A formulation for the treatment of ophthalmic diseases containing a chelating agent, a penetration enhancer, and hydroxyethylcellulose.

Abstract

To provide compositions for treatment of ophthalmic disorders including adverse ocular conditions associated with aging.SOLUTION: An ophthalmic formulation, comprising a chelator (such as EDTA and its salts), and a transport enhancer (such as Methyl Sulfonyl Methane; MSM) and an effective amount of a viscoelastic polymer (such as hydroxymethyl cellulose; HEC) is provided. Together, the combination of the two substances unexpectedly and beneficially reduces discomfort associated with and increases efficacy of chelator / transport enhancers as compared to formulations without the viscoelastic polymers.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of treatment of ophthalmic diseases, including harmful eye conditions that are often associated with aging. More specifically, the present invention relates to the treatment of conditions associated with the presence of polymer aggregates that may be present in the eye. In particular, the present invention relates to antimicrobial compositions containing transport promoters, chelating agents, and hydroxyethylcellulose (HEC). One exemplary embodiment relates to such a composition containing MSM, a chelating agent, and HEC. [Background technology]

[0002] Progressive age-related changes in the eye, including both normal and pathological changes, are an inevitable part of life in humans and other mammals. Many of these changes have serious effects on both the function and cosmetic appearance of the eye. These changes include: the development of cataracts; hardening, opacity, decreased flexibility, and yellowing of the lens; yellowing and opacity of the cornea; presbyopia; trabeculoplasty, which leads to increased intraocular pressure and glaucoma; increased suspended matter in the vitreous fluid; hardening of the iris and reduction of its dilatation; age-related macular degeneration (AMD); formation of atherosclerotic deposits in the retinal arteries; dry eye syndrome; and decreased sensitivity and light-level adaptability of the rods and cones of the retina. Age-related vision loss includes loss of visual acuity, visual contrast, color vision and depth perception, lens accommodation, photosensitivity, and dark adaptation. Age-related changes also include changes in iris coloration and the formation of arcus senilis.

[0003] The present inventors have previously disclosed formulations for the treatment of ophthalmic diseases comprising chelating agents and penetration enhancers. International application PCT / US2006 / 027686 (International Publication No. 2007011875) discloses a formulation for reducing intraocular polymer aggregates using a formulation comprising a metal chelating agent and charge masking agents such as MSM and EDTA. U.S. Patent Application 20060177430 discloses a formulation for the treatment of adverse ocular conditions comprising a biocompatible chelating agent, an effective penetration enhancer of an ocular penetration enhancer such as methylsulfonylmethane (MSM), and an anti-AGE (advanced glycation endproducts) agent.

[0004] However, while the administration of formulations containing chelating agents and MSM (or similar penetration enhancers) is effective in treating high molecular weight aggregation, it has been observed to cause discomfort in patients exhibiting significant stinging sensations in the eyes, and thus lead to patients discontinuing treatment. This may be partly caused by higher concentrations of chelating agents and / or penetration enhancers in the formulation.

[0005] Artificial tears are used to alleviate eye discomfort by using one or more lubricants, particularly carboxymethylcellulose, dextran, glycerin, hypromellose, polyethylene glycol 400 (PEG400), polysorbate, polyvinyl alcohol, povidone, or propylene glycol. The FDA has approved the use of artificial tears in the treatment of eye discomfort, specifying the ingredients and concentrations for such use. (Food and Drug Administration: “Ophthalmic Drug Products for Over-the-counter Human use; Final Monograph” 21 CFR Parts 349 and 369. Federal Register 1988, 53(43):7076-7093, available from www.fda.gov / downloads / Drugs / DevelopmentApprovalProcess / DevelopmentResources / Over-the-CounterOTCDrugs / StatusofOTCRulemakings / ucm094081.pdf). Other ingredients used in artificial tears include emollients, which are oily or fat-based agents used to soften and protect tissues, preventing cracking and dryness.

[0006] Efforts were made to solve the problem by using viscoelastic polymers (e.g., hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and polyvinyl alcohol) at standard concentrations (approximately 0.2%), similar to those used in artificial tears. These polymers and concentrations consistently resulted in more stinging pain for longer periods than when no polymers were used. [Overview of the project]

[0007] This invention is based on the remarkable observation that using hydroxyethylcellulose (HEC) at significantly high concentrations (0.5-5.0%) resulted in a substantial reduction in stinging pain.

[0008] Without being constrained by theory, it is hypothesized that at very high HEC concentrations, the release rate of EDTA / MSM dramatically decreases, significantly reducing stinging. The mucous membrane of the eye, particularly at the edge of the eye near the nose where most stinging occurs, no longer experiences the levels of chelating agent / MSM that caused stinging at lower levels of viscoelastic compounds.

[0009] In some embodiments, the present invention relates to a method of using a formulation comprising a transport promoter (e.g., MSM), a chelating agent (e.g., EDTA), and a 0.5% to 5% concentration of HEC and an ophthalmologically acceptable inert carrier for reducing adverse eye conditions caused by polymer aggregation.

[0010] The HEC concentration can be selected from 0.5%, 0.6%, 0.7%, 0.8%, 0.85%, 0.9%, 1.0%, 1.5%, 2.0%, 5.0%, or a range encompassed by these values. In a particular embodiment, the HEC concentration is 0.8% to 1.0%. In one embodiment, the concentrations are EDTA 1.3%, MSM 2.7%, and HEC 0.85%.

[0011] The method involves applying a therapeutically effective amount of chelating agent and formula (I) to the target body: [ka] [In the formula, R 1 and R 2 These are independently substituted C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 Aralkil and C2~C 12 Selected from heteroaralkyl groups, where Q is either S or P. This includes administering an effective amount of a formulation comprising an effective transport-promoting amount of a transport-promoting agent having [a certain characteristic].

[0012] The transport accelerator may be, for example, methylsulfonylmethane (MSM; also known as methylsulfone, dimethylsulfone, and DMSO2), and the chelating agent may be ethylenediaminetetraacetic acid (EDTA), etc.

[0013] The formulation may be administered in forms suitable for ophthalmic administration, including liquid and gel-based compositions. In addition, in preferred embodiments, the formulation may consist entirely of naturally occurring components and / or GRAS ("generally recognized as safe") components by the U.S. Food and Drug Administration.

[0014] In another embodiment, the present invention provides a method for inhibiting biofilm formation in the eye, comprising contacting bacteria with an effective amount of a formulation containing a transport promoter (e.g., MSM), a chelating agent (e.g., EDTA), and 0.5% to 5.0% HEC, thereby inhibiting biofilm formation in the eye.

[0015] A further embodiment of the present invention provides an ophthalmic implant for inhibiting biofilm formation, wherein the ophthalmic formulation comprises a transport promoter (e.g., MSM), a chelating agent (e.g., EDTA), and 0.5% to 5% HEC and a pharmaceutically acceptable vehicle.

[0016] The present invention also relates to methods for the prevention and treatment of adverse ocular conditions, including those relating to oxidative damage and / or free radical damage to the eye, and some relating to the formation or deposition of polymer aggregates. The formulation contains a therapeutically effective amount of an ophthalmologically active agent, a metal cation sequestrant, such as a chelating agent as described above, and such a transport promoter as described above. Examples of these adverse ocular conditions include conditions, diseases, or disorders of the cornea, retina, lens, sclera, and the anterior and posterior segments of the eye. As used herein, adverse ocular conditions may be “normal” conditions frequently seen in aging individuals (e.g., decreased visual acuity and contrast sensitivity) or pathological conditions that may or may not be related to the aging process. The latter adverse ocular conditions include a wide variety of eye disorders and diseases. Age-related eye problems that can be prevented and / or treated with the formulations of the present invention include, but are not limited to, opacity (both corneal and lens opacity), cataract formation (including secondary cataract formation), and other problems associated with lipid deposition, decreased visual acuity, decreased contrast sensitivity, photophobia, glare, dry eye, loss of night vision, pupillary constriction, presbyopia, age-related macular degeneration, increased intraocular pressure, glaucoma, and arcus senilis. "Age-related" means a condition that is generally recognized as occurring much more frequently in older patients, but can also occur in younger individuals. The formulations can also be used to treat ocular surface proliferations such as pinguecula and pterygium, which are typically caused by dust, wind, or ultraviolet light, but can also be symptoms of degenerative diseases associated with presbyopia. Another adverse condition that can be treated with the formulations, although not generally considered age-related, includes keratoconus. It should also be emphasized that the formulations can generally be advantageously used to improve visual acuity in any mammalian individual. In other words, intraocular administration of the formulation can improve visual acuity and contrast sensitivity, as well as color vision and depth perception, regardless of the patient's age or the presence of adverse eye conditions. The formulation is useful for treating adverse eye conditions in both humans and animals.

[0017] In some embodiments, the formulation is effective in alleviating dry eye symptoms, particularly dry eye associated with inflammation.

[0018] These and other embodiments will become apparent from the following description of preferred embodiments in conjunction with the following drawings, but changes and modifications therein may be affected without departing from the spirit and scope of the novel concepts of this disclosure.

[0019] Detailed description of the invention The terms used herein generally have their usual meanings in the art within the context of the present invention and in the specific context in which each term is used. Specific terms used to describe the present invention are discussed below or elsewhere in this specification to provide practitioners with additional guidance regarding the description of the present invention. Certain terms may be highlighted, for example, using italics and / or quotation marks. The use of highlighting does not affect the scope and meaning of the terms; the scope and meaning of the terms are the same in the same context, whether highlighted or not. It will be understood that the same thing can be said in multiple ways. Therefore, alternative languages ​​or synonyms may be used for one or more of the terms described herein, and this does not imply any special meaning regarding whether the terms are described in detail or not. Synonyms for certain terms are provided. The note of one or more synonyms does not preclude the use of other synonyms. The use of examples anywhere in this specification, including examples of terms described herein, is merely illustrative and in no way limits the scope and meaning of the present invention or the illustrated terms. Similarly, the present invention is not limited to the various embodiments given herein.

[0020] Where a range of values is provided, it is understood that each intermediate value between the upper and lower limit of said range and any other value or intermediate value within said range, down to one tenth of the unit of the lower limit, is encompassed within the present invention, unless otherwise clearly indicated by context. The upper and lower limits of these smaller ranges may independently be included in smaller ranges, and are also encompassed within the scope of the present invention, subject to any specifically excluded limitation in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present invention.

[0021] Throughout this application, various publications, patents, and published patent applications are cited. The disclosures of these publications, patents, and published patent applications referenced herein are hereby incorporated by reference into the present specification. Citation of any publication, patent, or published patent application herein does not constitute an admission that such publication, patent, or published patent application is prior art.

[0022] As used in this specification and the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a transport enhancer" includes both a plurality of transport enhancers and a single transport enhancer; reference to "a chelating agent" includes reference to two or more chelating agents as well as a single chelating agent, and the like. In this specification and in the claims that follow, reference will be made to a number of terms that are defined to have the following meanings.

[0023] When reference is made to a formulation ingredient, the term used, such as "agent", is intended to encompass not only the specific molecular entity itself, but also pharmaceutically acceptable analogs thereof, including but not limited to salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

[0024] As used herein, the terms "treat" and "treatment" refer to the administration of a drug or formulation to a symptomatic individual suffering from an adverse condition, disorder or disease, to reduce the severity and / or frequency of symptoms, eliminate symptoms and / or their underlying causes, and / or promote the improvement or repair of damage. The terms "prevent" and "prevention" refer to the administration of a drug or composition to a clinically asymptomatic individual who is susceptible to a particular adverse condition, disorder or disease, and thus relate to the prevention of the occurrence of symptoms and / or their underlying causes. Unless otherwise explicitly or implicitly specified herein, when the term "treatment" (or "treat") is used without reference to possible prevention, it is intended to also include prevention, and "a method for treating gingivitis" is to be construed as encompassing "a method for preventing gingivitis".

[0025] The terms "optional" or "optionally present" as used in the case of "any substituent" or "optional additive" mean that the component described thereafter (e.g., a substituent or an additive) may or may not be present, so the description includes both the case where the component is present and the case where it is absent.

[0026] "Pharmacologically acceptable" means a substance that is biologically or otherwise undesirable, for example, that can be incorporated into the formulation of the present invention without causing an undesirable biological effect or adverse interaction with any of the other components of the dosage form formulation. However, when the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it means that the excipient meets the necessary standards for toxicity and manufacturing testing and / or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmacologically active" (or simply "active") means a derivative or analogue that has the same type of pharmacological activity as the parent drug, as will be explained in more detail below. As used herein, the terms "to treat" and "to cure" mean reducing the severity and / or frequency of a symptom, eliminating a symptom and / or underlying cause, preventing the occurrence of a symptom and / or underlying cause, and improving or curing an undesirable condition or injury. Therefore, for example, “treating” a subject includes the prevention of adverse conditions in susceptible individuals, as well as the treatment of clinically symptomatic individuals by suppressing or reducing such conditions. The term “chelating agent” (or “active agent”) means a compound, complex, or composition that exhibits a desired effect under biological circumstances, i.e., when administered to a subject or introduced into cells or tissues in vitro. The term includes, but is not limited to, pharmaceutically acceptable derivatives of these active agents as specifically described herein, including salts, esters, amides, prodrugs, active metabolites, isomers, analogs, crystals, and hydrates. When the term “chelating agent” is used, or when a particular chelating agent is specifically identified, it should be understood that not only the agent itself, but also pharmaceutically acceptable salts, esters, amides, prodrugs, active metabolites, isomers, analogs, etc., of the agent are intended.

[0027] An “effective” or “therapeutably effective” amount of an active agent means an amount of the active agent sufficient to provide a non-toxic but beneficial effect. The “effective” amount of an active agent varies from subject to subject, depending on the individual’s age and general condition, as well as the specific active agent. Unless otherwise specified, the “therapeutably effective” amount as used herein is intended to include an amount effective for treating an adverse condition, as well as an amount effective for preventing and / or relieving an adverse condition.

[0028] The term "controlled release" refers to a drug-containing formulation or fraction in which the drug is not released immediately; that is, administration of a "controlled release" formulation does not cause immediate release of the drug into the absorption pool. This term is used synonymously with "non-immediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). Generally, as used herein, "controlled release" refers to a "sustained-release" formulation, not a "delayed-release" formulation. "Sustained-release" (synonymous with "long-term release") is used in its traditional sense to refer to a formulation that provides sustained release of a drug over an extended period.

[0029] An ingredient that is "pharmaceutically acceptable" or "ophthalmologically acceptable" means an ingredient that is not biologically or otherwise undesirable, i.e., it can be incorporated into the ophthalmic formulation of the present invention and administered topically to a patient's eye without causing undesirable biological effects or adverse interactions with any of the other ingredients in the formulation composition containing it. When the term "pharmaceutically acceptable" is used to refer to an ingredient other than a pharmacologically active agent, it means that the ingredient meets the necessary standards for toxicity and manufacturing testing, or is included in the Inactive Ingredient Guide created by the U.S. Food and Drug Administration.

[0030] The terms “peptide” and “peptidyl” are intended to refer to structures composed of two or more amino acids. The amino acids that form all or part of a peptide may be any of the 20 conventional natural amino acids, namely alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y). Any of the amino acids may be replaced by non-conventional amino acids, such as isomers or analogues of conventional amino acids (e.g., D-amino acids), non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, or constructs or structures designed to mimic amino acids. Examples of peptidyl compounds used herein include proteins, oligopeptides, polypeptides, lipoproteins, glycosylated peptides, and glycoproteins.

[0031] As will be apparent to those skilled in the art who have read this invention, each of the individual embodiments described and illustrated herein has individual elements and features that can be readily separated from or combined with features of any of several other embodiments without departing from the scope or spirit of the invention. The described methods can be carried out in the order of the described events or in any other logically possible order.

[0032] Unless otherwise specified, the present invention is not limited to specific formulation components, administration methods, chelating agents, or manufacturing methods, and these may change.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field relating to this invention. In case of any conflict, this document, including the definitions, shall prevail.

[0034] Ophthalmic disorders and adverse conditions All parts of the eye, including the cornea, sclera, trabecular meshwork, iris, lens, vitreous humor, and retina, are affected by the aging process, as described below.

[0035] The cornea is the outermost layer of the eye. It is a transparent, dome-shaped surface that covers the front of the eye. The cornea is composed of five layers. The epithelium is the layer of cells that make up the surface. It is only about 5-6 cell layers thick and regenerates quickly if the cornea is damaged. If the damage penetrates deeper into the cornea, scarring may occur, leaving a cloudy area and causing the cornea to lose its transparency and luster. Directly beneath the epithelium is Bowman's membrane, a very tough and difficult-to-penetrate protective layer. The corneal stroma, the thickest layer of the cornea, is just below Bowman's membrane and is composed of tiny, parallel-aligned collagen fibers that give the cornea transparency. Descemet's membrane is below the corneal stroma and just above the endothelium, the innermost layer of the cornea. The endothelium is only one cell layer thick and plays a role in pumping water from the cornea to the aqueous humor, keeping it transparent. If these cells are damaged or diseased, they do not regenerate.

[0036] As the eyes age, the cornea can become cloudy. This clouding can take various forms. The most common form affects the periphery of the cornea and is called an arcus senilis or arcus. This type of clouding initially involves lipid deposition in Descemet's membrane. Subsequently, lipids deposit in Bowman's membrane and possibly in the corneal stroma. Arcus senilis is usually not visually significant but is a noticeable sign of aging. Other age-related corneal opacities exist that can have several visual consequences. These include central cloudy dystrophy of Francois, which affects the middle layer of the corneal stroma, and posterior crocodile shagreen, a central clouding of the posterior corneal stroma. Clouding, due to light scattering, can lead to a progressive decline in visual contrast and visual acuity.

[0037] Corneal opacity can result from a number of causes, including, for example, degeneration of corneal structure; cross-linking of collagen and other proteins by metalloproteinases; ultraviolet (UV) damage; oxidative damage; and the accumulation of substances such as calcium salts, protein waste, and excess lipids.

[0038] There are no established treatments other than surgical intervention to delay or reverse corneal changes. For example, the cornea can be reshaped by first removing the epithelium, then scraping away the opacity with a blunt instrument, and finally smoothing the corneal surface with a laser. In severe cases of corneal scarring and opacity, corneal transplantation has been the only effective approach.

[0039] Another common eye disorder that negatively affects the cornea and other intraocular structures is keratoconjunctivitis sicca, commonly referred to as "dry eye syndrome" or "dry eye." Dry eye can result from many causes and is often a problem for older adults. The disorder is associated with a tingling sensation, excessive mucus production, burning, increased sensitivity to light, and pain. Dry eye is currently treated with "artificial tears," which are commercially available products containing lubricants such as low molecular weight polyethylene glycol. Surgical treatment is also not uncommon and usually involves inserting punctal plugs into the eye to retain lacrimal gland secretions. However, both types of treatment have their problems: surgical treatment is invasive and can be risky, while artificial tear products only provide very temporary and often inadequate relief.

[0040] The sclera is the white part of the eye. In young individuals, the sclera is pale, but as people age, it becomes yellowish as a result of age-related changes in the conjunctiva. Over time, exposure to UV light and dust can cause changes in the conjunctival tissue, which can lead to the formation of pinguecula and pterygium. These eye growths can further cause destruction of the scleral and corneal tissues. Currently, surgery, including conjunctival grafting, is the only approved treatment for pinguecula and pterygium.

[0041] The trabecular meshwork, also known as the trabecular meshwork, is a mesh-like structure located at the iris-scleral junction of the anterior chamber. The trabecular meshwork filters aqueous humor and controls its flow from the anterior chamber to Schlemm's canal. As the eye ages, debris and protein-lipid waste can accumulate and clog the trabecular meshwork, which is a problem that results in increased intraocular pressure, and can then lead to glaucoma, as well as damage to the retina, optic nerve, and other ocular structures. Glaucoma medications can help reduce this pressure, and surgery can create an artificial opening to bypass the trabecular meshwork and re-establish the flow of fluid from the vitreous humor and aqueous humor. However, there is no known way to prevent the accumulation of debris and protein-lipid waste within the trabecular meshwork.

[0042] Iris and Pupil: With age, the expansion and contraction of the iris in response to changes in lighting slow down, and its range of motion decreases. The pupil also gradually shrinks with age, significantly limiting the amount of light entering the eye, especially under low-light conditions. Age-related pupillary constriction, as well as iris hardening, slow adaptation, and contraction, are major causes of the difficulty older adults experience in seeing at night and adapting to changes in lighting. Changes in iris shape, hardness, and adaptability are generally thought to be due to fibrosis and cross-linking between structural proteins. Age-related protein and lipid waste deposits on the iris can also lighten its color. Both light-colored deposits on the iris and pupillary constriction are very noticeable age markers of appearance that can have social impacts on an individual. There is no standard treatment for any of these changes or for age-related changes in iris color.

[0043] As we age, the lens of the eye becomes yellow, harder, more rigid, less flexible, and can become cloudy, either broadly or in specific locations. Consequently, the lens transmits less light, leading to decreased visual contrast and visual acuity. Yellowing also affects color vision. When the lens hardens and the muscles are no longer able to adjust it, it results in a condition commonly known as presbyopia. Presbyopia, which almost always occurs after middle age, is the inability of the eye to focus properly. This age-related eye pathology itself manifests as a loss of accommodation, that is, a loss of the eye's ability to focus on near or far objects through the lens by changing its shape to become more spherical (or convex). Both nearsighted and farsighted individuals are affected by presbyopia. Age-related loss of accommodative amplitude is progressive, and presbyopia is perhaps the most common of all eye diseases, eventually affecting virtually every individual during a normal human lifespan.

[0044] These changes in the lens are thought to be due to glycation crosslinking between collagen fibers, accumulation of protein complexes, structural degradation due to ultraviolet light, oxidative damage, and degenerative changes in the lens structure, including the deposition of waste proteins, lipids, and calcium salts. The elastic and viscous properties of the lens depend on the properties of the fibrous membrane and cytoskeletal crystallins. The lens fibrous membrane is characterized by an extremely high cholesterol-to-phospholipid ratio. Changes in these components affect the deformability of the lens membrane. Loss of lens deformability is also due to increased binding of lens proteins to the cell membrane.

[0045] Compensatory options for alleviating presbyopia currently include bifocal reading glasses and / or contact lenses, monovision intraocular lenses (IOLs) and / or contact lenses, multifocal IOLs, monovision and ikeisokeratectomy using radial keratotomy (RK), photorefractory keratoplasty (PRK), and laser intracorneal resection (LASIK). Currently, no widely accepted treatment or therapy is available for presbyopia.

[0046] A condition commonly known as a cataract arises when the lens becomes cloudy. Cataracts are a progressive eye disease that subsequently leads to vision loss. Most cases of this eye disease are age-related senile cataracts. The incidence of cataract formation is estimated to be 60-70% in people in their 60s and nearly 100% in people over 80. However, currently there are no drugs that have been clearly proven to inhibit the development of cataracts. Therefore, the development of effective treatments has been desired. Currently, the treatment of cataracts relies on vision correction using glasses, contact lenses, or surgical procedures such as the insertion of an intraocular lens into the lens capsule after extracapsular extraction.

[0047] In cataract surgery, the development of secondary cataracts after surgery is a problem. Secondary cataracts are the same as the opacities present on the surface of the remaining posterior capsule after extracapsular cataract extraction. The mechanism of secondary cataracts is mainly as follows: After the removal of the lens epithelial cells (anterior capsule), secondary cataracts occur when remaining lens epithelial cells that are not completely removed during the removal of the lens cortex migrate to and proliferate in the posterior capsule, causing posterior capsule opacity. In cataract surgery, it is impossible to completely remove lens epithelial cells, and as a result, it is always difficult to prevent secondary cataracts. The incidence of posterior capsule opacity is said to be 40-50% in eyes that have not received an intracapsular posterior chamber lens implant, and 7-20% in eyes that have received an intracapsular lens implant. Furthermore, eye infections classified as endophthalmitis have also been observed after cataract surgery.

[0048] Vitreous fluid: Floating particles are debris particles that obstruct clear vision by projecting shadows onto the retina. Currently, there is no standard treatment for reducing or eliminating floating particles.

[0049] As we age, many changes can occur in the retina. The accumulation and leakage of atherosclerosis in the retinal arteries can lead to macular degeneration and a reduction in peripheral vision. Rods and cones slowly replenish their pigment, so their sensitivity can decrease over time. Gradually, all these effects can reduce vision and eventually lead to partial or complete blindness. Retinal diseases such as age-related macular degeneration are difficult to treat. Current retinal treatments include laser surgery to stop leakage from the blood vessels in the eye.

[0050] As suggested above, current attempts to treat many eye disorders and diseases, including age-related eye problems, often involve surgical intervention. Of course, surgical procedures are invasive and, moreover, often fail to achieve the desired therapeutic goals. Furthermore, surgery can be very expensive and can result in serious undesirable complications. For example, secondary cataracts can develop after cataract surgery, and infections can occur. Endophthalmitis has also been observed after cataract surgery. Moreover, advanced surgical techniques require a very well-developed medical infrastructure and are therefore not universally available. Thus, providing simple and effective pharmacological treatments that eliminate the need for surgery would be a great advantage.

[0051] There are products proposed to address specific individual age-related eye conditions. For example, artificial tears and herbal preparations have been suggested for the treatment of dry eye syndrome, while other eye drops are used to lower intraocular pressure, relieve discomfort, promote healing after injury, reduce inflammation, and prevent infection. However, self-administering multiple products several times a day is inconvenient and can lead to decreased patient compliance (resulting in reduced overall effectiveness), and may also involve adverse interactions between formulation components. For example, benzalkonium chloride, a common preservative, can react with other desirable components such as ethylenediaminetetraacetic acid (EDTA). Therefore, there is a need in this field for a comprehensive pharmaceutical formulation that can prevent, halt, and / or reverse a wide range of age-related vision problems and associated eye disorders.

[0052] Many harmful eye conditions are associated with the formation, presence, and / or proliferation of macromolecular aggregates in the eye. In fact, many pathological conditions are caused by or associated with the deposition and / or aggregation of proteins, other peptidyl species, lipoproteins, lipids, polynucleotides, and other macromolecules throughout the body. For example, advanced glycation end products (also known as AGEs) are formed when glucose or other reducing sugars bind to proteins, lipoproteins, and DNA through a process known as non-enzymatic glycation, and then crosslink them. These crosslinked macromolecules harden connective tissue and cause tissue damage in the kidneys, retina, blood vessel walls, and nerves. In fact, AGEs are involved in the pathogenesis of various debilitating diseases such as diabetes, atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, as well as in the normal aging process. Peptidyl deposits are also associated with Alzheimer's disease, sickle cell anemia, multiple myeloma, and prion diseases. Lipids, particularly sterols and sterol esters, represent a further class of biomolecules that form pathogenic deposits in vivo, including atherosclerotic plaques and gallstones. To date, no single formulation has been identified as capable of treating such multiple disorders.

[0053] Chelating agent / chelator Chelation is a chemical combination of a metal with a metal in a complex in which the metal is part of a ring. The organic ligand is called a chelator or chelating agent, and the chelate is a metal complex. The more rings that bind to the metal atom, the more stable the compound. The stability of a chelate is also related to the number of atoms in the chelate ring. Monodentate ligands with one coordinating atom, such as H2O and NH3, are readily decomposed by other chemical processes, while polydentate chelators, which provide multiple bonds to the metal ion, provide more stable complexes. Chlorophyll, the green plant pigment, is a chelate consisting of a central magnesium atom bound to four complex chelating agents (pyrrole rings). Heme is an iron chelate containing an iron(II) ion at the center of a porphyrin. Chelating agents provide a wide range of scavenging agents for controlling metal ions in aqueous systems. Chelating agents prevent undesirable interactions by blocking the normal reactivity of metal ions, thereby forming stable, water-soluble complexes with polyvalent metal ions. EDTA (ethylenediaminetetraacetic acid) is a good example of a common chelating agent that contains a nitrogen atom and a short-chain carboxyl group.

[0054] Examples of iron and calcium chelating agents include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,3-propylenediaminetetraacetic acid (PDTA), ethylenediamine disuccinic acid (EDDS), and ethylene glycol tetraacetic acid (EGTA). Suitable chelating agents known in the art that are biologically safe and capable of chelating iron, calcium, or other metals are suitable for the present invention.

[0055] Compounds useful as chelating agents in this specification include compounds that coordinate to or form complexes with divalent or polyvalent metal cations and thus serve as scavenging agents for such cations. Accordingly, the term "chelating agent" as used herein includes not only divalent and polyvalent ligands (typically referred to as "chelating agents") but also monovalent ligands that can coordinate to or form complexes with metal cations.

[0056] Suitable biocompatible chelating agents useful in connection with the present invention include, but are not limited to, EDTA, cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharmaceutically acceptable salts thereof, and monomeric polyacids such as any combination thereof. Other exemplary chelating agents include phosphates, such as pyrophosphates, tripolyphosphates, and hexametaphosphates.

[0057] EDTA and ophthalmologically acceptable EDTA salts are particularly preferred, and typical ophthalmologically acceptable EDTA salts are typically selected from EDTA diammonium, EDTA disodium, EDTA dipotassium, EDTA triammonium, EDTA trisodium, EDTA tripotassium, and EDTA disodium calcium.

[0058] EDTA is widely used as a chelating agent for metals in biological tissues and blood, and its inclusion in various formulations has been suggested. For example, U.S. Patent No. 6,348,508 by Denick Jr. et al. describes EDTA as a scavenger for binding metal ions. In addition to its use as a chelating agent, EDTA is also widely used as a preservative in place of benzalkonium chloride, as described, for example, in U.S. Patent No. 6,211,238 by Castillo et al. U.S. Patent No. 6,265,444 by Bowman et al. discloses the use of EDTA as a preservative and stabilizer. However, due to its poor penetration into biological membranes and biofilms, including skin, cell membranes, and even biofilms such as dental plaque, EDTA is generally not applied topically in formulations of significant concentrations.

[0059] Among the chelating / capsulation materials that may be included in the compositions described, biocompatible chelating agents include, but are not limited to, EDTA, cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharmaceutically acceptable salts thereof, and monomeric polyacids such as any combination thereof.

[0060] Other exemplary chelating agents include phosphates, e.g., pyrophosphates, tripolyphosphates, and hexametaphosphates; chelated antibiotics such as chloroquine and tetracycline; nitrogen-containing chelating agents containing two or more chelated nitrogen atoms in the imino group or aromatic ring (e.g., diimine, 2,2'-bipyridine); and polyamines, e.g., cyclam(1,4,7,11-tetraazacyclotetradecane), N-(C1~C 30Alkyl)-substituted cyclamates (e.g., hexadecyclamate, tetramethylhexadecylcyclamate), diethylenetriamine (DETA), Spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferoxamine (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy Examples include c-carbamoyl)propanoylamino]pentyl]-N-hydroxybutanediamide; also known as desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB or desferal), deferipron, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

[0061] Further preferred biocompatible chelating agents that may be useful in implementing this disclosure include Solomon et al., Med. Chem. 2: 133-138, As described in 2006, ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate Examples of EDTA-4-aminoquinoline conjugates include esters, ([2-(bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, and ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate).

[0062] Furthermore, natural chelating agents including, but not limited to, citric acid, phytic acid, lactic acid, acetic acid, and their salts; and other natural chelating agents such as curcumin (turmeric) (but not limited to these).

[0063] In some embodiments, the chelating agent incorporated into the formulation is a prochelator. A prochelator is a molecule that is converted into a chelating agent when exposed to appropriate chemical or physical conditions. For example, the BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelator is converted by hydrogen peroxide to the SIH (salicyaldehyde isonicotinoylhydrazone) iron-chelating agent, which inhibits iron-catalyzed hydroxyl radical generation.

[0064] Inactivated metal ion scavengers are sometimes referred to herein as “prochelating agents,” but the scavenging of metal ions may include scavenging and complexing processes that go beyond chelation itself. The term “prochelating agent” is similar to the term “prodrug” insofar as the prodrug is a therapeutically inactive agent until it is activated in vivo, and similarly, such prochelating agents cannot scavenge metals until they are activated in vivo.

[0065] Transport promoters: Transport promoters are selected to facilitate the transport of chelating agents through body tissues, extracellular matrix, and / or cell membranes. The “effective amount” of a transport promoter represents an amount and concentration sufficient to provide a measurable increase in the penetration of the chelating agent through one or more sites in the subject body in the formulation of the present invention compared to the case where the transport promoter is not present in the formulation.

[0066] In certain cases, the transport accelerator may be present in the formulation of the present invention in an amount ranging from about 0.01% by weight or less to about 30% by weight or more, typically in the range of about 0.1% by weight to about 20% by weight, more typically in the range of about 1% by weight to about 11% by weight, most typically in the range of about 2% by weight to about 8% by weight, for example, 5% by weight.

[0067] Transport accelerators are generally expressed by formula (I) [ka] This is shown.

[0068] In the formula, R 1 and R 2 are each independently selected from optionally substituted C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 aralkyl, and C2-C 12 heteroaralkyl, and Q is S or P. Compounds wherein Q is S, and R 1 and R 2 are C1-C3 alkyl are preferred, and methylsulfonylmethane (MSM) is the optimal delivery enhancer.

[0069] The terms “having a formula” or “having a structure” are not intended to be limiting and are used in the same way as the term “containing” is commonly used. With respect to the structures described above, the term “alkyl” refers to a linear, branched, or cyclic saturated hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, the term “alkyl” encompasses both unsubstituted and substituted alkyl groups, the substituents of which may be, for example, halo, hydroxyl, sulfhydryl, alkoxy, and acyl. The term “alkoxy” refers to an alkyl group linked via a single terminal ether bond; that is, an “alkoxy” group can be represented as an -O-alkyl group (where alkyl is as defined above). The term "aryl" refers to an aromatic substituent containing a single aromatic ring, or multiple aromatic rings that are condensed together, directly bonded, or indirectly bonded (so that different aromatic rings are bonded to common groups such as methylene or ethylene moieties). Preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two condensed or bonded aromatic rings, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone. Examples of "aryl" include unsubstituted and substituted aryl groups, the substituents of which may be as described above with respect to the "alkyl" group, which may be substituted. The term "aralkyl" refers to an alkyl group having an aryl substituent, where "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 14 carbon atoms, and particularly preferred aralkyl groups contain 6 to 8 carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, and 4-benzylcyclohexylmethyl.The term "acyl" refers to a substituent having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, where "alkyl," "aryl," and "aralkyl" are defined above. The terms "heteroalkyl" and "heteroaralkyl" are used to refer to heteroatom-containing alkyl and heteroatom-containing aralkyl groups, respectively, i.e., alkyl and aralkyl groups in which one or more carbon atoms are replaced by atoms other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur.

[0070] Next, in one embodiment, a method is provided for eliminating or reducing the size of polymer aggregates in the eye. The method comprises administering a therapeutically effective dose to the eye of a patient of a sterile ophthalmic formulation comprising (a) a non-cytotoxic chelating agent containing at least three negatively charged chelating atoms, (b) a charge masking agent containing at least one polar group, and (c) HEC at a concentration greater than 0.5%, and an ophthalmologically acceptable inert carrier. The polar group of the charge masking agent contains at least one, preferably at least two, heteroatoms having a Pauling electronegativity greater than about 3.00, where the heteroatoms are preferably oxygen atoms. The molar ratio of the charge masking agent to the chelating agent is sufficient to ensure that substantially all negatively charged chelating atoms are associated with at least one of the heteroatoms on the charge masking agent. The formulation can be applied to the eye in a form suitable for ophthalmic drug administration, for example, as a solution or suspension for administration as eye drops or eye wash, as an ointment, or in an ophthalmic implant that can be implanted in the conjunctiva, sclera, ciliary body slab, anterior segment or posterior segment. Such implants provide controlled release of the formulation to the ocular surface, typically a sustained release over a long period.

[0071] The formulation can also be applied to the skin around the eyes for penetration, provided that the compound used as a charge masking agent, such as methylsulfonylmethane, also functions as a penetration enhancer that allows the formulation to penetrate through the skin.

[0072] In another embodiment, the formulation is effective in alleviating dry eye symptoms, particularly dry eye associated with inflammation, and can be used in methods of treating dry eye. Subjects with extreme dry eye, such as those with Sjögren's syndrome, may still experience some stinging sensation due to the extreme dryness of their eyes.

[0073] Therefore, in addition to functioning as a preservative and stabilizer, chelating agents are multifunctional in the context of the present invention insofar as they play a role in reducing undesirable proteins or peptides, preventing the formation of mineral deposits, and / or reducing already formed mineral deposits, thereby reducing calcification.

[0074] The formulation also contains an effective amount of a transport promoter that facilitates the penetration of formulation components across cell membranes, tissues, and the extracellular matrix. “Effective amount” of the transport promoter means, as described above, a concentration sufficient to provide a measurable increase in the penetration of one or more formulation components across membranes, tissues, and the extracellular matrix. Suitable transport promoters include, by example, methylsulfonylmethane (MSM; also known as methylsulfone), a combination of MSM and dimethyl sulfoxide (DMSO), or a combination of MSM and, in less preferred embodiments, DMSO, with MSM being particularly preferred.

[0075] MSM is an odorless, highly water-soluble (34% w / v at 79°F) white crystalline compound with a melting point of 108–110°C and a molecular weight of 94.1 g / mol. MSM functions as a multifunctional agent according to this specification, insofar as it increases cell membrane permeability and also acts as a "transport enhancer" (TFA), assisting in the transport of one or more pharmaceutical components into the eye. Furthermore, MSM itself provides pharmacokinetics, functioning as an anti-inflammatory and analgesic. MSM also improves oxidative metabolism in biological tissues and is a source of organosulfur, which helps reduce scarring. In addition, MSM possesses unique and beneficial solubilizing properties in that it is soluble in water as described above, but exhibits both hydrophilic and hydrophobic properties due to the presence of polar S=O groups and nonpolar methyl groups. The molecular structure of MSM also allows for the formation of hydrogen bonds with other molecules, i.e., hydrogen bonds between the oxygen atoms of each S=O group and the hydrogen atoms of other molecules, and van der Waals associations between the methyl groups and the nonpolar moieties of other molecules (e.g., hydrocarbyl). Ideally, the concentration of MSM in this formulation is in the range of about 0.1% to 40% by weight, or about 1% to about 4, 5, 6, 7, 8, 10, or 15% by weight, preferably about 1.5% to 8.0% by weight.

[0076] Other optional additives in the formulation include a second accelerator, i.e., one or more further transport accelerators. For example, the formulation of the present invention may contain added DMSO. Since MSM is a metabolite of DMSO (i.e., DMSO is enzymatically converted to MSM), incorporating DMSO into the MSM-containing formulation of the present invention tends to gradually increase the proportion of MSM in the formulation. DMSO also functions as a free radical scavenger, thereby reducing the potential for oxidative damage. When DMSO is added as a second accelerator, its amount is preferably in the range of about 1.0% to 2.0% by weight of the formulation, and the weight ratio of MSM to DMSO is typically in the range of about 1:50 to about 50:1.

[0077] Hydroxyethylcellulose (HEC, also known as HESPAN; TYLOSE P; NATROSOL; HETASTARCH, and available commercially) is a nonionic cellulose ether produced from natural polymer cellulose through a series of chemical processes. It is available in the form of a white to off-white powder or granules, and is odorless, tasteless, and nontoxic. It can dissolve in water to form a clear, viscous solution. The solubility of HEC in water is ≤5% by weight at 20°C. The CAS database reference for HEC is 9004-62-0. [ka]

[0078] Hydroxyethylcellulose is soluble in hot or cold water, does not precipitate upon heating or boiling, and exhibits a wide range of solubility and viscosity properties, as well as non-thermal gelation. It is nonionic and can coexist with a wide range of other water-soluble polymers, surfactants, and salts, acting as a fine colloidal thickener in solutions containing high concentrations of electrolytes. While hydroxyethylcellulose can disperse in cold water without agglomeration, its dissolution rate is slow, generally requiring about 30 minutes. It can be rapidly dissolved by heating or adjusting the pH to 8-10.

[0079] The formulation may also contain microcirculation enhancers, i.e., agents that help promote blood flow in the capillaries. Microcirculation enhancers may be phosphodiesterase (PDE) inhibitors, such as type I PDE inhibitors. Such compounds act to increase intracellular levels of cyclic AMP (cAMP), as will be understood by those skilled in the art. A preferred microcirculation enhancer is vinpocetine, also known as apovincamine-22-ethyl. Vinpocetine, a synthetic derivative of the vinca alkaloid vincamine, is particularly preferred herein due to its antioxidant properties and protection against excessive intracellular calcium accumulation. Vincamine, as well as other vinca alkaloids, is also useful herein as a microcirculation enhancer. Preferably, the microcirculation enhancer present, such as vinpocetine, corresponds to about 0.01% to about 0.2% by weight, preferably about 0.02% to about 0.1% by weight, of the formulation.

[0080] formulation Various means can be used to formulate the compositions of the present invention. Techniques for formulation and administration can be found in “Remington: The Science and Practice of Pharmacy,” Twentieth Edition, Lippincott Williams & Wilkins, Philadelphia, PA (1995). For administration to humans or animals, the formulation must meet sterility, pyrogenicity, general safety, and purity standards comparable to those required by the FDA. Administration of the pharmaceutical formulation can be carried out in various ways as described herein.

[0081] Other possible additives for incorporation into formulations that are at least partially aqueous include, but are not limited to, thickeners, isotonic agents, buffers, and preservatives, provided that such excipients do not adversely interact with any other components of the formulation. It should also be noted that preservatives are generally not always necessary, given that the selected chelating agent itself functions as a preservative. Suitable thickeners are known to those skilled in the art of formulation, and examples include cellulosic polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC), as well as other swelling hydrophilic polymers (polyvinyl alcohol (PVA), hyaluronic acid or its salts (e.g., sodium hyaluronate)), and cross-linked acrylic polymers commonly referred to as "carbomers" (and available from BF Goodrich as Carbopol® polymers).

[0082] Gels with a viscosity exceeding 10,000 cps are generally considered optimal for both comfort and retention of the formulation on the eye; therefore, the preferred amount of thickener is such that a viscosity exceeding 10,000 cps is provided. Suitable isotonic and buffering agents commonly used in ophthalmic formulations may be used, provided that the pH of the formulation is maintained in the range of approximately 4.5 to approximately 9.0, preferably in the range of approximately 6.8 to approximately 7.8, and optimally at approximately 7.4 pH. Preferred buffering agents include carbonates such as sodium bicarbonate and potassium bicarbonate.

[0083] However, effective thickeners must be used in amounts that also exhibit important properties that allow for the use of low-concentration chelating agent / MSM combinations in order to achieve a significant effect without causing unpleasant eye symptoms such as severe stinging.

[0084] The formulations of the present invention also include a pharmaceutically acceptable ophthalmic carrier or vehicle, depending on the specific type of formulation. For example, the formulations of the present invention may be provided as an ophthalmic solution or suspension, in which case the carrier is at least partially aqueous. Ideally, an ophthalmic solution that can be administered as eye drops is an aqueous solution. The formulation may also be an ointment, in which case the pharmaceutically acceptable carrier consists of an ointment base. Preferred ointment bases as used herein have a melting or softening point close to body temperature, and ointment bases commonly used in ophthalmic formulations can be advantageously used. Common ointment bases include petrolatum and mixtures of petrolatum and mineral oil. Preferred pharmaceutical formulations and dosage forms are known to those in the field of pharmaceutical formulation and can be prepared using conventional methods described in relevant texts and literature, for example, Remington: The Science and Practice of Pharmacy, cited herein above.

[0085] The formulations of the present invention may also be prepared as hydrogels, dispersions, or colloidal suspensions. Except that formulations referred to in the art as “hydrogels” are typically more viscous than formulations referred to as “thickened” solutions or suspensions, hydrogels are formed by incorporating a swelling gel-forming polymer, such as those shown above, as a suitable thickener (i.e., MC, HEC, HPC, HPMC, NaCMC, PVA, or hyaluronic acid or its salts, e.g., sodium hyaluronate). In contrast to such pre-formed hydrogels, formulations may also be prepared to form a hydrogel in situ after application to the eye. Such gels are liquid at room temperature but gel at high temperatures, such as when left in contact with body fluids (hence, they are called “thermally reversible” hydrogels). Examples of biocompatible polymers that impart these properties include acrylic acid polymers and copolymers, N-isopropylacrylamide derivatives, and ABA block copolymers of ethylene oxide and propylene oxide (commonly referred to as "poloxamers" and available from BASF-Wyandotte under the trade name Pluronic®). Formulations can also be prepared in the form of dispersions or colloidal suspensions. Preferred dispersions are liposomes, in which case the formulation is encapsulated within "liposomes," which are microscopic vesicles composed of alternating aqueous compartments and lipid bilayers. Colloidal suspensions are generally formed from microparticles, i.e., microspheres, nanospheres, microcapsules, or nanocapsules, where microspheres and nanospheres are generally monolithic particles of a polymer matrix that encapsulate, adsorb, or otherwise contain the formulation, and in the case of microcapsules and nanocapsules, the formulation is actually encapsulated. The upper limit of the size of these microparticles is about 5 μm to about 10 μm.

[0086] The formulation may also be incorporated into a sterile ocular implant, which, after implantation into the conjunctiva, sclera, or ciliary body squamata, or into the anterior or posterior segment, provides controlled release of the formulation over a long period, typically ranging from about 12 hours to 60 days, and possibly up to 12 months or more. One type of ocular implant is an implant in the form of a monolithic polymer matrix that gradually releases the formulation into the eye via diffusion and / or matrix degradation. With respect to such implants, it is preferable that the polymer is completely soluble and / or biodegradable (i.e., physically or enzymatically degraded in the eye) so that removal of the implant becomes unnecessary. These types of implants are well known in the art and typically consist of water-swellable gel-forming polymers such as collagen, polyvinyl alcohol, or cellulosic polymers. Another type of implant that can be used to deliver the formulation is a diffusion implant in which the formulation is contained in a central reservoir surrounded by a permeable polymer membrane that allows the formulation to gradually diffuse from the implant. It is also possible to use permeable implants, i.e., implants that release the formulation as a result of increased osmotic pressure within the implant after application to the eye and subsequent absorption by the tear film.

[0087] Chelating agents may be administered in the form of salts, esters, crystalline forms, hydrates, etc., as needed and provided they are pharmaceutically acceptable. Salts, esters, etc., are known to those skilled in the field of organic synthesis chemistry and can be prepared, for example, using the standard procedures described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).

[0088] The amount of chelating agent administered depends on many factors and varies from subject to subject, depending on the specific chelating agent, the specific disorder or condition being treated, the severity of the symptoms, the subject's age, weight and general condition, and the prescribing physician's judgment. The term “dosage form” refers to the form of a pharmaceutical composition containing a sufficient amount of chelating agent and transport promoter to achieve a therapeutic effect with a single or multiple dose. The frequency of administration that provides the most effective results in an efficient manner without overdose varies depending on the properties of the particular active agent, including both pharmacological properties and physical properties such as hydrophilicity.

[0089] In further embodiments, the formulation may include, for example, anti-infective or antibiotic formulations encompassing fluoroquinolones, such as ciprofloxacin, levofloxacin, gentafloxacin, ofloxacin, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, and erythromycin; anti-inflammatory agents such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone, and triamcinolone; anti-angiogenic agents such as thalidomide, VEGF inhibitors, and matrix metalloproteinase (MMP) inhibitors; anti-cancer agents; and further ophthalmologically active agents selected from dry eye agents such as cyclosporine and mitomycin. Further examples of ophthalmologically active agents that can be incorporated into this formulation include anesthetics, analgesics, and cell transport / migration inhibitors; antiglaucoma agents including beta-blockers such as timolol, betaxolol, and atenolol; carbonic anhydrase inhibitors such as acetazolamide, metazolamide, dichlorfenamide, and diamox; neuroprotective agents such as nimodipine and related compounds; antibacterial agents such as sulfonamides, sulfacetamide, sulfamethizol, and sulfisoxazole; and antimicrobial agents such as fluconazole, nitrofurazone, amphotericin B, ketoconazole, and related compounds. Examples include antifungal agents; antiviral agents such as trifluorothymidine, acyclovir, ganciclovir, dideoxyinosine (DDI), zidovudine (AZT), foscamet, vidarabine, trifluorouridine, idoxuridine, and ribavirin; protease inhibitors and anticytomegalovirus agents; antiallergic drugs such as metapyriline, chlorpheniramine, pyriramine, and profenpyridamine; and decongestants such as phenylephrine, naphazoline, and tetrahydrazoline.

[0090] Typical ophthalmologically active drugs that can be incorporated into this formulation include acexidine, acetazolamide, anecoltab, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befnolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbacol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromoline, cyclopentolate, cyclosporine, dapiprazole, and demeris. Potassium, dexamethasone, diclofenac, dichlorfenamide, dipivefrin, dorzolamide, ecochiofart, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropin, fludrocortisone, fluorometholone, flurbiprofen, homivirsen, furamycetin, ganciclovir, gatifloxacin, gentamicin, homatropin, hydrocortisone, idoxuridine, indomethacin, isoflurofate, ketorolac, ketotifen, latanoprost, le Bobetaxolol, levobonolol, levocabastine, levofloxacin, rhodoxamide, loteprednol, medrizone, metazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, propalacaine, ranibizumab, rimexolone, s Copolamine, cezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinulone, trifluorometazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarbine, xylometazoline, pharmaceutically acceptable salts thereof, or any combination thereof, are listed above, but are not limited to these.

[0091] The formulations of the present invention may also be prepared as hydrogels, dispersions, or colloidal suspensions. Except that formulations referred to in the art as “hydrogels” are typically more viscous than formulations referred to as “thickened” solutions or suspensions, hydrogels are formed by incorporating a swelling gel-forming polymer, such as those shown above, as a suitable thickener (i.e., MC, HEC, HPC, HPMC, NaCMC, PVA, or hyaluronic acid or its salts, e.g., sodium hyaluronate). In contrast to such pre-formed hydrogels, formulations may also be prepared to form a hydrogel in situ after application to the eye. Such gels are liquid at room temperature but gel at high temperatures, such as when left in contact with body fluids (hence, they are called “thermally reversible” hydrogels). Examples of biocompatible polymers that impart these properties include acrylic acid polymers and copolymers, N-isopropylacrylamide derivatives, and ABA block copolymers of ethylene oxide and propylene oxide (commonly referred to as "poloxamers" and available from BASF-Wyandotte under the trade name Pluronic®). Formulations can also be prepared in the form of dispersions or colloidal suspensions. Preferred dispersions are liposomes, in which case the formulation is encapsulated within "liposomes," which are microscopic vesicles composed of alternating aqueous compartments and lipid bilayers. Colloidal suspensions are generally formed from microparticles, i.e., microspheres, nanospheres, microcapsules, or nanocapsules, where microspheres and nanospheres are generally monolithic particles of a polymer matrix that encapsulate, adsorb, or otherwise contain the formulation, and in the case of microcapsules and nanocapsules, the formulation is actually encapsulated. The upper limit of the size of these microparticles is about 5 μm to about 10 μm.

[0092] Methods of using the formulations of the present invention are also intended. The formulations of the present invention are useful for treating a wide variety of conditions associated with the formation and / or deposition of polymer aggregates. Numerous medical conditions are caused by or exacerbated by the in vivo formation or deposition of polymer aggregates, including crystalline aggregates, fibrillary aggregates, and amorphous aggregates. Certain peptidyl compounds, including selected oligopeptides, polypeptides, and proteins, are known to form crystals and fibrillaries associated with a variety of medical conditions, disorders, and diseases. For example, amyloid peptides, particularly β-amyloid, are known to form ordered fibrillary aggregates, including extracellular and vascular senile plaques associated with Alzheimer's disease.Han et al. (1995), “The Core Alzheimer's Peptide NAC Forms Amyloid Fibrils which Seed and are Seeded by .beta.-Amyloid: is NAC a Common Trigger or Target in Neurodegenerative Disease?” Chemistry and Biology 2:163-169;Serpell et al. (2000), “Molecular Structure of a Fibrillar Alzheimer's A.beta.,” Biochemistry 39:13269-13275; Jarrett and Lansbury (1992), “Amyloid Fibril Formation Requires a Chemically Discriminating Nucleation Event: Studies of an Amyloidogenic Sequence from the Bacterial Protein OsmB,” Biochemistry 31(49):12345-12352; and Jarrett et al. (1993), “The Carboxy Terminus of the See, “Beta Amyloid Protein is Critical for the Seeding of Amyloid Formation: Implications for the Pathogenesis of Alzheimer's Disease,” Biochemistry 32:4693–4697. Prion diseases, such as transmissible spongiform encephalopathy, are also characterized by abnormal protein deposition in brain tissue, which consists mainly of fibrillary amyloid plaques formed from prion proteins (PrP).Such diseases include scrapie-transmitted mink encephalopathy, chronic wasting disease in mule deer and elk, feline spongiform encephalopathy and bovine spongiform encephalopathy ("mad cow disease") in animals, as well as kuru disease, Creutzfeldt-Jakob disease, Gerstmann-Struessler-Scheinker disease, and fatal familial insomnia in humans. It has been proposed that the 15-mer amino acid sequence PrP96-111 is responsible for initiating prion formation in vivo by providing a seed for amyloid fibril formation. See Come et al. (1993), “A Kinetic Model for Amyloid Formation in the Prion Diseases: Importance of Seeding,” Proc Natl Acad Sc. USA 90:5959-5963. Fibrillin, associated with Martin's disease, is another example of a protein that forms ordered fibrillary structures that cause adverse pathological conditions. Fibrillary plaques formed from various collagens are also associated with certain medical conditions, such as heart disease and collagenous glomerulopathy; see Rossi et al. (2001), “Connective Tissue Skeleton in the Normal Left Ventricle and in Hypertensive Left Ventricle Hypertrophy and Chronic Chagasic Monocarditis,” Med Sci Mon 7:820-832; Yasuda et al. (1999), “Collagenofibrotic Glomerulopathy: A Systemic Disease,” Am J Kidney Dis 33:123-127.

[0093] Cystine can be treated to form crystalline deposits in other similarly problematic biomolecules, such as bone marrow (associated with rickets and synovitis), renal tubules and gastrointestinal tract (associated with cystinuria), as well as in various other body tissues such as the kidneys, eyes, and thyroid (associated with cystinosis, including nephrotic cystinosis and Fanconi syndrome, which are severe forms of cystinosis).

[0094] In some compositions, the ratio of EDTA to MSM is in the range of approximately 1:100 to 100:1, and the proportions of EDTA and MSM in the composition are approximately 0.1% to 15% by weight and approximately 0.1% to 40% by weight, respectively.

[0095] The formulation also contains an effective thickener used in amounts that exhibits the key characteristic of enabling the use of low-concentration chelating agent / MSM combinations, achieving a significant effect without causing unpleasant eye symptoms such as severe stinging. Swellable viscoelastic cellulose polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC) are preferred. HEC concentrations of 0.5% to 1.5%, specifically 0.8% to 1.0%, are preferred.

[0096] One major improvement of the formulations disclosed herein over previously tested ophthalmic formulations is a significant reduction in the discomfort associated with the use of conventional formulations. Attempts to reduce discomfort, such as stinging, by using viscoelastic polymers (such as hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and polyvinyl alcohol) at standard concentrations (approximately 0.2%), as used in artificial tears, have failed. These polymers and concentrations used consistently resulted in greater stinging for longer periods than when no polymer was used. In the case of HEC, stinging occurred at lower concentrations (e.g., 0.3%).

[0097] Surprisingly, when the HEC concentration was significantly increased to 0.8–1%, the stinging sensation decreased dramatically. In fact, in the presence of such high concentrations of HEC, the mucous membrane of the eye, particularly at the edge of the eye near the nose where most of the stinging occurs, did not experience the same levels of chelating agents / MSM that caused stinging with lower levels of viscoelastic compounds.

[0098] Previously used concentrations, EDTA 2.6% and MSM 5.4%, caused severe discomfort, manifesting as intense stinging pain upon initial application. This stinging sensation subsided over time, suggesting that at lower concentrations of this gradually dissipating chelating agent / MSM combination, stinging pain did not occur.

[0099] The second surprising effect was a significant reduction in the chelating agent / MSM levels required for efficacy. The slower release of EDTA / MSM from the highly viscous HEC solution greatly increases the amount of EDTA / MSM entering the aqueous and vitreous humor of the eye. In the presence of higher HEC concentrations, only half the concentration of EDTA / MSM was needed to achieve the same clinical effect as in the absence of HEC. EDTA 1.3%, MSM 2.7%, and HEC 0.8% were as effective as EDTA 2.6% and MSM 5.4%. [Examples]

[0100] The following embodiments are provided to those skilled in the art to explain the complete invention and how to create and use embodiments thereof, and are not intended to limit the scope of what the inventors consider to be their discoveries. Efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), but some experimental error and deviation should be taken into consideration. Unless otherwise specified, parts are by weight, molecular weight is weight-average molecular weight, temperature is in Celsius, and pressure is atmospheric pressure or close to atmospheric pressure.

[0101] Example 1: Increase in residence time of MSM / EDTA solution with increasing HEC concentration MSM / EDTA eye drops were prepared using various concentrations of HEC and tested in the human eye to estimate their residence time. To evaluate residence time, subjects were required to sense the presence of EDTA in the nasal cavity within seconds of application. The time interval between application and perception of EDTA was considered equivalent to the residence time in the eye. The results for five HEC concentrations in eye drops are shown in the table below. [Table 1]

[0102] At low concentrations, the subject becomes aware of the presence of the eye drops due to the stinging sensation. It causes further stinging at low concentrations. At higher concentrations (0.75 and 1%), the stinging sensation is significantly reduced.

[0103] This indicates that as the viscosity of the eye drops increases, the time it takes for the eye drops to travel non-linearly through the lacrimal punctum into the nasal cavity also increases. Actual intraocular residence times may be shorter than these figures.

[0104] Example 2: Enhancement of porcine intestinal membrane penetration with EDTA-sodium iron using hydroxyethylcellulose in an aqueous medium. The following experimental solutions were prepared: Control: 1% EDTA-ferrous sodium prepared with distilled water. Test solutions: 1% EDTA-ferrous sodium prepared with distilled water and 1%, 3%, and 5% hydroxyethylcellulose (HEC). [Table 2]

[0105] Example 3: Exemplary eye drop formulation according to the present invention Formulation A was prepared as follows: High-purity deionized (DI) water (500 ml) was filtered through a 0.2 micrometer filter. MSM, EDTA, and HEC were added to the filtered DI water and mixed until visual clarity indicating dissolution was achieved. The mixture was poured into a 10 mL bottle fitted with a dropper cap. On a weight percentage basis, the eye drops had the following composition: MSM 2.7% w / w; EDTA disodium 1.3% w / w; HEC 0.85% w / w.

[0106] All publications and patent applications cited herein are incorporated herein by attribution, as if each individual publication or patent application were specifically and individually indicated to be part of this specification by attribution.

[0107] Although the above invention is described in some detail as examples and embodiments for the purpose of clarifying understanding, it will be readily apparent to those skilled in the art in light of the teachings of the present invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims. The present invention includes the following aspects and embodiments. [Section 1] An ophthalmic preparation for the treatment of adverse eye conditions, (a) Chelating agents or their salts; (b) Transport enhancers that are charge masking agents; (c) A concentration of a viscoelastic material thickener sufficient to reduce side effects and improve efficacy; and (d) Pharmacologically acceptable inactive vehicle It is a formulation containing, The chelating agents and transport promoters are present in effective proportions to result in a significant reduction in polymer aggregation in the eye to which they are applied. The percentage of chelating agents in the composition is approximately 0.1% to 15% by weight, and the percentage of transport is approximately 0.1% to 40% by weight. formulation. [Section 2] The preparation described in item 1, wherein the transport promoter is MSM. [Section 3] The formulation described in item 1, wherein the amount of MSM is less than 5%. [Section 4] The formulation described in item 2, wherein the ratio of chelating agent to MSM is in the range of approximately 10:1 to 1:20. [Section 5] The formulation according to claim 1, wherein the viscoelastic polymer is selected from hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose (HEC), and polyvinyl alcohol. [Section 6] The formulation according to item 1, wherein the viscoelastic polymer is hydroxyethylcellulose (HEC). [Section 7] The formulation described in item 6, wherein the HEC concentration is 0.5% to 5.0%. [Section 8] The formulation described in item 6, wherein the HEC concentration is 0.5% to 1.0%. [Section 9] The formulation described in item 6, wherein the HEC concentration is 0.8% to 0.85%. [Section 10] The formulation according to claim 1, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and combinations thereof. [Section 11] The formulation according to claim 10, wherein the EDTA salt is selected from EDTA diammonium, EDTA disodium, EDTA dipotassium, EDTA triammonium, EDTA trisodium, EDTA tripotassium, EDTA tetrasodium, EDTA tetrapotassium, EDTA disodium calcium, and combinations thereof. [Section 12] The preparation according to item 1, wherein the chelating agent is selected from phosphates, pyrophosphates, tripolyphosphates, and hexametaphosphates. [Section 13] The preparation according to item 1, wherein the chelating agent is a chelating antibiotic, chloroquine, or tetracycline. [Section 14] The preparation according to item 1, wherein the chelating agent is a nitrogen-containing chelating agent, diimine, or 2,2'-bipyridine containing two or more chelated nitrogen atoms in the imino group or aromatic ring. [Section 15] The chelating agent is cyclam(1,4,7,11-tetraazacyclotetradecane), N-(C 1 ~C 30 Alkyl)-substituted cyclamates (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferoxamine (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(acetyl-hydroxy-amino) The preparation described in item 1 is a polyamine selected from pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butanediamide), desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal, deferipron, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol). [Section 16] The chelating agents are ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2- The formulation according to item 1, which is an EDTA-4-aminoquinoline conjugate selected from (bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, and ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate). [Section 17] The preparation according to item 1, wherein the chelating agent is a natural chelating agent selected from citric acid, phytic acid, lactic acid, acetic acid and their salts, and curcumin. [Section 18] The preparation described in item 1, wherein the vehicle is aqueous. [Section 19] The preparation described in item 1, wherein administration of the preparation reduces polymer aggregates in the eye. [Section 20] The formulation according to item 19, wherein the polymer aggregate is a peptidyl compound. [Section 21] The preparation described in item 19, wherein the polymer aggregates are proteins. [Section 22] The preparation described in item 19, wherein the polymer aggregate is a lipoprotein. [Section 23] The preparation described in item 1, wherein the preparation includes an ocular implant. [Section 24] The formulation described in item 1, wherein the formulation is for timed release. [Section 25] polymer aggregates The preparation described in item 19. [Section 26] The preparation according to item 1, comprising MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w. [Section 27] A method for reducing signs of adverse ocular syndrome by administering the preparation described in item 1 to the eye of a subject requiring reduction of signs of adverse ocular syndrome. [Section 28] The method according to item 27, wherein the harmful eye condition is the accumulation of polymer aggregates in the eye. [Section 29] The method according to item 27, wherein the formulation comprises a chelating agent and a penetration enhancer in an amount such that the formulation is effective in the presence of a viscoelastic polymer as at least 75% compared to its effectiveness in the absence of the viscoelastic polymer. [Section 30] The method according to item 27, wherein the formulation comprises MSM, MSM and HEC as a viscoelastic polymer as a penetration enhancer. [Section 31] The method according to item 30, wherein the preparation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w. [Section 32] The method according to item 27, wherein the formulation comprises a chelating agent, a penetration enhancer, and a viscoelastic polymer in an amount that significantly reduces the stinging sensation in the eye of the subject in the presence of the viscoelastic polymer compared to the stinging sensation in the absence of the viscoelastic polymer. [Section 33] The method according to item 27, wherein the formulation comprises MSM, MSM and HEC as a viscoelastic polymer as a penetration enhancer. [Section 34] The method according to item 30, wherein the preparation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w. [Section 35] A formulation for treating harmful eye conditions while reducing the sensation of stinging pain in the target body, (a) Chelating agents or their salts; (b) A charge masking agent that is methylsulfonylmethane (MSM); (c) A thickening agent which is hydroxyethylcellulose (HEC) in a concentration of 0.5% to 5.0%; and (d) Pharmacologically acceptable inactive vehicle A formulation containing, The HEC concentration is sufficient to reduce the release of the chelating agent / MSM combination in the eye and maintain a concentration level below the level at which stinging sensation occurs. The HEC concentration is sufficient to retain the chelating agent / MSM in the eye for a period effective in resulting in a significant reduction in adverse eye conditions. The percentage of chelating agents in the composition is approximately 0.1% to 3.0% by weight, and the percentage of transport is approximately 0.1% to 6.0% by weight. formulation. [Section 36] A formulation according to item 35, wherein an adverse eye condition is caused by polymer aggregation. [Section 37] The formulation described in paragraph 35, in which the adverse eye condition is caused by dry eye syndrome. [Section 38] A formulation described in paragraph 37, in which dry eye syndrome is caused by inflammation.

Claims

1. An ophthalmic formulation for treating adverse eye conditions while reducing side effects associated with the administration of a formulation containing methylsulfonylmethane (MSM) and a chelating agent, wherein the formulation is (a) Chelating agents or their salts; (b) A transport enhancer that is methylsulfonylmethane (MSM); (c) A viscoelastic polymer selected from hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose (HEC), and polyvinyl alcohol in a concentration that increases the penetration into the eye and the retention time of MSM and the chelating agent in the eye to which the ophthalmic formulation is applied; and (d) Pharmacologically acceptable inactive vehicle Includes, The percentage of chelating agents in the formulation is approximately 0.1% to 15% by weight, and the percentage of transport promoters is approximately 0.1% to 40% by weight. The increase in residence time and penetration of the formulation is sufficient to at least double the efficacy of the formulation compared to a formulation without a viscoelastic polymer, and the concentration of the viscoelastic polymer is at least 0.8%. formulation.

2. The formulation according to claim 1, wherein the viscoelastic polymer is HEC.

3. The formulation according to claim 1, wherein the amount of MSM is less than 8% w / w.

4. The formulation according to claim 1, wherein the ratio of chelating agent to MSM is in the range of approximately 10:1 to 1:

20.

5. The formulation according to claim 1, wherein the concentration of the viscoelastic polymer is 0.8% w / w to 5.0% w / w.

6. The formulation according to any one of claims 1 to 5, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and combinations thereof.

7. The formulation according to claim 6, wherein the EDTA salt is selected from EDTA diammonium, EDTA disodium, EDTA dipotassium, EDTA triammonium, EDTA trisodium, EDTA tripotassium, EDTA tetrasodium, EDTA tetrapotassium, EDTA disodium calcium, and combinations thereof.

8. The chelating agents are ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]propyl]-ethyl]-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-propyl]-propyl]-ethyl]-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-propyl]-ethyl]-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-ethyl] The formulation according to any one of claims 1 to 5, wherein the EDTA-4-aminoquinoline conjugate is selected from [xymethyl-amino)-ethyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, and ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate.

9. The formulation according to any one of claims 1 to 5, wherein the vehicle is aqueous.

10. The formulation according to any one of claims 1 to 5, wherein administration of the formulation reduces polymer aggregates in the eye.

11. The formulation according to claim 10, wherein the polymer aggregate is selected from peptidyl compounds, proteins, and lipoproteins.

12. The formulation according to any one of claims 1 to 5, wherein the formulation includes an ocular implant.

13. A formulation according to any one of claims 1 to 5, wherein the formulation is for timed release.

14. The formulation according to claim 1, wherein the formulation comprises 2.7% w / w MSM; 1.3% w / w EDTA disodium; and at least 0.8% HEC.

15. A formulation for treating adverse eye conditions while reducing stinging sensation in the eye associated with the administration of a formulation containing methylsulfonylmethane (MSM) and a chelating agent, wherein the formulation is (a) Chelating agents or their salts; (b) A charge masking agent which is methylsulfonylmethane (MSM); (c) A viscoelastic polymer, which is hydroxyethylcellulose (HEC), in a concentration sufficient to increase the penetration into the eye and the retention time of MSM and the chelating agent within the eye to which it is applied; and (d) Pharmacologically acceptable inactive vehicle Includes, The percentage of chelating agents in the formulation is approximately 0.1% to 3.0% by weight, and the percentage of MSM is approximately 0.1% to 6.0% by weight. The amount of viscoelastic polymer is sufficient to double the effectiveness of the chelating agent and MSM compared to the chelating agent and MSM without HEC, and the concentration of the viscoelastic polymer is at least 0.8%. formulation.

16. The formulation according to claim 1 or 15, wherein an adverse eye condition is caused by polymer aggregation.

17. The formulation according to claim 1 or 15, wherein the adverse eye condition is caused by dry eye syndrome.

18. The formulation according to claim 17, wherein dry eye syndrome is caused by inflammation.

19. The formulation according to claim 1 or 15, wherein the adverse eye condition is caused by cataracts.

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