IL163938A - Urea and urea derivatives for treatment or prevention of disorders of the eye - Google Patents

Description

163938/2 vn w>m IN ϊηο>υ!? Π ηΐΝ nnroi ΠΝ> ΙΝ UREA AND UREA DERIVATIVES FOR TREATMENT OR PREVENTION OF DISORDERS OF THE EYE FIELD OF THE INVENTION The present invention relates generally to pharmaceutical preparations, and more particularly agents (i.e. Urea, Urea derivatives, non-steroidal antiinflammatory drugs and Anti- metabolite drugs) used alone or in combinations with each other (or with other agents) to treat or prevent certain disorders of the eye.

BACKGROUND OF THE INVENTION Prior Ophthalmologic Uses of Urea United States Patent Nos. 5,629, 344 (Charlton) and 5,470,881 (Charlton) describe certain therapeutic applications of urea preparations to the eye. These prior patents specifically describe non-aqueous ointments and other non-aqueous preparations of urea for use in the eye, pointing out that aqueous solutions of urea were believed to be impractical for use in the eye. For example, these prior patents state as follows: "One of the reasons urea has not been used in treating eye disorders is that it will hydrolyze in aqueous vehicles thus producing ammonia as a byproduct. Ammonia is toxic to the eye, and thus urea in an aqueous solution would be impractical for use as an ophthalmic medicament." Thus, prior to Applicant's invention, aqueous solutions of urea or urea derivatives were thought to be unstable and potentially toxic to the eye.

Anatomic and Physical Properties of the Cornea The cornea is the first and most powerful refracting surface of the optical, system of the eye. Production of a sharp image at the retinal receptors requires that the cornea be transparent and of the appropriate refractive power. The average corneal thickness of a normal cornea is 0.56 mm in persons under 25 years of age; this thickness slowly increases with age to become 0.57 in persons over 65 years of age. The cornea is somewhat thicker in the periphery than the center. The thickness of the cornea is greatest after the eyes have been closed for some time, as after sleeping, this thickness decreases slightly when the eyes are opened and exposed to the dehydrating effects of the air.

The cornea is composed of six layers: a) Epithelium, b) Basement membrane, c) Bowman's membrane, d) Stroma, e) Descemet's membrane, f) Endothelium. a) Epithelium: The epithelium consists of 5-6 layers of cells. The most superficial cells are fiat overlapping squamous cells. The middle layer consists of cells that become more columnar as the deeper layers are approached. The innermost layer (basal) is made up of columnar cells packed closely together. All the cells are held together by a cement substance. Also, the cell surfaces form processes that are fitted into corresponding indentations of adjacent cells and connected in places by attachment bodies called desmosomes. The basal cells are connected to the basement membrane by hemidesmosomes. The epithelium represents 10% of the total wet weight of the cornea. Water in the epithelium represents 70% of the wet weight.

Although the epithelium consists of 5-6 layers of ceils, the healthy epithelium is very strongly attached to each other by desmosomes as well as to the Basement membrane by hemidesmosomes. ■ b) Basement membrane; Between the columnar epithelial cells and Bowman's membrane is a basement membrane from 60 - 65 nm thick. The basement membrane has been examined histochemical!y and found to be similar to other basement membranes. c) Bowman's membrane: Bowman's layer is a sheet of transparent tissue about 12μιη thick, without structure as seen by light microscopy. Under electron microscopy it appears to be made up of uniform fibrils, probably of collagenous material, running parallel to the surface, Bowman's layer possesses little resistance to any pathologic process, and is easily destroyed and never 'regenerates. d) Stroma: The Stroma comprises about 90% of the whole cornea. The ■ Stroma is composed of layers of lamellae, each of which runs the full length of the cornea; although the bundles interlace with one another, they .are nearly parallel to the " surface. The cell bodies, called keratocytes, are flattened , so they too lie parallel to the surface, and their cell processes interlace with one another. This arrangement of the fibers gives optical uniformity to the cornea. The Stroma comprises about 90% of the whole cornea. The Stroma is composed of differentiated connective tissue containing 75% to 80% water on a wet weight basis, The remaining solids 20% to 25% is collagen, other proteins, and glycosaminoglycans or mucopolysaccharides constitute the major part. The collagen fibrils are neatly organized and present the typical 64 to 66 nm periodicity of collagen fibrils separated from each other by the ground substance. The size, regularity, and precise spacing of the fibrillar structures are the physical characteristics essential for corneal transparency.

The glucosaminoglycans (GAG, mucopolysaccharides) represent 4% to 4.5% of the dry weight of the cornea. GAG are localized in the interfibriilar or interstitial space, probably attached to the collagen fibrils or to soluble proteins of the cornea. The GAG plays a role in corneal hydration through interaction with electrolytes and water. Three major GAG fractions are found in the cornea! Stroma: keratin sulfate (50%), chondroitin (25%), and chondroitin sulfate A (25%). GAG's have been implicated in the maintenance of the corneal hydration level and transparency. e) Descemet's Membrane: Is made of type IV collagen, unlike the corneal Stroma, there are no significant amounts of sulfated GAG in the Descemet's membrane. The collagen in this membrane is insoluble except in strong alkali or acid and is .more resistant to collagenase than corneal stroma collagen. -Jakus2 has observed with the electron microscope that this membrane has collagen like structure of great regularity. Descemet's membrane is highly elastic and represents a barrier to - perforation in deep corneal ulcers. f) Endothelium: The endothelium is a single layer of cells lining Descemet's membrane. Its inner surface is bathed by the aqueous humor. In humans the endothelium cell layer has limited, if any, reproductive capacity. Aging causes cell loss, and the remaining cells enlarge and spread so that Descemet's membrane remains completely covered .'therefore endothelial cell density, expressed as cells per unit area, decreases with age. Similarly, cell loss from trauma, inflammation, or surgery is compensated for by increased cell size and decreased cell density.

Corneal metabolism embraces a series of chemical processes by which energy is obtained and utilized for the normal functions of the cornea. In the cornea, energy is needed for maintenance of its transparency and dehydration, Energy in the form of ATP is generated by the breakdown of glucose into lactic acid and into carbon dioxide ■ and water (i.e., Krebs Cycle). The cornea obtains glucose mainly from the aqueous humor. The tears and limbal capillaries appear to contribute minimal amounts of glucose and Oxygen for corneal metabolism.

Most of the oxygen consumed by the cornea is taken in by the epithelium and the endothelium, The oxygen consumption of the epithelium and endothelium can be approximately '26 times that of the stroma. The corneal endothelium gets most of its required oxygen from the aqueous humor, while the corneal epithelium gets much of its oxygen from either the capillaries at ihe limbus or from the oxygen dissolved in -the pre-comea! film.

Mei ods for Ihe sfractive Correction of tlis Eye: Radial keratotomy (RK) is a surgical procedure to improve myopia by changing the corneal curvature. This is achieved by making several deep incisions in the cornea in a radial pattern. The eye surgeon makes 4, 8, or 16 incisions so as to flatten the curvature of the central cornea, thus correcting the patient's vision. The main drawbacks of RK include, a) It can only be used to correct low levels of myopia, b) This surgical procedure cannot correct hyperopia, c) RK procedure seriously weakens the cornea and creates corneal scars, d) The corneal curvature changes are temporary and frequently continue to change with time.

Photorefractive keratectomy (PRK) is a surgical procedure that uses the excimer laser, which is controlled by a computer. With the PRK procedure, the excimer laser ablates and sculpts the corneal surface to the desired shape to correct the patient's vision. There are a combination of lasers with a combination of computer controls that can reliably treat myopia, hyperopia, and astigmatism. Since PRK is a surgical procedure, it can result in complications. Infection is the most serious complication resulting from the ablation of a large area of the corneal epithelium. In addition delayed corneal healing because of the absence of the corneal epithelium, corneal haze, corneal scarring, over correction or under-correction and development of astigmatism are other complications of PRK. These complications must be treated with, medications or further surgery.

Laser in-situ keratomileusis" (LASIK) is a surgical procedure that is a variation on PRK involving an excimer laser and a precise cutting tool called a microkeratome. The microkeratome is used to make a 150-175 micron circular flap of the cornea. The circular flap is flipped back, as if on a hinge, to expose the stromal layer of the cornea. With the flap folded back, the refractive eye surgeon now ablates the stroma and makes the refractive correction using the excimer laser. The circular corneal flap is repositioned on the ablated cornea to complete the procedure. With a precision laser treatment and normal reattachment and healing of the corneal flap, the refractive results of good vision correction are very rapid. There is, however, a significant list of potential complications and risks associated with LASIK procedure; failure of the microkeratome to leave a hinge on the corneal flap with the first incision, !oss"of the corneal flap after the operation, slipping of the flap and healing off csnter, first incision is too deep or too shallow, corneal epithelium ingrowths into the stroma, infection of the cornea, corneal ectasia, loss of visual acuity from scarring and optical distortion of the collagen structure of the stroma.

Laser epithelial keratomileusis (LASEK) is a surgicai procedure that is a variation on PRK involving an excimer laser that combines the advantages and eliminates the disadvantages of PRK and LASIK. A 7.0 mm circular area of the epithelium is marked with a Hoffer trephine centered over the pupil. The corneal epithelium is removed by using a blunt spatula, or is exposed to 20% isopropyl alcohol solution which allows the corneal epithelium to be peeled off. Using the excimer laser the surgeon ablates and sculpts the corneal surface to the desired shape to correct the patient's vision. At the end of the procedure the corneal epithelial flap created by • the alcoholic solution is placed back onto the ablated cornea, a drop of antibiotic, a drop of non-steroidal anti-inflammatory agent and a therapeutic contact lens is applied to the corrected eye..The epithelial defect created by the scrapping of the corneal epithelium, or by peeling of the epithelium after the application of alcoholic solution is completely closed within a few days. With a precision laser treatment and normal healing of the corneal epithelium , the refractive results of good vision correction are very rapid. There are, however; a few potential complications and risks associated with LASEK procedure; infection of the cornea because of the epithelial defect as a result of epithelial scrapping , use of alcoholic solution causes extensive damage to the peeled corneal epithelium minimizing the benefits of the reapplied corneal epithelium.

Thermokeratoplasty is another corneal reshaping method. In this procedure heat at 55°C to 58°C is applied to the collagen fibers of the cornea to induce shrinkage without the destruction of the tissue. The shrinkage of the collagen fibers result in the change of the mechanical properties and flattening of the cornea, thus achieving refractive correction. U.S. Patent No. 4,881 ,543 describes the use of microwave electromagnetic energy to shrink the collagen of the cornea. U.S. Patent No. 5,779,696 describes the use' of light energy to reshape the cornea. All of these systems of Thermokeratoplasty have a shortcoming that is the treated corneas are unstable after the treatment.

Orthokeratology is a non-surgical procedure designed to correct refractive errors by reshaping the cornea to the corneal curvature required to achieve emmetropia. This is accomplished by applying a series of hard contact lenses that ' change the corneal curvature until the desired curvature is achieved. However once the desired curvature has been produced, retainer hard contact lenses must be worn to stabilize the results otherwise regression will occur.

Enzyme Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia. The system is enhanced by 'enzymatically. softening the cornea, and reshaping is. obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem.

Chemical Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia. The system is enhanced by applying topically or by intra-stromal injection a chemical that is not an enzyme and softening the cornea, and reshaping is obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem.

SUMMARY OF THE INVENTION The present invention provides the use of a composition for treating or preventing disorders of the eye of a human or veterinary patient by administering topically onto the eye or by injection into the eye (e.g. intravitreal, intrastromal or sub-conjunctival injection) a therapeutically effective amount of an aqueous solution containing an agent selected from: urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof. Included among the therapeutic purposes for which this method may be used are removal of the corneal epithelium, dissolution of the corneal proteoglycans, interface closure and organized healing of corneal stroma in refractive JLAS1K correction, dissolution of proteins and amino acids so as to compress the collagen fibrils for better visual acuity and better quality of vision, softening of the cornea prior to or during application of a contact lens or cornea-reshaping template for the non- surgical refractive correction of myopia, presbyopia, hyperopia, astigmatism and keratoconus, dissolution of newly synthesized proteoglycans thereby lessening or eliminating corneal haze and/or corneal opacification, dissolution of proteoglycans in the anterior chamber thereby increasing outflow of fluid which may lower of intra- ocular pressure in some glaucoma patients, causing a solvent action on fibroblasts, inhibiting fibroblasts, inhibiting or preventing corneal fibrosis and scar formation, inhibiting the proliferation of fibroblasts in ocular tissue, inhibiting VEGF activity in the cornea and the iris via an anti -angiogenic effect, thus eliminating both the progression and the regression of corneal new vessels and iris new vessels. By one or more of these therapeutic effects and/or other mechanisms of actionyet to be elucidated, the composition of the present invention may be usable to treat various disorders of the eye. As used in this patent application, the term "treat" shall not be limited only to treatment of existing diseases or disorders but also shall mean preventing, deterring, stopping, curing, or slowing the progression of such disorders. The disorders of the eye that may be treated by the method of the present invention include but are not limited to: refractive disorders, impaired visual acuity or diminished quality of vision, myopia, presbyopia, hyperopia, astigmatism, keratoconus, corneal fibrosis, scar formation, corneal opacities, pterigiums, corneal neovascularization, iris neovascularization, giaucoma.

Further in accordance with the invention, the agent may be administered in combination with an antimetabolite compound such as; mitomicyn, methotrexate, thiourea, hydroxyurea, 6-mercaptopurine, thioguanine, 5-fluorouracil, cyiosine arabinoside and 5-azacytidine.

Still further in accordance with the invention, the agent may be administered in combination with an antineoplastic agent such as Actinomycin D, daunorubicin, doxorubicin, idarubicin, bleomycins, or plicamycin may also be used in combination with these anti-metabolites.

Still further aspects, objects and advantages of the invention will be apparent to those of skill in the art who read and understand the following detailed description of the invention and the specific examples set forth therein.

DETAILED DESCRIPTION The following detailed description and the examples referred to therein are provided for the purpose of describing certain embodiments or examples of the invention only and shall not be construed as limiting the scope of the invention in any way.

Removal of the Corneal Epithelium One example of an application of the method of the present invention is for the removal of corneal epithelium. As explained above, the corneal epithelial cells are held together by a cement substance. In addition the surfaces of the cells form processes that are fitted into the corresponding indentations of the adjacent cells and connected by attachment bodies called desmosomes. In addition the basal cells of the epithelium are connected to the basement membrane by hemidesmosomes. When the corneal epithelium is damaged by chemical or physical means, swelling of the stroma follows. Abrasion of the cornea or any condition leading to the loss of epithelium is likely to produce localized areas of corneal swelling and cloudiness and allows microbial access and bacterial infections. Fortunately, the cornea! epithelium regenerates rapidly, and the excessive hydration and wound closure in the absence of bacterial infections is slight and transient.

Effecting mechanical or chemical de-epithelialization (debridement) while keeping the epithelium in tact an without damage is not an easy task. There are several methods that are utilized presently, but all these methods and materials cause severe damage to the corneal epithelium.

Mechanical de-epithelialization is typically performed under topical anesthesia with a local anesthetic with a blunt spatula after the epithelium is marked with a 7.0 mm Hoffertrephine centered overthe pupil. The resulting corneal wound usually takes several days to re-epithelialize. During this time any exposed corneal incision or wound is susceptible to bacterial contamination and infection.

Chemical de-epithelialization using alcohol is also typically performed under topical anesthesia with a local anesthetic. The epithelium is marked, and by a gentle depression on the trephine a circular cut is made with a 7.0 mm Hoffer trephine centered over the pupil. While the trephine is in place 5 - 10 drops of 20% Isopropyl Alcohol are dispensed into the trephine and kept in contact with the epithelium for several minutes. The alcoholic solution is removed with a dry sponge, and the trephine is removed from the cornea. Using a blunt spatula the epithelium is removed intact in one piece. This procedure is a simple way to de-epithelialize the cornea, however 50% - 70% of the epithelial cells are damaged because of the exposure to the alcoholic solution. Furthermore the 20% alcoholic solution is very irritating and inflammatory to the eye. After the surgical procedure, the resulting corneal wound is covered with the single piece of the alcohol removed epithelium. The resulting wound is temporarily covered with corneal epithelium which will take several days to re-epithelialize. During this time of wound healing the cornea is less susceptible to bacterial contamination and infection.

In accordance with the present invention, there is provided a new method for chemical removal of the corneal epithelium using an agent selected from: urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine}, reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate or other compounds capable of causing non enzymatic ■ dissolution of the proteoglycans or any possible combination thereof . This method may be performed under topical anesthesia with a local anesthetic. First, the epithelium is marked, and by a gentle depression on the trephine a circular cut is made with a 7,0 mm Hoffer trephine centered over the pupii. While the trephine is in place 5 - 10 drops of the agent (e.g., 0.01 % - 20% of aqueous urea solution) is dispensed into the trephine and kept in contact with the epithelium for several minutes. The agent {e.g., aqueous urea solution) is removed with a dry sponge, and the trephine is removed from the cornea. Using a blunt spatula the epithelium is removed intact in one piece. This procedure is a simple way to de-epitheltalize the cornea resulting in no damage to the epithelial cells. After the surgical procedure, the resulting corneal wound is covered with the single piece of the urea removed epithelium. The resulting wound is temporarily covered with corneal epitheiium which will re- epitheliaiize in 1-2 days. During this time of wound healing the cornea is !ess susceptible to bacterial contamination and infection. This chemical de-epitheliaiization of the cornea using an agent of the present invention (e.g., urea solution) may be useful as an adjunct to ophthalmic surgery for the treatment of herpetic epithelial keratitis, as well as for refractive correction of vision using the Laser epithelial keratomileusis (LESEK).

Enhanced Corneal Interface closure and Organized Healing of the corneal stroma in Refractive LASIK Correction.

The present invention also provides methods for enhancing healing of the cornea after LASEK surgery. In this method, an agent selected from: urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives {e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, is applied topically to the cornea following a LASiK procedure. For example, a few drops of the agent (e.g., 0.01 % - 20.0% aqueous urea solution) may be placed onto the surface of the excimer laser ablated stroma before the cut flap of the cornea! epithelium is repositioned on the laser ablated cornea. The urea solution placed at the interface of 5 the corneal epithelium and stroma, will result in the localized solubilization of the stromal proteoglycans and will compress the collagen fibril packing for better visual performance, but normal transparency.

Successful completion of Laser in-situ keratomileusis (LASIK) refractive correction results in the precision cutting of the cornea, excimer laser ablation of the I 0 stroma and the repositioning of the circular flap on the ablated cornea. Normal reattachment and healing of the corneal flap are very important parameters for good vision correction and rapid healing. The superficial placement of the microkeratome cut circular flap of the cornea onto the excimer laser ablated stroma results in an interface gap in the stroma between the upper and lower parts of the stroma. This ' 15 interface gap interferes with optimum vision correction, in addition the interface gap never completely comes together as a sing!e stoma indicating the lack of complete wound healing of the cornea.

In the present invention of enhanced corneal interface closure and organized healing of the LASIK refractive corrected cornea, a few drops of an agent of the present invention (e.g., 0.01 % - 20.0% aqueous urea solution) is placed onto the surface of the excimer laser ablated stroma before the microkeratome cut flap of the cornea is repositioned on the laser ablated cornea. The urea solution placed at the interface of the two corneal flaps will result in the localized solubilization the stromal proteoglycans and eliminate the interface gap, thus producing optimum vision ' correction. In addition the localized solubilization of the proteoglycans of the stroma will result in the compression of the collagen fibril packing for better visual performance, but norma! transparency.

Softening of the Corneal Stroma by topical or intrastromal application, for the 30 non-surgical Refractive correction of Myopia, Presbyopia, Hyperopia, Astigmatism and Keratoconus The present invention a!so provides methods for softening the cornea by administering to the cornea an agent selected from: urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acelyl salicylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof , in an amount thta is effective to cause temporary softening of the cornea so that it can be reshaped from a first configuration to a desired second configuration of emmetropia. The softening of the cornea could take place while the patient is wearing rigid contact lenses having a concave shape of the desired second configuration rendering the eye emmetropic. The cornea is thereafter permitted to shape to the desired second configuration under the influence of the lens. Since the corneal softening is a result of localized solubilization of the proteoglycans and not the chemical breakdown of the of the proteoglycan molecules, it is possible that the corneal softening effect of the agsni will dissipate much faster in the presence or absence of the molding rigid lens.

The shape of the cornea is based on the collagen fibrils of the stroma which are held in place at a much specified distance from each other in parallel along with the mucopolysaccharides cement layers between these collagen fibrils. The Urea and Urea derivatives have the ability of solubilizing the mucopolysaccharides as well as various proteins. The stroma is therefore softened and becomes more pliable and easy to mold to a more desirable shape. * In the preferred embodiment, the cornea softening agent comprises urea or a urea derivative together with pharmaceutically acceptable carriers and additives. The preparation may be supplied in a liquid or lyophilized form. The cornea softening agent in accordance with the present invention is administered to the cornea in a number of ways. Typically, the agent is administered either directly in the form of eye drops, or by the use of a corneal softening agent delivery vehicle, which may include special drug delivery systems including -liposomes, sustained release gels and implantable solid dosage forms as well as contact lens and biodegradable corneal collagen shield.

Non-Surgical Treatment and Elimination of Corneal Haze and Corneal Opacification A reduction of visual acuity and blindness may result from a lack of corneal clarity caused by corneal traumas, corneal scars, or any other cause of corneal opacification, Patients who have a reduction of visual acuity as a result of corneal opacities are estimated to be three million. The current treatment for corneal opacity is corneal transplantation using a surgical procedure called penetrating lamellar keratoplasty (PKP), using human corneal donor tissue. This surgical technique is considered safe and effective, however one of the risks includes graft rejection as well as viral and bacterial infections transmitted through the donor corneal tissue. The overall number of transplant surgical procedures that can be performed is limited by the availability of donor corneas for transplantation.

The present invention provides the use of a composition for providing corneal clarity or treating corneal scars, corneal opaci ication, and optical aberrations including corneal haze by administering to the eye an agent selected from: urea, a urea derivative, non enzymatic protein urea, non- enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, in an amount that is effective to accelerate the solubilization of corneal proteoglycans, mucopolysaccharides and various other proteins and lead to the reorganization of corneal collagen. The resulting reorganization will clear corneal scars, corneal opacities and corneal haze. For example, the agent (e.g., an aqueous solution of urea or a urea derivative) may be administered topically or by injection in an amount that reduces corneal collagen disorganization by chemical modification or dissolution of corneal stromal glycoprotein's and proteoglycans.

The role of corneal glycoprotein's and proteoglycans in the establishment and maintenance of corneal transparency is not well understood. Stromal proteoglycans have been hypothesized to play a role in the regulation of collagen fiber spacing.

Although the precise role of proteoglycans is still unclear, they are thought to influence the hydration, thickness and clarity of the cornea. The functional significance of hyaluronan in the cornea, except during development and in some corneal •abnormalities is still unknown.

In some opaque human corneal scars, the scars have been found to contain collagen fibrils with abnormally large diameter and irregular interfibrillar spacing. However, during wound healing of rabbit corneas, the early opaque scars contain , collagen fibrils of generally normal diameter that are irregularly spaced within the tissue. The collagen fibril diameter does not markedly change after a year of healing, but the spacing between the fibrils returns to normal and there is a concomitant decrease in the opacity of the scar.

In a 1983 paper authored by Hassell et al., showed that opaque scars that contained the large interfibrillar spaces also contained unusually large chondroitin . sulfate proteoglycans with glycosaminoglycan side chains of normal size. These opaque scars also lacked the keratan sulfate proteoglycan but did contain hyaluronic acid. The biochemical analysis of proteoglycans in rabbit corneal scars in corneal wounds compared to normal cornea adjacent to the scar demonstrates that the areas synthesize proteoglycans measurably different from one another.

Hassell et al. analyzed corneal specimens obtained during surgery from patients with macular corneal dystrophy. Hassell et al. found that cells from normal corneas synthesized both a chondroitin sulfate proteoglycan and a l

Claims (8)

163938/4 Claims:

1. The use of urea in the manufacture of a medicament in liquid or lyophilizcd form for topical administration to the cornea of a subject's eye for the treatment of a refractive disorder, myopia, hyperopia, astigmatism or keratoconus.

2. A use according to claim wherein the medicament has a pH of 4.0 to 8.0 and comprises: Urea USP/NF 0.001 - 4.0% Citric Acid USP/NF 0.00007% - 0.02% Sodium Chloride USP/NF 0.1% - 0.9% Sterile Water Q.S. 100%

3. A use according to claim 1 wherein the medicament has a pH of 4.0 to 8.0 and comprises: Urea USP/NF 0.001 - 4.0% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100%

4. A use according to claim 1 wherein the medicament has a pH of 4.0 to 8.0 and comprises: Urea USP/NF 0.01 - 20.0% Citric Acid USP/NF 0.00007% - 0.02% Sodium Chloride USP/NF 0.1 % - 0.9% Sterile Water Q.S. 100%

5. A use according to claim 1 wherein the medicament has a pH of 4.0 lo 8.0 and comprises: Urea USP/NF 4.0% Potassium Phosphate Dibasic USP/NF 5.0 millimolar Sterile Water Q.S. 100% 163938/4

6. A use according to claim 1 wherein the medicament has a pH of 4.0 to and comprises: Urea USP/NF 4.0% Potassium Phosphate Dibasic USP/NF 50.0 mitl imolar Sterile Water Q.S. 100%

7. A use according to claim 1 wherein the medicament has a pH of 4.0 to and comprises: Urea USP/NF 0.01% - 20.0% Sorbitol USP/NF 0.10% - 0.50% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 8. A use according to claim 1 wherein the medicament has ) and comprises: Urea USP/NF 0.01% - 20.0% Isopropyl Alcohol (90%) 0.5% - 20% Sodium Chloride USP/NF 0.1% - 0.9% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 9. A use according to claim 1 wherein the medicament has a pH of 4.0 to and comprises: Urea USP/NF 0.01 % - 20.0% Isopropyl Alcohol (90%) 0.5% - 20% Sterile Water Q.S. 100% 10. A use according to claim 1 wherein the medicament has a pH of 4.0 to and comprises: Urea USP/NF 0.01 % - 20.0% Isopropyl Alcohol (90%) 0.5% - 20% Propylene Glycol 0.10% - 50.0% 163938/4 Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 1 1. A use according to claim 1. wherein the medicament has a pH of 4.0 to 8.0 and comprising: Urea USP/NF 0.01 % - 20.0% Propylene Glycol 0.1.0% - 50.0% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 1.2. A use according to claim 1 wherein the medicament has a pH of 4.0 to 8.0 and comprises: Urea USP/NF 0.01% - 20.0% Polyethylene Glycol 0.1.0% - 50.0% Sodium Chloride USP/NF 0.10% - 0.90% Sterile Water Q.S. 100% 13. The use of hydroxyurea or thiourea in the preparation of an aqueous solution for topical administration to the cornea of a subject's eye for the treatment of a refractive disorder, myopia, hyperopia, astigmatism or keratoconus. 14. A use according to claim 13 wherein the aqueous solution has a pH of 4.0 to 8.0 and comprises: Hydroxyurea USP/NF 4.0% Sodium Chloride USP/NF 0.10% - 0.90% ' Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 15. A use according to claim 13 wherein the aqueous solution has a pH of 4.0 to 8.0 and comprises: Hydroxyurea USP/NF 4.0% Potassium Phosphate Dibasic USP/NF 5.0 - 50.0 miliimolar 163938/4 Sterile Water Q.S. 100% 16. A use according to claim 13 wherein the preparation has a pH of 4.0 to comprises: Hydroxyurea USP/NF 4.0% Sorbitol USP/NF 0.10% - 0.50% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% 17. A use according to claim 13 wherein the aqueous solution has a pH of 4.0 nd comprises: Hydroxyurea USP/NF 0.01 % - 1.5.0% Sodium Chloride USP/NF 0.10% - 0.90% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100%

8. A use according to claim 13 wherein the aqueous solution has a pH of 4.0 nd comprises: Thiourea 0.010% - 10.0% Sodium Chloride USP/NF 0.10% - 0.90% Citric Acid USP/NF 0.00007% - 0.02% Sterile Water Q.S. 100% For the Applicant Seligsohn Gabrieli & Co.