MXPA00008785A - Use of corneal hardening agents in enzyme orthokeratology - Google Patents

Abstract

An Enzyme Orthokeratology method is provided for correcting refractive errors in the eye of a subject mammal. Accelerating reshaping of the cornea is accomplished by administering a corneal hardening amount of a corneal hardening agent to the eye of the subject. Reformation is accomplished under the influence of a rigid contact lens or a series of lenses having a concave curvature that will correct a refractive error. The cornea rapidly reshapes its convex curvature to the concave curvature of the contact lens, rendering the eye emmetropic. The cornea is permitted to"harden"to retain the new emmetropic shape. After"hardening"has occurred, the lens rendering the eye emmetropic is removed.

Description

USE OF CORNEA HARDENING AGENTS IN ENZYMATIC ORTHOPERATOLOGY DESCRIPTION OF THE INVENTION The present invention relates to methods to accelerate the reconfiguration of the non-surgical cornea that involves the release of corneal hardening agents which facilitates the reconfiguration of the cornea. Cornea to correct refractive errors of the eye. The cornea is the transparent dome in front of the eye. Approximately eighty percent of the focus, or refractive power, of the eye in the cornea. When the cornea is deconfigured or the axial length of the eye is too long or too short, or when the lens of the eye is functioning abnormally, errors of refraction of myopia (short view) astigmatism (blurred vision) or hyperopia (presbiopia) may result. Throughout history, humanity has experimented with ways to improve the addition. Although these forms have provided many people with a reasonable quality of life, they still have limitations. Lenses correct the refractive errors of the eye by changing the angle at which light enters the cornea by refracting the light with a lens before it reaches the cornea. But for many lifestyles, lenses are very inconvenient. And for some people they do not give the desired quality of vision. When the lens is removed the refractive error still exists. Contact lenses correct refractive errors of the eye by replacing the defective cornea curve with the frontal curve of a contact lens that is calculated to return to the emetropic eye, which is a state where visual correction is not necessary . But wearing contact lenses also has a price. The user must spend considerable time and money on the maintenance and application of contact lenses. There is still a limitation regarding the types of activities in which one can participate. And, finally, long-term lens users can develop an intolerance to wear their lenses as well as long-term damage. When the lens is removed, the refractive error still remains. Radial keratotomy ("RK") is a surgical procedure to improve myopia by changing the curve of the cornea over the pupil. The surgeon makes various incisions waves in the cornea in a radial or lightning-like pattern. The incisions attempt to flatten the central cornea to correct the patient's vision. However, RK can only be used to correct low amounts of myopia. It can not address hyperopia problems. The main drawback is that the cornea is severely weakened and frequently continues to change shape over time. A newer type of RK that involves being shorter incisions is replacing the standard RK. But new techniques using computerized titration, precisely calculated cutting patterns, and lasers will likely result in the rapid decline of RK. Photorefractive keratectomy ("PRK") is a surgical procedure similar to RK that involves the use of an excimer laser, which is controlled by a computer that measures the configuration of the eye and establishes the power of the laser. With the PRK process the excimer laser allows the ability to sculpt rather than cut the surface of the cornea. There is a combination of laser machines that with a combination of computer controls can treat myopia reliably, hyperopia, and astigmatism. However, since PRK is a surgical procedure, it can result in complications. Infection is the most serious complication. Other possible problems include delayed healing of the surface, haze of the cornea or scarring, over or undercorrection, and the development of astigmatism. Some individuals may have a response to poor or excessive healing. Complications should be treated with medications or additional surgery. Keratomileusis in si tu laser ("LASIK") is a surgical procedure that is a variation of the PRK that involves an excimer laser and an accurate cutting machine called a microkeratome. An ophthalmologist uses the microkeratome to form a circular skirt over the cornea. The skirt is pulled back as if it were on a hinge, to expose the inner layers of the cornea. With the skirt folded back, the doctor now * refractive correction on the inner layers of the cornea using the excimer laser. Finally, the skirt is repositioned to complete the procedure. With a precision laser treatment and refixation and normal healing of the skirt, the refraction results can be fast and magnificent. There is, however, a very significant list of complications and potential risks that include failure of the microkeratome to leave a hinge of the cornea flap in the first incision, loss of the cornea flap during the operation, loss of the flap of the cornea. the cornea after the operation, sliding of the skirt and center out of healing, first incision too wave or too shallow, invasion of the surface tissue within the central tissue of the cornea, infection of the cornea, loss of visual acuity by scarring or optical distortion due to the skirt that is not correctly replaced, technical problems with complex and bothersome automated cutting devices, and the procedure being more dependent on the operating capabilities of the surgeon than the computerized precision of the procedure. Thermokeratoplasty is another method of reconfiguration of the cornea. In thermokeratoplasty heat is applied to the cornea to induce shrinkage. Stromal collagen collagen shrinks when heated to a temperature of 55 ° C to 58 ° C without tissue destruction. If the shrinkage pattern is appropriately selected the resulting change in field tension and the mechanical properties caused by collagen collagen fibers can be used to reconstitute the cornea. A variety of methods are known with which to practice thermokeratoplasty. For example, U.S. Patent No. 4,881,543 discloses a method and apparatus for heating the central stroma of the cornea with electromagnetic microwave energy at the shrinkage temperature of the collagen and while circulating a cold fluid on the anterior surface of the cornea. In another example, U.S. Patent No. 5,779,696 describes the use of light energy to reconfigure the cornea in a process known as photothermalkeratoplasty. All these processes suffer from a variety of defects that include a common imperfection in which the corneas in the treated subjects are unstable after the thermokeratoplasty procedure is concluded. Orthokeratology is a non-surgical procedure designed to correct refractive errors by reconfiguring the cornea to the curvature required for hemetropia. This is accomplished by applying a series of progressive contact lens changes that retract the eye to achieve a curvature of the cornea. However, once a desired curvature of the cornea has occurred, adherent contact lenses should be used to stabilize the results or regression that may occur. Enzymatic Orthokeratology is related to traditional orthokeratology in that it is mainly defined as a contact lens procedure to correct refractive errors by reconfiguring the cornea to the curvature required for hemetropia. The program is supplemented by the chemical smoothing of the cornea. By providing drugs that soften the cornea, the cornea is chemically reconfigured by being molded to the concave surface of a contact lens having a predetermined curvature. The radius of the contact lens is selected to return the emetropic eye. Adhesive contact lenses will not be required for good visual acuity after removal of the cornea contact lens and regression will not be a problem. However, the length of the treatment program varies from weeks to months with progressive changes of the contact lens and subsequent periodic examinations.

Notwithstanding the foregoing, there remains a need for non-surgical methods to correct refractive errors of the eye that can correct various degrees of refractive error and produce relatively permanent results in a much shorter period of time. An Enzymatic Orthokeratology method is provided for correcting refractive errors in the eye in a mammalian subject. The accelerated reconfiguration of the cornea is achieved by administering a hardening amount of the cornea from a hardening agent of the cornea to the eye of the subject. The reformation is achieved under the influence of a rigid contact lens or a series of lenses having a concave curvature that will correct a refractive error. The cornea quickly reconfigures its convex curvature to the concave curvature of the contact lens, returning to the emetropic eye. The cornea is allowed to "harden" to retain the new hemetropic form. After "hardening" has occurred, the lens that returns to the emetropic eye is removed. A method for correcting refractive errors in an eye of a mammalian subject, comprises the steps of selecting a pharmaceutically acceptable cornea hardening agent on the basis of being able to harden the cornea in the eye of the subject without causing damage to the cornea, administering to the eye of the subject a hardening amount of the cornea of the agent such that the cornea can be reconfigured from a first configuration to a second desired configuration, adjusting the cornea with a rigid contact lens having a concave curvature of the second desired configuration , allowing to reconfigure the cornea in the second desired configuration under the influence of the lens, and removing the lens when the cornea is able to maintain the second desired configuration without the support of the lens. Preferably, the types of refractive errors are selected from the group consisting of myopia, hyperopia and astigmatism and the corneal hardening agent is a crosslinker such as an aldehyde. The aldehyde can be selected from the group consisting of acetaldehyde, glyceraldehyde, phenylacetaldehyde, valeraldehyde, 3,4-dihydroxyphenylacetaldehyde, mutarrotational isomers of aldehydes, ascorbic acid and dehydroascorbic acid. The hardening agent of the cornea can also be an enzyme, where the enzyme measured the crosslinking reactions. Examples of a suitable enzyme include glycosyloxidase or prolyloxidase. In one embodiment, corneal hardening agents can be administered by injection into the eye, by local administration to the eye in the form of eye drops or by means of a contact lens. In another embodiment, the additional step of administering to the eye a cornea softening amount of a pharmaceutically acceptable corneal softening agent sufficient to soften the cornea of the eye so that the cornea can be reconfigured is performed as part of the method for correcting an error. of refraction. In this embodiment, the cornea softening agent is an enzyme that degrades proteoglycans in the cornea, such as hyaluronidase. Another embodiment of the present invention is a device for performing refractive corrections in an eye of a mammalian subject, comprising: a corneal hardening agent in unit dosage form and a rigid corrective lens having a desired concave structure. Still another embodiment of the present invention is a reaction mixture comprising: the eye of a mammalian subject, a cornea hardening agent in unit dosage form; and a rigid corrective lens having a desired concave structure. Still another embodiment is a method for rehabilitating the irregularity of the cornea and correcting the refractive error in an eye of a mammalian subject with an irregular cornea configuration comprising the steps of: identifying a subject with an irregular cornea configuration, selecting an agent pharmaceutically acceptable cornea hardener on the basis that it is capable of hardening the cornea in the eye of the subject without causing damage to the corneaadminister to the eye of the subject a hardening amount of the cornea of the agent so that the cornea can be reconfigured from a first configuration to a second desired configuration, adjusting the cornea with a rigid contact lens having a concave curvature of the second desired configuration , allowing reconfiguring the cornea in the second desired configuration under the influence of the lens and removing the lens when the cornea is able to maintain the second desired configuration without the support of the lens. Subjects can be identified for this procedure by diagnosing them by having a condition selected from the group consisting of: keratoconus, cornea warping induced by contact lens, contact lens intolerance, corneal ulcers, corneal fusion disorders, recurrent corneal erosions, pterygium, and irregular cornea configuration or uncorrected refractive error due to corneal surgery. Another embodiment of the present invention is a method for improving the clinical success of surgery to the eye involving the manipulation of a cornea of a mammalian subject comprising the steps of: identifying a subject that has undergone manipulation of the cornea, selecting a pharmaceutically acceptable corneal hardening agent on the basis of being able to harden the cornea in the eye of the subject without causing damage to the cornea, administer to the eye of the subject a hardening amount of the cornea of the agent in such a way that the cornea can be reconfigured from a first configuration to a second desired configuration, adjust the cornea with a rigid contact lens having a concave curvature of the second desired configuration, which allows reconfiguring the cornea in the second desired configuration under the influence of the lens, and removing the lens when the cornea is able to maintain the second desired configuration without the support of the lens. In this modality, manipulations of the typical cornea are selected from the group consisting of radial keratotomy, photorefractive keratotomy, LASIK, thermokeratoplasty, photothermalkeratoplasty, corneal transplant surgery, cataract surgery, and reconfiguration of the cornea by laser. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a plan view of a rigid gas permeable lens of Enzymatic Orthokeratology for use in the treatment of myopia. Enzymatic Orthokeratology includes the use of one or more enzymes and / or the use of other agents together with a program of another contact lens technology. In a traditional Orthokeratology program, a deconfigured cornea is treated with a corrective lens to alter its shape and eliminate vision impairment. This procedure bends or compresses the unconfigured cornea from a defective first position to a second, more optimal position. This procedure produces a reconfigured cornea in which the visual defect has been eliminated. Unfortunately, these effects are not permanent. Since the fundamental structural components of the cornea are not changed, the shape of the cornea now in a second optimized position will eventually revert to the first defective position in the absence of corrective lenses. In contrast to traditional Orthokeratology, the methods of Enzymatic Orthokeratology according to the invention alter the configuration of the cornea using a corrective lens and preserve the second desired position induced by corrective lenses. This preservation is achieved by altering and hardening the structural components of the cornea. The hardening of the cornea is achieved by inducing cross-linking agents between the cornea components. The crosslinkers are chemical bonds formed between the components of the cornea. These crosslinkers retain a structural change induced in the cornea as a result of using corrective lenses. In this way, the corneas treated with Enzymatic Orthokeratology according to the invention can take and retain a new configuration that eliminates a deterioration of vision, preferably without any need for the continued use or support of contact lenses.

In the methods of Enzymatic Orthokeratology provided herein, enzymes and / or other agents alter and modify the structural components of the cornea. These enzymes or agents can be administered to harden the cornea in the second desired configuration induced by methods that correct the configuration of the cornea such as Orthokeratology. The term "hardening" is used herein to indicate modification or cross-linking of corneal components. This hardening results in an increased capacity of a treated cornea to retain the second desired configuration after the active treatment regimen has ended. I. STRUCTURE AND COMPONENTS OF THE CORNEA The cornea itself is composed of five layers. The outermost layer is the epithelium, which is 4-5 cells thick. Below the epithelium is the acellular membrane of Bowmans. The middle layer is the stroma, which is composed of scattered corneal fibroblasts (keratocytes) between the organized lamella of collagen, proteoglycans and glycoproteins. Under the stroma is another acellular layer called the Descement membrane. The innermost layer of the cornea, comprised of a single layer of flattened cells, is the endothelium. The stroma forms the volume of the cornea. It is composed of highly organized collagen, which explains the transparency of the structure. The acellular stromal components consist mainly of collagen, proteoglycans and glycoproteins. The collagen is organized inside the lamella which in turn is made of parallel, flattened clusters of collagen fibrils. Keratocytes secrete the stromal lamellae. Of the various types of collagen in existence, more than one type of collagen has been identified through the stroma. The stroma of the cornea is composed of 78% water, 1% salts and 21% biological macromolecules, almost 75% of which are collagen fibrils. Collagen is a family of fibrous proteins of novel structure and function. It is the most abundant protein in mammals and serves, in part to keep the cells together. There are a number of types of collagen, classified by their amino acid structures. Structurally, a fibril of collagen is composed of three chains of proteins wound one on top of the other in a triple-helical conformation. Collagen has a very unusual amino acid sequence. Approximately every third amino acid residue is a glisine. In contrast, hemoglobin has a lysine content of only five (5) percent. In addition, collagen has an unusually high concentration of the 4-hydroxyproline and 5-hydroxylysine derivatives of proline and lysine. These amino acid derivatives play a crucial role in determining the structure of the collagen fibril since it is frequently modified and frequently form crosslinkers. The amino acids of lysine can be modified to alter the structure of the corneas. These residues can be cross-linked through a condensation of aldol. These crosslinkers serve to strengthen the collagen fibers, presumably by reinforcing the collagen triple helix. The importance of these crosslinkers is apparent when one considers the disease of scurvy. Scurvy is caused by a deficiency of ascorbic acid. Ascorbic acid is a cofactor in the formation of hydroxypyridinium crosslinkers between two hydroxylysine residues and one lysine residue. The degradation of connective tissue that is a hallmark of scurvy is due, in part, to a lack of collagen crosslinkers. The modification of collagen proline residues can also affect the structure of the protein. It has been shown that the extension of proline hydroxylation affects the thermal stability of collagen. Collagens from a variety of sources exhibiting varying degrees of hydroxylation were examined to determine their respective melting temperatures. Interestingly, collagens containing a high percentage of hydroxyproline melted at a higher temperature than collagen with a lower hydroxylation percent. The connective tissue of the cornea is also rich in proteoglycans. Proteoglycans are composed of a hyaluronate core, a protein core, and glycosaminoglycans, which are proteoglycan monomers with repeating disaccharide units. Approximately 60% of the glycosaminoglycans in the cornea are formed of keratan sulphate, while the remaining 40% is mainly chondroitin sulfate. II HARDENING AGENTS USED IN ENZYMATIC ORTHOPERATOLOGY A number of enzymes and agents can be used to perform the hardening function of the cornea of Enzymatic Orthokeratology according to the invention. Of particular interest are crosslinking agents and corneal hardening enzymes. However, Enzymatic Orthokeratology according to the invention is not limited to the use of these enzymes and agents, and includes chemicals that can be administered to harden a cornea through various different mechanisms of action. Federal laws require that the use of pharmacists in the treatment of patients be tested by a Federal government agency, the Food and Drug Administration. Similar approvals are required by most foreign countries. Only pharmaceutical-quality forms of the enzymes and agents are used in the practice of the present invention in accordance with the laws of the state forum. Corneal hardening agents are selected on the basis of safety and efficiency. As in conventional Enzymatic Orthokeratology, the present invention relates to traditional Orthokeratology in that it is primarily defined as a contact lens procedure for correcting refractive errors by reconfiguring the cornea to the curvature required for hemodypia. However, the program is supplemented by chemically hardening the cornea. The cornea is chemically reconfigured by being molded to the concave surface of a contact lens having a predetermined curvature. The radius of the contact lens is selected to return the emetropic eye. Adhesive contact lenses will not be required for good visual acuity after removing the contact lens from the cornea and regression will not be a problem. The complications and risks of surgery will be prevented by virtue of following these non-surgical stages. A. Aldheidos Used in Enzymatic Orthokeratology An aldehyde is a carbonyl group bonded to a carbon atom and a hydrogen atom. Formaldehyde, the simplest example of an aldehyde, is an exception to this rule since it has two hydrogen atoms attached to the carbonyl group. A carbonyl group is a carbon-oxygen double bond with carbon that has two sites available for bonding with other atoms, the chemical nature of the carbonyl group, especially the double bond in oxygen's ability to orbit six free electrons, taking two from twice link, makes this group extremely reactive. A chemical reaction in which aldehydes are frequently compromised is called the aldol condensation reaction. In one aspect of the present invention, the aldehydes are reacted with one another to form crosslinkers within the corneal components using the aldol condensation reaction. In a typical aldol condensation reaction the carbonyl group undergoes enolization in which an enolate anion is formed. An enolate anion is formed when a pair of electrons is changed to the carbonyl group carbon from a neighboring carbon atom. A proton acceptor can remove a proton from the neighboring carbon atom in the reaction, and if that acceptor is a hydroxyl then water is formed. As the electrons change to the carbon of the carbonyl group, a double bond forms between itself and the atom of the neighboring carbon. This change in electrons causes a pair of electrons to change from the carbonyl carbon to the carbonyl oxygen, creating a negative charge on the oxygen. The resulting carbon-carbon double bond of the enolate reaction is extremely • reactive. 5 The electrons of the carbon-carbon double bond of the enolate bond attack the carbonyl group of a neighboring aldehyde molecule resulting in the binding or condensation of the two molecules. The resulting compound is an alkoxide which can then be protonated to produce a hydroxyaldehyde.

The aldol condensation reaction can be used in the present • invention for crosslinking various structural molecules of the cornea, including lysine residues located in the collagen proteins of the cornea at a neutral pH without the addition of an additional acidic catalyst or strong base. 15 Collagen from the cornea contains an unusually large number of lysine residues. The amino groups at the ends of the lysine side chains are used to crosslink lysine-containing collagen proteins. In the positively charged ammonium state, lysyl oxidase oxidizes the carbon to which the ammonium group binds. The nitrogen group exits resulting in the creation of a lysine aldehyde derivative called alisine. The aldehyde groups of neighboring plants can be converted into aldol condensation. The reaction of the two side chains results in a crosslinking between the two amino acids.

Lysyl oxidase also plays a role in the formation of a lysine product of three forms known as a hydroxypyridinium crosslinking. Four residues in each tropocollagen molecule can participate in this type of crosslinkers. These include a lysine residue near the amino terminus, a lysine near the carboxyl terminus, hydroxylysins in the helical region near the ends of the collagen molecule. Hydroxypyridinium crosslinkers are typically formed between the amino terminal residues of a collagen molecule and the carboxyl terminus of a neighboring molecule. In a proposed reaction route, hydroxylysine is first converted to hydroxyalisin by lysyl oxidase. A mechanism of formation has been proposed in which two divalent ketoamine crosslinkers can interact to produce a trivalent 3-hydroxypyridinium crosslinking. The formation of hydroxypyridinium crosslinkers can be an important mechanism in the operation of the present invention. The present invention contemplates the use of a variety of different aldehydes to crosslink the structures of the cornea constituents, particularly collagens and proteoglycans. Those aldehydes include acetaldehyde, glyceraldehyde, phenylacetaldehyde, valeraldehyde, 3,4-dihydroxyphenylacetaldehyde, glycoaldehyde (the aldehyde form of ethylene glycol), pyruvaldehyde, dihydroxy acetone, acetol, glyoxal, and mutarotational isomers of aldehydes including glucose, fructose, lactose, and other sugars Other crosslinking agents contemplated include additional aldehyde compounds and ascorbic acid and dehydroascorbic acid. Hydrogen-containing aldehydes can be useful crosslinking agents because they can react with N-acetyl groups of the glycosaminoglycan chains in cornea proteoglycans to produce long chain polymeric proteoglycans. In one embodiment of the present invention, the major aldehyde used to harden a cornea is glyceraldehyde. The scientific names commonly used for this aldehyde include: glyceraldehyde, 2,3-dihydroxypropional and β-dihydroxypropionaldehyde. Glyceraldehyde is the simplest aldose and a derivative of this molecule glyceraldehyde 3-phosphate is a metabolic product intermediary of carbohydrate metabolism. The fact that a glyceraldehyde derivative plays such an important role in cellular metabolism implies the safety of this compound when used to reconfigure the cornea in an otherwise healthy eye. The glyceraldehyde can be obtained from a variety of sources including SIGMA Chemical Company, Inc., St.

Louis, Mo; Aldrich Chemical Company, Inc., Milwaukee, Wl; Fluka Chemical Corp., Ronkonkoma, NY; Fisher Scientific, Pittsburgh, PA. Glyceraldehyde exists as a solid • unburned with a melting point of 145 ° C. It is a monosaccharide 5 with the empirical formula (CH20) 3 and a molecular weight of 90.08. The current purity may vary among commercial glyceraldehyde suppliers, ranging from approximately 95% to 98%. The invention should only be practiced with the purest form of this compound. 10 To support the present invention, the solution • glyceraldehyde ophthalmic was prepared under sterile conditions by dissolving glyceraldehyde in a volume of 0.9% sodium chloride solution, USP, (McGaw Pharmaceuticals, Irvine, CA) followed by subsequent sterile filtration. Others drugs such as proparacaine or tropicamide may be included to anesthetize the cornea. The optimal glyceraldehyde concentration may vary depending on the protocol, the nature of the delivery vehicle, and the number of administrations. In general, glyceraldehyde concentrations will vary within the range of about 0.01% to 10% by weight in volume (w / v). In one embodiment, the concentration range of the glyceraldehyde solution will vary from 1% to 5% (w / v). In yet another modality, the concentration of 3% of glyceraldehyde.

It is further noted that aldehydes other than glyceraldehyde are contemplated for use in the present invention. Such compounds include acetaldehyde, • glyceraldehyde, phenylacetaldehyde, valeraldehyde, 3,4- 5 dihydroxyphenylacetaldehyde, glycoaldehyde (the aldehyde form of ethylene glycol), pyruvaldehyde, dihydroxy acetone, acetol, glyoxal, and mutarotational isomers of the aldehydes including glucose, fructose, lactose, etc. Suitable alternative aldehydes have biochemical characteristics similar to those of glyceraldehyde which possesses a-hydrogen which includes biodegradability, low toxicity, and easy resorption within the treated area. B. Enzymes Used in Enzyme-Orthokeratology In one aspect of the present invention, enzymes are used as corneal hardening agents. These enzymes increase the rigidity of the cornea by modifying the structural components of the cornea. These structural modifications comprise intravalent and / or intermolecular covalent crosslinkers, hydroxylation, or other modifications. In In one example, the formation of collagen crosslinkers is exploited to increase corneal stiffness or hardness using the methods of the present invention. In one embodiment, lysyl oxidase is used as an enzymatic hardening agent of the cornea. The enzyme lysil oxidase plays a central role in the formation of collagen crosslinker. Lysyl oxidase is a 30-kd metalloenzyme, which converts the amine side chains of specific lysine and hydroxylysine residues of collagen to aldehyde. Once the enzyme has converted the lysine residues of collagen to its aldehyde derivatives, the neighboring lysine residues can form crosslinkers upon undergoing the aldol condensation reaction described above. The formation of collagen crosslinkers serves to reduce the mobility of the individual collagen molecules within the cornea matrix, thereby increasing the stiffness of the structure. In another embodiment, enzymes with hydroxylated collagen residues can be used as corneal hardening agents. Certain lysine and proline residues which are hydroxylated by lysylhydroxylase and prolylhydroxylase respectively in vivo are known in the art. These modifications can also be exploited to induce stiffening or hardening of the cornea. For example, it has been shown that the degree of proline hydroxylation affects the thermal stability of collagen. The thermal stability of a protein reflects the structural stability of the molecule and may indicate the presence of stabilizing components within the protein. Collagen from a variety of sources exhibiting varying degrees of hydroxylation was examined to determine their respective melting temperatures. Interestingly, collagen containing a higher percentage of hydroxyproline melted at a higher temperature than collagen with lower percentages of hydroxylation. This correlation between the respective melting temperatures and the degree of proline hydroxylation implies that an increase in this modification can stabilize the collagen protein. Consequently, hydroxylases can also be used to induce hardening of the cornea. 10 In another embodiment, hydroxylation can be used • as a preliminary enzymatic step to prepare the cornea collagen for glycosylation. Here, the lysine or proline residues in the collagen would be hydroxylated with glycyl hydroxylase or prolyl hydroxylase respectively.

These residues could then be glycosylated through the action of an enzyme such as galactosyltransferase and / or glucosyltransferase. These modifications would also result in the induction of hardening of the cornea and are therefore WJ both suitable for use in the present invention. In addition to these enzymes, other enzymes known in the art that alter and modify the structure of proteins can be used with the methods of the present invention. For example, glucose oxidase, in conjunction with glucose, can be used to form oxidative crosslinkers, which are discuss in more detail later. Suitable enzymes induce protein modifications that increase the rigidity of the cornea. C. Oxidative Hardening Agents Used in Enzymatic Orthokeratology An additional group of reagents that are known in the art to induce protein cross-linking are oxidative cross-linking reagents. These reagents act by producing oxygen free radicals. In turn, oxygen free radicals interact with unstable sites in the cornea resulting in the induction of inter and intramolecular chemical bonds. A group of these reagents includes various sulfate compounds that are used to form crosslinkers. Examples of these compounds include copper sulfate (CuS04) and iron sulfate (FeSO, j). Ascorbic acid and CuS04 or Fe2 (S04) 3 and other copper and iron complexes act as oxidative crosslinking agents. Examples of these complexes include cuproxoline, celuroplasmin, transferrin, lactoferrin, cupric gluconate and others. Chromium sulfate Cr2 (S04) 3 is another sulfate compound that is used as an oxidative crosslinking agent. The use of ultraviolet (UV) light to induce oxidative crosslinkers is also contemplated. The judicious use of UV alone or in combination with various photosensitizers is contemplated for use to induce oxidative crosslinkers.

Examples of photosensitizers include riboflavin, psoralen, rose bengal, methylene blue, and others. These oxidative crosslinking methods can be used alone to induce crosslinkers in a subject, or they can be used in combination with the aldehyde or enzymatic crosslinker methods when they are compatible. For example, UV and ascorbic acid can be used in conjunction to induce crosslinking. Conversely, CuS04 and lysyl oxidase can not be used simultaneously since, as is well known in the art, CuS04 inhibits the activity of lysyl oxidase. D. Determination of Cornea Hardening Agents and Their Dosages The hardening chemicals of the cornea, such as various agents and enzymes, used in the methods of the present invention, in addition to the appropriate dosages of such agents and enzymes can be determined by one of experience. in the technique through routine experimentation. Such experimentation may comprise testing a dose of an enzyme or agent in donor globes (eyes) mounted in plastic model basins or testing such dose in laboratory animals. Briefly to determine an appropriate hardening amount of the cornea of a known hardening agent or enzyme, or an agent or enzyme to be tested for its ability to produce corneal hardening, a dose of the agent or enzyme is administered to a cornea in one eye donated or a cornea from a test animal, and the hardening and toxic effect of the agent is determined later. To determine whether an enzyme or agent is effective to harden a cornea without producing toxicity, or, if it is a known hardening agent, whether a particular dosage will produce hardening of the cornea without causing particular toxicity will produce hardening of the cornea without causing toxicity, or if it is a known hardening agent, if a particular dosage will produce hardening of the cornea without causing toxicity, the enzyme or agent is first mixed in a carrier vehicle that is pharmaceutically acceptable to a mammal. Preferably the enzyme or agent is in a lyophilized form (dry powder), and is dissolved in isotonic saline. However, one of ordinary skill in the art will understand that a variety of pharmacologically acceptable carriers that do not interfere with the functioning of an enzyme or agent can be used. A test dose of the enzyme or agent in solution is then administered to a cornea test to determine its hardening of the cornea and toxic effect. In a procedure for testing candidates, the enzyme or test agent is first administered to donor globes (eyes of a human donor) mounted in plastic basins. This method is particularly preferred to determine the effect of an enzyme or agent on a human cornea because in this way a human cornea can be tested without subjecting a living person to experimentation. A donor balloon used in this procedure is prepared for experimentation by injecting it with enough saline to maintain the intraocular pressure of the balloon at approximately 20 mm Hg. The test dose of the enzyme or agent is then administered to the donor's cornea. Such administration can be, for example, by injection of the enzyme into the cornea. Normally, the lens will become opaque following this stage due to the introduction of water into the eye and a change in the refractive index of the eye. After a trial period of time, the assembled balloon is then examined to determine if any hardening of the cornea or toxicity has occurred, and if so, the degree of such hardening and toxicity. Examination of the cornea can be performed, for example, through the slit lamp examination to determine the clarity of the cornea.; pachymetry to measure the thickness of the cornea; Computer-assisted topography of the cornea to evaluate topographic changes in the surface; measurement of the resistance to the tension of the cornea; measurement of cornea distension, keratometry to measure the central curvature of the cornea; and retinoscopy to measure the refractive error of the cornea. The determined values of these tests are compared with the values determined before the • administration of the agent or enzyme. In addition, a cornea treated in a mounted balloon may undergo a number of other tests to determine the resistance and viability of the cornea after treatment. For example, light microscopy, scanning, x-ray refraction analysis and electron transmission can be used to examine the morphology of the cornea; HE • prepare culture tissue to determine the viability of corneal cells after treatment, biochemical studies of the collagen and other structural components of the cornea can be made after treatment. Previous tests of donated balloons and corneas can be used to verify that the use of a particular enzyme or agent does not compromise the transparency of the cornea, decreases the viability of the cornea cells, ^ or damage the structural integrity of the cornea. It is also It is desirable to test the use of an enzyme or agent in the cornea of a test animal, however, to ensure that the candidate has no unexpected effect on living mammals that is not discovered during the donated eye tests. To test the effect of a particular enzyme or test agent, A test dose in a pharmacologically acceptable carrier solution is administered to a test animal, in this case a mammal, to deliver that agent to the animal's cornea. After the administration of an agent to the cornea of the animal, the cornea of the animal can be subjected to the following examinations: slit lamp examination to determine the clarity of the cornea, anterior chamber and iris; pachymetry to measure the thickness of the cornea; computer-assisted cornea topography to evaluate the change Topographic of the surface of the cornea; measurement of • elasticity of the cornea; phonometry to measure intraocular pressure; fundoscopic examination to evaluate the optic nerve and retina; Keratometry to measure the central curvature of the cornea; retinoscopy to measure the error of refraction; dyed with fluorescein or Rose Bengal to identify damage to the epithelium of the cornea; and indirect ophthalmoscopy. The values determined through these tests can be compared to the values determined before the w? administration of the enzyme or agent, as well as the values determined for the untreated eye of the animal. In addition, a treated cornea of a test animal may be subjected to the number of other tests to determine the resistance and viability of the cornea after treatment. For example, light microscopy can be used, scanning, and electron transmission to examine the morphology of the cornea; a tissue culture is prepared to determine the viability of the cornea cells after treatment; and biochemical studies of the • collagens and other structural components of the cornea 5 after treatment. Other enzymes and hardening agents of the cornea not described herein and known and unknown agents can be determined as described below in relation to the determination of enzymes and doses of enzymes. In another embodiment of the invention, a cornea softening agent is first administered to a plurality of donor globes or to the corneas of an experimental animal, as described above. The agents corneas softeners include various enzymes and agents, for example, protease enzymes and degrading proteoglycans, advantageously, and aluronidase. When experimental animals are used, once the corneas have started to (soften, a cornea of the experimental animal is treated then with a test dose of the enzyme or agent to be tested for its hardening and toxic effect to determine if the dose of the enzyme or agent can harden or toxify the cornea. The other cornea is left alone as a control. When donor balloons are used, a plurality of corneas can be tested, as long as one is left untreated as a control. The treated corneas can then be tested with a dose of an enzyme or test agent. The cornea control and the tested corneas should be treated for approximately the same amount of time to validate a comparison of the effectiveness of the enzymes and test agents in the corneas tested. After a period of time, the hardness or degree of hardening of a previously smoothed cornea as well as the toxicity is compared using the procedures described above in reference to determine the degree of hardening of the cornea and the toxicity induced by an enzyme or experimental agent. . If the treated cornea is harder than the control, the candidate's test dose can be determined as being useful to induce hardening of the cornea, and if the cornea treated is the same as the control then it can be concluded that the test dose of the The candidate is safe since it does not cause damage to the cornea. An optimal dose can be established using this method. The present invention further provides for the preparation and use of hardening of the cornea and softening agents of individual components. The equipment will comprise a first container having a hardening agent and a second container having a softening agent. In addition, the kit will include instructions for preparing the agents to be used individually by combining them with a pharmaceutically acceptable carrier. The kit may include a variety of different reagents necessary to practice the method of the present invention. For example, the equipment may contain corneal reconfiguration lenses for use by one of skill in the art to reconfigure the cornea of a subject. Additionally, the equipment may contain various means for administering the active agents of the present invention, such as syringes and needles, eye droppers and other necessary equipment, such equipment being well known to those skilled in the art. III Methods for Administration of Corneal Hardening Agents Enzymes and prior corneal hardening agents can be administered in any manner known in the art. For example, in one embodiment, an enzyme or agent is injected directly into the eye in a location close to the cornea. In this embodiment, the enzyme or agent must be mixed in a pharmacologically acceptable carrier which does not alter the effectiveness of the enzyme or agent contained therein. In another embodiment of the present invention, enzymes and hardening agents of the cornea are administered to the eye of a subject by local application in the form of eye drops. A sufficient number of drops is applied to deliver a desired concentration of enzyme or agent to the subject's cornea. The method of administering eye drops may be superior to injection based on administration based on less discomfort to the cornea of the subject resulting from an injection technique. In yet another embodiment, alternative means may be used to aid diffusion through the eye within the cornea. Such methods include, for example, use of lipozomas to supply the enzyme or active agent.

• The enzyme or agent is packed into lipozomas which can pass through the soluble lipid membrane of the cornea epithelium and into the cornea stroma. Other means to assist diffusion include the use of a current electrical to make the external membrane of the eye more permeable to the passage of enzymes and agents, known as iontophoresis. Using this procedure, an electrical current that travels through a saline solution causes the agent to pass into the eye as charged particles. Compounds that enhance the ability of the active compounds of the present invention to penetrate the cornea are contemplated. A variety of compositions are visualized for use as vehicles by which it administers the active agents of the present invention to the eye of a mammal subject. A list of substances includes: acidifying agent, aerosol propellant, air displacement, denatured alcohol, alkalizing agent, anti-caking agent, antifoaming agent, preservative • antimicrobial, antioxidant, regulatory agent, 5-capsule lubricant, chelating agent, coating agent, color, complexion agent, desiccant, emulsifying and / or solubilizing agent, filtration rate, flavors and perfumes, slip and / or anti-caking agent, humectant, ointment base, plasticizer, polymer membrane, solvent, sorbent, sorbent, carbon dioxide, firming agent, • base for suppository, suspending agent and / or increasing viscosity, sweetening agent, tablet binder, capsule and / or tablet solvent, tablet disinfectant, tablet and / or capsule lubricant, Tonicity, vehicle, viscosity increase, water repellent agent, wetting agent and / or solubilizer. In an embodiment using glyceroldehyde, ethylene diamine tetraacetic acid (EDTA) chelator divalent cation and jfl) a phosphate buffered saline at a pH of 8.0-8.5 was effective. In alternative modalities, sustained release vehicles are used. Sustained release vehicles are compositions that act to maintain the active ingredients of the present invention in functional association with the cornea. The compounds and compositions in sustained release technology are well known in the art. (See, Controlled Drug Delivery, 2nd ed., Joseph R. Robinson &Vincent H.L. Lee, Eds, Marcel Dakker, Inc., New • York, 1987). By keeping the active ingredients in association with the cornea to be treated, a sustained release vehicle acts to increase the efficiency of the active ingredients of the present invention. This increase in efficiency can be attributed to the sustained release vehicle that acts to increase concentration Local area of the active ingredients of the present invention ^^ with respect to the cornea treated at levels greater than would be possible without the sustained release vehicle. Sustained release vehicles for use with the present invention maintain or localize the agents of the present invention in proximity to the cornea and have no detrimental effects on the cornea or the activity of the agents of the present invention. In a preferred embodiment, the sustained release vehicle is B soluble water. Examples of sustained release vehicles Suitable include: cellulose ethers such as methylcellulose, methylhydroxypropylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose. Cellulose esters such as cellulose acetate phthalate and phthalate hydroxypropylmethylcellulose; polymers derived from at least one acrylic acid, acrylic acid esters, methacrylic acid and methacrylic acid esters such as methyl methacrylic acid-methyl methacrylate polymer acid and methacrylic acid-ethylacrylate copolymers are also contemplated for use with the present invention. Additional polymers contemplated for use with the present invention include polymers derived from methyl vinyl ether and maleic anhydride, polyvinyl pyrrolidone, polyvinyl alcohols and the like, as well as mixtures of any of the compounds named above. • Those of ordinary skill in the art will know at what concentrations to use these compounds. In one embodiment, polymer concentrations vary from about 0.001% to about 5.0%. In other In this embodiment, the concentrations vary from approximately 0.1% to approximately 1.0%. An example of a sustained release formulation containing the corneal hardening glyceraldehyde agent would comprise 3% glyceraldehyde, 0.5% sodium carboxymethylcellulose and volume carrying total to 100 milliliters. In yet another embodiment of the present invention, enzymes and corneal hardening agents are delivered to the cornea through the use of a contact lens. As will be discussed in more detail later, the methods of The present invention involves the application of a rigid contact lens to a cornea in a first suboptimal conformation to reconfigure that cornea to a second desired conformation. In one embodiment of the present invention, the adjustment of the contact lens and the administration of an enzyme or curing agent of the cornea occurs simultaneously. In an alternative embodiment of the present invention, the adjustment of the contact lens and the administration of an enzyme or curing agent of the cornea occurs sequentially. 10 As an example of a modality of this • Invention, a hardening amount of the cornea of a curing agent of the cornea is loaded into a chamber within a rigid contact lens, preferably one that is gas permeable. Alternatively, the enzyme or The agent can be charged to or impregnated into a soft lens capable of collecting the enzyme or agent by soaking the soft lens in a solution containing the enzyme or agent. The enzyme or agent can also be charged in a combination of a soft and a rigid lens. In all of the following embodiments of a contact lens for administering an enzyme or corneal hardening agent, the enzyme or agent is administered as it diffuses from (is released from) the camera into the lens or lens material (if the enzyme or agent is soaked in a lens soft). Dosages for different refractive conditions and contact lens supply vehicles can be optimized through routine experimentation by one skilled in the art. According to a method for administering the compound using the contact lenses of the present invention, the enzymes and curing agents of the cornea can be applied to the eye through the use of rigid contact lenses. These lenses can be made of known lens materials of fluorosilicone acrylate, which is permeable to gases. The lens is provided with a • internal chamber to store the cornea hardening enzyme or agent. The chamber preferably comprises a radially symmetrical space that circulates the entire lens between the anterior surface or the back surface of the lens. Rigid lenses for the present purpose can be conveniently made by cutting, molding, or grinding a rear component and a front component B from the button of the contact lens which, during the In the manufacture, it can be secured together to form a unitary lens using bonding techniques or adhesives known in the art. The chamber can be formed by cutting an annular gap in the lathe inside the convex surface of the posterior component of the lens before the final fabrication of the lens. Any of a variety of dimensions may be used in accordance with the present invention, which provides a preferred lens with an annular chamber having a width of about 1.0 mm to about 1.5 mm of a • depth from approximately 0.5 mm to approximately 5 0.10 mm. A plurality of microscopic voids is provided in the posterior portion of the lens to allow fluid communication between the camera and the eye, thereby facilitating the release over time of the enzyme and agent hardener of the cornea inside the cornea. These holes • can be provided by drilling mechanically or by laser or by molding before assembling the anterior component and the posterior component of the lens. In one mode the holes are drilled using a mechanical drill that has a small microcarbon drill. The pumping action of the eyelids combined with the natural laceramiento assists the enzyme or hardening agent of the cornea through small holes. Preferably, the fl ows are produced by a mechanical drill with a drill bit. microcarbon and will have a diameter of about 0.002 mm to about 0.010 mm, preferably about 0.005 mm. The number and diameter of the holes can be varied to affect the release characteristics over time, as will be apparent to one with experience in the technique. In general, however, for the diameter ranges specified above, from about 3 to about 10 holes are contemplated for use. In a lens modality, the posterior portion of • the lens has a thickness at the center point of about 0.12 mm and an annular gap is turned to a depth of about 0.075 mm. A number of holes, each having a diameter of about 0.005 mm, is drilled through the bottom of the chamber and spaced equidistantly around the periphery of the chamber for provide communication with the back surface of the • lens. The number of holes in a lens will vary, depending on the desired rate of administration of the cornea hardening enzyme or agent from the chamber. The anterior portion of the lens, which has a The thickness at the center point of about 0.12 mm is then secured to the back portion to close the annular gap and form a chamber, thereby forming a lens having a total central thickness of about 0.24 mm. The link can be achieved by applying a small amount of a Binding agent such as the Concise enamel link system sold by 3M (St. Paul, Minnesota). Other means for joining the posterior and anterior portions of the contact lens will be apparent to those of skill in the art. The rear curvature radius of the lens is selected which will reconfigure the curvature of the anterior cornea to a configuration required to return the emetropic eye (without any correction). The posterior and anterior configurations of the contact lens according to the present invention are similar to those used in the adjustment procedures of conventional Orthokeratology. In general, the convex anterior surface of the lens approximates a substantially uniform radius of curvature along all planes, and may vary from a design aspheric, a tenticular design, a spherical design, or any other configuration necessary to accommodate the adjustment needs of a patient. The concave posterior surface of the lens is divided into several discrete zones, each having a unique curvature. For example, a curve The posterior central base can be arranged symmetrically and radially around the central point of the lens. An intermediate posterior curvature can be arranged annularly around the radial outer periphery of the central base fl of the posterior curve. Adjacent to the side radially towards outside the posterior medial curve there may be a third peripheral posterior curvature. Thus, it can be considered that the lens comprises three distinct zones a central optical zone, an intermediate zone, and a peripheral zone. Preferably, according to the present In accordance with the invention, an annular chamber may be arranged within the intermediate zone. In another aspect of the present invention, a contact lens is provided which is composed of • two layers which are laminated together. In this advantageous design 5 for a contact lens of the present invention, larger chambers can be created to store the corneal enzyme or hardening agent. In this contact lens, a front portion of the contact lens having a contact lens may be fabricated. anterior surface and a posterior surface. also can • A rear portion of the contact lens is fabricated with an anterior surface and a posterior surface. The outer perimeter of the back surface of the anterior portion can be designed to have the same radius of curvature than the outer perimeter of the anterior surface of the posterior portion. In this way, when the back surface of the anterior portion and the anterior surface of the posterior portion are laminated together, a seal may be formed between the outer perimeters of the portions previous and subsequent. However, in a central portion of the anterior portion, the posterior surface may have a radius of curvature steeper than the anterior surface of a central portion of the posterior portion. Because of this radio When the forward portion and the back portion are laminated together, a chamber is formed between the central portion of the anterior portion and the central portion of the posterior portion of the contact lens. The volume of the chamber can be adjusted by changing the radius of curvature of the posterior surface of the central portion and of the anterior surface of the central portion, as will be apparent to one of skill in the art. One or more holes can be made in the central portion of the back portion of the contact lens of this design. The holes can be produced by mechanical drilling with a microcarbon drill or by means of a laser such as an argon laser, and will have a diameter of about 0.002 mm to about 0.010 mm, and preferably about 0.005 mm. He The number and diameter of the pits may vary to affect the release characteristics over time, as will be apparent to one of skill in the art. Thus, the rate at which a dose of an agent or hardening enzyme of the cornea is dispensed from the chamber is controls mainly by the size and number of holes "* • present in the central portion of the posterior portion of the lens.In general, however, for the diameter ranges specified above, approximately 3 to approximately 10 holes are contemplated for use. holes can be separated around the central portion of the posterior portion of contact lenses to provide communication between the camera and the eye surface of a subject using the lens. • In a preferred embodiment of this lens, the rear portion of the lens may have a thickness at the center point of about 0.125 mm. The anterior portion of the lens may have a thickness at the center point of approximately .125 mm. When the anterior portion and the posterior portion meet, a lens is created which has a total thickness in the center of approximately • 0.24 mm If it is desired to change the shape of a cornea with increased speed, a lens of increased thickness can be used which exerts more pressure on the cornea to conform to the desired configuration. The link can be achieved by applying a sufficient amount of a bonding agent such as the Concise enamel bonding system sold by 3M (St. Paul, Minnesota). Other linking methods will also be apparent to one of skill in the art. fc As with other modalities of this In an embodiment, the concave radius of curvature of the posterior surface of the posterior portion of the lens is selected to reconfigure the curvature of the anterior cornea to a desired shape required to modify the curvature of the cornea and reduce the refractive error. Thus, posterior and anterior contact lens configurations of this aspect of the present invention are similar to those used in conventional orthokeratology adjustment procedures, as described • previously and as those are known by experts in the technique. A lens of this embodiment of the present invention can be made of fluorine silicone acrylate lens materials. Such rigid lenses can be made by cutting around, molding or grinding a later component and a previous component of a contact lens button.

• After the anterior and posterior components are manufactured, they can be secured together to form a unitary lens using bonding techniques, adhesives, or any other bonding method known in the art. For example, a system of The enamel bond can be used to join the anterior and posterior contact lens portions. An example of such a system is the Concise enamel bond system sold by 3M (St. Paul, Minnesota). In an alternative mode of a lens • Contact of this aspect of the present invention, a lens is provided which has a peripheral camera instead of a camera in the central portion of the lens. In this embodiment, the lens may be composed of a front portion and a rear portion which are laminated together. In this embodiment, a camera is provided in an intermediate proportion of the lens. In another embodiment, the camera can be formed in the intermediate portion of the lens by providing an area of the back surface of the anterior portion of the lens, which has a steeper radius of curvature than that found in the remainder of the posterior surface of the lens. the anterior portion of the lens. As in the above embodiment of a contact lens in a chamber, the volume of the cornea hardening enzyme or agent that may be contained in the lens and thus delivered to a subject is determined primarily by the radius of curvature of the surface of the inner portion of the lens in the intermediate portion of the lens, as well as by the radius of curvature of the anterior surface of the posterior portion of the lens in the intermediate portion of the lens. The posterior portion of the lens is also provided with holes through the posterior portion of the lens in the intermediate portion of the lens. These holes serve to allow the transfer of the contents of the camera from the camera to the eye of the subject. The number and size of the holes will greatly determine the rate at which an enzyme or corneal hardening agent is delivered to the eye. Although the embodiments of a contact lens in the camera have been described as being produced by laminating together an anterior portion and a posterior portion of the lens, one of skill in the art will recognize that other methods of forming the previously described chambers also • They're possible. 5 Day and / or night use of these Enzymatic Orthokeratology lenses can be made. The cornea can usually be reconfigured in a matter of several hours to a few days. The progress of the reconfiguration can be monitored using conventional methods. The lens of the present invention can be used • to correct myopia, astigmatism, and hyperopia. According to a further delivery method of the present invention, a soft lens band or shield can be soaked or loaded with a dose of the enzyme or corneal hardening agent. The soft lens can then be properly fixed to the cornea and used for a matter of hours to release the enzyme or agent within the cornea. After the cornea is sufficiently hardened by the enzyme or agent, the soft lens dissolves or becomes pick up One type of soft lens for use with this method is a collagen material which tends to take a relatively high volume of the solution containing the enzyme or agent and release it relatively slowly. The material can to be highly purified bovine collagen. The diameter varies from approximately 13.5 mm to approximately 16 mm. The curves of the base preferably range from about 8.0 mm to about 9.5 mm. The DK • (which is a measure of the oxygen permeability of a material) should be approximately 50 and the hydration percentage of H20 should be approximately 83%. A lens that can be found particularly well suited for practicing this aspect of the present invention is the Medilens corneal shield available from Chiron Ophtalmics, Inc. of Irvine, California. The shield for • Cornea Medilens is a thin, transparent, foldable film made of bovine tissue. This tissue has a high percentage of collagen that looks a lot like the collagen molecules of the human eye. 15 Medilens corneal shield is established to provide protection and lubrication to the ocular surface, dissolving gradually within approximately 24 hours. The dry weight of the lens is approximately 5.5 mg, m and the wet weight after loading it with a solution that contains an agent or enzyme is approximately 34 m. Loading is achieved by soaking the lens in a solution, as previously described for approximately 60 minutes at room temperature. It has been measured that the lens shot has been approximately 28.5 mg and the hydration of the lens is approximately 84%. In terms of volume, the lens jack is approximately 200-300 L. Other types of soft lens materials tend to take less of the solution containing an enzyme or agent • and also to release it more quickly. Examples of such materials are common materials for hydrophilic soft lenses such as etafilcon A, and phemfilcon A, available as Acucue ™ from Johnson & Johnson Vision Products, Inc. (New Brunswick, NJ) and Wesley Jessen (Des Plaines, IL). These lenses may be of available variety or long term of use. The lenses that have an H20 content of • between about 58% and about 70% may be useful in the present method. Simultaneously or sequentially with the release by the soft lens or other delivery vehicle of the corneal hardening enzyme or agent within the cornea, a rigid contact lens is then attached to the cornea. The rigid contact lens quickly reconfigures the treated cornea. A contact lens is used which has a posterior radius w that will reconfigure the anterior cornea to a curvature required for emmetropia. The reconfiguration process can take several hours up to a few days. In one embodiment, the rigid contact lens can be adjusted over the central portion of a soft contact lens which has been charged with an enzyme or corneal hardening agent while the soft contact lens is in the eye of a patient. Due to the intraocular pressure of the eye, the treated cornea will tend to steep the • curvature. While this may be desirable in the case of 5 hyperopia, this should be controlled when treating myopia and other conditions. And even when farsightedness is treated, the amount of deepening in the curvature of the cornea must be controlled. Therefore, it may be desirable to place a rigid contact lens on a soft lens that is supplying the enzyme or agent to control the change in the shape of the cornea before the time when a rigid lens fits directly over the eye to reconfigure the cornea. In another embodiment, a rigid lens may be fused to the central portion of a soft contact lens which supplies the corneal enzyme or hardening agent to the cornea. In this way, the chances of having errors due to improper adjustment of the rigid lens on the soft lens can be avoided. According to an additional modality of the In the present invention, a saturn-type contact lens, such as the Softperm lens sold by Pilkington Hind (St. Helens, UK) can be used. This type of lens comprises a lens with a rigid center and a peripheral skirt with a soft lens. The rigid, gas-permeable center It preferably does not contain enzyme or agent while the peripheral skirt of soft lens can be soaked in a solution containing the enzyme or the corneal agent. The peripheral skirt of the saturn lens can • manufactured from synergicon A copolymer available from Wesley 5 Jessen (Des Plaines, IL). The rigid non-hydrophilic center typically can be about 5.5 mm to 6.5 mm in diameter and has only about 0.2% H20 absorption. The outer periphery is polymerized in a soft hydrophilic skirt that extends circumferentially around the outer periphery of the center and may have • a width of approximately 3.0 to 4.0 mm, and approximately 25% absorption of H20. The base curve of this saturn lens varies from approximately 7.2 mm to 8.2 mm. 15 As the saturn lens is used, the cornea hardening enzyme or agent is released into the cornea from the soft peripheral skirt, modifying the cornea in hours. The rigid center of the Saturn lens begins • immediately reconfigure the cornea. The rigid center has a posterior radius of curvature that will reconfigure the anterior cornea to a curvature required for emmetropia as discussed. The cornea is reconfigured from several hours to a few days. The soft lens skirt gives additional comfort and less edge feel which helps the process of Orthokeratology and encourages the use of adherent lens.

The cornea hardening enzyme or agent dissipates from the cornea in a few days while the cornea adds its new shape. Saturn lens or other • rigid adherent can preferably be used for a few more days to stabilize the new shape of the cornea. Then the lens is removed. A "soft-fused lens" contact lens system can also be used to release the corneal hardening enzyme or agent within the cornea and reconfigure it simultaneously. In this embodiment of the present invention, an annular ring of soft lens type material is fused to the inner intermediate curve and the peripheral curve of a contact lens permeable to rigid gases. The resulting fused (soft) lens is soaked in the enzyme or agent, and the chemical is retained in the soft lens portion. The chemical is then released over time into the cornea, which modifies it. The gas-permeable center preferably rigid has a posterior central curvature that reconfigures the curvature of the anterior cornea to a shape in which it corrects the refractive error, preferably a shape that returns to the emmetropic eye. The center of the rigid contact lens is preferably a fluorosilicone acrylate material with a DK of about 60.92. The diameters vary from about 7.5 mm to 10.5 mm and the base curves of the rigid lenses range from about 7.0 mm to 9.0 mm. The "fused" soft lens portion is a soft hydrophilic lens material such as etafilcon A or • phemfilcon A. The union of the annular ring to the rigid contact lens is achieved by an adhesion process. The width of the soft annular ring varies between approximately .75 and 1.5 mm on each side. IV. The Procedure for the Use of Hardening Agents in Enzymatic Orthokeratology 10 A. General Procedure • The present invention contemplates the use of corneal hardening agents to alter the shape of the cornea of a subject from a suboptimal position to a second optimized position desired. A contact lens for Enzymatic Orthokeratology must fit appropriately to the surface of the cornea. When the cornea hardening agent is applied, the cornea hardens to ensure the proper cornea shape in its • place. The method of Enzymatic Orthokeratology provided herein may include the use of a corneal softening agent. The smoothing agent of the cornea helps to alter the shape of the cornea of a subject. An Enzymatic Orthokeratology contact lens should adjusted correctly. When a corneal hardening agent is applied, the cornea hardens to achieve the proper corneal shape. After hardening of the cornea, the lens • corrective is removed and the cornea of the subject retains the desired altered conformation. Unlike traditional orthokeratological methods, the present invention does not require the use of adhesive lenses to prevent or inhibit complete regression of the cornea to the suboptimal original condition. Also, the time course of the treatment of the The present invention can be reduced compared to that of • Methods of Enzymatic Orthokeratology. The time course of the treatment using the present invention can be shortened since the use of a corneal hardening agent eliminates the need to wait for the treatment to act. cornea smoothing agent. The reduction of the treatment time can provide increased success rates since the levels of participation of the subject are minimized. fl B. Rigid Contact Lens Design 20 A preferred embodiment of the rigid contact lens designed for Enzymatic Orthokeratology comprises a lens made of fluorosilicon acylate material (methyl-methacrylate difluoroitaconate siloxanil copolymer), available from Paragon Optical Co., Inc. (Reading, Pa). The high oxygen permeability of this material DK60 - DK151 x 10-11, allows sleeping with the lenses if necessary. The lens also has excellent humidification. In a preferred lens design, the preferred lens • has a reverse geometry sculpture. The design 5 constitutes a plurality of curved planes comprising the geometry of the lens which is used to alter the shape of the cornea during the Enzymatic Orthokeratology procedure. In one embodiment, the lens contains four curves which comprises the geometry of the lens. In other modality, reverse geometry lenses have two curves • steeper than the curve of the base. The shape and design of these lenses produces the desired results in the reconfiguration of a subject's cornea from a suboptimal first position to an optimal second position within of the hours until application days. Figure 1 shows a plan view of a rigid gas permeable lens for Enzymatic Orthokeratology 10 for use in the treatment of myopia. The shape • The lens is determined by the deformation of the cornea that will be corrected. Accordingly, the lenses of the present invention are formed to correct various irregularities of the cornea. The lenses of the present invention use hydrodynamic principles and a push-pull system to alter the shape of a cornea to a desired shape. In the embodiment shown in Figure 1, the flat base curve 12 pushes against and compresses the central cornea within a significantly reduced or longer radius.

• Simultaneously the central cornea is pushed or redistributed 5 within the steep curvature zone 14. The central zone 16 of the curve centers the lens and limits the flow of the cornea in response to the forces imposed by the flat base curve and the steep curve. The flat peripheral curve 18 allows the exchange of tears and the movement of the lens on the surface of the eye. A preferred embodiment of rigid contact lenses designed for enzymatic orthokeratology comprises a lens made of fluorosilicon acrylate material (methyl-methacrylate difluoroitaconate copolymer siloxanil) available from Paragon optics. The high oxygen permeability of this material allows sleeping with the lenses if necessary. The lens has excellent humidification with a low moistening angle. flp Zone 12 flat base curve (Figure 1) corrects the refractive error of the eye to improve visual acuity without help. Generally the diameter of the curve (optical zone) 12 of flat base varies from about 6.0 mm to 7.0 mm and is equal to the base curve in millimeters. The area 14 of the steep curve lies outside the zone 12 flat base curve and has a width range of approximately 0.6 mm to 0.8 mm. The radius of curvature of the steeply curved area 14 may be 5 to 10 diopters higher than the base curve of the lens depending on the refractive error. Generally, the ratio of the base curvature (BC) to the flatter central corneal curvature (K) in the first conformation (ratio BC / K) multiplied by a factor of 2 determines the radius of curvature of the steep zone. For example, the base curve of the lens is adjusted to 4 diopters flatter than the curvature of the central cornea (ratio BC / K = 4F). The radius of the steep zone = (BC / K) * 2 or 8 diopters steeper than the BC lens. The central curve zone 16 lies immediately adjacent to the steep curve zone 14 and the range of this zone varies from approximately 0.8 to 1.0 mm. Generally, the curvature of the central curve zone 16 will equal the curvature of the base curve zone 12 plus two to three diopters. The peripheral curve zone 18 is flatter than the base curve 12 of the lens. The width of the peripheral curve zone 18 varies from 0.4 mm to 0.5 mm. The zone 18 of peripheral curve allows the circulation of tears and the exchange of oxygen during the blinking. The total diameter of the lens is determined by the diameter of the base curve plus the steep zone, plus the central zone to the peripheral curve. The diameter of the lens varies from approximately 10 mm to 13 mm. The power of the lens is based on the refractive error of the patient and the ratio of the base curve of the lens to the curvature of the central cornea. Generally the thickness of the lens is .24 mm for power 0; .01 mm should • subtract for less correction diopter and .02 mm should add for each diopter over. The concave posterior curvature of the flat base curve zone 12 is preferably calculated to reconfigure the cornea from a first suboptimal conformation to a second optimal conformation, thus making the eye emetropic when the cornea is molded to , 10 this curvature. The frontal curvature of the curve zone 12 • flat base is a calculated radius to give the subject no I refraction error and 20/20 visual acuity helped while using the lens. All the parameters of the rigid contact lens vary depending on the refractive error, curvature and size of the cornea, and adjustment formula, as is known in the art. An additional embodiment of a rigid contact lens designed specifically for use in the treatment of farsightedness is contemplated. Such a contact lens must be Rigid, such as previously described lenses made of fluorosilicone acrylate material. In this embodiment, the concave (posterior) portion of the lens may be a spherical or an aspheric curve. A central portion of the lens is formed so that the concave surface of the The central portion is configured in such a way as to produce emmetropia. This central portion has a base curve that can be 1-5 dioptres steeper than the curvature of the central cornea. The peripheral curves are much flatter • that standard contact lenses and diameters are 5 major. The steeper base curve of the lens is designed to steep the curvature of the central cornea to reduce farsightedness and improve short and far visual acuity without help. In an alternative lens design, the lenses of Rigid contacts contemplated for Enzymatic Orthokeratology comprise a lens made of an acrylate fluorosilicone material (methyl-methacrylate difluoroitaconate siloxanil copolymer) available from Paragon optics. The high oxygen permeability of this material DK60-DK151 x 10 * 11, allows you to sleep with the lenses if necessary. The lens has excellent humidification with a low wetting angle. The base curve of the lens varies from 6.5 mm to 9.0 mm, depending on the central curvature of the cornea flS. The total diameter of the lens is the base curve in mm from +1.3 mm up to 2.0 mm, and the range is approximately 7.5 mm up to 15 mm. The central optical zone is transparent and corrects the refractive error of the eye to produce excellent visual acuity. The diameter of the optical zone varies from 6.5 mm up to 9.0 mm. The intermediate zone contains a chamber to release the enzyme or agent solution within the cornea. The width of the intermediate zone would range from .35 mm to 1.0 mm. The intermediate curve may be steeper or flatter than the curve • lens base depending on the refractive error. The peripheral curve 5 is flatter than the base curve of the lens. The width of the peripheral zone varies from .35 mm to 1.0 mm. The peripheral curve allows the circulation of tears and the exchange of oxygen during the blinking. The power of the lens is based on the error of refraction of the patient and the ratio of the base curve of the • lens to the central curvature of the cornea. Thickness .24 mm for 0 power; .01 mm should be subtracted for each correction diopter minus, and .02 mm should be added for extra diopter. The concave posterior curvature of the optical zone (curve base) is preferably calculated to make the emmetropic eye when the cornea is molded to this curvature. With myopia the base curve adjusts to 1-3 diopters flatter than the central curvature of the cornea. This can be accomplished with 1 • up to 3 lenses. The frontal curvature of the optical zone is a calculated radius to give the subject no refractive error and 20/20 assisted visual acuity while using the lens. The final lens will have a refractive power of 0. All the parameters of the rigid contact lens vary depending on the refractive error, the curvature and size of the lens. the cornea, and the adjustment formula, as is known in the art. This lens design can also be used without loading to reconfigure the cornea. An additional embodiment of the rigid contact lens design is used in the treatment of astigmatism. With astigmatism, the cornea exhibits an unequal curvature, (ie flatter curvature in a meridian and steeper curvature in the opposite meridian). In a lens design, a base curve to spherical peripheral curves is used to reconfigure the cornea in a more spherical configuration. The lens has a uniform eccentricity change which reduces the curvature in the steepest meridian. This characteristics makes the cornea spherical, reduces astigmatism, and improves visual acuity without help. A second design incorporates a toric base curve with a base prism to orient the steeper and flatter curves of the lens in the proper direction to correct the unequal curvature of the cornea. The lenses of this embodiment are constructed of materials similar to those described above, however, 60-92 DK lenses are preferred. Yet another embodiment of a rigid contact lens is specifically designed for use in the treatment of hyperopia. Such a contact lens must be rigid, such as previously described lenses made of a fluoro-silicone acrylate material. In this embodiment, the concave (posterior) portion of the lens is formed with a peripheral portion which has a base-to-spherical curve. A central portion of the lens is formed so that the concave surface of the central portion is configured to produce emmetropia. This central portion has a base curve 5 which is 1-5 dioptres steeper than the base curve of the peripheral portion of the lens, and has a radius of curvature that is up to 1 mm steeper than the peripheral portion. The base curve of the central portion of the lens can also be designed to produce a desired radius of curvature of a cornea which does not return the emmetropic cornea but still emptiness the base curve of the cornea. C. Procedure of Enzymatic Orthokeratology for Myopia Myopia is a condition in which, typically, the configuration of the eye is elongated, resulting in the focus of the parallel rays of light on the front of the retina. A corrective lens with a corrective curvature is used in this procedure that has a base curve more flp flat than that of the central curvature of the cornea to the amount of myopia in diopter. The internal radius of the intermediate zone can be up to 8 diopters steeper than the base curve. The central curvature of the steepest cornea is reconfigured to a flatter curvature and the curvature for flatter central is reconfigured to a configuration steepest. The result is a spherical cornea from the center to the center with a flatter central curvature. This eliminates myopia because the light is refracted further back on the retina rather than in front of the retina and there is less spherical aberration. As will be apparent to one of skill in the art, a number of other lens designs can be used to treat myopia having various diameters of base curves and thicknesses. Included in such designs are contact lenses that have base to spherical curves and peripheral curves those that have spherical base curves and peripheral to spherical curves. The following example illustrates a method for correcting myopia using Enzymatic Orthokeratology of the present invention. In this example, a patient exhibits uncorrected visual acuity of 20/300 (UVA) or 3 diopters of myopia; a flatter central curvature of 45 diopters or 7.5 mm; and a paracentral curvature of 40 diopters and the cornea is positively set to plus 0.30. The patient is treated according to the methods of the present invention. Using the methods described above, an appropriate concentration of glyceraldehyde was determined for use in the present invention. In one embodiment, a range of glyceraldehyde concentrations from about 0.1% to 5.0% are contemplated for use in the present invention. In another embodiment, a range of concentrations of about 1% to 4% is additionally contemplated. Finally, in yet another modality, the use of a glyceraldehyde solution of approximately 3% to induce • cross-linking of the cornea is contemplated by the present invention. A hardening amount of the cornea of a corneal hardening agent is administered to the patient. An agent is a 3% glyceraldehyde solution. The 3% glyceraldehyde solution is prepared under sterile conditions dissolving 1.5 grams of glyceraldehyde in 50 mL of chloride • 0.9% USP sodium. This solution is then filtered sterile and aliquots are taken. The route of administration may include a single intrastromal injection, or it may consist of local applications to the corneas of the subject. In a modality where the intrastroma injection step is used, subjects receive an intrastromal injection of the single cornea of approximately 20 L of a 3% glyceraldehyde solution using an appropriate injection technique. For example, the subject is administered a optical anesthetic such as a 0.5% proparacaine solution (Baush and Lomb, Tampa FL). The eye to be injected is gently proctosed and the needle of the syringe is gently inserted into the supertemporal quadrant within the stroma of the cornea. The hardening agent is then injected as a simple bolus into the stroma of the cornea. With the injection, the hardening agent reticles the components of the cornea for a period of time, from minutes to days, as appropriate, hardening the cornea. The application of a glyceraldehyde solution to 3% can be performed alternately through eye drops of one to four drops from one to four times daily. The 3% glyceraldehyde solution is applied in a drip form to treat the corneas. The method used comprises gently tilting the head of the subject to allow the drop to fall on the cornea and not adjacent structures, keeping the upper eyelid open, applying a drop of the solution to the subject's eye, and allowing the subject to blink. The administration of the corneal hardening agent can occur every hour or daily from one to 100 days (100). Rigid gas-permeable corrective contact lenses fit the subject's garlic to mediate reconfiguration of the cornea. The corrective lens provides a scaffold on which the cornea can be reconfigured within the second desired configuration. The dimensions of the corrective lenses used in the treatment are determined by the deformation of the subject's eyes as determined by standard diagnostic techniques known to one skilled in the art. The corrective lenses in this example have a base curve of 42 diopters or 8.0 mm (3 diopters more flat than the central curvature). The width of the optical zone is 8.0 mm. The power of the lens is flat (0). The size of the lens is 9.6 mm (8.0 + 1.6 mm) its thickness is 0.20 mm. The intermediate radius of curvature is 7.5 mm or 45 diopters (3 diopters steeper than the curvature of the case) with a width of 0.50 mm. The peripheral curvature has a radius of 10.0 mm, with a width of 0.30 mm. In another embodiment of the present invention the lens is loaded with a dose of corneal hardening agent. The contact lens fits properly to the cornea and the agent is released into the cornea over the course of a few minutes to a few days, -like is appropriate. The enzyme enters the stoma where the connective tissue layer hardens. The treated cornea reconfigures its anterior central curvature (45 diopters) to the posterior base curve of the lens (42 diopters). The new flp anterior central curvature of the cornea becomes 42 diopter (3 diopters flatter than its original 45 diopters). The anterior cornea for central (40 diopters) is steep at 42 diopters = 8.0 mm. The cornea now has a spherical configuration. The three original diopters of myopia are now reduced to a visual acuity without correction (flat or emétrope), and without help (natural) improved to normal 20/20 from 20/300. Before, during, and after treatment, the patient's optical health can be monitored. The monitoring methods include standard physical examinations performed by a person skilled in the art. Additionally, slot lamp biomicroscopy can be used to assess the patient's optical health. A slit lamp such as a Nikon FS-2 Slit Lamp can be used for patient examination. Such examination may include the steps of dilating the subject's eyes by placing a drop of tropicamide at 1.0%. (Bausch and Lomb, Tampa, FL) and 2.5% phenylephrine (Bausch and Lomb, Tampa, FL). After dilation the subject is then placed in front of a slit lamp and examined for edema. The anterior chambers of the subject can then be examined by depth of chamber, cell and aqueous brightness, and fibrin. The iris of each subject can be examined by atrophy, symmetry, or connection. The lenses can also be examined for the presence of cellular debris, capsule, or protein abnormalities of the lens. The vitreous humor of each one can also be examined by the presence of cells or other abnormalities. Finally, Fluress (local fluorescein) (Akorn Pharmaceuticals, Abita Springs, LA) can be placed to examine the subjects for any epithelial defect that may be present. In this case, the application of the cornea hardening agent acts to cross-link the amino acid residues in the stromal collagen, which in turn results in an increase in corneal rigidity. Since the hardening of the cornea takes place while maintaining the cornea in the second desired conformation by the lens, the hardened cornea hardens in the second desired configuration. As a result of the application of the hardening agent, the treated corneas retain the proper configuration when removing the corrective lenses. 10 In an alternative mode of the procedure of • Enzymatic Orthokeratology described above, a softening amount of the cornea of a corneal softening agent is administered prior to the addition of a curing agent of the cornea. For example, 500 are administered international units (Ul) of hyaluronidase by intra-stroma injection into the eyes of the subject. Hyaluronidase is manufactured as a sterile lyophilized product and packaged in ampoules, each containing 6,000 IU of a highly purified flB hyaluronidase (Biozyme, Blaenavon, UK).

In addition to the enzyme, the product may include 1.22 mg of potassium phosphate, monobasic; 1.92 mg of dibasic potassium phosphate; and 5 mg of lactose. Within 3 hours of attempted use, the ampoules are reconstituted with 0.24 mL of 0.9% sodium chloride USP and 20 L is removed into the syringes to supply the 500 International Units (IU) desired. A syringe suitable for use in this method is a 0.3 cc syringe for insulin equipped with a 29-gauge half-inch needle (Becton-Dickinson, Franklin • Lakes, NJ) or its equivalent. With injection, the corneal softening agent hydrolyzes the carbohydrate substrate for a period of time, from minutes to days, as appropriate, smoothing the cornea and preparing it for reconfiguration. At this point, the cornea smoothing agent is allowed to dissipate or its activity is inhibited, and a The corneal hardening procedure is continued to achieve a desired configuration of the cornea. D. Procedure of Enzymatic Orthokeratology for Astigmatism Astigmatism is a refractive error of the lens system, usually caused by an oblong configuration of the cornea. In this condition, the central curvature of the cornea is uneven, resulting in a shrinkage of the image on the retina. The central horizontal and vertical meridians are of different curvatures. Contact lenses Corrective astigmatism can use toric and aspheric corrective base curves, intermediate curves, and peripheral curves that can incorporate prism and / or truncation. The initially flatter central meridian of the eye is reconfigured to take a steeper curvature and the The initial steep curvature and the initial steep central meridian are reconfigured to take a flatter curvature. This process reconfigures the central curvature of the cornea in a spherical configuration and eliminates astigmatism. • To correct astigmatism using 5 Enzymatic Orthokeratology, the following procedure is used. In one embodiment of the present invention, the lens material is fluorosilicon acrylate. The base curves (6.0 mm / 8.5 mm) can be again toric, front toric or toric. The curvature of the central cornea more flat is aligned with a steeper base curvature. The central curvature of the steepest cornea is aligned with a flatter base curvature. Also, aspheric or spherical base curvatures and peripheral curves can be used. The lens diameter is the base curve in millimeters plus 1.3 to 1.8 mm.

The range is from approximately 7.5 mm to approximately 11. 5 mm The diameter of the optical zone equals the base curve in mm and varies from approximately 6.5 to approximately 9. 5 mm The intermediate radius of curvature varies from fl approximately 1 diopter to approximately 2 diopter flatter than the base curve. The width is from about 0.35 to about 1.0 mm. The peripheral curves vary from about 2 to about 4 diopters flatter than in the base curve. The width is 0.35 to 1.0 mm. Intermediate and peripheral curves can be aspheric. Prism and / or truncation is used to keep the lenses aligned in the proper position to reconfigure the astigmatic cornea. The thickness of the lens varies with the power of the lens. If the power of the lens zero = • 0.20 mm, subtract 0.01 mm for each diopter of less and 5 add 0.02 mm for each diopter of more power. The power of the lens is calculated based on the refractive error of the patient and the ratio of the base curve / curvature of the cornea. Astigmatic lenses can be loaded with an agent or enzyme hardening the cornea as a supply vehicle, or the design of the • lens can be used without charging to reconfigure the cornea E. Procedure of Enzymatic Orthokeratology for Hyperopia Hyperopia results from a short distance suboptimal from the surface of the eye to the retina. To correct farsightedness, the central curvature of the cornea must be reconfigured to a steeper curvature. The light that enters such an eye requires a larger refraction since B the image projected through the cornea is focused behind of the retina and you need to move forward in the retina. The base curve of the lens can be adjusted steeper than the central curvature of the cornea with a flatter peripheral and peripheral aspheric curve. A hole can be used in the center of the lens to encourage and give space for steep the central cornea. Alternatively, a contact lens as described above can be used to correct hyperopia. To correct hyperopia using Orthokeratology • Enzymatic, the following procedure is used. In one embodiment of the invention, a fluorosilicone-acrylate material is used to form the corrective lens. A hole that varies from 2.5 mm to 4.5 mm in diameter is provided in the center. The base curve of the lens fits more steeply than the central curvature of the cornea. The lens corrective has a corrective curvature where curves • base vary from 5.5 mm to 8.0 mm and the diameter is the base curve in millimeters + 1.0 mm up to 1.5 mm (range from 6.5 to 9.5 mm). Smaller diameters are used because the curvature of the lenses is steeper than the central cornea.

The intermediate and peripheral curves should be aspheric curves of 1 to 3 diopters flatter than the base curve. The width of these curves is 0.35 mm to 1.0 mm. The optical zone is between 5.5 mm to 8.0 mm. The thickness of the lens • depends on the power needed for correction. In the hyperopia, the lenses will be thicker. If the power is flat (0) the thickness = 0.20 mm, then add 0.2 for each diopter extra. The lens power is calculated based on the refraction error of the patient adjusted for the base curve / curvature ratio of the cornea. The lenses Hyperopic drugs can be loaded with a corneal hardening agent or enzyme as a delivery vehicle, or the design of the lens can be used without charging to reconfigure the cornea. • V. Other Therapeutic Uses of Enzymatic Orthokeratology The present method for reconfiguring a cornea can be used to effect other therapeutic benefits than to correct refractive errors. Additional therapeutic benefits include softness of the cornea, improve or rehabilitate irregularities of the cornea and stabilization of corneal structures. • A contemplated use of the present invention is to rehabilitate the irregularities and improve the refractive errors that result from various corneal surgeries including photorefractive keratectomy (PRK) (an example of which is described in the North American Patent No. 5,699,810), laminar corneal surgery (LASIK) LASIK (an example of which is described in the Patent American Patent No. 5,697,945), radial keratotomy (RK) (a # example of which is described in the North American Patent No. 5,611,805), thermokeratoplasty, photothermalkeratoplasty (examples of which are disclosed in U.S. Patents Nos. 5,749,871 and 5,779,696, corneal transplant surgery, and cataract surgery.) For example, photorefractive kerarectomy (PRK), is an extremely common worldwide procedure. The present invention could be used to preserve and stabilize the surgical reconfiguration of the cornea postoperatively. In this modality, a patient who has • suffered the PRK procedure would be identified and an acceptable corneal hardening agent 5 would be selected. After the application of stabilizing contact lenses, a hardening amount of the cornea of the cornea hardening agent would be administered to the patient. Contact lenses and application of hardening agent would remain over the patient's eyes for a period • adequate time to ensure the stabilization of the cornea reconfigured surgically. The same treatment would be applicable to patients who had received LASIK or RK. Similarly, the present invention can also improve the chances of success for other corneal procedures, such as corneal transplant surgery and cataract surgery. One of the most common reasons for flP clinical failure of surgical procedures such as corneal transplants, for example, is the existence of residual refractive error such as irregular astigmatism after an otherwise successful surgery. The present methods could be used to correct the refractive error that occurs as a result of disease, surgery, or other conditions. Also, the present invention can promote faster healing and allow early removal of sutures, which are normally left in place for 6 to 12 months. Increased healing is promoted by the • hardening of the postoperative cornea, since this hardening decreases the need for sutures. The present invention can also be effective in treating a number of corneal pathologies that result in corneal irregularities. Diseases or conditions of the cornea such as keratoconus, fusion disorders of the cornea, corneal ulcers, recurrent corneal erosions, pterygium can be treatable using the methods of the present invention. Also, the cornea warping induced by contact lens, contact lens intolerance and erosion induced by contact lens also could be combated by stabilizing and hardening the cornea using the corneal hardening agents of the present invention. To use the above methods of the present invention to effect this additional clinical benefits, The first one identifies the subjects that have an irregularly structured cornea or that have suffered a manipulation of the cornea. Such identification is normally achieved by an eye specialist or other practitioners skilled in the art who can diagnose an individual as having a cornea irregularly configured or that has undergone manipulation of the cornea. The previously described methods of another enzymatic pathology are then used to reconfigure the individual's cornea to a • desired configuration. The following examples illustrate embodiments of the present invention. Such examples are illustrative only and do not mean that they limit the scope of the present invention. Example 1 10 PROTECTION OF GLYCERALDEHYDE PROVIDED BY DROPS • LOCAL OPHTHALMIC AND INTRACTS OF CORNEA In this Example, the protection of Dutch Belted rabbit corneas treated with glyceraldehyde after the administration of the cornea smoothing enzyme and hyaluronidase was investigated. This study involves the use of five (5) pigmented Dutch Belted rabbits, two (2) in the control group and three (3) in the group treated with glyceraldehyde. All rabbits received a complete examination with slit lamp on the first day of the study to establish the baseline using the following technique. A Nikon FS-2 Slit Lamp was used for testing the test animals. For each animal examined, the eyes were dilated by placing a drop of 1.0% tropicamide (Bausch and Lomb, Tampa, FL) and 2.5% phenylephrine (Baush and Lomb, Tampa, FL).

The animal was then placed in front of a slit lamp. The corneas of each animal were examined for edema and the surface area involved with edema was estimated. The anterior chambers of the animals were carefully examined for depth of chamber, aqueous cell and brightness and fibrin. The iris of each animal was examined by atrophy, symmetry, or connection. The lens was examined and it was noted if cell debris, capsule or lens protein abnormalities were present. The vitreous humor of each animal was then examined for the presence of cells or other abnormalities. Finally, Fluress (local fluorescein) (Akorn Pharmaceuticals, Abita Springs, LA) was placed in the animals examined and it was noted if epithelial defects were present. 15 The following grading system was used to evaluate the experimental animals. A. Cells and Brightness (C / F) 0 no observed cells fl out 1 to 5 cells observed per beam field light slit +1 5 to 10 cells observed per slit light beam field +2 10 to 20 cells observed per slit light beam field 25 +3 20 to 50 cells observed per light beam field slit +4 more than 50 cells observed per slit light beam field B. Edema / Clarity of the Cornea 5 0 without edema / clarity observed trace weak opacification of the cornea, still able to see fine details of the iris +1 light opacification of the cornea, still able to see most of the details of the 10 iris. • +2 moderate opacification of the cornea, able to see large details of the iris. +3 Severe opacification of the cornea, able to see the iris, although without details. 15 +4 complete opacification of the cornea, unable to see the iris. C. Connection of Iris 0 without connection view 1-12 Corresponds to the number of hours of the clock connections observed with each hour of the clock corresponding to approximately 30 ° of iris envelope D. Lenses 0 -without opacification (ie cataract) or mechanical defect (possibly secondary to processed trauma) present 1-12 -catarata or observed lens defect (these observations have not been evaluated • qualitatively) 5 E. Cells Vitreas 0 -with no vitreous cells seen trace -1 to 5 cells observed per field of light beam +1 -5 to 10 cells observed per field of beam 10 of light • +2 -10 to 20 cells observed per field of beam of light +3 -20 to 50 cells observed per field of light beam 15 +4 -more than 50 cells observed per light beam field F. Fibrin 0 -without sight fibrin • trace -a thin thin strand identified 20 +1 -thick strand or 2-3 fine strands present +2 -2 thick strands or more than 3 thin thin strands present +3 -small strands of various sizes present 25 +4 - thick, opaque fibrin three-dimensional strands present G. Epithelium N defects - no defect in the epithelium • SPK - superficial punctate keratopathy - more than 3 5 minutes of (<0.3mm) F-staining lesions - epithelial defect focal-a larger staining patch (> 0.3mm) Subsequent to this baseline examination, all rabbits received 500 IU of a hyaluronidase formulation bilaterally within the stroma of the cornea on Day 1 of # Study. The hyaluronidase formulation was prepared as follows. The formulation was manufactured at Prima Pharm, Inc. (San Diego, CA) as a sterile lyophilized product and packaged in ampoules, each containing 6,000 IU of a highly purified hyaluronidase. In addition to the enzyme was included in the formulation: 1.22 mg of potassium phosphate monobasic, 1.92 mg of potassium phosphate dibasic, and 5 mg of lactose. Within three hours of attempted use, the flk vials were reconstituted with 0.24 mL of sodium chloride to 0.9% USP and 20 L were taken in syringes to supply the 500 IU desired. The syringes used were insulin syringes of 0.3 cc equipped with a 29-gauge needle (Becton-Dickinson, Franklin Lakes, New Jersey) or their equivalents. The formulation of hyaluronidase was administered by intrastroma injections of the cornea. First, the animals were anesthetized with ketamine 30 mg / kg and xylazine 7 mg / kg. The animals were then placed on an examination board and administered two (2) drops of 0.5% proparacaine 5 (Bausch and Lomb, Tampa, FL), an optical anesthetic. The eye to be injected was gently proptose and the needle of the syringe was gently introduced into the superotemporal quadrant within the stroma of the cornea. The complete 20 L were then injected as a single bolus inside of the cornea stroma. After the injections, the • rabbits were returned to their boxes for recovery. The rabbits did not receive additional manipulations except for care and exams until Day 8 of the Study. The administration of the test agents began on Day 8 of Study. The control animals were administered a balanced salt solution (BSS) (IOLAB Corporation, Claremont, CA) three times daily in both eyes. The experimental animals received an intrastroma f injection of the simple cornea of 20 L of glyceraldehyde solution to 3% using the injection technique discussed above. The glyceraldehyde solution was prepared under sterile conditions in Prima Pharm by dissolving 1.5 grams of glyceraldehyde in 50 mL of 0.9% USP sodium chloride, sterile filtration, and taking aliquots of the solution. 25 Subsequent administrations of the BSS to control animals or glyceraldehyde solution to the experimental animals was done through eye drops. The experimental rabbits received a drop of glyceraldehyde solution three times a day. The procedure used involves removing the animals from their boxes, gently tilt the head of the animal to allow the drop to fall on the cornea and not on the adjacent structures (eg, eyelids, etc.), keeping the upper eyelid open, applying a drop of the solution to the eye of the test animal , and letting the animal blink. The Balanced Saline solution was administered to the group of control animals in an analogous manner. Rabbits that received local drops received glyceraldehyde or BSS for a total of 50 days. The data was collected from the animals in the Study Days 1 (baseline), 2, 4, 8 (before and 4 hours after injection), 9, 11, 16, 22 and 31. The animals received a complete slit lamp examination and the criteria discussed above It was documented. The animals were sacrificed and their eyes were harvested on Day 58 of the Study. The animals in the study were euthanized using an intravenous injection of pentobarbital (2 mg / kg). In the eyes of the animals, the eyeball was removed immediately after sacrifice using Castro-Viejo scissors. The corneas of the eyes were then removed and placed on the end of a glass tube and cut in half. These samples were instantly frozen in liquid nitrogen. The corneas • transported on dry ice to a facility that has a triestate and embedded in O.C.T. embedding compound. (Miles Labs, Elkhart, IN). The corneas were then sectioned, stained with hematoxylin / eosin. The cuts were sent to a Certified Veterinary Pathologist for interpretation. The data was analyzed and any abnormality seen in the clinical examination became • numerical score as follows: Result Normal score 0 trace 1 + 1 2 +2 3 + 3 4 + 4 5 Connections were recorded by a clock system where each number corresponds to the number of clock hours (30 °) of observed connections (ie, 15 0 = normal, 12 = 360 ° of envelopment). The criteria of epithelium, conjunctiva and lens were recorded as normal = 0 and abnormal = l. Although the statistical power of the study was small with only 2 and 3 rabbits in the control and treatment groups respectively, a statistical analysis was performed. The group mean for each clinical score • was compared using a students t test assuming 5 equal variances. The statistical analysis of the clinical observations did not show differences between the groups of animals. The histopathological examination of the harvested corneas showed extended vacuolization of the cells contained therein. This result was considered a • Artifact possibly due to instantaneous freezing and subsequent tissue processing of the harvested corneas. In light of this observation, the methods used for fixing and processing the tissue used in Example 2 was changed. However, it should be noted that there were no appreciable differences noted by the revision pathologies between the corneas of the control and treated groups. Example 2 • PROTECTION OF THE USE OF GLYCERALDEHYDE IN EYES TREATED AND WITHOUT 20 TREATING WITH HIALURONIDASE WHICH INCLUDES EVALUATION OF THE FEASIBILITY OF THE EPITHELIUM OF CORNEA AND OFTHALMOSCOPY INDIRECT This example further examines the protection of glyceraldehyde treatment in an animal model. The experiment described in Example 2 involves the study of six (6) pigmented Dutch Belted rabbits, two (2) in the control group and four (4) in the experimental group treated with glyceraldehyde. On Day 1 of Study, all rabbits # received a complete ophthalmic examination that includes 5 slit lamp biomicroscopy and indirect ophthalmoscopy. The slit lamp biomicroscopy was performed substantially as described in Example 1. However, Rose Bengal stain applied in the present using Rose Bengal Ophthalmic Strips (Barnes, Hind, • Inc., Sunnyvale, CA). This procedure involves a sterile strip dipped in 0.9% sodium chloride applied to the extraocular muscles and sclera of an examined rabbit. The rabbit was left to blink by applying the stain and then examined the treated eye. Slit lamp biomicroscopy was performed including Rose Bengal stain on study days 1 (baseline), 8, 9, 11, 15, 34, 45 and 63. The animals were recorded and the results recorded. • using the criteria described in Example 1. 20 Indirect ophthalmoscopy was performed using a Heinz Indirect Ophthalmoscope with a 20D manual lens. First an animal's eyes were dilated to be examined with a 2.5% phenylephrine and 1.0% topicamide solution (Bausch and Lomb, Tampa, FL) as described in Example 1. The examination room was darkened and the animal to be examined was transferred to an examination table. The 20D lens of the indirect ophthalmoscope was cleaned in the head lamp was adjusted in such a way that the lamp • focused just below the horizontal meridian of the examiner. First the inferior vitreous and the retina were examined, exploring to cover the nasal and temporal periphery. The examiner then moved temporarily away and examined the retina and the peripheral vitreous by examining inferiorly and superiorly. The examiner moved afterwards nasally and repeated the top-down exam. I also know • examined the superior retina, the optic disk and the vitreous. Finally, the middle retina and the vitreous were examined. Any scar, detachments, irregularities, hemorrhages, or other abnormalities were noted for each animal. The indirect ophthalmoscopy was performed in Study Days 1, 34 and 63. After the baseline examinations, the rabbits were anesthetized and received an intrastromal injection of the • cornea of 500 IU of hyaluronidase in OD (right eye) using Only the method described in Example 1 was administered. The administration of the test agents in the test agents in the form of local eye drops started on Study Day 8. The control animals were given a balanced salt solution (BSS). ) (IOLAB Corporation, Claremont, CA) four times a day in each eye.

The experimental animals received a 3% glyceraldehyde solution. The glyceraldehyde solution was prepared under sterile conditions in Advanced Corneal Systems (Irvine, CA) by dissolving 18 grams of glyceraldehyde 5 in 600 mL of 0.9% USP sodium chloride, sterile filtration and taking aliquots of the 3% glyceraldehyde solution ( p / v) in droppers of 10 ml. The experimental rabbits received a drop of glyceraldehyde solution four times a day using the technique described in Example 1. rabbits received local drops for a total of 63 days.

• On Study Day 71 (after 63 days of drops), scrapes of the cornea were performed as follows. Photographs were taken of the eyes without instruments taken after fluorescein staining. Staining with Fluorescein was performed as described in Example 1. The animals examined were then placed under general anesthesia using ketamine / xylazine also as described in Example 1. Two (2) drops of proparacaine were placed in the • both eyes of the animal examined as an anesthetic. The animal to be examined was then placed on an examination table with one eye gently proptosed. A 10 x 15 mm strip of epithelium from the central cornea was stripped with a # 11 sterile scalpel blade (Feather Safety Razor Co., Ltd., Japan). The animal examined was then returned to the Slit lamp, local fluorescein was applied, and the eye was photographed. The animals were examined by re-epithelialization on days 1, 2 and 3 after scraping. The photographs were taken and the re-epithelialization rate was • determined and documented. 5 The study animals were slaughtered on the Day of Study 74 with an intravenous injection of pentobarbital (2 mg / kg). The eyes of the study animals were enucleated immediately after sacrifice and placed in labeled tubes containing approximately 5 mL of a fixative Karnovsky of medium resistance (2.5% glutaraldehyde, 2.5% • of paraformaldehyde, 2.5 mM CaCl2, 100 mM sodium Cacodylate, pH 7.4) for about 1 hour. The eyes were removed and small windows (1 x 3 mm) were made in the cornea / iris to allow the penetration of the fixative into the glass. The eyes were then placed in 25 mL of fresh fixative, Fixed eyes were sent to Consolidated Veterinary Diagnostics, Inc. (West Sacramento, CA) where they underwent routine tissue processing, sectioning, and hematoxylin / eosin staining. HE examined by a Certified Veterinary Pathologist. The evaluation of the data indicates that the glyceraldehyde treatment of the eyes did not produce significant changes in the structure of the eye compared with the controls. This conclusion is supported by the presence observed from aqueous cells and brightness in the experimental animal group. The baseline examinations of the study animals indicate that the group treated with glyceraldehyde had watery cells and brightness and that the control animals did not.

• However, the data indicated that the animals improved 5 during the time and that the cell / brightness was absent by day 14. These results suggest that the administration of glyceraldehyde in the test animals seems to damage the resolution of the cell and the brightness. In addition, the baseline exams using indirect ophthalmoscopy revealed no abnormalities beyond • of a few daily scars of speckled pigmentation of the retina which remained unchanged throughout the study. Additionally, scraped corneas of animals treated with glyceraldehyde healed at a speed equivalent to those of treated control eyes (BSS). The eyes that suffered scraping of the cornea and a subsequent healing period were sent to Consolidated Veterinary Diagnostics for tissue processing and pathological interpretation. In total, four eyes were evaluated of the group treated with glyceraldehyde and two eyes of the group BSS. One of the two control eyes (BSS) had a focus of stromal change described as an increased number of stromal nuclei and nuclear fragmentation in the subepithelial stroma near the limbus. This description would imply an answer to the wound (presumably scraping). One of the four eyes treated with glyceraldehyde had a superficial scar on the stroma of the cornea and disorganization of Bowman's membrane (also presumably due to scraping). 5 Example 3 STUDY OF LARGE SCALE PROTECTION UNDER CONDITIONS OF GOOD LABORATORY PRACTICES Example 3 describes a large-scale study of twenty-seven (27) pigmented Dutch Belted rabbits for demonstrate the protection of glyceraldehyde treatment at • 3%. This study was conducted in compliance with the requirements of good laboratory practices of the U.S. Food and Drug Administration. Here, 27 eyes were chosen at random to form the control group and the remaining 27 eyes formed the experimental group. All animals received ophthalmic examinations consisting of slit lamp biomicroscopy (as described in Experiment 2) and intraocular pressure (IOP) measurements as generally practiced in the art, before the start of the procedure. experiment to establish the conditions of the baseline. After the baseline examinations, all rabbits received 500 IU in 20 L of hyaluronidase within the stroma of the cornea bilaterally using the injection method described in Experiment 1. They were not performed exams or treatments on animals until Study Day 8. On Study Day 8, the animals received slit lamp exams and IOP measurements. The treatment with local eye drops began • immediately after the Day 8 exams. Each rabbit 5 received two drops of the test agent four times a day at 05:00, 09:00, 13:00 and 17:00. The 3% glyceraldehyde solution was prepared in 0.9% USP sodium chloride under Good Manufacturing Practices (GMP). 0.9% sodium chloride for injection was also prepared using GMP. Each rabbit eye in the experimental group received the • 3% glyceraldehyde solution while the control eyes received 0.9% sodium chloride solution. The installation for contracted test animals placed the eye drops using the method described in Experiment 1 according to GLP. The rabbits received two applications of the specified test agent in each eye for a total of 32 days. The animals were examined using biomicroscopy of < (B slit lamp and intraocular pressure measurements are took Study Days 1 (baseline) 8, 9, 12, 15, 22 and 40. On Study Day 40, after 32 days of drops, the animals were sacrificed and the eyes were harvested according to the methods described in Experiment 2. The eyes were fixed on a Karnovsky fixator of medium strength as described in Experiment 2 and sent to a Certified Veterinary Pathologist for interprion. Intraocular pressure measurements were made. He • Statistical analysis of the IOP measurements included the 5 analyzes of the mean IOP values in millimeters of mercury (mm Hg). Additionally to normalize the variations of the baseline in the intraocular pressure, the IOPs were converted to a percentage of the original pressure (baseline) using the following formula: (measurement on the day examination (Hg mm) / baseline measurement (Hg mm)) * 100.

• These means were then compared in a paired t-test. Many of the host / toxicology response rates were completely normal for all 20 eyes examined over seven (7) time points documented. None of the 14 criteria (conjunctiva, corneal edema record,% of the surface area of the cornea edema involved, Rose Bengal record,% of area area involved in Rose Bengal, epithelial fl flats, superficial punctate keratopathy,% of surface area involved in superficial punctate keratopathy, watery cell and brightness, fibrin, iris abnormalities, lens abnormalities, vitreous cells, intraocular oppression) showed statistically significant differences in the control and treated groups. glyceraldehyde for any time point.

The histopathology results of this experiment showed a minimal to light lymphoplasmacytic infiltrate of the cornea stroma at the limbus which is • commonly seen in rabbits. There was also acute conjunctivitis 5 from minimal to medium attributable to terminal manipulation of all animals. Other changes such as focal increase in cellularity of the cornea stroma and a reduplication of the Descement membrane in both groups treated with glyceraldehyde and 10 treated with saline were also rarely noticed. These changes were the • consequence of overly aggressive injection of the cornea and not associated with the treatment with the drops. The results of this experiment indicate that the use of the 3% glyceraldehyde solution in rabbits does not produced significant harmful effects. Thus, the 3% glyceraldehyde solution can be used safely to facilitate the reconfiguration of the corneal structure. In addition, the results taken from this experiment and the ^ B Examples 1 and 2 indicate that glyceraldehyde treatment to 3% is safe. Example 4 extends the results described above to a small-scale protection study on the effects of 3% glyceraldehyde treatment in human patients without vision.

Example 4 INOCUITY OF ENZYMATIC CORNEOPLASTY WITH HYALURONIDASE AND LOCAL APPLICATION OF GLYCERALDEHYDE TO% IN TWO HUMAN PATIENTS WITHOUT VIEW 5 The two patients (Nos. 1108 and 1105) each received an intrastromal injection of 500 IU of hyaluronidase. Patients were observed for 20-28 days after injection using methods similar to those described in Example 1. At the end of the period of observation, patients were equipped with lenses • Corrective ones that have a reverse geometry sculpture as described above, which they used for an average of 8-12 hours / days. Patient 1108 used the lenses for 21 days while patient 1105 used the lenses for 50 days. Patient 1108 Patient 1108 was treated according to the protocol outlined above. After it had expired W that the period of 21 days of use of the lens, was instructed to patient to apply two (2) drops of the 3% glyceraldehyde solution for 4 times a day. The application of 3% glyceraldehyde continued for thirty-six (36) days after the use of the lens had ceased. After the end of treatment with 3% glyceraldehyde, it was examined to the patient occasionally and the final examination was administered 126 days after cessation of glyceraldehyde treatment. The results of the observations taken to the patient indicate that patient 1108 manifested keratitis • Surface dotted while using the RGP lens. However, since this condition has been previously seen in reports in the literature that discuss the use of RGP lenses, it is considered unlikely that the observed condition is a result of the treatment protocol. The patient's observations did not indicate any harmful effect on the stroma of the endothelial cells of • this patient during the time period of treatment with glyceraldehyde. There were also no adverse reactions observed after the end of the 36-day treatment protocol, which includes the time of the final exam. 15 Patient 1105 This patient was treated as described above and used the RGP lenses for 50 days. In contrast to patient 1108, patient 1105 was treated flp with the 3% glyceraldehyde solution for one (1) month while the patient was wearing RGP contact lenses. The 3% glyceraldehyde solution was applied by drip four times a day for a total period of 43 days. During the period of use of the lens the patient 1105 exhibited signs of superficial punctate keratopathy (SPK) of the cornea epithelium. This condition was probably born from the use of contact lenses. During the period of use of the lens and the application of glyceraldehyde at 3%, it was not observed that the SPK level increased. Thus, the • Application of the glyceraldehyde solution did not help to exacerbate the condition. This conclusion is supported by the effect of the removal of the lens on the observed SPK condition. At the end of the use of the lens while continuing the 3% glyceraldehyde treatment, the SPK level was observed to decrease.

In addition, at the end of the 43-day glyceraldehyde treatment protocol within 48 hours of cessation of glyceraldehyde solution application, the corneas looked normal under slit lamp biomicroscopy and were free of any SPK. Similarly, the epithelium of the cornea, the stroma and the endothelial cells of the treated eyes looked normal. In a follow-up examination of patient 1105 at 98 days after the cessation of glyceraldehyde treatment, < the patient's corneas looked normal. 20 This initial study of two human patients without sight indicates that treatment of the human eye with a 3% glyceraldehyde solution does not produce observable negative results. The SPK observed in patients can be attributed to a result of the use of the lens contact and not to a result of treatment with glyceraldehyde. Based on these results, the treatment of the present invention is considered harmless. The studies that • consist of larger test groups followed for emphasize this point and to investigate the innocuousness of other embodiments of the present invention. Example 5 describes a safety study involving five sightless patients who underwent nonenzymatic corneoplasty using contact lenses corrective and the application of a glyceraldehyde solution • 3%. EXAMPLE 5 SAFETY OF NON-ENZYMATIC CORNEOPLASTY AND LOCAL APPLICATION OF 3% GLYCERALDEHYDE IN FIVE HUMAN PATIENTS WITHOUT 15 VISTA In this study, five unseen patients with healthy corneas were treated with contact lenses and a 3% glyceraldehyde solution to determine the safety J of this procedure. Here, patients were equipped with and used contact lenses for seven (7) days. After this period a 3% glyceraldehyde solution was applied (described above) to the eyes and the use of the contact lens continued for twenty-eight (28) days. After this period the use of the contact lens and the treatment with glyceraldehyde.

Patients were examined individually for the effects of treatment after removal of the lenses and cessation of glyceraldehyde treatment. The first test was on the last day of treatment, and five (5) subsequent tests were administered over a period of one month. Normal corneas were observed in all patients with only minor incidents of SPK reported.

• Patient 1211 Day Results 10/14/97 Normal cornea with + 1 SPK 10/16/97 Normal cornea with + 1 SPK 10/17/97 Normal cornea 10/21/97 Normal cornea with + 1 SPK 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea with ± SPK 12/16/97 Normal cornea Patient 1212 Day Results 10/14/97 Normal cornea 10/16/97 Normal cornea 10/17/97 Normal cornea 10/21/97 Normal cornea 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18 97 Normal cornea 12/16/97 Normal cornea Patient 1213 Day Results • 10/14/97 Normal cornea with + 1 SPK 10/16/97 Normal cornea with + 1 SPK 10/17/97 Normal cornea 10/21/97 Cornea normal with ± 1 SPK 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea with ± 1 SPK # 12/16/97 Normal cornea Score: 0 = Normal +2 = Intermediate staining +1 = A few spots +3 = Severe staining of staining The results of this study further support the conclusion that 3% glyceraldehyde is harmless for use in the eyes of human patients to facilitate the alterations of the cornea structure achieved in the Enzymatic Orthokeratology protocol of the present invention. Example 6 10 THE SAFETY OF ENZYMATIC CORNEOPLASTY WITH HIALURONIDASE AND LOCAL APPLICATION OF 3% GLYCERALDEHYDE IN SEVEN HANDSOME NON-VISTA PATIENTS The methodology used in this study was similar to that discussed in Example 4. The subjects were injected • intraestromatically with 500 IU of a solution of hyaluronidase 5 on the first day of the study after an initial eye examination. The injected enzyme was allowed to digest the substrate of the cornea for seven (7) days. At that time contact lenses were fixed to the treated eyes of the subjects. The subjects used the lenses for another seven days, time in the which local application of 3% glyceraldehyde solution • was applied for the first time. The 3% glyceraldehyde solution was applied in 2 drops, 4 times during the day for the next 28 days. At the end of the 28 days, the contact lenses were removed and the glyceraldehyde treatments were finished. The subjects were examined and the data were recorded throughout the treatment period after cessation of treatment. The subject's eyes were monitored by • changes in the condition of the eye and those data are summarized later. As indicated by the data, the subjects treated did not show significant negative effects as a result of the enzymatic injection or the application of glyceraldehyde. The only apparent negative effects of the treatment were incidents of edema and manifestations minors from SPK. These negative manifestations resolved favorably for most patients Patient 1201 Day Results 9/9/97 Normal cornea 9/16/97 Normal cornea, + 1 edema, +1 SPK 9/23/97 Normal cornea, + 1 SPK 9/30/97 Normal cornea, + 1 SPK 10 / 7/97 Normal cornea, + 1 SPK 10/16/97 Normal cornea, + 1 SPK • 10/28/97 Normal cornea 11/10/97 Normal cornea 12/16/97 Normal cornea Patient 1203 Day Results 9/9/97 Normal cornea 9/16/97 Normal cornea, + 1 SPK • 9/23/97 Normal cornea, + 1 SPK 9/30/97 Normal cornea, + 1 SPK 10/15/97 Normal cornea, + 1 SPK 10/16/97 Normal cornea 10/18/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea Patient 1204 • Rededidated Day 9/9/97 Normal cornea + 1 Edema 9/16/97 Normal cornea, + 1 Edema, + 1 SPK 10/14/97 Normal cornea, + 1 SPK 10/16/97 Normal cornea, + 1 SPK 10/21 / 97 Normal cornea, + 1 SPK • 710/28/97 Normal cornea, + 1 SPK 11/10/97 Normal cornea, + 1 SPK 11/18/97 Normal cornea, + 1 SPK 12/16/97 Normal cornea, + 1 SPK Patient 1205 Day Res litados 9/9/97 Normal cornea, + 1 Precipitated 9/16/97 Normal cornea, + 1 Ppt • 10/14/97 Normal cornea, + 1 Ppt, + 1 SPK 10/16/97 Normal cornea , + 1 Ppt 10/21/97 Normal cornea, + 1 Ppt 10/28/97 Normal cornea, + 1 Ppt 11/10/97 Normal cornea, + 1 Ppt 12/15/97 Normal cornea, + 1 Ppt Peiciente 1206 Day Results 9/9/97 Normal cornea, + 1 Edema, + 1 SPK 9/16/97 Normal cornea 10/14/97 Normal cornea, + 1 SPK 10/16/97 Normal cornea, + 1 SPK 10/21/97 Normal cornea, + 1 SPK 10/28/97 Normal cornea, + 1 SPK 11/18/97 Normal cornea, + 1 SPK Patient 1209 Day Results 9/9/97 Normal cornea, + 1 Edema 9/16/97 Normal cornea, + 1 Edema, + 1 SPK /16/97 Normal cornea, + 1 SPK 10/18/97 Normal cornea, + 1 SPK /21/97 Normal cornea, + 1 SPK 11/10/97 Normal cornea, + 1 SPK 11/18/97 Normal cornea, + 1 SPK • 12/16/97 Normal cornea Score: 0 = Normal +2 = Intermediate staining +1 = A few spots +3 = Severe staining of staining The results of this study indicate that the treatment of human eyes with 3% glyceraldehyde • after intrastroma injection is also safe for use in the eyes of human patients to facilitate alterations of the corneal structure achieved in the Enzymatic Orthokeratology protocol of the present invention. Example 7 10 ELASTICITY MEASUREMENTS OF CORES TREATED WITH ENZYMATIC ORTHOPERATOLOGY • A precision spherical glass indenter was used to contact the surface of the cornea of subjects treated with the methods of the present invention. to measure the changes in the elasticity of the cornea. The method used involves applying the indenter in the form of a small spherical ball to flex gently on a test cornea to establish an initial value of deflection. The measurements were taken using an interferometer • to see the deflection. After this application, the relaxation period 5 was measured by observing the change in the impression made by the indenter. The range of motion indentation was characterized using a precision linear differential transducer (LVDT) device that measures the linear travel of a platform carrying the indenter probe. The average travel distance of the probe was set at approximately 700 micrometers. The depth of contact of the indenter probe was measured by evaluating the surface of the cornea immediately after indentation and measuring the local height values caused by probe contact. This value was measured to vary from 266 to 300 micrometers. The residual impression caused by the indenter was observed to decrease as a function of time. A digital timer was used to mark the start and end times during the observation. Changes in printing were easily observed during this period. It was considered that the final end point was when the disturbance of the local optical strip was recovered by mixing it with the stripes neighboring optics without disturbing. There is a confirmed component of subjective evaluation error contained within these results. However, given the time scales involved, the value of this error is considered small.

• For example, it was observed that an eye treated with 5 hyaluronidase uses thirty (30) minutes or more to recover from indentation when compared to a normal eye that was observed to recover in two (2) minutes. This large difference in values makes the subjective nature of the observations tolerable. 10 The method to induce inflection of the cornea involves first contacting the test cornea with the indenter. After the initial contact with the cornea was established, the probe moved up into the cornea at a predetermined distance. 700 were used microns to achieve an adequate deflection. The topography was taken immediately after the deflection to record the impression made on the cornea. The observations of the cornea were then made with intervals of one (1) minute to note the change in the impression made. This proved to be quite valuable when noticing the elastic response of the cornea subsequent to the impression. Another topography was made after five (5) minutes to record the final condition of the impression. These measurements were taken to establish a baseline of elasticity and to determine the effect of different treatments of Enzymatic Orthokeratology on the elasticity of the cornea. The measurements taken indicate that the eyes injected with the hyaluronidase solution of the present • invention suffer a significant reduction in corneal elasticity 5 compared to baseline measurements. By comparing the time required for a cornea to recover from an impression made using the indentation probe, eyes treated with hyaluronidase take much longer to recover than the untreated eye. The untreated cornea normal recovers from printing within 1-3 minutes • while the eye treated with hyaluronidase takes 6-30 minutes or more to recover, depending on the age of the patient. These results indicate that the treatment of a cornea with a softening agent of the cornea such as hyaluronidase reduces the elasticity of the cornea. Conversely, treatment of a cornea with a corneal hardening agent results in an increase in the elasticity of the cornea. Using the method of the present test, the elasticity of the test eyes was measured before and after treatment with the glyceraldehyde solution of the present invention. After treatment with glyceraldehyde, the corneas became more elastic, as determined and the fastest recovery time of the indentation. The recovery curve changed with the continuous application of the solution in the form of drops over a period of two weeks. After approximately two weeks, patients treated with glyceraldehyde exhibited a recovery time of 20-30 • seconds. Interestingly, these patients showed little change in elasticity after this point but maintained the rapid recovery times observed. The results of this study indicate that the methods of the Enzymatic Orthokeratology of the present invention are effective in altering the rigidity or elasticity of the cornea. The results also show that the • application of the corneal hardening agent of the present invention induces corneal rigidity. EXAMPLE 8 THE SAFETY AND EFFICIENCY OF HYALURONIDASE AND LOCAL 3% GLYCERALDEHYDE SOLUTION IN THE TREATMENT OF MYOPIA IN A HUMAN PATIENT In this study, a single subject was selected to test the safety and efficiency of using hyaluronidase and • a glyceraldehyde solution to treat visual acuity sub-optimal. In this study, the subject was medically evaluated first and a baseline was established. A medical history of the subject was taken and an examination of the subject's eyes was also made. The subject's eyes were tested to determine: refraction, cell count, pressure Intraocular (IOP), pachymetry, topography of the cornea and elasticity of the cornea. A slit lamp examination was also performed to establish eye health. Also, the presence of any discomfort was noted • general or ocular of the subject. 5 After establishing a baseline reading (UVA 20/300), the subject was administered a simple intrastromal injection of 50 IU of hyaluronidase before the orthokeratological treatment. After 7 days of incubation of the subject's eyes with the injected material, The subject was fitted with corrective contact lenses for nighttime use. The subject used corrective lenses day and night for a period of seven (7) days. At this point, the visual acuity of the subject was 20/15. After 7 days of the use of corrective lenses (11/15/98); the subject began receiving an application of the local 3% glyceraldehyde solution in ophthalmic drops for four times a day (08:00, 12:00, 16:00, and 20:00) for 15 days, along with the use of the lens for the day for stabilization. After 15 days, the use of the lens and the drops discontinued. The visual acuity of the subject was then monitored for 196 days to determine the effect of the treatment on visual acuity without help from the subject. As is apparent from Table I, the visual acuity without the help of the subject retained its improved state considerably after the support lens was removed. In fact, the results of Table I clearly indicate that the combined administration of hyaluronidase and the glyceraldehyde solution of the present invention, together with • corneoplasty, were effective to correct the visual acuity without the patient's help for more than 6 months. These results clearly indicate the effectiveness of the methods of the present invention. Table I Corneoplasty Procedure 10 with • Patient No. CG08-OD Treatments with 50 I.U. • • • • • -46- Example 9 THE SAFETY AND EFFICIENCY OF HYALURONIDASE AND THE SOLUTION OF GLICERALDEH TO 3% LOCAL IN THE TREATMENT OF MODERATE MYOPIA IN HUMAN PATIENTS Given the favorable results obtained in the Example 8, an additional study was undertaken to test the innocuousness and efficiency of the method of the present invention using a larger group of subjects, in this study, a group of subjects were randomly selected and separated into three test groups to test the safety and efficiency of using hyaluronidase and a glyceraldehyde solution to treat subjects with sub-optimal visual acuity. Groups one and two received an intrastroma injection of hyaluronidase (50 and 500 IU, respectively), while three groups received a saline control injection. After an incubation period of two weeks after the injection, the three groups were equipped with corrective lenses to optimize the visual acuity of the subjects. The corrective lenses were left in place for a period of time sufficient to alter the configuration of the subject's eyes to achieve optimal visual acuity. This period of time was generally over two days. Once acceptable visual acuity was achieved, subjects in all three groups received a 3% localized glyceraldehyde solution in the form of ophthalmic drops four times a day while using corrective lenses. Treatment with glyceraldehyde was generally administered for one month. The use of the lens occurred from 8 to 12 hours during the day. At the end of the treatment period the use of the lens and the administration of the glyceraldehyde solution was terminated. The general health and visual acuity of the subjects were monitored 3 to 5 months after the end of treatment. The results of this study are reported later. Subject Criterion To participate in this study, a subject had to manifest myopia by requiring less than 4 diopters of correction and astigmatism requiring less than one diopter correction. In addition, the subjects had to be 18 years of age or older, and have the ability to give a consent report by reading and signing an Informed Consent Form that describes the present study and its attendant risks. The subjects also had to be willing to participate in all scheduled exams.

• Finally, the subjects, if they were female, had to be 5 post-menopausal, sterilized, using an effective form of birth control, or otherwise unable to have children. The male subjects were also acceptable. Subjects were excluded from the study if they were participating in another research study or were hypersensitive to study medication or reagents # study. Subjects with abnormalities of the cornea in motion that would prevent an accurate reading with an applanation tonometer or a tonopen and subjects with ongoing eye infection, inflammation or a history of corneal injuries herpetic patients who cleared within a month or less before the study, were also excluded. The subjects were allowed to take systemic medications that were considered necessary for the well-being of the subject and that did not interfere with the study. As well, systemic and / or local anti-inflammatories, antibiotics, and / or cycloplegics to treat or assess ocular conditions were for use at the discretion of the investigator. The use of such drugs by the subjects, if any, was reported to the study administrator. 25 Subjects who qualified for the study based on the criteria described above and who agreed to participate were randomized into one of three groups and then treated according to the protocols of the • individual groups. 5 First Group: 50 IU Hyaluronidase Injection, Corrective Lenses and 3% Gliceraldehyde Solution Before starting the experiment protocol, the test subjects were initially examined to establish a baseline from which the future ones would be compared. treatment results. For each subject, a • Medical history and a detailed examination of the eyes was also performed. The eyes of each subject were tested to determine: refraction, cell count, intraocular pressure (IOP), pachymetry, corneal topography and elasticity of the cornea. Slit lamp examination was also performed to establish eye health. Also, the presence of any general or ocular discomfort of the subject was noted. flv After establishing the reading of a baseline, to the subject of group I, a simple intrastromal injection of 50 IU of hyaluronidase was administered before the orthokeratology treatment. After 14 days of incubation, subjects with corrective contact lenses were adapted for overnight use. The subjects used the corrective lenses day and night for a period of two (2) to seven (7) days or until a visual acuity of 20/20 was achieved. Subjects who achieved acceptable visual acuity (approximately 20/20) received an application • of the local 3% glyceraldehyde solution in 5 ophthalmic drops four times a day (08:00, 12:00, 16:00, and 20:00) for a period of one month together with the use of glasses for the day for stabilization. The use of lenses lasted from 8 to 12 hours per day. The subjects were examined periodically during the glyceraldehyde treatment to monitor the changes in the health of treated eyes. All exams • described above were performed during each visit except the medical history, which did not require repetition, and the cell count, which was not performed again until the terminal period of the study. 15 At the end of the treatment period, the stabilizing lenses and administration of the 3% glyceraldehyde solution was terminated. After the termination of the treatment, the subjects were immediately examined • after the treatment is finished, once a week during the first four weeks after the term, and then monthly to measure the changes in visual acuity of the treated eyes. Eye health was also monitored. The sequela was characterized characterized by the appearance or worsening of serious ocular symptoms or slit lamp findings observed during these exams. The proportions of subjects with such findings were analyzed. The time course for the retention of • Visual acuity correction is shown in Table II. The baseline visual acuity of the subjects varied from a low of 20/63 in the eyes of a subject (OCS / 022R) to a high of 20/300. All group members achieved an acceptable level of correction for their visual acuity (20/20 in all subjects except ARR / 001: 20/25 and JLV / 015: 20/40).

These results show that all the subjects responded • initial orthokeratological treatment. During the course of the monitoring period, each subject maintained a degree of the initial correction in visual acuity when compared to the baseline. The Retention in correction was measured by orthokeratological treatment. The visual acuity measurements for the subjects are shown in Table II. Examining subjects in order of length of monitoring, ARR / 001 had a baseline measurement of 20/80 and was measured in 20/40 at 5 months following JCV / 002 had a base line of 20/300 and measured 20/125 in the following 4 months. At the point of the following three months, SRA / 007 had a visual acuity of 20/50, FAH / 009 had a visual acuity of 20/63, and JLV / 015 had a visual acuity of 20/25. Comparing these results with measurements of the baseline of these subjects of 20/200, 20/200 and 20/80, respectively, while the use of hyaluronidase, corrective lenses and the glyceraldehyde solution of the present invention act to correct • the visual acuity of these subjects. Similarly, when comparing visual acuity measurements for other subjects who have not yet completed the treatment protocol it shows that the methods of the present invention are effective in correcting the visual acuity of the test subjects. For example, at the point of two months, LMR / 028 had a visual acuity of 20/125, below • from a baseline of 20/300; GJM / 029 had a visual acuity of 20/40, below a baseline of 20/200; and ECF / 033 had a visual acuity of 20/125, an improvement over the baseline of 20/300. Subjects JRF / 010R and JL / 024R changed from 20/80 and 20/100 respectively, to 20/20 and 20/40 respectively. Only OCS / 022R failed to show an improvement over baseline measurement of 20/62 since this subject measured 20/80 in the following three weeks. However, given • the early state of the data collection of this individual, it is possible, and still possible in view of the results obtained for the other subjects, that the measurements for OCS / 022R will improve. The results shown in Table II indicate that glyceraldehyde treatment of a subject's eyes together with the injection of 50 IU of hyaluronidase is effective to facilitate the correction of the visual acuity of the subject. Group II: Injection of 500 IU of Hyaluronidase, Corrective Lenses and 3% Gliceraldehyde Solution • The subjects of group II were treated as those 5 of group I in preparation for their participation in the study reported here. Before beginning the protocol of the experiment, the test subjects were initially examined to establish a baseline from which the results of the treatment would be compared. ^^ 10 After establishing a baseline reading, group II subjects were fitted with contact lenses and wearing corrective lenses at night for a period of two (2) to seven (7) or until a Acceptable visual acuity (approximately 20/20). Group II of the test subjects received 500 IU of hyaluronidase per injection when compared to 50 IU of group I. Two groups of subjects received 500 IU of hyaluronidase. The results obtained from the first group are shown in Table ff III A and the results from the second group are shown in the Table III A and are identified in the table by the notation Gr. SAW. There were no significant differences in the treatment protocols between these two groups. Subjects who achieved acceptable visual acuity received the local 3% glyceraldehyde solution in the form of ophthalmic drops for 4 times a day (08:00, 12:00, 16:00, and 20:00) for a period of one month along with the use of lenses for the day for stabilization. During this period, the use of the lenses occurred for approximately 8-12 hours per day and • there was no night use of the lenses. 5 Subjects were periodically examined during glyceraldehyde treatment to monitor changes in the health of treated eyes. All the exams described above were performed during each visit except the medical history, which did not require repetition, and the cells, which was not performed again until the period »Study terminal. At the end of the treatment period, stabilizing lenses were removed, and administration of the 3% glyceraldehyde solution was terminated. After the At the end of the treatment, the subjects were examined immediately after the treatment ended, once a week for the first four weeks after the end, and then monthly to measure changes in the visual acuity of the treated eyes. The health of the eye also was monitored. The sequelae characterized by the appearance of worsening of serious ocular symptoms or slit lamp findings observed during these examinations was evaluated. The proportions of subjects with such findings were analyzed. 25 Visual acuity data for this group are shown in Tables IIIA and IIIB. The values of the table shown are the best values when compared between the results of the two methods. The visual acuity of the subject baseline f varied from 20/50 to 20/500 in Table 5 IIIA and 20/60 to 20/400 in Table IIIB. All the members of the group achieved an acceptable visual correction to their visual acuity that varies from 20 / 12.5 to 20/20 with the subject YAM / 013 measuring at 20/40 in Table IIIA and 20/15 to 20/25 with the subject LMR / 104 measuring at 20/50. 10 The visual acuity for each subject was monitored and f tabulated to observe the degree of correction maintained by the treated subject after the corrective lenses were removed. Generally, all subjects retained at least a portion of the improvement during the baseline-mediated for the orthokeratological treatment. At the fourth month point, subject ECS / 004 had a UVA of 20/50, a marked improvement over the baseline of the subject of 20/160. At the point of three months the subject PIQ / 008 had a UVA of 20/80 when compared with a baseline measurement 20/400; Subject YAM / 013 had a UVA of 20/40 when compared to a baseline measurement of 20/100; subject YOC / 017 had a UVA of 20/20 from a baseline of 20/50; subject FGM / 018 had a UVA of 20/25 when compared to a baseline of 20/80; the subject JPG / 019 had a UVA of 20/15 when compared to a baseline of 20/170; and subject OOS / 031 had a UVA of 20/50 when compared to a baseline of 20/200. The results of the two-month time point were similar to the results of three months. For example, subject FMP / 023 had a UVA at two months of 20/20 when compared to a baseline of 20/70; subject ERG / 026 had a UVA of 20/25 when compared to a UVA of 20/50 baseline and subject ELG / 030 had a UVA of 20/100 when compared to the baseline measurement of 20/300. • The results shown in Table IIIB also show the effectiveness of the treatment. At the two-month date, the subjects treated with 500 IU of hyaluronidase (Gr. VI) showed a marked improvement on the measurements of their baseline. For example, at the date of two months, the subject AVM / 102 had a UVA of 20/20, an improvement over the UVA baseline of 20/160; LLG / 103 had a UVA of 20/50 when compared to a UVA baseline of 20/160; the subject • IEV / 105 had a UVA of 20/80 when compared to a line base of 20/200; and subject GVC / 106 had a UVA of 20/63 when compared to a baseline of 20/160. At the one-month time point, subject NMD / 101 had a UVA of 20/60 when compared to the measurement of a baseline of 20/200; the subject LMR / 104 had a UVA of 20/80 when compared with measuring a baseline of 20/200; finally, subject NCS / 107 had a UVA of 20/20 when compared with the measurement of a baseline of 20/60. The results shown in Tables IIIA and IIIB indicate that a combination of hyaluronidase and glyceraldehyde treatment of the subject's eyes is effective in retaining the benefits of orthokeratology well after the subject has ceased to wear corrective lenses. Group III: Corrective Lenses and Treatment of 10% Gliceraldehyde Solution in the Absence of Hyaluronidase • According to groups I and II, the test subjects were initially examined to establish a baseline from which future results of the study would be compared. treatment. After the establishment of a reading of baseline, group III subjects were adapted with contact lenses and corrective lenses were used at night for a period of two (2) to seven (7) days or until acceptable visual acuity was achieved (approximately 20/20 ). TO ^ difference of groups I and II, the test subjects of the Group III in this group did not receive hyaluronidase injection during the course of treatment. Subjects who achieved acceptable visual acuity received the local 3% glyceraldehyde solution in the form of ophthalmic drops four times a day (08:00, 12:00, 16:00, and 20:00) for a period of one month along with the use of lenses for the day for stabilization. During this period, the use of the lenses occurred for approximately 8-12 hours per day and there was no nighttime use of the lenses. • The subjects were periodically examined during the 5 glyceraldehyde treatment to monitor changes in the health of the treated eyes. All the exams described above were performed during each visit except the medical history, which did not require repetition, and the cell count, which was not performed again until the period study terminal. # At the end of the treatment period, the stabilizing lenses were removed, and administration of the 3% glyceraldehyde solution was terminated. After the end of the treatment, the subjects were examined immediately after that the treatment ended, once a week for the first four weeks after the end, and then monthly to measure the changes in visual acuity of the treated eyes. The health of the eye was also monitored. HE • valued the sequel characterized by the appearance of worsening of serious ocular symptoms or slit lamp findings observed during these exams. The proportions of subjects with such findings were analyzed. The visual acuity data for this group are shown in Table IV. The values of visual acuity are samples obtained using the Snellen chart test and the protocol for the study of diabetic retinopathy for early treatment (ETDRS). The values of the table shown are the best values when compared between • the results of the two methods. The visual acuity of the subject's baseline line ranged from 20/80 to 20/300. All the members of the group achieved an acceptable correction in their visual acuity that varied from 20 / 12.5 to 20/20 and all but one subject. During the course of the next three or four months, each subject maintained a degree of initial correction # of visual acuity during the baseline mediated by the orthokeratological treatment. At the five-month time point, subject GVC / 006 had a UVA of 20/100 when compared to a UVA baseline of 20/200. Three subjects measured at the time point of the fourth month ESV / 005, JAM / 012, and MCS / 016, had UVA of 20/100, 20/100 and 20/80, respectively. The baseline for these subjects was 20/100, 20/200 and 20/300, respectively. The most important retained improvements at the time point in the following three months was in subjects SGS / 011, MCS / 016 and AJG / 014. SGS / 011 started the study with a baseline of 20/200 and showed a visual acuity of 20/40 at the point of the following three months. Subject MCS / 016 started the study with a visual acuity of 20/300 and was measured at the three month point in 20/60. He subject AJG / 014 had a baseline of 20/80 and was measured at the time point of three months at 20/50. Subjects ERR / 021 and ARP / 032 have only progressed through two months of the study. These subjects had UVA of 20/60 each at the two-month time point. Their respective baseline measurements were of /80 and 20/120. The results shown in Table IV indicate that glyceraldehyde treatment of a subject's eyes is effective in extending the retention time for accumulated benefits from an orthokeratology treatment course., even in the absence of hyaluronidase. Although this invention has been described in terms of certain embodiments, these embodiments are indicated for illustrative purposes and are not intended to limit the scope of the invention. It will be apparent to those skilled in the art that various other modifications can be made to these embodiments without departing from the scope of the invention, which is appropriately determined with reference to the following claims.

Claims (38)

1. CLAIMS 1. A method for correcting refractive errors in an eye of a mammalian subject eye characterized in that it comprises: selecting a pharmaceutically acceptable cornea hardening agent on the basis of being able to harden the cornea in the eye of the mammalian subject without causing damage to the cornea; administering to the eye of the mammalian subject a quantity of the cornea hardening agent so that the cornea can be reconfigured from a first configuration to a second desired configuration; adjusting the cornea with a rigid contact lens having a corrective curvature of the second desired configuration; allow to reconfigure the cornea in the second desired configuration under the influence of the lens; and removing the lens when the cornea is able to maintain the second desired configuration without the support of the lens.
2. 2. The method according to claim 1, characterized in that the refractive error is selected from the group consisting of myopia, hyperopia and astigmatism.
3. 3. The method according to claim 1, characterized in that the agent is a crosslinker.
4. 4. The method according to claim 3, characterized in that the crosslinker is an aldehyde.
5. The method according to claim 4, characterized in that the aldehyde is selected from the group consisting of acetaldehyde, glyceraldehyde, phenylacetaldehyde, valeraldehyde, 3,4-dihydroxyphenylacetaldehyde, mutarotational isomers of aldehydes, acid-ascorbic acid and dehydroascorbic acid.
6. 6. The method of compliance with the claim 1, characterized in that the agent is an enzyme.
7. 7. The method of compliance with the claim 6, characterized in that the enzyme mediates the crosslinking reactions.
8. 8. The method of compliance with the claim 7, characterized in that the enzyme is lysyl oxidase or prolyl oxidase.
9. The method according to claim 1, characterized in that the agent is administered by injection into the eye.
10. 10. The method according to claim 1, characterized in that the agent is administered by local administration into the eye in the form of eye drops.
11. 11. The method according to claim 1, characterized in that the agent is administered by means of a contact lens.
12. 12. The method in accordance with the claim ^ fß 1, further characterized in that it comprises the step of 5 administering to the eye a cornea softening amount of a pharmaceutically acceptable corneal softening agent sufficient to soften the cornea of the eye so that the cornea can be reconfigured.
13. 13. The method according to claim 10 12, characterized in that the cornea smoothing agent is an enzyme that degrades the proteoglycans in the cornea.
14. 14. The method according to claim 13, characterized in that the enzyme that degrades proteoglycan is hyaluronidase.
15. 15. A device for performing refractive correction in an eye of a mammalian subject, characterized in that it comprises: f a corneal hardening agent in unit dosage form; and a rigid corrective lens having a desired concave structure.
16. 16. A reaction mixture characterized in that it comprises: an eye of a mammalian subject; a corneal hardening agent in unit dosage form; and a rigid corrective lens that has a • desired concave structure.
17. 17. A method for rehabilitating the irregularity of the cornea and correcting the refractive error in an eye of a mammalian subject with an irregular cornea configuration characterized in that it comprises: identifying a subject with irregular corneal configuration; selecting a pharmaceutically acceptable corneal hardening agent on the basis of being able to harden the cornea in the eye of the mammalian subject without causing damage to the cornea; 15 administering to the eye of the mammalian subject a quantity of corneal hardening agent so that the cornea can be reconfigured from a first configuration to a second desired configuration; i * J adjust the cornea with a rigid contact lens 20 having a concave curvature of the second desired configuration; allow to reconfigure the cornea to the second desired configuration under the influence of the lens; and removing the lenses when the cornea is able to maintain the second desired configuration without the support of the lens.
18. 18. The method according to claim 17, characterized in that the subject is identified as # diagnose the subject when he has a condition 5 selected from the group consisting of keratoconus, cornea warping induced contact lens, contact lens intolerance, corneal ulcers, corneal fusion disorders, recurrent corneal erosions, terigo, and irregular corneal configuration or error of refraction 10 uncorrected due to corneal surgery.
19. 19. A method for improving the clinical success of eye surgery involving the manipulation of a cornea of a mammalian subject, characterized in that it comprises the steps of: identifying a subject who has undergone corneal manipulation; selecting a pharmaceutically acceptable cornea hardening agent on the basis of being able to • hardening the cornea in the eye of the mammalian subject without causing damage to the cornea; administering to the eye of the mammalian subject a quantity of the corneal hardening agent; adjust to the cornea with a rigid contact lens having a desired configuration; Allowing the cornea to harden within the desired configuration under the influence of the lens; and removing the lens when the cornea is able to maintain the second desired configuration without the support of the • lens. 5
20. 20. The method according to the claim 19, characterized in that corneal manipulation is selected from the group consisting of radial keratotomy, photorefractive keratectomy, LASIK, thermokeratoplasty, photothermalkeratoplasty, corneal transplant surgery, cataract surgery and reconfiguration of the cornea by laser. •
21. 21. Use of a pharmaceutically acceptable cornea hardening agent selected on the basis of being able to harden the cornea of an eye of a patient subject without causing damage to the cornea by manufacturing a cornea. 15 medicament for the treatment of refractive errors in the eye for administration to patients having a cornea to be reconfigured from a first configuration to a second desired configuration receiving concomitantly a rigid contact lens that 20 has a concave curvature of the second desired configuration.
22. 22. The use according to claim 21, characterized in that the refractive error is selected from the group consisting of myopia, hyperopia and astigmatism.
23. 23. The use according to claim 21, characterized in that the agent is a crosslinker.
24. 24. The use according to claim 23, characterized in that the crosslinker is an aldehyde.
25. 25. The use according to claim 24, characterized in that the aldehyde is selected from the group consisting of acetaldehyde, glyceraldehyde, phenylacetaldehyde, valeraldehyde, 3,4-dihydroxyphenylacetaldehyde, mutarotational isomers of aldehydes, ascorbic acid and dehydroascorbic acid.
26. 26. The use according to claim 21, • characterized in that the agent is an enzyme.
27. 27. The use according to claim 26, characterized in that the enzyme mediates the crosslinking reactions.
28. 28. The use according to claim 27, characterized in that the enzyme is lysyl oxidase or prolyl oxidase.
29. 29 The use according to claim 21, • characterized in that the agent is administered by injection into the eye.
30. 30. The use according to claim 21, characterized in that the agent is administered by local administration into the eye in the form of eye drops.
31. 31. The use according to claim 21, characterized in that the agent is administered by means of a contact lens.
32. 32. The use according to claim 21, • characterized further by comprising the use of an agent of 5 pharmaceutically acceptable cornea smoothing.
33. 33. The use according to claim 32, characterized in that the corneal softening agent is an enzyme that degrades the proteoglycans in the cornea.
34. 34. The use according to claim 33, characterized in that the enzyme that degrades proteoglycan • it is hyaluronidase.
35. 35. The use of a pharmaceutically acceptable cornea hardening agent selected on the basis of being able to harden the cornea of an eye of a patient subject 15 without causing damage to the cornea by the manufacture of a medicament for the treatment of corneal irregularity and refractive errors in the eye with irregular corneal configuration for administration to patients with • irregular cornea configuration and having a cornea 20 to be restructured from a first configuration to a second desired configuration that concomitantly receives a rigid contact lens having a concave curvature of the second desired configuration.
36. 36. The use according to claim 35, characterized in that the patient is identified upon diagnosing the patient when he has a condition selected from the group consisting of: keratoconus, cornea warping induced by contact lens, intolerance to • contact lens, corneal ulcers, corneal fusion disorders, recurrent corneal erosions, pterygium, and irregular corneal configuration or uncorrected refractive error due to corneal surgery.
37. 37. Use of a pharmaceutically acceptable cornea hardening agent selected on the basis of being 10 capable of hardening the cornea of an eye of a patient subject • Without causing damage to the cornea for the manufacture of a medically to improve the clinical success of surgery to the eye involving the manipulation of the cornea for administration to patients who have undergone manipulation 15 of cornea and having a cornea that is to be reconfigured from a first configuration to a second desired configuration by concomitantly receiving a rigid contact lens having a concave curvature of the • second desired configuration.
38. 38. The use according to claim 37, characterized in that the manipulation of the cornea is selected from the group consisting of radial keratotomy, photorefractive keratectomy, LASIK, thermokeratoplasty, photothermalkeratoplasty, corneal transplant surgery, 25 cataract surgery and reconfiguration of the cornea by laser.