NZ751915B2 - Non-irritating ophthalmic povidone-iodine compositions - Google Patents

Abstract

ophthalmic preparation comprising: a. povidone-iodine at a concentration from about 0.1 % to about 2.5% said ophthalmic preparation, b. at least one member selected from the group consisting of a lubricant and a cooling agent, at a concentration which is not irritating to the eye; and c. optionally, one or more of the members selected from the group consisting of camphor, borneol, a lubricant, an emollient, a steroidal anti-inflammatory compound, and a non-steroidal anti-inflammatory compound. The compositions are useful to relieve mild ocular irritation, enhance ocular comfort, and to provide a refreshing effect and improved sensation, when the povidone-iodine solution is applied to the eye. An exemplary composition would be: 0.36%, 0.48%, or 0.6% PVP-I, by weight, as desired in the final product, and combining with 0.5% carboxymethylcellulose sodium, boric acid, calcium chloride, magnesium chloride, sodium borate, sodium chloride, and purified water. In an embodiment, a preserved ophthalmic solution comprises hydrochloric acid and/or sodium hydroxide to adjust pH. ally, one or more of the members selected from the group consisting of camphor, borneol, a lubricant, an emollient, a steroidal anti-inflammatory compound, and a non-steroidal anti-inflammatory compound. The compositions are useful to relieve mild ocular irritation, enhance ocular comfort, and to provide a refreshing effect and improved sensation, when the povidone-iodine solution is applied to the eye. An exemplary composition would be: 0.36%, 0.48%, or 0.6% PVP-I, by weight, as desired in the final product, and combining with 0.5% carboxymethylcellulose sodium, boric acid, calcium chloride, magnesium chloride, sodium borate, sodium chloride, and purified water. In an embodiment, a preserved ophthalmic solution comprises hydrochloric acid and/or sodium hydroxide to adjust pH.

Description

TITLE OF THE INVENTION Non-Irritating Ophthalmic Povidone-Iodine Compositions This application is a divisional of NZ 734815, which is itself a divisional of NZ 717107, which is itself a divisional of NZ 700140, which is itself a divisional of NZ 600594, which is the national phase entry in New Zealand of PCT international application (published as ), filed 15 December 2010.

BACKGROUND Ophthalmic compositions used for treatment of eye redness, ocular symptoms of allergies, and microbial infection are often irritating to the eye upon instillation. For example, certain iodine-containing ophthalmic compositions can be irritating to the eye upon instillation.

The use of a cooling agent, such as menthol, to provide a cooling effect on the skin and in the oral cavity is known. Cooling agents have also been added to food products such as chewing gum or mints, as well as to cigarettes, in order to provide a sensation of "coolness or freshness" during consumption. Menthol has also been added to topical pharmaceutical compositions to alleviate the sensation of inflammation and itch associated with bug bites and mild abrasions.

The sensation of coolness on the skin and mucosal surfaces resulting from the application of menthol is believed to be due to a specific action on sensory nerve endings. It is believed that cooling agents such as menthol exert their effect on cold receptors by interfering with the mobility of calcium ions across the cell membrane. Certain preparations of menthol, for example, have been perceived as being irritating to the eye, and consequently, menthol has not been utilized extensively in ophthalmic preparations.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprises” are to be interpreted in similar manner. (followed by 1a) BRIEF SUMMARY OF THE INVENTION In a first aspect, the present invention provides an ophthalmic preparation comprising: povidone-iodine (PVP-I) at a concentration of 0.36%, 0.48%, or 0.6% by weight, a cooling agent, at a concentration of 0.01% to 10% by weight; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti-inflammatory compound, wherein said cooling agent is a terpene, and the pH of the preparation is in the range of 3.5 to 6.5 In a second aspect, the present invention provides use of: povidone-iodine; a cooling agent; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti-inflammatory compound; in the manufacture of an ophthalmic preparation for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye, wherein said povidone- iodine is at a concentration of 0.36%, 0.48%, or 0.6% by weight, said cooling agent is a terpene and is at a concentration of 0.01% to 10% by weight, and the pH of the preparation is in the range of 3.5 to 6.5.

In a third aspect, the present invention provides use of: povidone-iodine; a cooling agent; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti-inflammatory compound; in the manufacture of an ophthalmic preparation for treating and/or prophylaxis of a microorganism infection of a tissue, wherein said povidone-iodine is at a concentration of 0.36%, 0.48%, or 0.6% by weight, said cooling agent is a terpene and is at a concentration of 0.01% to % by weight, and the pH of the preparation is in the range of 3.5 to 6.5.

In a fourth aspect, the present invention provides the ophthalmic preparation of the first aspect for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye.

In a fifth aspect, the present invention provides the ophthalmic preparation of the first aspect for treating and/or prophylaxis of a microorganism infection of a tissue.

In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.

Disclosed herein is an ophthalmic preparation comprising povidone-iodine at a concentration from about 0.1% to about 2.5%, a lubricant and/or a cooling agent. The lubricant and/or cooling agent are present in the preparation at a concentration which is not irritating to the eye. Optionally, an ophthalmic preparation also contains one or more of camphor, borneol, a lubricant, an emollient, a steroidal anti-inflammatory compound, and a non-steroidal anti- inflammatory compound. (followed by 2) In an aspect, PVP-I is present at a concentration of 0.2 to 2.0%, 0.3% to 1.5%, 0.36% to 1.0%, and 0.4% to 0.75%. In another aspect, PVP-I is present at a concentration of about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% and about 1.0%.

In an embodiment, the ophthalmic preparation includes a non-steroidal anti­ inflammatory compound such as ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celccoxib, naproxen, rofccoxib, and any combination thereof.

In another embodiment, the ophthalmic preparation includes a steroidal anti­ inflammatory compound such as dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholone alcohol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, and any combination thereof.

In an aspect, the ophthalmic preparation comprises at least one viscosity increasing agent. A viscosity increasing agent may include polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropylmcthylccllulosc, hydroxycthylccllulosc, carboxymethylccllulosc, hydroxypropylccllulose, and any combination thereof.

In an aspect, the ophthalmic preparation comprises at least one artificial tears-based lubricant. An artificial tears-based lubricant may include propylene glycol, glycerin, polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl alcohol, polyethylene glycol, light mineral oil, hydroxypropyl methylcellulose, hypromellose, carbopol, carbomer 940 (polyacrylic acid), polyvinyl pyrrolidone, white petrolatum, soy lecithin, and sodium carboxyl methylcellulose.

In an aspect, the ophthalmic preparation comprises at least one bioadhesive agent. A bioadhesive agent may include polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinylalcohol, gellan gum, tragacanth, acacia, and sodium carboxymethyl cellulose.

Disclosed herein is a method for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye comprising administration of one or more doses of an ophthalmic preparation as disclosed herein to an eye.

In one aspect, a method includes prophylaxis of infection following corneal abrasion or ocular surgery.

In an aspect, a method is used to treat a disorder such as conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus- related keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian gland disfunction, blepharitis, uveitis, and a microorganism infection of at least one tissue of the eye.

Disclosed herein is a method for treating and/or prophylaxis of a microorganism infection of a non-ophthalmic tissue, comprising contacting the tissue with a composition as disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are ophthalmic compositions comprising povidone-iodine in the range of about 0.01% to about 10% (weight/weight or weight/volume) and a cooling effective amount of a chemical agent to relieve mild ocular irritation, enhance ocular comfort, and to provide a refreshing effect and improved sensation, when the povidone-iodine solution is applied to the eye. Such an agent includes different chemical classes, including, but not limited to, cooling agents such as menthol, menthol derivatives including methone glycerin acetyl and menthyl esters, carboxamides, menthane glycerol kctals, alkyl substituted ureas, sulfonamides, terpene analogs, furanones, and phosphine oxides; or camphor, and borneoi.

As will be understood by the skilled artisan, various cooling agents may have different properties, and the amount and type of cooling agent to use may depend upon the components of a desired composition, as well as the desired therapeutic or soothing effect, or the degree of the effect, sought. Cooling agents may be used in a concentration range from about 0.001% to about 10%, about 0.005% to about 10%, about 0.01% to about 10%, about 0.05% to about %, about 0.1% to about 10%, about 0.25% to about 9%, about 0.5% to about 8%, about 0.75% to about 7%, about 0.9% to about 6%, or about 1.0% to about 5.0%. In an embodiment, a cooling agent is present in a composition at a level of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%. In an embodiment, a cooling agent is present in a composition at a level of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3%, 4%, or 5%.

The ophthalmic composition may further comprise an artificial tear-based lubricant to improve the comfort. Artificial-tear based lubricants include, but are not limited to, propylene glycol, glycerin, polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl alcohol, polyethylene glycol, light mineral oil, hydroxypropyl methylcellulosc, hypromellose, carbopol, carbomer 940 (polyacrylic acid), polyvinyl pyrrolidone, white petrolatum, soy lecithin, and sodium carboxyl methylcellulosc, as well as other agents known to those skilled in the art, or any combination thereof. Typically, such lubricants arc employed at a level of from 0.1% to 2% by weight. In an embodiment, the lubricants arc 1.0% propylene glycol, 0.3% glycerin, 2.7% blended polyvinyl alcohols, 1% polyvinyl alcohol, 1% polyethylene glycol, light mineral oil, 0.3% hydroxypropyl methylcellulosc, 1.0% soy lecithin, 0.25% or 0.5% sodium carboxyl methylcellulose. In an embodiment, a lubricant is present in a composition at a level of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%. In an embodiment, a lubricant is present in a composition at a level of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, about 1.0%, about 1.1%, about 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0%.

In an embodiment, a composition comprises povidone-iodine (PVP-1) at a concentration in the range of about 0.1% to about 2.5%. In another embodiment, a composition comprises povidone-iodine (PVP-I) at a concentration in the range between 0.2 and 1.5%, and in yet another embodiment, between 0.3% and 1.0%. In an embodiment, a composition comprises PVP-I at a concentration in the range of about 0.2 to about 2.0%, about 0.3% to about 1.5%, about 0.36% to about 1.0%, and about 0.4% to about 0.75%. In an embodiment, a composition comprises PVP-I at a concentration of about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%. In an embodiment, a composition comprises povidone-iodine PVP-I at a concentration of 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%. In another embodiment, a composition comprises PVP-I at a concentration of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

Disclosed herein is a composition comprising povidone-iodine at a concentration from about 0.1% to about 10%, a lubricant, and a cooling agent at a concentration which is non-irritating to a non-ophthalmic tissue. Optionally, the composition may further comprise one or more of camphor, bomeol, a lubricant, an emollient, a steroidal anti-inflammatory compound, and a non-steroidal anti-inflammatory compound.

In yet another embodiment, an ophthalmic composition set forth herein is useful for a non- ophthalmic application.

Methods In an aspect, a composition of the invention is useful in the treatment of infections of the conjunctiva and cornea. In another aspect, the broad spectrum antimicrobial activity of povidone-iodine enables a composition of the invention to be used to treat ocular conjunctival or corneal infection caused by mycobacteria, viruses, fungi, and amoeba. Additionally the composition is useful in the infectious prophylaxis of patients recovering from ophthalmic surgery. There are no currently available povidone-iodine solutions that are comfortable for repeat application in the eye. The present invention provides, in part, compositions that meet this need and/or that at least provide the public with a useful choice.

In an embodiment of the invention, an ophthalmic composition is provided that is suitable for topical administration to an eye, effective for treatment and/or prophylaxis of a microorganism infection or a disorder of at least one tissue of the eye. Prophylaxis may be, for example, prophylaxis from infection following surgery, prophylaxis from infection after birth for the newborn, or prophylaxis from accidental contact with contaminating material.

Accidental contact with contaminating material may occur, for example, during surgery or during food processing.

Surprisingly, it was discovered that the compositions set forth herein, comprising povidone-iodine combined with cooling agents set forth herein, and/or camphor, and/or bomeol, and/or lubricants, and/or emollients, when present in a suitable pH range, eliminated the undesired irritating effect of PVP-I to the eye.

In an embodiment, an ophthalmic composition may further comprise one or more of (1) a penetration enhancer which enhances the penetration of povidone-iodine into the tissues of the eye (this may be a topical anesthetic) (2) a co-solvent or a nonionic surface agent - surfactant, which, for example, may be about 0.01% to 2% by weight; (3) a viscosity increasing agent, which, for example, may be about 0.01% to 2% by weight; and (4) a suitable ophthalmic vehicle.

The ophthalmic composition may be in the form of a solution, a suspension, an emulsion, a preparation, an ointment, a cream, a gel, or a controlled-release/sustain-release vehicle. By way of a non-limiting example, the composition may be in the form of a contact lens solution, eyewash, eyedrop, and the like.

In an aspect, the ophthalmic composition may be used for treatment and/or prophylaxis of a microorganism infection. The microorganism may be a bacterium, a virus, a fungus, or an amoeba, a parasite, or a combination thereof. In an embodiment, the bacteria may be a mycobacterium.

In an aspect, an ophthalmic composition may be used to treat a disorder such as, but not limited to, conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus-related keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian gland dysfunction, blepharitis and uveitis. In another aspect, an ophthalmic composition may be used for prophylaxis of disorders such as conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus-related keratitis, ocular surface irregularity, tear deficiency, diy syndrome, meibomian gland dysfunction, blepharitis and uveitis.

Disclosed herein is a method for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye comprising the step of administering one of more doses of an ophthalmic composition, discussed above, to the eye. The eye disorder may be, for example, a microorganism infection of at least one tissue of the eye, conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes virus-related keratitis, ocular surface irregularity, tear deficiency, dty syndrome, meibomian gland dysfunction, and blepharitis. The microorganism may be bacteria (e.g., mycobacteria), virus, fungi, or amoebae.

In an embodiment, the dose volume administered to a subject may be between about microliters and about 200 microliters, in another embodiment, between about 20 microliters and 100 microlilcrs, and in another embodiment, between about 50 microliters and about 80 microliters, or about one drop per eye. Two or more drops may be added to an eye.

Treatment or soothing of an eye may be effected by adding a single drop of composition disclosed herein, or by adding two or more drops, as required to achieve the desired result.

In an embodiment, administration frequency may be between 1 and 24 times a day. In an embodiment, administration frequency may be between 1 and 48 times a day. In another embodiment, administration frequency may be between 2 and 24 times a day. In another embodiment, administration frequency may be between 2 and 4 times a day. In another embodiment, administration frequency may be twice a day. In another embodiment, administration frequency may be once a day. In another embodiment, administration frequency may be less frequent than once a day. In another embodiment, administration frequency may be on demand, as therapeutic or soothing treatment is required or desired.

In an embodiment, a composition disclosed herein is used for prophylaxis and/or treatment of a non-ophthalmic tissue by contacting the tissue with the composition.

Additional Conmositions Compositions and preparations disclosed herein may further comprise one or more non-steroidal anti-inflammatory compounds. Non-steroidal anti-inflammatory compounds include, but are not limited to, ketotifen fumaratc, diclofenac sodium, ncpafcnac, bromfcnac. flurbiprofen sodium, suprofen, cclecoxib, naproxen, rofecoxib, and any combination thereof.

Compositions and preparations disclosed herein may further comprise one or more steroidal anti-inflammatory compounds. Steroidal anti-inflammatory compounds include, but are not limited to dexamethasone, dexamethasonc alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholone alcohol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, and any combination thereof. Steroidal and non-steroidal compounds may be combined in a single composition or preparation contemplated or disclosed herein. In an embodiment, a steroidal anti­ inflammatory compound or a non-steroidal anti-inflammatory compound is present in the composition or preparation at a level of about 0.01% to about 10%. In an embodiment, a steroidal anti-inflammatory compound or a non-steroidal anti-inflammatory compound is present in the composition or preparation at a level of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%.

The compositions and preparations disclosed herein can be administered as solutions, suspensions, emulsions (dispersions), gels, creams, or ointments in a suitable ophthalmic vehicle. In any of the compositions of this disclosure for topical administration, such as topical administration to the eye, the mixtures arc preferably formulated as aqueous solutions at a pH of 3.5 to 6.5. Preferentially the pH was adjusted to between 4 and 5. This pH range may be achieved by the addition of acids/bases to the solution.

In an embodiment, an ophthalmic composition may comprise an optional co-solvent.

In another embodiment, the solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such co-solvents or surfactants include polysorbate -20, -60, and -80, a polyoxyethylcnc/polyoxypropylcnc surfactant (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, tyloxapol, PEG 35 Castor oil (Cremophor EL), polyoxyl 40 Stearate (Myrj 52), other agents known to those skilled in the art, or a combination thereof. Typically, such co-solvents arc present at a level of from about 0.01% to about 2% by weight.

In an embodiment, a composition may comprise an optional agent that can increase viscosity. As will be understood by the skilled artisan when armed with the present disclosure. it may be desirable to increase viscosity above that of a simple aqueous solution in order to increase ocular absorption of the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity­ enhancing agents include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropylmethyl cellulose, hydroxycthyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, other agents known to those skilled in the ait, or any combination thereof. Such agents arc typically employed at a level of from about 0.01% to about 2% by weight.

In another aspect, bioadhesive agents may comprise the compositions, in order to increase the retention time of the drug gradient over a biological substrate. The bioadhesive agents include, but are not limited to, polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylccllulo.se (HPMC), sodium alginate, pectin, gelatin, carbomcr, polyvinylalcohol, gcllan gum, tragacanth, acacia, and sodium carboxymethyl cellulose, as well as other agents known to those skilled in the art, or any combination thereof.

In yet another embodiment, compositions of the invention may comprise viscoelastic agents such as methyl cellulose, carboxymethyl cellulose, hydroxycthyl cellulose, polyvinyl alcohol, dextran, chondroitin sulfate and salts thereof, and hyaluronic acid and salts thereof.

In another aspect, compositions of the invention may comprise one or more buffering agents, isotonizing agents, solubilizers, stabilizers, chelating agents, and any combinations thereof. Such additional components may be used at concentrations that provide enhanced comfort or therapeutic properties to the PVP-I compositions disclosed herein. In another aspect, such additional components may be used at concentrations in which the additional component itself has a therapeutic and/or soothing effect, in addition to the effect obtained from the PVP-I compositions disclosed herein.

EXAMPLES The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1: Preparation of non-irritating PVP-1 ophthalmic solution 1 By way of a non-limiting example, a PVP-I ophthalmic solution is prepared using 0.36%, 0.48%, or 0.6% PVP-I, by weight, as desired in the final product, and combining with 1.8% povidone, ethanol (0.1%), boric acid, camphor, poloxamcr 407, polysorbatc 80, potassium chloride, sodium borate, sodium chloride, and purified water.

Example 2: Prenaration of non-irritatim> PVP-I ophthalmic solution 2 By way of a non-limiting example, a PVP-I ophthalmic solution is prepared using 0.36%, 0.48%, or 0.6% PVP-I, by weight, as desired in the final product, and combining with 0.2% polysorbatc 80, ethanol (0.1%), boric acid, edetate disodium, menthol, sodium borate, and purified water.

Example 3: Preparation of PVP-I preserved ophthalmic solution 3 By way of a non-limiting example, a PVP-I ophthalmic solution is prepared using 0.36%, 0.48%, or 0.6% PVP-I, by weight, as desired in the final product, and combining with 0.5% carboxymcthylccilulosc sodium, boric acid, calcium chloride, magnesium chloride, sodium borate, sodium chloride, and purified water. In an embodiment, a preserved ophthalmic solution comprises hydrochloric acid and/or sodium hydroxide to adjust pH.

The invention has been described herein by reference to certain embodiments.

However, as variations thereof will become apparent to those skilled in the ail, when armed with the disclosure set forth herein, the invention is not to be considered as limited thereto.

All patents, patent applications, and references cited herein arc hereby incorporated by reference in their entirety.

Claims (27)

WHAT WE CLAIM IS:

1. An ophthalmic preparation comprising: povidone-iodine (PVP-I) at a concentration of 0.36%, 0.48%, or 0.6% by weight, a cooling agent, at a concentration of 0.01% to 10% by weight; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti- inflammatory compound, wherein said cooling agent is a terpene, and the pH of the preparation is in the range of 3.5 to 6.5.

2. The ophthalmic preparation of claim 1, wherein the PVP-I is present at a concentration of 0.36% by weight.

3. The ophthalmic preparation of claim 1, wherein the PVP-I is present at a concentration of 0.48% by weight.

4. The ophthalmic preparation of claim 1, wherein the PVP-I is present at a concentration of 0.6% by weight.

5. The ophthalmic preparation of any one of claims 1-4, wherein said non-steroidal anti- inflammatory compound is selected from the group consisting of ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, and any combination thereof.

6. The ophthalmic preparation of any one of claims 1-5, wherein said steroidal anti- inflammatory compound is selected from the group consisting of dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholone alcohol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, and any combination thereof.

7. The ophthalmic preparation of any one of claims 1-6, wherein the steroidal anti- inflammatory compound is dexamethasone.

8. The ophthalmic preparation of any one of claims 1-7 wherein said preparation further comprises a viscosity increasing agent.

9. The ophthalmic preparation of claim 8 wherein said viscosity increasing agent is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and any combination thereof.

10. The ophthalmic preparation of any one of claims 1-9, wherein the preparation comprises at least one artificial tears-based lubricant.

11. The ophthalmic preparation of claim 10, wherein said artificial tears-based lubricant is selected from the group consisting of propylene glycol, glycerin, polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl alcohol, light mineral oil, hydroxypropyl methylcellulose, hypromellose, polyacrylic acid, polyvinyl pyrrolidone, white petrolatum, soy lecithin, sodium carboxyl methylcellulose, and any combination thereof.

12. The ophthalmic preparation of any one of claims 1-11, further comprising at least one bioadhesive agent.

13. The ophthalmic preparation of claim 12, wherein said bioadhesive agent is selected from the group consisting of polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinylalcohol, gellan gum, tragacanth, acacia, sodium carboxymethyl cellulose, and any combination thereof.

14. The ophthalmic preparation of any one of claims 1 to 13, wherein the cooling agent is menthol.

15. Use of: povidone-iodine; a cooling agent; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti- inflammatory compound; in the manufacture of an ophthalmic preparation for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye, wherein said povidone-iodine is at a concentration of 0.36%, 0.48%, or 0.6% by weight, said cooling agent is a terpene and is at a concentration of 0.01% to 10% by weight, and the pH of the preparation is in the range of 3.5 to 6.5.

16. The use of claim 15, wherein the ophthalmic preparation is as defined in any one of claims 2-14.

17. The use of claim 15 or 16 wherein said ophthalmic preparation is for prophylaxis of infection following corneal abrasion or ocular surgery.

18. The use of claim 15 or 16 wherein said eye disorder is selected from the group consisting of conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus-related keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian gland disfunction, blepharitis, uveitis, and a microorganism infection of at least one tissue of the eye.

19. The use of any one of claims 15, 16 and 18, wherein the eye disorder is conjunctivitis.

20. Use of: povidone-iodine; a cooling agent; and optionally, a steroidal anti-inflammatory compound, or a non-steroidal anti- inflammatory compound; in the manufacture of an ophthalmic preparation for treating and/or prophylaxis of a microorganism infection of a tissue, wherein said povidone-iodine is at a concentration of 0.36%, 0.48%, or 0.6% by weight, said cooling agent is a terpene and is at a concentration of 0.01% to 10% by weight, and the pH of the preparation is in the range of 3.5 to 6.5.

21. The ophthalmic preparation of any one of claims 1-14 for treating and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye.

22. The ophthalmic preparation of claim 21 for prophylaxis of infection following corneal abrasion or ocular surgery.

23. The ophthalmic preparation of claim 21 wherein said eye disorder is selected from the group consisting of conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus-related keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian gland disfunction, blepharitis, uveitis, and a microorganism infection of at least one tissue of the eye.

24. The ophthalmic preparation of claim 21 or 23 wherein the eye disorder is conjunctivitis.

25. The ophthalmic preparation of any one of claims 1-14 for treating and/or prophylaxis of a microorganism infection of a tissue.

26. An ophthalmic preparation of any one of claims 1-11 and 21-25 substantially as herein described with reference to any example thereof.

27. Use of any one of claims 15-20 substantially as herein described with reference to any example thereof.