JP6320616B1 - Novel ophthalmic compositions and methods of use - Google Patents

Abstract

Describes stable topical formulations useful in the treatment of ocular viral infections, Acari infections, fungal and bacterial infections, and methods of using the compositions to treat ocular viral infections, Acari infections, fungal infections and bacterial infections Is done. [Selection figure] None

Description

  [0001] Millions of human patients suffer from viral infections or viral warts infection, acne infections, fungal or yeast infections, or bacterial infections of the skin, including the skin of the eye, eyelid or periocular area .

  [0002] Eye or eyelid infection can occur indirectly through direct human-to-human skin contact or indirectly from contaminated surfaces in public access areas such as public swimming pools or gymnasiums. Exposure to infectious agents can occur through slight abrasions, and infection is promoted through epithelial maceration. Self-inoculation is also common.

  [0003] Common warts, the medical term for warts, is a collective term for all warts. Warts can be attributed to viral infections most often associated with human papillomavirus (HPV) or infectious molluscumoma virus (MCV). Various non-genital systems of skin warts occur in 20% of school children with equal frequency in both sexes.

  [0004] Viral infection or viral wart infection, Acne mite infection, fungal or yeast infection, or bacterial infection of the eyelid, conjunctiva, cornea, ocular surface or meibomian gland is blepharitis and / or blephar conjunctivitis or conjunctivitis, ie eyelid Or it can manifest as an infectious and inflammatory condition of the ocular surface.

  [0005] Blind conjunctivitis and blepharitis are commonly appearing conditions that affect about 15% of the population, resulting in inflammatory, infectious or mixed states of the eyelids. Blepharitis can include dermis, eyelashes, conjunctiva, mucocutaneous transition or meibomian glands, such as Staphylococcus, Corynebacterium and Propionibacterium species, etc. Most often caused by gram-positive bacterial infections. However, other factors that cause blepharitis include viral, acne (mite) or yeast infection, seborrhea, rosacea and hormonal dysregulation.

  [0006] Blisteritis left untreated can cause dry eye deterioration, cilia loss, and corneal ulceration, resulting in an increased risk of endophthalmitis after cataract surgery. For ease of understanding, endophthalmitis is generally classified as inflammation that affects the structure of the front of the eyelid margin, the rear of the lid margin, or both.

  [0007] Anterior blepharitis most commonly manifests as scab formation of the anterior and eyelashes of the eyelid, with or without the presence of collarettes. Other symptoms may also include skin or eyelash detachment associated with seborrhea or ocular inflammation, especially Moraxella or virus.

  [0008] Posterior blepharitis is also commonly referred to as meibomian gland disease. The meibomian glands are involved in the release of lipids into the tear film and effectively relieve evaporative tear loss. In addition to the chronic irritation common to all blepharitis, inflammation and erythema, the posterior variant is further characterized by meibomian gland enrichment, orifice keratinization, telangiectasia and posterior thickening of the lid margin It can be. Bacterial lipases arising from ocular flora can also act on the secretion of meibomian glands that produce free fatty acids, which further interfere with the ocular surface.

  [0009] Current treatments for bacterial, acne, fungal / yeast and viral infections, including warts, and ophthalmic conditions such as blepharitis, are effective in that they treat only some of the causative factors of the infection. Cannot be. Many current treatments incorporate undesirable ingredients such as steroids or other potentially harmful components.

  [00010] A recent discovery by Capriotti et al. Discloses a composition comprising an iodophor such as povidone-iodo (PVP-I) as an active ingredient, where dimethyl sulfoxide (DMSO) is useful in the treatment of fungal infections of the skin and nails It was shown that. See, for example, US Publication No. US 2014/0205559 (Capriotti No. 559), which is incorporated herein by reference in its entirety.

  [00011] Various organic solvents, including dimethyl sulfoxide (DMSO), are known to enhance the transdermal absorption of certain drugs, but DMSO can only be a low molecular weight or low molecular weight (LMW) compound or drug. Not enhancing penetration has long been accepted in the pharmaceutical field and was not expected to enhance penetration of polymers, eg, high molecular weight (HMW) compounds greater than about 10,000 daltons such as povidone-iodo. It was only recently and unexpected that DMSO was demonstrated to enhance povidone-iodine (PVP-I) penetration. PVP-I preparations range in molecular weight from 1,000 to 1,000,000 or more. Topical pharmaceutical compositions are only approved for use with PVP grade K29-32. One acceptable PVP grade is PVP K30, which has a MW of 30,000-60,000 daltons (average MW is about 40,000 daltons). Thus, prior to the teaching of Capriotti 559, those skilled in the art have used DMSO in topical pharmaceutical compositions to enhance skin penetration of large molecules, polymers or high molecular weight substances, such as PVP-I. Probably not.

  [00012] In addition, DMSO is recognized and recognized in the art to be toxic to the eye and is considered an acceptable ingredient in compositions intended for topical administration to the eye or periocular region. It was not done. Thus, not only is DMSO generally recognized as unacceptable for use as a penetration enhancer of high molecular weight polymer compounds such as povidone-iodo, but DMSO is a component specifically for use in ophthalmic preparations. As an ingredient for topical ophthalmic preparations, among others.

  [00013] In addition, gel formulations comprising povidone-iodine and DMSO are generally referred to in Capriotti No. 559 and related publications, but certain formulations comprising povidone-iodine, DMSO and gelling agent are: It has been discovered that it is not stable for a sufficient period of time to provide a feasible pharmaceutical product with an acceptable shelf life. Only when a specific amount of povidone-iodine is combined with a specific amount of DMSO and a specific amount of gelling agent to produce a feasible pharmaceutically acceptable product with an acceptable and approved shelf life It was observed to be sufficiently stable.

  [00014] In US Patent Application Publication No. 2017/000019, Capriotti et al. Described topical ophthalmic gel compositions for treating certain ophthalmic conditions. However, the composition has been shown to be unstable when the concentration of gelling agent, eg HEC, is less than 2% (w / w) of the composition. This result is consistent with the knowledge in the art that it is extremely difficult to stabilize compositions containing gelling agents at low concentrations. The stability and effectiveness of a topical gel composition comprising PVP-I in DMSO has been retained when the gelling agent is preferably supplied at a concentration of 2.5% to 5%. 2017/000019 was described.

  [00015] The problem of providing a topical ophthalmic preparation that contains a lower concentration of gelling agent but retains the stability and effectiveness of the period reflected in the acceptable shelf life of the composition is: Still exists in the art. Providing a topical ophthalmic composition comprising a gelling agent at a concentration of less than 2% will ensure proper administration or application of the product, residence time at the site of treatment or anesthesia reasons (product appearance / feel and patient tolerance). Can be advantageous. Accordingly, the discovery of compositions comprising PVP-I in DMSO and water with or without an organic co-solvent and a gelling agent at a concentration of less than 2%, which is stable and effective for an acceptable period of time, is In particular, it can be a significant advance in the field of ophthalmic treatment.

US publication number US2014 / 0205559 US Patent Application Publication No. 2017/000019 PCT / US2012 / 036942 PCT / US2012 / 065298

REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro 19th Edition 1995) Ghosh, T .; K. Et al., TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997)

  [00016] Thus, the present invention is a significant advance in the art, and topical ophthalmic gel compositions, particularly concentration combinations, comprising certain ingredients, namely PVP-I, DMSO and a gelling agent, Surprising and unpredictable discovery that can produce beneficial and unexpected results in the preparation and stabilization of ophthalmic formulations for treating ocular infections such as blepharitis, conjunctivitis, keratitis or other ophthalmic conditions Is disclosed.

  [00018] The present invention is a topical gel composition comprising an iodophor, a penetration enhancer and a gelling agent, which may cause an eye condition such as warts or blepharitis, a virus, acarid mite, a fungus / yeast or It relates to topical gel compositions that are particularly effective in treating bacterial infections. Thus, the present invention further includes a method of treating a viral, acne, fungal / yeast or bacterial infection using the topical gel composition disclosed herein. The composition can further comprise additional pharmaceutically acceptable excipients, or solvents or cosolvents.

  [00019] The compositions of the present invention are active pharmaceuticals approved or approved by the US Food and Drug Administration (FDA) for use in pharmaceutical preparations for topical or ophthalmic administration. An ingredient (API) is preferably included. Preferred compositions of the present invention further comprise inert ingredients or excipients approved by the FDA for topical and / or ophthalmic administration. APIs or inert ingredients or excipients approved by the FDA are referred to herein as “pharmaceutically acceptable”. Accordingly, a topical composition, formulation or preparation of the present invention comprising a pharmaceutically acceptable API, inactive ingredient or excipient is referred to herein as a “pharmaceutically acceptable” topical composition. Called.

  [00020] Similarly, ophthalmic compositions of the present invention that include active or inactive ingredients that are approved by the FDA and that are acceptable for use in ophthalmic preparations are "pharmaceutically acceptable ophthalmic compositions". Or “ophthalmically acceptable” composition, including API, excipients, or “pharmaceutically acceptable” solvents for ophthalmic use.

  [00021] More particularly, the present invention relates to iodophors having a molecular weight in excess of 10,000 Daltons, such as povidone-iodo such as povidone-iodo K30, dimethyl sulfoxide (DMSO) and gelling agents, and optionally additional pharmaceuticals. Or a topical composition that includes an ophthalmically acceptable excipient or solvent or cosolvent. In a preferred embodiment, the composition has a pH value of less than 4.5. Preferably, the pH value is 4.4 or less, 4.3 or less, 4.2 or less, 4.1 or less, 4.0 or less, 3.9 or less, 3.8 or less, 3.7 or less, 3. It can be 6 or less, 3.5 or less, 3.4 or less, 3.3 or less, or 3.2 or less. In this embodiment, the pH value is not limited as long as it is less than 4.5. However, the lower limit of the pH value is, for example, 0, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.45, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2. It can be 9, 3.0, 3.1, or 3.2.

  [00022] Compositions of the present invention treat eye, eyelid, conjunctiva, cornea, ocular surface, meibomian gland or periocular area viral infection or viral wart infection, mite infection, fungal or yeast infection, or bacterial infection Can be useful in methods to do so.

[00023] The topical gel compositions of the present invention are unexpectedly highly stable at room temperature in the presence of aqueous or anhydrous components.
[00024] The topical ophthalmic gel compositions of the present invention comprise from about 0.1% to about 1.5% povidone-iodine (PVP-I), from about 30% to about 99% dimethyl sulfoxide (DMSO) and about From 0.5% to less than 2% gelling agent can be included. The topical gel composition of the present invention is substantially free of gelling agent and comprises about 0.1% to about 1.5% povidone-iodine and about 30% to about 99% DMSO. Compared to, it shows unexpectedly higher efficacy in the treatment of skin infections or blepharitis.

  [00025] A preferred topical ophthalmic gel composition comprises about 0.15-1.5% povidone-iodo (PVP-I). More preferred compositions can comprise from about 0.25% PVP-I to 0.5% PVP-I. PVP-I grade K30 is preferred for use in the present compositions.

  [00026] Preferred topical ophthalmic gel compositions comprise about 30% to about 99% DMSO. More preferred compositions can comprise about 30% to about 70% DMSO. The most preferred compositions of the present invention comprise about 40% to about 49% DMSO, and even more preferably comprise about 44% DMSO.

  [00027] Preferred topical ophthalmic gel compositions comprise from about 0.25% to less than 2.0% gelling agent. More preferred compositions comprise about 0.5% to about 1.75% gelling agent, about 0.75% to about 1.75% gelling agent, about 1.0% to about 1.5% It may comprise a gelling agent, and more preferably about 1.5% gelling agent.

  [00028] A particularly useful topical ophthalmic gel composition prepared for testing comprises 0.25% PVP-I, 44% DMSO, 0.25% to 1.75% hydroxyethylcellulose and 100%. A sufficient amount of aqueous solvent is included. A preferred aqueous solvent is water or an aqueous isotonic solution.

  [00029] Gelling agents useful for preparing the topical ophthalmic gel compositions of the present invention can include gums, agar, carrageenan, petrolatum or cellulose polymers and the like, as is well known in the art. One preferred cellulose polymer useful as a gelling agent is hydroxyethyl cellulose or a salt thereof. An alternative cellulose polymer gelling agent is hydroxymethylcellulose or a salt thereof. An alternative cellulose polymer gelling agent is carboxymethyl cellulose or a salt thereof.

  [00030] The topical ophthalmic gel composition of the present invention preferably comprises povidone-iodo or PVP-I having an average molecular weight greater than 10,000. More preferably, the composition of the present invention comprises PVP-I having an average molecular weight of about 20,000 to about 1,000,000. One preferred embodiment includes PVP-I having an average molecular weight between about 30,000 and about 60,000 or greater. Each of the PVP-I components having an average molecular weight in the range of 10,000 to about 1,000,000 is referred to herein and means “high molecular weight PVP-I” or “HMW PVP-I”.

  [00031] A topical ophthalmic gel composition is one that is ophthalmically acceptable, including one or more ophthalmically acceptable ingredients. Advantageously, the ophthalmic gel composition embodiments described herein are substantially free of gelling agent (or less than the concentration required to form a gel). More in the treatment of eye or eyelid infection conditions as compared to liquid compositions comprising about 0.1% to about 10% povidone-iodine and about 30% to about 99% DMSO. Great potency or stability can be shown.

  [00032] The most preferred topical ophthalmic gel compositions are pharmaceutical grade povidone-iodo in the range of 0.15% to 0.5%, DMSO greater than 30% to 90% DMSO and 0.50% to 2 Including a gelling agent in a range of less than 0.0%. All ratios are w / w unless otherwise specified. This most preferred composition can also include a co-solvent such as polyethylene glycol (PEG). Preferred compositions of the present invention are unexpectedly stable and effective in treating certain eye infections.

  [00033] Preferred embodiments of the composition include an acidic solution and more particularly a gel solution, wherein povidone-iodine is dissolved or solubilized in the final composition. Preferably, the composition is not an emulsion or suspension of the component microparticles in a gel or final composition.

  [00034] Preferred embodiments of the topical gel compositions of the present invention do not include additional APIs or anti-inflammatory drugs such as steroids, such as corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs). Thus, the compositions of the present invention are free of steroids, free of NSAIDs, free of steroids, free of NSAIDs, or have no anti-inflammatory properties (anti-inhibition indicated by certain ingredients comprising the composition). (Except inflammatory properties). Advantageously, the compositions of the present invention are free of additional anti-inflammatory agents, free of steroids, or free of NSAIDs present in the compositions for the treatment of the described ophthalmic conditions. Useful.

[00035] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising 0.75% to less than 2% hydroxyethyl cellulose and water or an isotonic co-solvent;
A gel composition formulated as a topical ophthalmic gel that does not contain additional anti-inflammatory drugs or is “non-anti-inflammatory”.

[00036] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising 0.5% to less than 2.0% hydroxyethyl cellulose and water or an isotonic cosolvent, comprising:
A gel composition formulated as a topical ophthalmic gel that does not contain a steroid (or is “steroid free”).

[00037] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising 0.25% to less than 2.0% hydroxyethyl cellulose and water or an isotonic co-solvent;
It is a gel composition formulated as a topical ophthalmic gel without steroids.

[00038] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising 0.25% to 1.6% hydroxyethyl cellulose and water or an isotonic cosolvent,
A gel composition formulated as a topical ophthalmic gel without steroids.

[00039] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising from 0.25% to less than 2% methylcellulose and water or an isotonic cosolvent,
It is a gel composition formulated as a topical ophthalmic gel without corticosteroids.

[00040] A preferred embodiment of the composition of the present invention is:
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising 1.0% to less than 2% hydroxyethyl cellulose and water or an isotonic cosolvent, comprising:
It is a gel composition formulated as a topical ophthalmic gel that does not contain an NSAID.

  [00041] The method according to the present invention comprises the topical ophthalmic gel composition of the present invention, i.e., iodophor, DMSO and gelling agent, until the ophthalmic infection is removed or substantially inhibited. One or more optional topical administrations or applications of the topical composition generally include. In a preferred method, the gel composition preferably has a result of at least once a day (QD), or more preferably at least twice a day (BID), typically from about 1 week to about 24 weeks. It is administered directly to the site of infection as needed (PRN) until known. Advantageously, the composition of the present invention can be administered directly to the eye or the periocular region and does not exhibit any ocular toxicity.

  [00042] A preferred embodiment of the present invention is a method of treating an eye or eyelid infection condition wherein an effective amount of a stable topical ophthalmic gel composition is applied to the site of infection to reduce or eliminate infection. A method comprising the steps of:

  [00043] The methods of the present invention include blepharitis, conjunctivitis, corneal ulcers, HSV keratitis, caused by or associated with one or more infectious agents such as bacteria, acne mites, fungi or yeast, or viruses. It may be useful for the treatment of conjunctival neoplasms, AC inflammation, postoperative endophthalmitis, and endophthalmitis after intravitreal or anterior chamber injection.

  [00041] The present invention relates to topical gel compositions comprising a disinfectant, a penetration enhancer and a gelling agent. Preferably, the composition comprises povidone-iodine as a disinfectant, dimethyl sulfoxide (DMSO) as a penetration enhancer, a cellulosic gelling agent (hydroxyethylcellulose (HEC), carboxymethylcellulose, sodium carboxymethylcellulose and other cellulose polymers, and Such salts). The composition can optionally further comprise a lubricant or co-solvent, or other pharmaceutically or ophthalmically acceptable excipient. For example, a composition for treating an ophthalmic condition such as blepharitis may comprise an ophthalmically acceptable excipient.

  [00042] The compositions of the present subject matter are surprisingly useful for the treatment of viral, acne, fungal / yeast or bacterial infections of the eye, eyelid, conjunctiva, cornea, ocular surface and meibomian glands that can cause blepharitis is there.

  [00043] Specific but non-limiting examples of formulations of the present invention that provide useful pharmaceutical preparations are dissolved in DMSO containing one or additional co-solvents in solution and are gel or semi-solid As a solid PVP-I.

  [00044] In another embodiment, DMSO can be added to an aqueous solution of PVP-I. In one example, DMSO can be present as a co-solvent with water ranging from 10% to 99%. One embodiment of such a formulation includes water or sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water, and other aqueous or isotonic buffers known to those skilled in the art. A wide range of excipients can be included.

  [00045] The ratios described herein are (w / w) with respect to the specified components in the total composition unless otherwise indicated. For example, a composition comprising 1% PVP-I and 45% DMSO has 1% by weight PVP-I relative to the total composition.

  [00046] In certain embodiments, the composition comprises povidone-iodine in the range of about 0.01% to about 15%. In another embodiment, the composition comprises povidone-iodo in the range of 0.05% to 12.5%. In another embodiment, the composition comprises povidone-iodo in the range of 0.05% to 10.0%. In another embodiment, the composition comprises povidone-iodo in the range of 0.1% to 10.0%. In another embodiment, the composition comprises povidone-iodo in the range of 0.1% to 1.0%. In another embodiment, the composition comprises povidone-iodo in the range of 0.15% to 1.55%. In another embodiment, the composition comprises povidone-iodo in the range of 0.25% to 0.5%.

  [00047] In certain embodiments, the composition comprises about 0.01%, about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0. .30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70 %, About 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.1%, about 1.2%, It includes about 1.3%, about 1.4%, about 1.5%, or any range of povidone-iodine that can be determined from the above ratios. All percentages are expressed as w / w unless otherwise specified.

  [00048] In certain embodiments, the composition comprises DMSO and PVP-I. In certain embodiments, the composition consists essentially of DMSO and PVP-I and a gelling agent in an aqueous or anhydrous diluent. In certain embodiments, the composition consists of DMSO and PVP-I and a gelling agent and a co-solvent in an aqueous or anhydrous diluent. In certain embodiments, the composition is anhydrous. In certain embodiments, the composition is substantially anhydrous. In certain embodiments, the composition comprises a measurable amount of water.

  [00049] In certain embodiments, DMSO, such as anhydrous DMSO, is used in the composition. In certain embodiments, substantially anhydrous DMSO is used in the composition. It will be appreciated by those skilled in the art that DMSO can be produced and / or obtained in various grades, and one of the various grades of DMSO preparation that can vary is the water content. By way of example, DMSO may be completely anhydrous (also referred to herein simply as “anhydrous”), may be substantially anhydrous, or contains measurable water. May be. It will be appreciated that the amount of water that can be measured in a DMSO preparation can vary based on the limitations of the equipment and techniques used to make such measurements.

  [00050] In certain embodiments, DMSO that is not completely anhydrous can be substantially anhydrous and contains water at a level below detectable levels. In certain embodiments, DMSO that is not completely anhydrous may contain water, wherein the water content is at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.04. %, At least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.1%, at least about 0.2% At least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, At least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 5%, at least about 7.5%, at least about 10%, at least about 12.5 % , Or greater than this. It will be appreciated that DMSO may contain one or more other impurities in addition to water.

  [00051] In one embodiment, the composition comprises United States Pharmacopeia (UPS) grade DMSO, active pharmaceutical ingredient (API) grade DMSO, analytical grade DMSO, and American Chemical Society (ACS) spectroscopic grade DMSO. At least one of them. In some embodiments, the composition comprises DMSO having <0.1% water by KF titration and> 99.9% as determined on an anhydrous basis.

  [00052] As explained above, the percent amount of DMSO in the composition is weight to weight ratio (w / w) with respect to one or more other components of the composition, unless otherwise indicated. It is described in. In certain embodiments, weight% DMSO is the remaining weight percent after addition of PVP-I. As a non-limiting example, the composition can comprise 1 weight percent (1%) PVP-I and 99 weight percent (99%) DMSO. In the examples described above, the DMSO component of the composition may be completely anhydrous, substantially anhydrous, or contain measurable water. In certain embodiments, the weight percent DMSO is the weight percent remaining after addition of PVP-I and any other components (eg, co-solvent, water, additional active ingredients, etc.). In certain embodiments, the weight percent DMSO is the remaining weight percent after addition of the iodophor and, if present, other components. In certain embodiments, the weight percent penetrant in the composition is the remaining weight percent after addition of the iodophor and, if present, other components.

  [00053] In certain embodiments, the composition comprises DMSO in the range of 30% to 99.99%. In certain embodiments, the composition comprises DMSO in the range of 35% to 99.99%. In another embodiment, the composition comprises DMSO in the range of 40% -99.9%. In another embodiment, the composition comprises DMSO in the range of 30% -97%. In another embodiment, the composition comprises DMSO in the range of 35% -75%. In another embodiment, the composition comprises DMSO in the range of 40% -50%. In another embodiment, the composition comprises DMSO in the range of 40% -49%. In another embodiment, the composition comprises DMSO in the range of 43% -45%. In another embodiment, the composition comprises 44% DMSO.

  [00054] In certain embodiments, the composition comprises less than 2% gelling agent. In certain embodiments, the composition comprises a gelling agent in the range of 0.10% to less than 2.0%. In another embodiment, the composition comprises a gelling agent in the range of 0.25% to 1.75%. In another embodiment, the composition comprises a gelling agent in the range of 0.5% -1.6%. In another embodiment, the composition comprises from about 0.25% to about 1.95% gelling agent. In another embodiment, the composition comprises 1.75% gelling agent.

  [00055] In certain embodiments, the composition comprises a co-solvent ranging from 1% to 99.99%. In another embodiment, the composition comprises a cosolvent ranging from 5% to 99.9%. In another embodiment, the composition comprises a co-solvent ranging from 10% to 99.9%. In another embodiment, the composition comprises a co-solvent ranging from 20% to 99.9%. In another embodiment, the composition comprises a cosolvent ranging from 30% to 99.9%. In another embodiment, the composition comprises a cosolvent ranging from 40% to 99.9%. In another embodiment, the composition comprises a co-solvent ranging from 50% to 99.9%. In another embodiment, the composition comprises a co-solvent ranging from 60% to 99.9%. In another embodiment, the composition comprises a co-solvent ranging from 70% to 99.9%. In another embodiment, the composition comprises in the range of 80% to 99.9% co-solvent, and in yet another embodiment, 90% to 99.9% co-solvent.

  [00056] In certain embodiments, the composition comprises about 1% co-solvent. In other embodiments, the composition comprises about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, About 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24 %, About 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, About 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49 %, About 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, About 62%, about 63%, about 64%, about 65%, about 66%, about 6 %, About 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, About 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92 %, About 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% co-solvent.

  [00057] Examples of co-solvents include, but are not limited to, alcohol, silicone, polyethylene glycol, propylene glycol, glycerin, petrolatum, hydroxymethylcellulose, methylcellulose, and combinations thereof. In certain embodiments, the co-solvent is polyethylene glycol.

  [00058] In certain embodiments, the composition comprises DMSO in the range of about 0.01% to 99.99% and further comprises at least one penetrant in the range of 0.01% to about 99.99%. . In certain embodiments, the composition comprises DMSO and further comprises at least one penetrant in the range of about 0.1% to about 50%. In another embodiment, the composition comprises DMSO and further comprises at least one penetrant in the range of about 5% to about 50%. In another embodiment, the composition comprises DMSO and further comprises at least one penetrant in the range of about 10% to about 99%. In certain embodiments, the composition comprises DMSO, at least one co-solvent, and at least one penetrant. In certain embodiments, the co-solvent is also a penetrant.

  [00059] In certain embodiments, where possible, the composition may include a pharmaceutically acceptable salt of the compound in the composition. In certain embodiments, the composition comprises an acid addition salt of the compound. In certain embodiments, the composition comprises a base addition salt of the compound. As used herein, the term pharmaceutically acceptable salt or complex refers to a salt or complex (eg, solvate, polymorph) that retains the desired biological activity of the parent compound. Show minimal undesirable toxicological effects.

  [00060] In various embodiments, the compositions encompassed herein include, but are not limited to, protective agents, adsorbents, demulcents, emollients, preservatives, antioxidants, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro), incorporated herein by reference, including moisturizers, buffering agents, solubilizers, skin penetrants and surfactants. Ed. 19th edition 1995); Ghosh, T .; K. Pharmaceutically acceptable excipients such as those listed in TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997).

  [00061] Protecting agents and adsorbents include, but are not limited to, powders, zinc stearate, collodion, dimethicone, silicone, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allantoin, glycerin, petrolatum and Zinc oxide is included.

[00062] Demulsifiers include, but are not limited to, benzoin, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinyl alcohol.
[00063] Emollients include, but are not limited to, animal and plant fats and oils, myristyl alcohol, alum and aluminum acetate.

  [00064] Preservatives include, but are not limited to, chlorine dioxide, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetylimide, decalinium chloride and cetylpyridinium chloride; mercury agents such as nitric acid Phenylmercury, phenylmercuric acetate and thimerosal, etc .; alcoholic agents such as chlorobutanol, phenylethyl alcohol and benzyl alcohol; antibacterial esters such as esters of parahydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chloro Cresol, benzoic acid and polymyxin are included.

  [00065] Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid. included.

[00066] Suitable humectants include, but are not limited to, glycerin, sorbitol, polyethylene glycol, urea and propylene glycol.
[00067] Suitable solubilizers include, but are not limited to, quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin and polysorbate.

  [00068] Suitable skin penetrants include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethysulfoxide, fatty acid esters (eg, myristic Isopropyl acid, methyl laurate, glycerol monooleate and propylene glycol monooleate); and N-methylpyrrolidone.

  [00069] In certain embodiments, the composition comprises PVP-I, DMSO and polyethylene glycol and a gelling agent. In certain embodiments, the composition comprises 0.25% PVP-I, 44% DMSO, 10% polyethylene glycol and 1.75% gelling agent. In certain embodiments, the composition comprises PVP-I, DMSO, hydroxyethyl cellulose, propylene glycol and glycerin. In certain embodiments, the composition comprises 2% PVP-I, about 40% DMSO and 10-33% propylene glycol, a gelling agent and at least one additional inert ingredient.

  [00070] In one embodiment, the present invention provides 40-50% (w / w) DMSO, 0.25% -0.55% PVP-I (w / w) and hydroxypropylmethylcellulose or hydroxymethylcellulose or Hydroxyethyl cellulose or carboxymethyl cellulose and salts thereof are included.

  [00071] In one embodiment, the composition is a solution and may be formulated as a semi-solid, such as a gel, ointment or cream; a tincture; a foam; an aerosol or another common pharmaceutical dosage form. it can. In one embodiment, the composition is a 0.25% PVP-I / 44% DMSO solution dissolved in a 1.75% gel such as hydroxyethylcellulose having a pH of less than 4.5.

Stability A. Visible loss of chromophore
[00072] Topical ophthalmic compositions containing various amounts and combinations of povidone-iodine, DMSO and gelling agent components have been prepared to demonstrate unpredictable stability for the subject compositions and gel formulations The surprising result is that lowering the pH of the gel allows stabilization of gelling agents at concentrations lower than those already taught that are possible with similar PVP-I / DMSO compositions It has been shown.

  [00073] Compositions that are highly unstable and therefore not suitable or useful as topical ophthalmic preparations will lose color and appear colorless within about 72 hours of making the preparation . The colorless state is the result of the loss of titratable iodine as compared to the amount of iodine in the povidone-iodo starting material. For compositions that become colorless within 72 hours of preparation, no further validation of titratable iodine is necessary.

  [00074] Compositions were prepared with 0.15%, 0.25%, and 0.5% povidone-iodine. For these compositions, DMSO was supplied in an amount of 0% or in an amount of 30% to 90%. A specific composition containing DMSO was prepared containing 44% DMSO. Gelling agents are in amounts of 0%, 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75% and 1.95% Supplied.

  [00075] Do all prepared compositions of aqueous, only PVP-I and water, 0% DMSO and 0% gelling agent substantially lose most of these tones within 72 hours at room temperature? Or completely colorless and was not determined to be stable for further use.

  [00076] For a preparation comprising 0.15% povidone-iodine and DMSO in the range of 30% to 90%, the composition retains color tone when the gelling agent is supplied at 0.75% And stable. The long-term stability of the composition that retained color for 72 hours or longer was confirmed by a modified USP assay for titratable iodine compared to the povidone-iodine starting material. The stable composition of the present invention retained at least 85% of titratable iodine in the povidone-iodo starting material for up to 2 weeks when stored at room temperature and not shielded from light.

  [00077] For a preparation comprising 0.25% povidone-iodine and DMSO in the range of 30% to 90%, the composition has a hue when the amount of gelling agent is 0.5% or more. It was held and stable. The long-term stability of the composition that retained color for 72 hours or longer was confirmed by a modified USP assay for titratable iodine compared to the povidone-iodine starting material. The stable composition of the present invention retained at least 85% of titratable iodine in the povidone-iodo starting material for up to 1 month upon storage.

  [00078] For a preparation comprising 0.5% povidone-iodine and DMSO in the range of 30% to 90%, the composition has a color tone when the amount of gelling agent is 0.75% or more. It was held and stable. The long-term stability of the composition that remained in color for 72 hours or longer was confirmed by a modified USP assay for titratable iodine compared to the povidone-iodine starting material. The stable composition of the present invention retained at least 85% of titratable iodine in the povidone-iodo starting material at room temperature for up to 1 month.

  [00079] These experimental results show that amounts within specified ranges are 0.15% to 0.5% povidone-iodine, 30% to 90% DMSO and 0.5% to 1.75%. While the stability of a particular combination of ingredients of the gelling agent is stable, a composition in a particular range of amounts deviating from these particular ingredients [specifically, at least 0.5% (w / w) Those that do not contain a gelling agent] prove to be unstable. Preferred gelling agents are cellulose polymers such as hydroxyethylcellulose (HEC), hydroxymethylcellulose (HMC), hydroxypropylmethylcellulose (HPMC). The most preferred gelling agent is hydroxyethyl cellulose (HEC).

  [00080] A table showing the results of stability experiments using selected compositions is presented below:

  [00081] In one embodiment, the formulation is stable for at least 6 months, 12 months, 18 months, and 24 months at room temperature of 25 ° C. Stability is defined as a final PVP-I concentration of at least 85% to 120% of the concentration of the label, according to the USP titration method for povidone-iodine.

  [00082] In one embodiment, the formulation is stable for at least 6 months, 12 months, 18 months and 24 months at a temperature of 2-8 ° C. Stability is defined as a final PVP-I concentration of at least 85-120% of the concentration of the label according to the USP method (eg, 2% PVP-I where the label yields 0.2% iodine). 90% would be 0.18% elemental iodine).

  [00083] In one embodiment, the formulation is stable for at least 6 months, 12 months, 18 months and 24 months at room temperature -10 to -25 ° C. Stability is defined as a final PVP-I concentration of at least 85-120% of the concentration of the label according to the USP method (eg, 2% PVP-I where the label yields 0.2% iodine). 90% would be 0.18% elemental iodine).

  [00084] In one embodiment, the formulation is stable at room temperature 15-30 ° C for at least 6, 12, 18, and 24 months. Stability is defined as a final PVP-I concentration of at least 85-120% of the concentration of the label according to the USP method (eg, 2% PVP-I where the label yields 0.2% iodine). 90% would be 0.18% elemental iodine).

  [00085] In one embodiment, the formulation is stable for at least 1 month, 3 months, 6 months, 12 months, 18 months and 24 months at a room temperature of 40 ° C. Stability is defined as a final PVP-I concentration of at least 85-120% of the concentration of the label according to the USP method (eg, 2% PVP-I where the label yields 0.2% iodine). 90% would be 0.18% elemental iodine).

Methods of preparation and use
[00086] It is known to those skilled in the art that aqueous PVP-I solutions are difficult to stabilize at low PVP-I concentrations over long periods of time. As a non-limiting example, at a concentration of PVP-I of less than about 0.6% (w / w, aqueous), the PVP-I aqueous solution rapidly decays, iodinated components and iodine. Resulting in a composite mixture consisting of a composition free of

  [00087] As described herein, surprisingly, a PVP-I gel as low as 0.15% in an aprotic DMSO solvent system encompassed by the disclosure described herein It has been found that the solution can be easily prepared and can be maintained as a stable composition for an extended period of time. Similarly, as already described, a hydrated DMSO solution prepared from aqueous PVP-I and sufficient (about 2% or more) gelling agent is a PVP-I component at room temperature for at least 12 months. Demonstrate improved component stability. Surprisingly, for the first time and contrary to the teachings of the prior art, even when gelling agents, specifically gelling agents HEC as low as 0.5%, are used, using an acidic solution of HEC, It has been demonstrated in the present application that low concentrations of PVP-I / DMSO gel can be stabilized.

  [00088] In certain embodiments, the composition comprises dry solid or dry powder PVP-I that is dissolved or suspended in a composition comprising or consisting of DMSO. In another embodiment, DMSO is added to an aqueous preparation comprising or consisting of PVP-I.

  [00089] A person skilled in the art how to prepare a composition based on the disclosure herein and, among other possible components of the composition encompassed herein, in particular iodine, It will be understood without undue experimentation that the desired amount of iodophor and DMSO will be reached.

  [00090] As a non-limiting example, a therapeutically effective pharmaceutical composition is prepared using solid PVP-I dissolved or suspended in DMSO. In one aspect, the composition is anhydrous. In one aspect, the composition is substantially anhydrous. In another embodiment, DMSO can be added to an aqueous solution of PVP-I to prepare a therapeutically effective pharmaceutical composition. In certain embodiments, DMSO is used as a co-solvent with water and other non-aqueous co-solvents in the range of 30% to 99%. In certain embodiments, the formulation comprises one or more excipients. As non-limiting examples, excipients include but are not limited to sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water, and others known to those skilled in the art. included.

  [00091] In an embodiment, the composition comprises PVP-I (w / v, aqueous) added to a pure sufficient amount of DMSO to comprise 0.15-1.5% PVP- containing DMSO. Prepared by providing the resulting solution of I (w / w). In another embodiment, the composition comprises 0.1%, 0.2%, 0.25%, 0% of solid PVP-I dissolved in pure sufficient amount of DMSO and comprising DMSO as solvent. Prepared by obtaining either a 3%, 0.35%, 0.4%, 0.45% or 0.5% PVP-I (w / w) composition. In yet another embodiment, the composition dissolves solid PVP-I in a pure sufficient amount of DMSO and any of the described and / or included herein is described. It is prepared by obtaining a composition. A similar composition comprising aqueous PVP-I (with and without commonly used and / or known excipients) and DMSO and 10% PVP-I stock aqueous solution and pure DMSO Can be prepared from The gelling agent is less than 2.0% (w / w) of the final concentration of the composition, preferably about 0.5% to 1.75%, about 0.5% to 1.0%, and 1 Can be added in an amount of 5%. Acidification of the composition can be achieved by adding any number of commonly used acidifying agents, including but not limited to HCl.

  [00092] However, one skilled in the art understands that either appropriate solid and liquid PVP-I starting compositions can be used if appropriate dilutions and adjustments are made to provide the desired final PVP-I concentration. Let's be done. Similarly, any starting composition of iodophor or elemental iodine can be used if appropriate dilutions and adjustments are made to provide the desired final iodophor or elemental iodine concentration, respectively.

  [00093] In view of the skill in the art, based on the disclosure described herein, specific dosages of the compounds and compositions encompassed herein are clinical and / or drug It will be appreciated that it can be determined empirically by kinetic experiments and that such dosages can be adjusted according to pre-specified efficacy and / or toxicity criteria. The specific dose and treatment regimen for any particular patient will depend on the activity of the specific compound used, patient characteristics, drug combination, the judgment of the treating physician, and the nature and severity of the particular disease or condition being treated It will also be understood that it depends on various factors, including the degree.

  [00094] In certain embodiments, the therapeutic composition is prepared by optimizing one or more compounds for use in a dosage form, wherein the dosage form is typically used for the compound. Different from what is done. In certain embodiments, compounds that are typically not administered in topical dosage forms are developed for use in topical dosage forms. The chemical and biological assays necessary for such development are known to those skilled in the art. The disclosure herein provides one of ordinary skill in the art with guidance regarding how to prepare such compounds and compositions containing such compounds.

  [00095] In certain embodiments, a method of treating a subject having an ocular surface disorder that has been complicated by microbial colonization and / or infection is described herein for treating an ocular surface disorder. The treatment of the ocular surface disease prevents or slows the progression of the infection, prevents the spread of the infection, includes the administration of the described, described and / or included compositions. Including at least one of eradicating at least a portion and eradicating all of the infection.

  [00096] In certain embodiments, the therapeutic composition is administered on a once daily schedule. In certain embodiments, the therapeutic composition is administered twice daily. Typically, the gel composition of the present invention is administered as a ribbon having a length of about 1 cm to about 5 cm and a diameter of up to 1 cm on the eye, under the eyelid, or in the periocular region of the eye to be treated. can do.

  [00097] In certain embodiments, the therapeutic composition is administered three times daily, four times daily, five times daily, or more. In certain embodiments, the therapeutic composition is administered less frequently than once a day. In certain embodiments, the therapeutic composition is once every two days, once every three days, once every four days, once every five days, once every six days, or every seven days. It is administered once. In certain embodiments, the therapeutic composition is administered less frequently than once a week. In certain embodiments, the therapeutic composition is administered once a month. In embodiments, the therapeutic composition is administered twice a month.

  [00098] In certain embodiments, the therapeutic dosing regimen is continued for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In certain embodiments, the therapeutic dosing regimen is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, or at least 16 Continued for a week. In certain embodiments, the therapeutic dosing regimen is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 Continued for months.

  [00099] The present invention is further illustrated by the following examples. In one aspect, the following examples demonstrate effective and / or successful treatment of a specified condition using the compositions and methods encompassed by this disclosure. It should be appreciated that variations based on the features of the present invention are within the skill of those in the art and that the scope of the present invention is not limited by the examples. In order to properly determine the scope of the invention, those skilled in the art should consider the claims hereof and their equivalents. The entire disclosures of International Patent Applications PCT / US2012 / 036942 and PCT / US2012 / 065298 are hereby incorporated by reference as if fully set forth herein. In addition, all citations herein are incorporated by reference and all percentages are on a weight / weight basis unless specifically stated otherwise.

  [000100] Additional examples of useful compositions described for the present invention include creams, petrolatum balms, ointments, spray formulations, and other formulations well known to those skilled in the art suitable for topical administration to the ocular surface. Included or additional examples are “ophthalmically acceptable” compositions.

  [000101] The examples and descriptions provided herein are not intended and are not intended to limit the breadth of protection provided within the full scope and spirit of the described invention. .

  [000102] The results of clinical treatment using the composition according to the invention are shown in Table 14A below:

Treatment example
[000103] The following are examples of clinical treatments that can be performed using the compositions of the present invention, both male and female, young, middle-aged and elderly patients that may result from such treatment Are based on the stability and efficacy demonstrated by the compositions developed and tested according to the present disclosure, which would have been unpredictable in view of the prior art Expected.

(1)
An 82-year-old woman could exhibit obvious binocular discomfort, pain, redness and leakage. Ophthalmoscopic examination revealed 2+ erythematous conjunctiva in both eyes with mild conjunctival edema and leakage. When the eyelids were flipped outward, the papillary and follicular reactions were mixed. The patient was diagnosed with bacterial conjunctivitis and a dosing regimen was used, thus about 1.27 cm (about 1.27 cm of a composition containing 1.5% HEC, 0.25% PVP-I and 44% DMSO. A 1/2 inch ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice daily for 7 days. After 3 days of treatment, both conjunctival edema and erythema began to improve. By day 5, the remaining inflammation was reduced and no visual examination was noticeable. The patient found complete symptom relief and the patient regained normal function.

(2)
An 87-year-old woman presented with recurrent, obvious binocular discomfort, pain, redness and green leakage. The woman had previously been admitted to the ICU, where she was diagnosed with a multi-drug resistant MRSA eye infection. Ophthalmoscopic examination revealed a 4+ erythematous conjunctiva in both eyes with mild conjunctival edema and leakage. The eyelid test was positive for common mixed blepharitis with eyelid edema and erythema. This patient was diagnosed with MRSA, a multidrug resistant bacterial blepatic conjunctivitis, and a dosing regimen was used, thus 1.0% HEC, 0.50% PVP-I and 44% DMSO. Approximately 1/2 inch ribbon or gel eye drop of the composition comprising it is administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice a day for 10 days. After 3 days of treatment, both conjunctival edema and erythema began to improve. By day 6, eyelid edema and erythema began to relieve. On the 8th day, the remaining inflammation was resolved and no visual examination was noticeable. The patient was found to have fully symptomatically regained normal function with no recurrence.

(3)
A 77-year-old man presented with obvious binocular discomfort, itching, redness and eyelid inflammation. Ophthalmoscopic examination revealed a slight erythematous conjunctiva in both eyes without conjunctival edema or leakage. Eyelid examination revealed 3+ eyelid edema with erythema and non-cylindrical collarettes. There was a concentration and plugging of 2+ meibomian glands. This patient was diagnosed with mixed anterior and posterior blepharitis and a dosing regimen was used, thus approximately about a composition comprising 0.75% HEC, 0.25% PVP-I and 44% DMSO. A 1.27 cm (1/2 inch) ribbon or gel eye drop was administered directly to the skin of the infected eyelid below the eyelid margin. This composition was administered twice daily for 14 days. After 5 days of treatment, both conjunctival edema and erythema began to improve. By the 10th day, the viscosity of the posterior eyelid meibum had decreased and the occlusion was resolved. At the end of the 2 week treatment cycle, the remaining inflammation was reduced and no visual examination was noticeable. The patient recognized complete symptom relief and returned to normal function.

(4)
A 72-year-old woman presented with obvious binocular discomfort, itching, redness and eyelid inflammation. The woman has not been successful in treating blepharitis in the past. Ophthalmoscopic examination revealed a slight erythematous conjunctiva in both eyes without conjunctival edema or leakage. Eyelid examination revealed 3+ eyelid edema with erythema and cylindrical collet at the bottom of the eyelashes. Wet mount prep under 25x magnification revealed the presence of Demodex folliculorum. This patient was diagnosed with blepharitis caused by acne and used a dosing regimen, thus about 1.27 cm of a composition comprising 1.75% HEC, 0.50% PVP-I and 44% DMSO. (1/2 inch) ribbon or gel eye drop was administered directly to the skin of the infected eyelid below the lid margin. This composition was administered twice daily for 14 days. After 5 days of treatment, both conjunctival edema and erythema began to improve. By day 7, there is no longer a cylindrical collet. At the end of the 2 week treatment cycle, the remaining inflammation was reduced and no visual examination was noticeable. The patient found complete relief of symptoms and returned to normal function.

(5)
A 68 year old man presented with obvious binocular discomfort, itching, crusting, redness and eyelid inflammation. The man also had a rhinomas and intermittent facial flushing. Ophthalmoscopic examination revealed a slight erythematous conjunctiva in both eyes without conjunctival edema or leakage. Eyelid examination revealed 2+ eyelid edema with erythema and scales. 2+ meibomian gland obstruction was also present with tortuous posterior lid margin capillary dilatation. This patient was diagnosed with rosacea blepharitis and a dosing regimen was used, thus about 1.27 cm of a composition comprising 1.25% HEC, 0.25% PVP-I and 44% DMSO. (1/2 inch) ribbon or gel eye drop was administered directly to the skin of the infected eyelid. This composition was administered twice daily for 14 days. After 5 days of treatment, both conjunctival edema and erythema began to improve. By the 10th day, the adhesion of the posterior lid meibum had decreased and the occlusion was resolved. At the end of the 2 week treatment cycle, the remaining inflammation was reduced and the capillary dilation of the lid margin was considerably weakened. There was nothing particularly noticeable in the visual inspection. The patient found symptomatic relief and returned to normal function.

(6)
A 52-year-old man presented with obvious binocular discomfort, pain, redness and turbidity-free leakage. The man admitted recent contact with others in his family in contact with epidemic conjunctivitis. Ophthalmoscopic examination revealed erythematous conjunctiva in both eyes with mild conjunctival edema and leakage. There is no subepithelial invasion or pseudomembrane. Turning the heel outward reveals that it is a common follicular reaction, and the nodes in front of the pinna are palpable. The patient was diagnosed with viral conjunctivitis and used a dosing regimen, thus about 1.27 cm (about 1.27 cm of a composition comprising 1.75% HEC, 0.25% PVP-I and 44% DMSO. A 1/2 inch ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice daily for 10 days. After 3 days of treatment, both conjunctival edema and erythema began to improve. By day 5, the remaining inflammation was reduced and no visual examination was noticeable. The patient continues to take medication for a total period of 7 days to reduce the chance of viral shedding. The man acknowledged complete symptom relief and regained normal function.

(7)
A 27-year-old woman presented with obvious binocular discomfort, pain, itching, redness and no cloudiness. The woman admitted recent contact with others in her family in contact with epidemic conjunctivitis. Ophthalmoscopic examination revealed erythematous conjunctiva in both eyes with mild conjunctival edema and leakage. There was subepithelial invasion of the cornea and early pseudomembrane was visualized in the lower lid of the eyelid. Turning the heel outward revealed a common follicular reaction, and the nodes in front of the pinna were palpable. This patient was diagnosed with epidemic keratoconjunctivitis secondary to adenovirus infection and a dosing regimen was used, thus a composition containing 1.25% HEC, 0.25% PVP-I and 44% DMSO About 1.27 cm (1/2 inch) ribbon or gel eye drop of the article was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice daily for 10 days. After 3 days of treatment, both conjunctival edema and erythema began to improve. By day 5, the remaining inflammation was reduced and no visual examination was noticeable. The patient continues to take medication for a total period of 7 days to reduce the chance of viral shedding. The patient acknowledged complete symptom relief and regained normal function.

(8)
A 35-year-old man presented with obvious one-eye discomfort, redness and leakage after hitting plant matter in his eyes. Ophthalmoscopic examination revealed a 2+ erythematous conjunctiva with mild conjunctival edema and leakage. Corneal examination was positive for staining 2 × 2 mm corneal ulceration with infiltration and showed crenate, feathered edges. Corneal cultures revealed the growth of filamentous fungi. This patient was diagnosed with a fungal corneal ulcer associated with trauma and the dosing regimen was used, thus a composition comprising 1.75% HEC, 0.50% PVP-I and 44% DMSO. Approximately 1/2 inch ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 1 month. After 5 days of treatment, both conjunctival edema and erythema began to improve. By the second week, corneal infiltration begins to shrink, the cornea re-epithelializes and no marginal white cells are present. At the end of 3 weeks, there is still a small pinpoint infiltration, and by the end of this month, the cornea is free of turbidity, compact in the middle, and still has an inert scar. All remaining inflammation was alleviated and nothing was noticeable by visual inspection. The patient recognized complete symptom relief and regained normal function.

(9)
A 22-year-old woman presented with obvious single-eye discomfort, redness and leakage after sleeping overnight with contact lenses. Ophthalmoscopic examination revealed a 2+ erythematous conjunctiva with mild conjunctival edema and leakage. Corneal examination was positive for stained 3 × 2 mm corneal ulceration with infiltration, pus and 25% interstitial thinning. By corneal culture, Pseudomonas spp. The growth of was revealed. This patient was diagnosed with a bacterial corneal ulcer and the dosing regimen was used, thus about 1. of a composition comprising 0.75% HEC, 0.50% PVP-I and 44% DMSO. A 27 cm (1/2 inch) ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 3 weeks. After 5 days of treatment, both conjunctival edema and erythema began to improve. By the second week, corneal infiltration begins to shrink, the cornea re-epithelializes and no marginal white cells are present. At the end of 3 weeks, the cornea was free of turbidity, compacted in the middle, and there was an inert scar in the area of the previous ulcer. There was nothing particularly noticeable in the visual inspection. The patient recognized complete symptom relief and regained normal function.

(10)
A 27-year-old woman presented with obvious single-eye discomfort, redness, and leakage after sleeping overnight with contact lenses and using suspect contact lens solutions. Ophthalmoscopic examination revealed a 2+ erythematous conjunctiva with mild conjunctival edema and leakage. Corneal examination was positive for annular ulcer with disproportionate pain to the examination. By corneal culture, Acanthamoeba spp. The growth of was revealed. This patient was diagnosed with corneal ulcers with Acanthamoeba and used a dosing regimen, thus about 1. of a composition comprising 1.50% HEC, 0.50% PVP-I and 44% DMSO. A 27 cm (1/2 inch) ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 3 weeks. After 5 days of treatment, both conjunctival edema and erythema began to improve. By the second week, the corneal annular infiltration begins to shrink, the cornea re-epithelializes and there are no surrounding marginal white cells. At the end of 3 weeks, the cornea was free of turbidity and became compact in the center. There was nothing particularly noticeable in the visual examination. The patient recognized complete symptom relief and regained normal function.

(11)
A 45-year-old male business professional presented with obvious single-eye discomfort, pain and redness. The patient remembers that a similar episode occurred several years ago. Ophthalmoscopic examination revealed a 2+ erythematous conjunctiva. Corneal examination was positive for stained dendritic corneal ulceration. This patient was diagnosed with herpes simplex virus epithelial keratitis, and a dosing regimen was used, thus about a composition comprising 1.25% HEC, 0.50% PVP-I and 44% DMSO. A ½ inch ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 2 weeks. After 5 days of treatment, the erythema of the eye began to improve and the dendrites weakened. By the second week, the dendrites were completely resolved and the cornea was re-epithelialized, becoming turbid and compact. There was nothing particularly noticeable in the visual inspection. The patient recognized complete symptom relief and regained normal function.

(12)
An 81-year-old woman presented with obvious single-eye discomfort, pain, redness, and decreased vision. At visual inspection, there was a peeled skin rash, including both the face and scalp. An ophthalmoscopic examination revealed 2+ erythematous conjunctiva without leakage. Corneal examination was positive for bulging epithelial dendriform lesions. This patient was diagnosed with ocular shingles and a dosing regimen was used, thus about 1.27 cm of a composition comprising 1.00% HEC, 0.50% PVP-I and 44% DMSO. (1/2 inch) ribbon or gel eye drops were administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 2 weeks. After 5 days of treatment, the conjunctival erythema began to improve and the dendritic lesions weakened. By the second week, these lesions were completely resolved and the cornea was re-epithelialized, becoming turbid and compact. There was nothing particularly noticeable in the visual inspection. The patient recognized complete symptom relief and regained normal function.

(13)
A 68-year-old woman presented with obvious one-eye discomfort, pain and redness. The woman remembers that a similar episode occurred several years ago and states that she has a history of herpes infection of the eye. An ophthalmoscopic examination revealed 2+ erythematous conjunctiva without leakage. Corneal examination revealed an intact corneal epithelium, but the corneal matrix exhibits 2+ edema that presents the underlying corneal deposits in the form of money. This patient was diagnosed with herpes simplex virus interstitial keratitis and endothelial keratitis, and a dosing regimen was used, thus 0.75% HEC, 0.50% PVP-I and 44% Approximately 1/2 inch ribbon or gel eye drops of a composition containing DMSO was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 2 weeks. After 5 days of treatment, erythema in the eye began to improve and interstitial edema began to recede. By the second week, the changes in the endothelium are reversed and posterior corneal deposits are no longer present. There was nothing particularly noticeable in the visual inspection. The patient recognized complete symptom relief and regained normal function.

(14)
A 26-year-old woman presented with obvious binocular discomfort, itching, redness and eyelid inflammation. The woman had a history of HIV and was immunocompromised. Ophthalmoscopic examination revealed a slight erythematous conjunctiva in both eyes without conjunctival edema or leakage. Eyelid examination revealed 1+ eyelid edema with multiple dome-shaped papules with a central umbilical fossa present in both the erythema and the lower eyelid. The patient was diagnosed with infectious molluscum and used a dosing regimen, thus about 1. of a composition comprising 1.50% HEC, 0.50% PVP-I and 44% DMSO. A 27 cm (1/2 inch) ribbon or gel eye drop was administered directly to the skin of the infected eyelid below the eyelid margin. This composition was administered twice daily for 14 days. After 5 days of treatment, both conjunctival erythema and eyelid erythema began to improve. By day 8, the lid papules with umbilical fossa have returned to normal and at the end of the treatment cycle these are no longer present. In the remainder of the eye study, there was nothing noticeable and the patient found complete symptom relief.

(15)
A 77-year-old man presented with a unilateral mass located near the edge. Ophthalmoscopic examination revealed hyperconjunctiva with white plate growth, including both conjunctiva and cornea stained with rose bengal. Biopsy revealed corneal and conjunctival epithelial neoplasms consistent with a carcinoma in situ. The patient was diagnosed with CIN and used a dosing regimen, thus about 1.27 cm (1/1 of a composition containing 1.5% HEC, 0.25% PVP-I and 44% DMSO. 2 inches) of ribbon or gel eye drops were administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered 4 times a day for 3 months. After 1 week of treatment, erythema began to improve. By the first month, the mass had significantly decreased in size. By the second month, there are only a few remaining areas of irregular conjunctiva. By the third month, the conjunctiva was not turbid, and no visual examination was noticeable. The patient recognized complete symptom relief and regained normal function. Biopsy after treatment was negative for the neoplasm.

(16)
A 66-year-old woman presented with obvious binocular discomfort, pain, redness and foreign body sensation. Ophthalmoscopic examination revealed a +1 erythematous conjunctiva in both eyes with punctate epithelial erosion and reduced Schirmer test. The eyelid examination was within the normal range. This patient was diagnosed with dry eye deficiency and used a dosing regimen, thus about 1 of the composition containing 0.25% HEC, 0.25% PVP-I and 44% DMSO. A 1/2 inch ribbon or gel eye drop was administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice a day for one month. After 5 days of treatment, the conjunctival erythema began to improve and the patient's symptoms also began to improve. By the second week, corneal spotted epithelial erosion was resolved. At one month, the Schermer test was normal and the patient experienced complete resolution of symptoms.

(17)
A 72-year-old woman presented with obvious binocular discomfort, pain, redness and foreign body sensation. Ophthalmoscopic examination revealed a +1 erythema conjunctiva in both eyes, with punctate epithelial erosion and normal Schirmer test and reduced tear film destruction time. By eyelid test, it was positive for mild meibomian gland capping with concentration. This patient was diagnosed with evaporative dry eye and a dosing regimen was used, thus about 1.27 cm of a composition comprising 0.50% HEC, 0.25% PVP-I and 44% DMSO. (1/2 inch) ribbon or gel eye drops were administered directly to the surface of the infected eye between the corneal surface and the lower eyelid. This composition was administered twice a day for one month. After 5 days of treatment, the conjunctival erythema began to improve and the patient's symptoms also began to improve. By the second week, corneal spotted epithelial erosion was resolved. At one month, the tear film disruption test normalized and the patient experienced complete resolution of symptoms.

(18)
An 86-year-old man with wet macular degeneration visited his male ophthalmologist for intravitreal injection with an anti-VEGF agent. An ophthalmoscopic examination revealed mild bullitis in both eyes, and the posterior segment was positive for choroidal neovascular complex. The eyelid examination was within the normal range. This patient was diagnosed with wet macular degeneration and an administration regimen was used to sterilize the ocular surface prior to intravitreal injection, thus 0.75% HEC and 0.1% prior to the procedure. An approximately 1.27 cm (1/2 inch) ribbon or gel eye drop of a composition comprising 50% PVP-I and 44% DMSO is applied directly to the ocular surface between the corneal surface and the lower eyelid. Was administered. This was repeated four times while looking at the eyes upward, downward, adduction and abduction. This procedure was then performed without complications or infection.

(19)
An 86-year-old male with wet macular degeneration visited the male ophthalmologist to remove the mass of the eyelid. Ophthalmoscopic examination revealed that there was mild binocular blepharitis and a pedunculated neoplasm that included part of the eyelid. The patient is diagnosed with a neoplastic mass of the eye scheduled for surgical resection. Prior to the procedure, a dosing regimen was used to disinfect the eyelids, eyelashes and cheeks, thus about 1 of the composition comprising 1.75% HEC, 0.50% PVP-I and 44% DMSO. A 27 inch (1/2 inch) ribbon or gel eye drop was administered directly to the eyelids, eyelashes and cheeks. This was repeated twice while looking at the eyes upward, downward, adduction and abduction. This procedure was then performed without complications or infection.

(20)
An 89-year-old woman with wet macular degeneration visited the woman's ophthalmologist for cataract surgery. Previous ophthalmoscopic examination revealed mild binocular blepharitis and 3+ nuclear sclerosis. The eyelid examination was within the normal range. This patient was visually diagnosed with mature cataract and a dosing regimen was used to disinfect the ocular surface prior to cataract surgery and 0.50% HEC and 0. An approximately 1.27 cm (1/2 inch) ribbon or gel eye drop of a composition comprising 50% PVP-I and 44% DMSO is applied directly to the ocular surface between the corneal surface and the lower eyelid. Was administered. This was repeated four times while looking at the eyes upward, downward, adduction and abduction. This procedure was then performed without complications or infection.

While the above description will enable those skilled in the art to reproduce and use what is currently considered the best form, those skilled in the art will recognize the specific embodiments, methods provided above. And the existence of variations, combinations, derivatives, analogs and equivalents of the examples will be understood and appreciated. Accordingly, the present invention should not be limited by the above.
The description of the scope of claims at the time of filing is shown below.
[Claim 1]
0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising from 0.25% to less than 2.0% gelling agent and water or an isotonic cosolvent,
A gel composition that is a topical ophthalmic gel, has a pH of less than 4.5, and does not contain additional anti-inflammatory agents.
[Claim 2]
The stable gel composition of claim 1 comprising 0.15% to 1.25% PVP-I.
[Claim 3]
The stable gel composition of claim 1 comprising 0.25% to 1.0% PVP-I.
[Claim 4]
The stable gel composition of claim 1 comprising about 0.25% PVP-I.
[Claim 5]
The stable gel composition of claim 1 comprising about 0.50% PVP-I.
[Claim 6]
The stable gel composition of claim 1 comprising about 0.75% PVP-I.
[Claim 7]
The stable gel composition of claim 1 comprising 30% to 70% DMSO.
[Claim 8]
The stable gel composition of claim 1 comprising 40% -49% DMSO.
[Claim 9]
The stable gel composition of claim 1 comprising 44% DMSO.
[Claim 10]
The stable gel composition of claim 1 comprising about 0.25% gelling agent.
[Claim 11]
The stable gel composition of claim 1 comprising about 0.50% gelling agent.
[Claim 12]
The stable gel composition of claim 1 comprising about 1.0% gelling agent.
[Claim 13]
The stable gel composition of claim 1 comprising about 1.25% gelling agent.
[Claim 14]
The stable gel composition of claim 1 comprising about 1.50% gelling agent.
[Claim 15]
The stable gel composition of claim 1 comprising 1.75% gelling agent.
[Claim 16]
The stable gel composition according to claim 1, wherein the gelling agent is a cellulose polymer.
[Claim 17]
The stable gel composition according to claim 1, wherein the gelling agent is hydroxyethyl cellulose (HEC).
[Claim 18]
0.25% PVP-I,
44% DMSO,
A gelling agent greater than 0.25% and less than 2.0%, and a co-solvent,
The stable gel composition of claim 1, which is free of steroids and free of NSAIDs.
[Claim 19]
The stable gel composition of claim 18, wherein the co-solvent is water or an aqueous isotonic solution.
[Claim 20]
The stable gel composition of claim 18, wherein the gelling agent is a cellulose polymer.
[Claim 21]
20. The stable gel composition according to claim 19, wherein the cellulose polymer is hydroxyethyl cellulose (HEC).
[Claim 22]
A stable gel composition according to claim 1, wherein the composition is a topical ophthalmic preparation, each component is ophthalmically acceptable, and the ophthalmic gel composition is povidone- Such a composition retains at least 85% of titratable iodine in the iodo starting material.
[Claim 23]
2. The stable gel composition of claim 1 that retains at least 85% of titratable iodine in the povidone-iodo starting material for at least one month.
[Claim 24]
The stable gel composition of claim 1 which retains at least 85% of titratable iodine in the povidone-iodo starting material for up to 12 months.
[Claim 25]
A method for preventing infection of the eye or eyelid,
Applying an effective amount of the stable topical ophthalmic gel composition of claim 1 to the eye or eyelid or periocular skin surface prior to eye surgery or invasive procedures including intraocular or intravitreal injection A method comprising the steps of:
[Claim 26]
The infectious condition is selected from the group consisting of blepharitis, conjunctivitis, corneal ulcer, bacterial keratitis, viral keratitis, postoperative endophthalmitis, and endophthalmitis after intravitreal or anterior chamber injection 26. The method of claim 25.
[Claim 27]
26. The method of claim 25, wherein the infectious condition is caused by or associated with one or more infectious agents selected from the group consisting of bacteria, acne mites, fungi or yeast, and viruses.
[Claim 28]
26. The method of claim 25, wherein the condition is blepharitis, blephar conjunctivitis, conjunctivitis, keratitis or infectious corneal ulcer.
[Claim 29]
28. The method of claim 27, wherein the infectious agent is a virus.
[Claim 30]
28. The method of claim 27, wherein the infectious agent is a mite.
[Claim 31]
A method of treating an eye or eyelid infection condition comprising:
A method comprising applying an effective amount of the stable topical ophthalmic gel composition of claim 1 to the site of infection as needed to reduce or eliminate infection.
[Claim 32]
The infectious condition is selected from the group consisting of blepharitis, conjunctivitis, corneal ulcer, bacterial keratitis, viral keratitis, postoperative endophthalmitis, and endophthalmitis after intravitreal or anterior chamber injection 32. The method of claim 31.
[Claim 33]
32. The method of claim 31, wherein the infectious condition is caused by or associated with one or more infectious agents selected from the group consisting of bacteria, acne mites, fungi or yeast, and viruses.
[Claim 34]
32. The method of claim 31, wherein the condition is blepharitis, blephar conjunctivitis, conjunctivitis, keratitis or infectious corneal ulcer.
[Claim 35]
34. The method of claim 33, wherein the infectious agent is a virus.
[Claim 36]
34. The method of claim 33, wherein the infectious agent is a Acne mite.

Claims (34)

0.15% to 1.5% povidone-iodine (PVP-I),
30% to 97% dimethyl sulfoxide (DMSO),
An ophthalmically acceptable stable gel composition comprising from 0.25% to less than 2.0% gelling agent that is a cellulose polymer and water or an isotonic cosolvent,
A gel composition that is a topical ophthalmic gel, has a pH of less than 4.5, and does not contain additional anti-inflammatory agents.   The stable gel composition of claim 1 comprising 0.15% to 1.25% PVP-I.   The stable gel composition of claim 1 comprising 0.25% to 1.0% PVP-I.   The stable gel composition of claim 1 comprising about 0.25% PVP-I.   The stable gel composition of claim 1 comprising about 0.50% PVP-I.   The stable gel composition of claim 1 comprising about 0.75% PVP-I.   The stable gel composition of claim 1 comprising 30% to 70% DMSO.   The stable gel composition of claim 1 comprising 40% -49% DMSO.   The stable gel composition of claim 1 comprising 44% DMSO. Containing about 0.25% of the gelling agent, stable gel composition of claim 1. Containing about 0.50% of the gelling agent, stable gel composition of claim 1. Comprising about 1.0% of the gelling agent, stable gel composition of claim 1. Containing about 1.25% of the gelling agent, stable gel composition of claim 1. Containing about 1.50% of the gelling agent, stable gel composition of claim 1. Containing 1.75% of the gelling agent, stable gel composition of claim 1. The stable gel composition according to claim 1, wherein the gelling agent is hydroxyethyl cellulose (HEC). 0.25% PVP-I,
44% DMSO,
Less than 0.25 percent and 2.0 percent of the gelling agent, and
Including the isotonic co-solvent,
The stable gel composition of claim 1, which is free of steroids and free of NSAIDs. The stable gel composition of claim 17 , wherein the co-solvent is an aqueous isotonic solution . The stable gel composition of claim 18 , wherein the cellulose polymer is hydroxyethyl cellulose (HEC). A stable gel composition according to claim 1, wherein the composition is a topical ophthalmic preparation,
Each component is ophthalmically acceptable and the ophthalmic gel composition is povidone-
Such a composition retains at least 85% of titratable iodine in the iodo starting material. At least 8 of titratable iodine in povidone-iodo starting material for at least 1 month
The stable gel composition of claim 1, which retains 5%. At least 85 titratable iodine in povidone-iodo starting material for up to 12 months
The stable gel composition of claim 1, which retains%. A composition according to claim 1 for use in a method of preventing an eye or eyelid infection state, the method comprising:
Applying an effective amount of the stable topical ophthalmic gel composition of claim 1 to the eye or eyelid or periocular skin surface prior to eye surgery or invasive procedures including intraocular or intravitreal injection The composition comprising the steps of: The infectious condition is selected from the group consisting of blepharitis, conjunctivitis, corneal ulcer, bacterial keratitis, viral keratitis, postoperative endophthalmitis, and endophthalmitis after intravitreal or anterior chamber injection 24. The composition of claim 23 . The infectious condition is caused by or associated with one or more infectious agents selected from the group consisting of bacteria, acne mites, fungi or yeast, and viruses,
24. The composition of claim 23 . 24. The composition of claim 23 , wherein the condition is blepharitis, blephar conjunctivitis, conjunctivitis, keratitis or infectious corneal ulcer. 26. The composition of claim 25 , wherein the infectious agent is a virus. 26. The composition of claim 25 , wherein the infectious agent is a mite. A composition according to claim 1 for use in a method of treating an eye or eyelid infection condition, the method comprising:
Stable topical ophthalmic gel composition of claim 1 in an effective amount, comprising applying to the site of infection in order to remove or reduce the infection, the composition. The infectious condition is selected from the group consisting of blepharitis, conjunctivitis, corneal ulcer, bacterial keratitis, viral keratitis, postoperative endophthalmitis, and endophthalmitis after intravitreal or anterior chamber injection 30. The composition of claim 29 . The infectious condition is caused by or associated with one or more infectious agents selected from the group consisting of bacteria, acne mites, fungi or yeast, and viruses,
30. The composition of claim 29 . 30. The composition of claim 29 , wherein the condition is blepharitis, blephar conjunctivitis, conjunctivitis, keratitis or infectious corneal ulcer. 32. The composition of claim 31 , wherein the infectious agent is a virus. 32. The composition according to claim 31 , wherein the infectious agent is Acne mite.