HYPROMELLOSE 2906) including (a) METHOCEL F50 (Premium) having 27-30 weight percent methoxyl content and 4-7.5 weight percent hydroxypropyl content, (b) METHOCEL F4M (Premium LV).
METHOCEL K, (USP grade 2208/HYPROMELLOSE 2208) including (a)METHOCEL K3 (Premium LV) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 2.4-3.6 cps (b) METHOCEL K100 (Premium LV) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 80.0-120.0 cps (c) METHOCEL K4M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3000.0-5600.0 cps (d) METHOCEL K15M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 11,250.0 - 21,000.0 cps (e) METHOCEL K100M (Premium) having 19-24 weight percent methoxyl content, 4-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 80,000.0 - 120,000.0 cps.
METHOCEL A15 (Premium LV); METHOCEL A4C (Premium); METHOCEL A15C (Premium); METHOCEL A4M (Premium),
HPMC USP Grade 1828 having 16.5-20 weight percent methoxyl content, 23-32 weight percent hydroxypropyl content.
Most preferred grade for use in the compositions of the present invention is METHOCEL E4M (USP 2910), characterized by having : 28-30 weight percent methoxyl content, 7-12 weight percent hydroxypropyl content and viscosity of a 2% aqueous solution of 3500-5600 cps (centipoises per second).

It is to be understood, however, that the invention is not limited to any specific hydroxypropyl methylcellulose; and that any equivalent hydroxypropyl methylcellulose of pharmaceutical grade may be used to achieve equivalent results.
The polymer HPMC may be used in the compositions of the present invention in an amount ranging from about 0.05% to about 8.0 % by weight of the composition, preferably in an amount ranging from about 0.1% to about 4.0 % by weight of the composition, more preferably in an amount ranging from about 0.5% to about 2.0 % by weight of the composition, the amount being varying depending upon the grades of the polymer used.
The compositions of the present invention further comprise another pharmaceutically acceptable
polymer, polyvinylpyrrolidone (PVP), a tertiary amide polymer. This is a linear polymer of 1-
vinyl-2-pyrrolidone groups, in which the degree of polymerization results in polymers of various
molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of
water, expressed as a K-value, which ranges from 10 to 120, constituting its various grades. The
polyvinylpyrrolidone that can be used in the compositions of the present invention may be
selected from any of the available grade of polyvinylpyrrolidone. Such materials are sold by ISP
Technologies, Inc., under the trademark PLASDONE.
The PVP grade which may be selected to be used in the compositions of the present invention
include, but is not limited to:
PVP K-l 1/14, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 1.3
cps to about 2.3 cps at 20°C,
PVP K-l 6/18, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 1.5
cps to about 3.5 cps at 20°C,
PVP K-24/27, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 3.5
cps to about 5.5 cps at 20°C,
PVP K-28/32, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about 5.5
cps to about 8.5 cps at 20°C,
PVP K-85/95, whose 10% w/v aqueous solution has a dynamic viscosity in the range of about
300.0 cps to about 700.0 cps at 20°C,
The preferred grades which can be used in the compositions of the present invention include PVP K-30, PVP K-60 and PVP K-90. The most preferred grade used in the compositions of the present invention is PVP K-90, whose 10% w/v aqueous solution has a dynamic viscosity in the range of

about 300.0 cps to about 700.0 cps at 20°C, and has an approximate molecular weight of about
1,000,000.
It is to be understood, however, that the invention is not limited to any specific
polyvinylpyrrolidone; and that any equivalent polyvinylpyrrolidone of pharmaceutical grade, may
be used to achieve equivalent results.
Polyvinylpyrrolidone (PVP) is chosen because it is particularly useful as a wetting agent, besides acting as a viscosifying agent. PVP has a number of other characteristics that makes it useful in combination with the various well known components in ophthalmic solutions. Polyvinylpyrrolidone acts as a detoxicant, binding anti-toxins present in eye fluids and rendering them harmless. Additionally, PVP acts as a demulcent lubricant by means of a combination of adhesive and lubricating properties that aid in the spreading of the viscous solution over the eye. PVP provides tear film stability and wetting of the corneal surfaces, and also allows the use of benzalkonium chloride in effective preservative concentrations in the solution. PVP may be used in the compositions of the present invention in an amount ranging from about 0.01 % to about 10.0 % by weight of the composition, preferably in an amount ranging from about 0.1 % to about 8.0 % by weight of the composition, more preferably in an amount ranging from about 0.3 % to about 5.0 % by weight of the composition, the amount being varying depending upon the grades of the polymer used.
In one embodiment of the present invention, a preferred combination of hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) that can be used in the compositions of the present invention is HPMC whose 2 % w/v aqueous solution has a viscosity in the range of about 3500 cps to about 5600 cps at 20°C (called HPMC E4M) and polyvinylpyrrolidone whose 10 % w/v aqueous solution has a viscosity in the range of about 300 cps to about 700 cps at 20°C (called PVP K90) . This combination may be used preferably in a weight by weight ratio (HPMC E4M:PVP K90) ranging from about 80:20 to about 10:90.
In preferred embodiment of the present invention, the composition comprises HPMC E4M in an amount 0.5 % by weight of the composition and polyvinylpyrrolidone K-90 in an amount 2.0 % by weight of the composition. This combination may be used in a weight by weight ratio (HPMC E4M:PVP K90) ranging from about 80:20 to about 10:90, wherein the viscosity is greater than 25 cps, preferably greater than 35 cps and the percent transmission is greater than 85%, preferably greater than 95%.

The present invention provides a long-acting, ophthalmic composition suitable for once-a-day
instillation.
The compositions of the present invention may further comprise pharmaceutically acceptable
excipients conventional to the pharmaceutical art. Typical of such pharmaceutically acceptable
excipients include osmotic/tonicity-adjusting agents, preservatives, one or more pharmaceutically
acceptable buffering agents and pH-adjusting agents, solubilizing agents, vehicles and other
agents conventional in art that may be used in formulating an ophthalmic composition.
The ophthalmic compositions/solutions are required to be isotonic with respect to the ophthalmic fluids present in the human eye. These solutions are characterized by osmolalities of 250-375 mOsm/kg. Osmolality of the solutions is adjusted by addition of an osmotic/tonicity adjusting agent. Osmotic agents that may be used in the compositions of the present invention to make it isotonic with respect to the ophthalmic fluids present in the human eye, are selected from the group comprising sodium chloride, potassium chloride, calcium chloride, sodium bromide, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, and the like, and mixtures thereof. In preferred embodiments of the present invention, mannitol is used as the osmotic agent. Mannitol may be present in the compositions of the present invention in an amount ranging from about 2.0 % to about 6.0 % by weight of the composition, preferably from about 3.0 % to about 5.0 % by weight of the composition and most preferably in an amount of about 4.5 % by weight of the composition.
Further, the ophthalmic compositions of the present invention comprise preservatives in antimicrobially effective amounts. Antimicrobial effective amounts of a preservative may be determined by performing preservative efficacy tests or antimicrobial effectiveness tests. These tests are inter alia described in chapter 51 of the United States Pharmacopoeia 29-National Formulary 24 (USP 29-NF 24). The preservatives may be used in an amount within the concentration ranges described in standard reference books like 'Remington's Pharmaceutical Sciences' and 'Handbook of Pharmaceutical Excipients'.
The preservative may be selected from: Quaternary ammonium compounds such as benzalkonium chloride (BKC) and benzethonium chloride; Organic mercurials such as phenylmercuric acetate, phenylmercuric nitrate and thimerosal; Parabens such as methyl and propyl paraben; ethyl paraoxybenzoate or butyl paraoxybenzoate; Acids and their pharmaceutically acceptable salts such as sorbic acid, potassium sorbate, boric acid, borax, salicylic acid ; Substituted alcohols and phenols such as chlorobutanol, benzyl alcohol; phenyl ethanol; Amides such as acetamide; and the like, and combinations thereof.

Preferably the ophthalmic compositions of the present invention comprise 'quaternary ammonium compound' as a preservative, particularly benzalkonium chloride. Benzalkonium chloride is characterized as a mixture of alkyldimethyl benzylammonium chlorides. It is employed in the compositions of the present in a preferable concentration of about 0.01 to about 0.02 % by weight of the composition.
In order to achieve, and subsequently maintain, an optimum pH, the ophthalmic compositions essentially contain a pH adjusting agent and/or a buffering agent. The preferred range of pH for an ophthalmic formulation is about 6.8 to about 7.8, and the most preferred pH is about 7.4. The ophthalmic compositions of the present invention comprise a pharmaceutically acceptable pH adjusting agent that may be selected from the group comprising acetic acid or salts thereof, boric acid or salts thereof, phosphoric acid or salts thereof, citric acid or salts thereof, tartaric acid or salts thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, trometamol, and the like and mixtures thereof. Particularly, preferred pH adjusting agents that may be used in the composition of the present invention include acetic acid, sodium carbonate and sodium hydroxide. These agents are used in amounts necessary to produce a pH ranging from about 6.0 to about 8.0.
Besides above mentioned ingredients, the formulation of the invention may include a number of additional components to provide various effects, as is well known in this field. For example, the composition may include edetate disodium, which may function as a co-preservative and chelating agent.
The ophthalmic compositions of the present invention may be prepared by following a general method described below:
Take WFI in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. Disperse the two polymers HPMC and PVP K-90 gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. Prepare a solution of the therapeutically active agent Timolol Maleate and the osmotic agent (mannitol, if present), in the WFI. Add this to the PVP K-90 dispersion under stirring. Mix homogeneously the HPMC phase with the PVP K-90 dispersion under stirring. With the stirring being continued, add the preservative (benzalkonium chloride) solution to this. Adjust the pH to about 7.4 with acetic acid or sodium hydroxide. Make up the volume to 100% with WFI. Autoclave the bulk solution for 20 min at 121°C, filter if required, and cool. This results in the desired ophthalmic composition of the present invention.

The exact procedure varies slightly depending upon the ingredients used. The detailed description is included in the examples.
The present invention provides a method of treatment of glaucoma, comprising once-a-day administration of the ophthalmic composition of the present invention comprising a therapeutic agent (beta-blocker), topically to the eye and attaining sustained release of the active agent, thereby reducing and controlling the elevated intraocular pressure, especially the elevated IOP associated with glaucoma.

EXAMPLES
While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.
EXAMPLE 1
An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 1.
TABLE 1

S.No. Ingredients Concentration (% w/v)
1. Timolol Maleate (equivalent to Timolol) 0.5
2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5
3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0
4. Sodium carbonate 0.5
5. Benzalkonium chloride solution 0.02
6. Acetic acid q.s
7. Water for Injection (WFI) q.s.
Procedure:
WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, Sodium Carbonate was dissolved in required volume of WFI to get a preconcentrate (10%w/v) solution. To this, the drug Timolol Maleate was added and it is kept for lh to form an oily base of Timolol. The oily base so obtained was added to the PVP K-90 dispersion under stirring, the stirring being continued until the oily droplets dissolve. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion under stirring. Further, benzalkonium chloride solution (BKC solution) was added with stirring and the pH was adjusted to about 7.4 with acetic acid. Finally the volume was adjusted to 100% with WFI; the bulk solution was autoclaved for 20 min at 121°C and cooled to obtain the final formulation.

EXAMPLE 2
An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 2.
TABLE 2

S.No. Ingredients Concentration (% w/v)
1. Timolol Maleate (equivalent to Timolol) 0.5
2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5
3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0
4. Benzalkonium chloride solution 0.02
5. Acetic acid 0.05
6. Sodium Hydroxide q.s.
7. Water for Injection(WFI) q.s.
Procedure:
WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, the drug Timolol Maleate was dissolved in required quantity of WFI. The drug solution was added to the PVP K-90 dispersion under stirring followed by addition of required amount of acetic acid with stirring. The pH was adjusted to 7.0 with sodium hydroxide solution. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion, followed by addition of BKC solution under stirring. The pH was adjusted to 7.4 with sodium hydroxide or acetic acid solution. Finally the volume was adjusted to 100% with WFI; the bulk solution was autoclaved for 20 min at 121°C and cooled to obtain the final formulation.
EXAMPLE 3
An ophthalmic composition for once- a- day instillation, according to the present invention is shown in Table 3

TABLE 3

S.No. Ingredients Concentration (% w/v)
1. Timolol Maleate (equivalent to Timolol) 0.1
2. Hydroxypropylmethylcellulose E4M (HPMC-E4M) 0.5
3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0
4. Benzalkonium chloride solution 0.02
5. Acetic acid 0.05
6. Sodium Hydroxide q.s.
7. Water for Injection(WFI) q.s.
The ophthalmic composition of this example 3 was prepared by following the same method as described in example 2 above.
EXAMPLE 4
An ophthalmic composition for once-a-day instillation, according to the present invention is shown in Table 4.
TABLE 4

S.No. Ingredients Concentration (% w/v)
1. Timolol Maleate (equivalent to Timolol) 0.5
2. Hydroxypropylmethylcellulose E4M (HPMC E4M) 0.5
3. Polyvinylpyrrolidone K-90 (PVP K-90) 2.0
4. Mannitol 4.5
5. Benzalkonium chloride solution 0.02
6. Acetic acid 0.05
7. Sodium Hydroxide q.s.
8. Water for Injection(WFI) q.s.

Procedure:
WFI was taken in two sets of stainless steel (SS316) vessels each fitted with an overhead stirrer. HPMC-E4M and PVP K-90 was dispersed gradually in WFI in the two vessels separately, under stirring, to obtain homogeneous dispersions. In another beaker, the drug Timolol Maleate and the osmotic agent Mannitol, was dissolved in required quantity of WFI. This solution was added to the PVP K-90 dispersion under stirring followed by addition of required amount of acetic acid with stirring. The pH was adjusted to 7.0 with sodium hydroxide solution. The HPMC-E4M phase was mixed homogeneously with the PVP K-90 dispersion under stirring followed by addition of BKC solution with stirring. The pH was adjusted to 7.4 with sodium hydroxide or acetic acid solution. Finally the volume was adjusted to 100% with WFI; the bulk solution was filtered using 0.2um glass fiber; autoclaved for 20 min at 121 °C and cooled to obtain the final formulation.
EXAMPLE 5
Studies were carried out by varying the ratio of HPMC-E4M and PVP K-90, (keeping the concentration of HPMC-E4M constant at 0.5%w/v), and their effects on the viscosity of the formulation, and on the percent transmission were determined. The percent transmission and viscosity of the formulation was determined by the methods given below.
Determination of percent transmission: Optical Study.
The optical study involving the determination of percent transmission of the formulation was carried out using the UV-1700 Spectrophotometer, Shimadzu, Japan. The result obtained for various formulations is shown in Table 5 and 6.
Determination of Viscosity: Rheological Study.
The rheological study involving the determination of viscosity of the formulation was carried out using the Brookfield dv-(iii) Ultra Programmable Rheometer (Spindle CPE 40, Entry Code: 40).
Procedure- 0.5 g of formulation was taken in rheometer cup and a spindle was immersed in the test fluid through a calibrated spring which measures viscosity by sensing the torque required to rotate the spindle at constant speed while immersed in the sample fluid. The torque is proportional to the viscous drag on the immersed spindle, and thus to the viscosity of the fluid. The viscous drag of the fluid against the spindle was measured by the spring deflection. Spring

deflection was measured with a rotary transducer. By rotating the spindle at several different speeds, shear dependent behavior of fluids can be also detected and analyzed. The Table 5 below describes the various compositions obtained by varying the ratio of HPMC-E4M:PVP K-90 from 100:0 to 0:100. It also includes the determined values of percent transmission and viscosity (in cps) for the corresponding compositions.
TABLE 5

Ingredients Concentration (%w/v)
HPMC E4M :PVP K90-100:0 HPMC E4M :PVP K90-80:20 HPMC E4M :PVP K90-60:40 HPMCE4M :PVP K90-50:50 HPMC E4M :PVP K90-40:60 HPMC E4M :PVP K90-20:80 HPMCE4M :PVP K90-15:85 HPMC E4M :PVP K90-10:90 HPMC E4M:PVP K90-0:100
Hydroxypropyl methylcellulose E4M 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0
Polyvinyl pyrrol i done K90 0 0.13 0.3 0.5 0.8 2.0 2.83 4.5 0.5 2.0
Water for Injection q.s q.s q.s q.s q.s q.s q.s q.s q.s
% Transmission 99.8 99.5 99.6 99.5 99.4 97.5 90.1 85.1 100.0 100.0
Viscosity 20.14 23.28 24.33 24.85 28.25 42.38 57.03 60.95 1.57 7.59
The values indicate that the viscosity (in cps) of the composition increases by increasing percent
PVP by weight of the total polymer or by increasing the weight by weight ratio of Hydroxypropyl
methylcellulose (HPMC-E4M): Polyvinylpyrrolidone (PVP K90) from 100:0 to 0:100.
At ratio from 80:20 to 10:90 ratio (HPMC-E4M: PVP K-90), synergistic viscosity was observed.
Also the compositions were clear aqueous solutions having percent transmission greater than 85
%.
EXAMPLE 6
Study regarding determination of concentration of the drug retained in the rabbit's aqueous humor on topical application of the developed ophthalmic composition of Example 3 above, to the rabbit eye, and comparison of the concentration-time profile so obtained with the instillation of the marketed product NYOGEL (Novartis Pharmaceuticals Ltd). The method followed is described below and the observation is represented in figure 1.

Method: Two male NZ (Newzealand) rabbits weighing 1.5-3.0 Kg were taken. To both eyes of the first rabbit, a single dose of 70 ml of composition of Example 3 of the present invention, having timolol maleate in a concentration of 0.1% by weight of the composition, was instilled and to both eyes of the second rabbit, a single dose of 70 ml of the marketed product NYOGEL composition having timolol maleate in a concentration of 0.1% by weight of the composition, was instilled. At 15 min, 30 min, lh & 3hr post instillation of drug, animals were sacrificed by intravenous injection of thiopental sodium and aqueous humor was aspirated with insulin syringe (lml, BD Ultra fine) after puncturing the anterior chamber at the limbus and the samples were stored at -70°C till analysis. These aqueous humor samples were analyzed by HPLC and the data obtained for various compositions was compared (see figure 1).
On analyzing the results obtained, as represented by figure 1, it is clear that composition of the present invention (Example 3- having timolol maleate in a concentration of 0.1% by weight of the composition) is able to provide comparatively much higher concentration of the drug; viz. a better Cmax and AUC; at the site of action, and the concentration is sustained for a much longer period of time in the desired therapeutic range, as compared to that provided by the marketed product NYOGEL (which is also a once-a-day preparation and having timolol maleate in a concentration of 0.1% by weight of the composition). Thus, the compositions of the present invention prove to be very effective ophthalmic compositions for once-a-day instillation, suitable for glaucoma therapy.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof

ABSTRACT
An ophthalmic composition comprising therapeutically effective amount of a beta-blocker and a pharmaceutical^ acceptable polymer consisting of a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone, wherein the composition is a clear aqueous solution with a viscosity greater than 15 cps.
To,
The Controller of Patents, The Patent Office,
Mumbai - 400 037

Documents:

477-mum-2008-abstract(9-3-2009).pdf

477-mum-2008-abstract.doc

477-mum-2008-abstract.pdf

477-MUM-2008-ANNEXURE A(18-12-2012).pdf

477-MUM-2008-ANNEXURE A-C(21-10-2013).pdf

477-MUM-2008-ANNEXURE B(18-12-2012).pdf

477-MUM-2008-ANNEXURE C(18-12-2012).pdf

477-MUM-2008-CANCELLED PAGE(18-12-2012).pdf

477-MUM-2008-CANCELLED PAGE(21-10-2013).pdf

477-mum-2008-claims(9-3-2009).pdf

477-MUM-2008-CLAIMS(AMENDED)-(18-12-2012).pdf

477-MUM-2008-CLAIMS(AMENDED)-(21-10-2013).pdf

477-MUM-2008-CLAIMS(MARKED COPY)-(18-12-2012).pdf

477-MUM-2008-CLAIMS(MARKED COPY)-(21-10-2013).pdf

477-MUM-2008-CORRESPONDENCE(1-4-2010).pdf

477-mum-2008-correspondence(17-3-2008).pdf

477-MUM-2008-CORRESPONDENCE(29-7-2011).pdf

477-MUM-2008-CORRESPONDENCE(9-3-2009).pdf

477-mum-2008-correspondence-received.pdf

477-mum-2008-description (provisional).pdf

477-mum-2008-description(complete)-(9-3-2009).pdf

477-mum-2008-drawing(9-3-2009).pdf

477-mum-2008-drawings.pdf

477-MUM-2008-EP DOCUMENT(18-12-2012).pdf

477-mum-2008-form 1(17-3-2008).pdf

477-MUM-2008-FORM 18(1-4-2010).pdf

477-MUM-2008-FORM 18(29-7-2011).pdf

477-MUM-2008-FORM 2(9-3-2009).pdf

477-mum-2008-form 2(title page)-(complete)-(9-3-2009).pdf

477-mum-2008-form 2(title page)-(provisional)-(7-3-2008).pdf

477-MUM-2008-FORM 3(18-12-2012).pdf

477-MUM-2008-FORM 3(9-3-2009).pdf

477-MUM-2008-FORM 5(9-3-2009).pdf

477-MUM-2008-FORM PCT-IB-373(18-12-2012).pdf

477-MUM-2008-FORM PCT-ISA-237(18-12-2012).pdf

477-mum-2008-form-1.pdf

477-mum-2008-form-2.doc

477-mum-2008-form-2.pdf

477-MUM-2008-OTHER DOCUMENT(21-10-2013).pdf

477-MUM-2008-PETITION UNDER RULE-137(18-12-2012).pdf

477-MUM-2008-REPLY TO EXAMINATION REPORT(18-12-2012).pdf

477-MUM-2008-REPLY TO HEARING(21-10-2013).pdf

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Patent Number

259169

Indian Patent Application Number

477/MUM/2008

PG Journal Number

10/2014

Publication Date

07-Mar-2014

Grant Date

28-Feb-2014

Date of Filing

07-Mar-2008

Name of Patentee

SUN PHARMA ADVANCED RESEARCH COMPANY LTD.

Applicant Address

17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	ARINDAM HALDER	SUN PHARMA ADVANCED RESEARCH COMPANY LTD, NIMA COMPOUND, NEAR PRATHAM ENCLAVE, TANDALJA ROAD, BARODA-390020.
2	AJAY JAYSINGH KHOPADE	SUN PHARMA ADVANCED RESEARCH COMPANY LTD, NIMA COMPOUND, NEAR PRATHAM ENCLAVE, TANDALJA ROAD, BARODA-390020.
3	SUBHAS BALARAM BHOWMICK	SUN PHARMA ADVANCED RESEARCH COMPANY LTD, NIMA COMPOUND, NEAR PRATHAM ENCLAVE, TANDALJA ROAD, BARODA-390020.

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA