RU2363459C2 - Agents for application into eye cornea or stroma for treatment of prevention of ophthalmological disorders - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: present group of inventions relates to medicine, more specifically to ophthalmology and treatment of pathological processes in the cornea. For this purpose pharmaceutical compositions are locally used, containing one active component in form of urea or urea derivative, and a second active component in form of a compound, chosen from a group consisting of citric acid, dibasic potassium phosphate, isopropyl alcohol, sorbite, propylene glycol, polyethyleneglycol, block-polymer polyatomic alcohol and antimetabolites, in sufficient quantities with pH between 4.0 and 8.0. ^ EFFECT: softening of the cornea during surgery-substitute refractive vision correction, as well as increased clarity of the cornea due to readjustment of collagen. ^ 26 ex, 20 cl

Description

Cross references to related applications

This application claims the priority of provisional application US No. 60/363979, filed March 14, 2003, incorporated herein by reference. This application is also a partial continuation of the simultaneously pending US application with serial number 10/215680 "Means for introducing into the vitreous body for the treatment or prevention of ophthalmic disorders", filed August 9, 2002 and is a continuation of the US application with serial number 09/517798 filed March 2, 2000. The latter is currently US Pat. No. 6,462,071 B1.

The scope of the present invention

The present invention relates mainly to pharmaceutical preparations and therapeutic treatments used to treat or prevent certain ophthalmic disorders; in particular, it relates to agents (for example, urea, urea derivatives, non-steroidal anti-inflammatory drugs and antimetabolic drugs) used for these purposes individually or in combination with each other (or with other agents).

BACKGROUND OF THE INVENTION

Previous applications of urea in ophthalmology

US Pat. Nos. 5,629,344 (Charlton) and 5,470,881 (Charlton) describe some therapeutic uses of urea preparations. These patents describe specific non-aqueous ointments and other non-aqueous preparations of urea used for the eyes; it is noted that these aqueous solutions of urea, apparently, are unsuitable for ophthalmic use. For example, these patents state the following: “One of the reasons why urea was not used to treat ophthalmic disorders is that it will be hydrolyzed in an aqueous carrier, forming ammonia as a by-product. "Ammonia is a substance toxic to the eyes, and therefore urea in an aqueous solution is unsuitable as an ophthalmic drug." Thus, previously (prior to the present invention of the applicant), aqueous solutions of urea and urea derivatives were considered unstable as well as potentially toxic to the eyes.

Anatomical and physical properties of the cornea

The cornea is the first and most powerful reflective surface of the optical system of the eye. To obtain a clear image of the retina receptors, it is necessary that the cornea is transparent and possesses the necessary refractive power. In persons younger than 25 years, the average thickness of a healthy cornea is 0.56 mm, with age, the thickness of the cornea increases slightly, and in people over 65 this value reaches 0.57 mm. On the periphery, the thickness of the cornea is slightly larger than in the center. The thickness of the cornea is of the highest importance if the eyes have been closed for some time (for example, after sleep); when the eyes open and are exposed to the dehydrating effect of air, the thickness slowly decreases.

The cornea consists of 6 layers: a) anterior epithelium; b) the basement membrane; c) bowman membrane; d) stroma; e) descemet membrane; e) endothelium.

a) The anterior epithelium contains 5-6 layers of cells. The cells located on the surface are flat and overlap with scaly cells. The middle layer consists of cells, which become more columnar with increasing depth. The layer located at the very depth (the basal layer) consists of columnar cells tightly adjacent to each other. All of these cells are held together with a binder. In addition, cell surfaces form processes that enter the corresponding grooves of neighboring cells and are connected locally by attachment to bodies called the desmosome (adhesion spot). Basal cells are connected to the basement membrane using hemidesmosomes. In the wet state, the epithelium is 10% of the total weight of the cornea, and the water content in it is 70% of the total weight in the wet state.

Despite the fact that the epithelium contains 5-6 layers of cells, in a healthy epithelium, attachment to each of these layers is very strong, it is carried out using desmosomes (just as adhesion to the basement membrane is carried out using hemidesmos).

b) The basal membrane is located between the columnar cells of the epithelium and the Bowman membrane, the thickness of the basement membrane is 60-65 nm. Histochemical examination of the basement membrane of the eye showed its identity with other basement membranes.

c) Bowman's membrane. The Bowman's membrane is a layer of transparent fabric, whose approximate thickness is 12 microns; on an optical microscope, its structure is not detected. An electron microscope shows that this membrane consists of homogeneous fibrils (apparently fibrils of a collagen-like substance) located parallel to the surface. The Bowman membrane has poor resistance to any pathological process, it is easily destroyed and is never regenerated.

d) Stroma is approximately 90% of the cornea. The stroma consists of layers of plates (lamella), each of which occupies the entire length of the cornea; despite the fact that their bundles are interlaced with each other, they are almost parallel to the surface. Cell bodies, called keratocytes, are flattened, and therefore they also lie parallel to the surface, and their cell processes intertwine with each other. This structure of these fibers makes the cornea optically homogeneous. Stroma accounts for approximately 90% of the cornea. The stroma forms a differentiated connective tissue containing 70-80% water (based on weight in the wet state). The remaining 20-25% solids are collagen and other proteins, and the main part is glucosaminoglycans or mucopolysaccharides. Collagen fibers are clearly ordered, usually they are distributed with a period of 64-66 nm and are separated from each other by the base material. The size, regularity, and precise positioning of these fibrillar structures in space are those physical characteristics that are essential for the transparency of the cornea.

Glucosaminoglycans (GAG, mucopolysaccharides) make up 4-4.5% of the cornea weight in the dry state. GAGs are located in the interfiber or interstitial space; they are probably attached to collagen fibers or to soluble proteins of the cornea. By interacting with electrolytes and water, GAG plays a significant role in corneal hydration. Three main fractions were found in the stroma of the cornea: keratin sulfate (50%), chondrotin (25%) and chondrotisulfate A (25%). It is understood that the level of hydration of the cornea and its transparency is supported by glucosaminoglycans.

e) Descemet's membrane is constructed from type IV collagen; unlike the corneal stroma, Descemet's membrane does not contain significant amounts of glucosaminoglycan sulfates. The collagen of this membrane is insoluble (with the exception of strong bases or acids) and it is more resistant to collagenase than collagen stroma. Using a Jakus electron microscope, it was found that the collagen of this shell has a structure with greater regularity. Descemet's membrane has high elasticity and it represents a barrier to perforation of deep corneal ulcers.

f) The endothelium is a layer of cells lining the Descemet's membrane. The inner surface of the endothelium is washed by aqueous humor. The endothelial layer in humans has limited reproductive capacity. Aging causes cell loss, and the remaining cells grow and spread in such a way that they completely cover the Descemet's membrane. Consequently, with a person's age, the density of endothelial cells, expressed as the number of cells per unit area, decreases. Similarly, cell loss due to trauma, inflammation, or surgery is compensated for by an increase in cell size and a decrease in cell density.

Corneal metabolism includes a number of chemical processes by which energy is acquired and used for the normal functioning of the cornea. In the cornea, energy is required to maintain the transparency of the cornea and for its dehydration. Energy in the form of adenosine triphosphate (ATP) is produced by the breakdown of glucose into lactic acid, carbon dioxide and water (Krebs cycle). The cornea receives glucose mainly in the form of aqueous humor. It turned out that in the processes of corneal metabolism, minimal amounts of glucose and oxygen give tears.

Most of the oxygen consumed by the cornea is supplied by the epithelium and endothelium. Oxygen consumption by epithelium and endothelium can be 25 times higher than in the case of stroma. The corneal endothelium receives the largest part of the necessary oxygen from aqueous humor, while the corneal epithelium receives a greater amount of oxygen either from the capillaries of the limbs or from oxygen dissolved in the precorneal film.

Methods of refractive vision correction

Radial keratectomy (RK) is a surgical technique for reducing myopia by changing the curvature of the cornea. This is achieved by the fact that several deep notches are made in the cornea in the radial direction. In order to reduce the curvature of the central part of the cornea, the ophthalmologist makes 4, 8 or 16 incisions, thereby correcting the patient's vision. The main disadvantages of radial keratectomy are the following: a) this method can only be used to correct low myopia; b) such a surgery cannot correct hyperopia; c) this operation seriously weakens the cornea and creates scars on it; d) the change in the curvature of the cornea is temporary and often over time, such changes continue.

Photorefractive keratectomy (PRK) is a surgical technique that uses a computer controlled excimer laser. According to this technique, the surface of the cornea is excised using an excimer laser and, in order to adjust the patient’s vision, give it the desired shape. With some combination of lasers and a computer control unit, myopia, farsightedness and astigmatism can be reliably cured. Since photorefractive keratectomy is a surgical technique, it can cause a number of complications. The most serious complication is an infection caused by excision of a large area of the corneal epithelium. In addition, the complications of this method is that the healing of the cornea is delayed due to the lack of corneal epithelium, there is also darkening and scarring of the cornea, excessive or insufficient vision correction, and the development of astigmatism. These complications require medical or additional surgical treatment.

In-situ Laser Keratomiliasis (LASIK) is a surgical procedure that is a variant of photorefractive keratectomy and uses an excimer laser, as well as an accurate cutting tool called microkeratome. The specified microkeratome is used in order to obtain a circular flap of the cornea with a size of 150-175 microns. This circular flap is folded back (as if it were on a hinge) so that the stroma layer of the cornea is exposed. When this flap is turned away, the surgeon-ophthalmologist with the help of an excimer laser excises the stroma and carries out refractive correction. To complete the procedure, an annular corneal flap is returned to the excised cornea. Thanks to precise laser processing, normal reattachment of the corneal flap and its healing, good vision correction is achieved very quickly. However, a significant list of potential complications and risks is associated with the LASIC technique, namely: the inability to leave the hinge on the corneal flap during the first cut with keratoma; loss of a corneal flap after surgery; slipping the flap and healing away from the center; too large or insufficient depth of the first notch; germination of the corneal epithelium in the stroma; corneal infections; corneal ectasia; loss of visual acuity due to scarring and optical distortion of the collagen structures of the stroma.

Laser epithelial keratomiliasis (LASEK) is a surgical procedure that is a variant of photorefractive keratectomy and uses an excimer laser; this procedure combines the advantages of photorefractive keratectomy and the LASIK method, but lacks their disadvantages. A 7.0 mm circular site of epithelium is labeled with a Hoffer trepan centered over the pupil. The corneal epithelium is removed using a blunt spatula, or exposing it to a 20% solution of isopropyl alcohol, which allows you to exfoliate this epithelium. An excimer laser excites the corneal surgeon and gives it the desired shape in order to adjust the patient’s vision. At the end of the procedure, a corneal epithelium flap formed with an alcohol solution is again returned to the excised cornea, and a drop of antibiotic, a drop of non-steroidal anti-inflammatory agent are applied to the corrected eye and a therapeutic contact lens is put on. The defect in the epithelium that arose during curettage of the corneal epithelium or during its exfoliation after application of an alcohol solution is completely delayed for several days. Thanks to accurate laser processing, normal reattachment and healing of the corneal flap, good vision correction is achieved very quickly. However, using the LASEK technique, some potential complications and risks are associated, namely: corneal infections caused by an epithelial defect as a result of curettage; the use of an alcoholic solution causes severe damage to the exfoliated corneal epithelium, while minimizing the gains gained by reapplying the corneal epithelium.

Another method for re-forming the cornea is thermokeratoplasty. According to this method, in order to cause scarring of the cornea without destroying it, heat is supplied to the collagen fibers of this tissue in the range from 55 to 58 ° C. Corrugation of collagen fibers leads to a change in the mechanical properties of the cornea and its flattening, while refractive correction is achieved. US Pat. No. 4,881,543 discloses the use of microwave electromagnetic energy to shrink corneal collagen. US Pat. No. 5,779,696 describes the use of light energy to change the shape of the cornea. All these systems of thermokeratoplasty have the disadvantage that after such treatment the cornea becomes unstable.

Orthokeratology is a non-surgical technique designed to correct refractive errors by re-forming the cornea; this is done to give the cornea such curvature that is necessary to achieve emmetropia. The technique is implemented by applying a series of solid contact lenses that change the curvature of the cornea until the desired curvature is achieved. However, upon reaching the desired curvature, in order to stabilize the results obtained, a holder of solid contact lenses should be worn, otherwise a regression will occur.

Enzyme orthokeratology is related to traditional orthokeratology in that it is mainly characterized as a technique for correcting refractive errors of the eye by re-forming the cornea; Using contact lenses, the cornea gives the curvature necessary for emmetropia. This method is improved due to enzymatic softening of the cornea, re-formation of the cornea occurs in a shorter time; after removing contact lenses from the eye, the lens holder may not be necessary, and regression will not be a problem.

Chemical orthokeratology is related to traditional orthokeratology in that it is characterized mainly as a technique for correcting refractive errors of the eye by re-forming the cornea; Using contact lenses, the cornea gives the curvature necessary for emmetropia. This method is improved by topical application of a chemical compound that is not an enzyme and softens the cornea, or by injection of this compound into the stroma; re-formation of the cornea takes place in a shorter time, and after removing contact lenses from the eye in the lens holder may not be necessary, and regression will not be a problem.

Summary of the present invention

The present invention provides methods for treating or preventing ophthalmic disorders in humans or animals by topical application to the eye or by injection into the eye (by injection into the vitreous body, into the stroma or under the conjunctiva) of a therapeutically effective amount of an aqueous solution containing an agent selected from the group consisting of : urea, derivatives of urea, non-enzyme proteins of urea, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g. adenine, adenosine, cytosis yin, cytadine, guanine, guanitadine, guanidine, guanidine chloride, guanidine salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds; this agent can cause non-enzymatic dissolution of proteoglycans or their possible combinations. Other therapeutic purposes for which the use of this method is possible are: removal of the corneal epithelium; dissolution of proteoglycans of the cornea; closing the interface and healing of corneal stroma during refractive correction using the LASIK method; dissolution of proteins and amino acids to compress collagen fibers in order to increase visual acuity and better quality of vision; softening of the cornea before the use of contact lenses or in the process of their use; or re-formation of the cornea for the purpose of non-surgical refractive correction of myopia, presbyopia, hyperopia, astigmatism and staphyloma of the cornea; dissolving newly synthesized proteoglycans, thereby reducing or eliminating corneal darkening and / or corneal opacity; dissolution of anterior chamber proteoglycans, enhancing fluid outflow (which can reduce intraocular pressure in some glaucoma patients), causing fibroblast dissolution, inhibiting fibroblasts, inhibiting or inhibiting corneal fibrosis and scarring, inhibiting fibroblast proliferation in the eye tissue, inhibiting the activity of vascular endothelial growth factor (VEGF) in the cornea and iris by antiangiogenic effects, therefore, eliminating both the growth of new vessels of the cornea and iris, and their return of the previous state. According to one or more of the indicated therapeutic effects and / or other mechanisms of action (which need to be clarified), the method of the present invention can be used to treat various ophthalmic disorders. Used in the present patent description, the term "treatment" should not be limited only to the treatment of existing diseases or disorders, it should also mean the prevention of the disease, the retention of its development, termination, cure or delay the development of such disorders. Ophthalmic disorders that can be treated by the method of the present invention include (but are not limited to): impaired refraction, weakened visual acuity or decreased quality of vision, scarring, corneal clouding, pterygium, corneal neovascularization, iris neovascularization, and glaucoma.

Further, in accordance with the present invention, a specific agent can be administered together with antimetabolites such as mitomycin, methotrexate, thiourea, hydroxyurea, 6-mercaptopurine, thioguanine, 5-fluorouracil, cytosine, arabinose and 5-azacytidine.

In addition, in accordance with the present invention, a particular agent can be administered together with antitumor agents such as actinomycin D, daunorubicin, doxorubicin, idarubicin, bleomycin or plicamycin; they can also be used in combination with these antimetabolites.

Other objectives and advantages of the present invention will become apparent to those skilled in the art who will become familiar with and understand the following detailed description of the present invention and its specific examples.

Detailed description of the present invention

The following detailed description and related examples are provided only to characterize specific embodiments or examples of the present invention, and should in no way be considered as limiting the scope of the present invention.

Corneal Epithelium Removal

One example application of the method of the present invention is its use to remove corneal epithelium. As explained above, corneal epithelial cells are held together with a binder. In addition, cell surfaces form processes that enter the corresponding grooves of neighboring cells and are connected locally by attachment to bodies called a desmosome. In addition, basal epithelial cells are connected to the basement membrane with the help of hemidesmosomes. As a result of chemical or physical damage to the corneal epithelium, stroma swells. Corneal scars or any other condition leading to epithelial loss, apparently, can create localized areas of swelling and clouding of the cornea, which allows access of bacteria and bacterial infections. Fortunately, the corneal epithelium regenerates quickly, and in the absence of a bacterial infection, excessive hydration and healing of wounds is easy and fast.

Carrying out mechanical or chemical de-epithelialization while maintaining the epithelium intact and without damage is not an easy task. Currently, several methods are used for this, but all these methods and materials cause serious damage to the corneal epithelium.

Mechanical de-epithelialization is usually performed with local anesthesia using a local anesthetic, using a blunt spatula. The process is carried out after the plot of the epithelium is labeled with a 7.0 mm Hoffer trepan, centered over the pupil. Repeated epithelization of the resulting corneal wound usually takes several days. During this period, any open corneal incision or wound is susceptible to microbial contamination and infection.

Chemical de-epithelialization with alcohol is also usually performed under local anesthesia using a local anesthetic. A mark is made on the epithelium, and a gently pressed 7.0 mm trephine of Hoffer makes a circular incision centered over the pupil. When the trepan is in this place, 5-10 drops of 20% isopropyl alcohol are injected into it, and left in contact with the epithelium for several minutes. The alcohol solution is removed with a dry sponge, and the trepan is removed from the cornea. Through the use of a blunt spatula, the epithelium remains intact in a single piece. This technique is a simple way to corneal epithelialization, however, 50-70% of epithelial cells are damaged due to exposure to alcohol. In addition, a 20% alcohol solution causes severe burning and inflammation of the eyes. The corneal wound formed after surgery is covered by a single epithelial site removed with alcohol. This wound is temporarily closed by the corneal epithelium, its repeated epithelization should take several days. During this period, a protracted corneal wound is less susceptible to microbial contamination and infection.

In accordance with the present invention, there is provided a new method for chemically removing corneal epithelium using an agent selected from the group consisting of: urea, urea derivatives, urea nonenzyme protein, nonenzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g. adenine, adenosine, cytosine , cytadine, guanine, guanitadine, guanidine, guanidine chloride, guanidine salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds that are capable of causing nonenzymatic dissolution of proteoglycans or their possible combinations. This method can be carried out with local anesthesia with a local anesthetic. First, the epithelium is marked, and by gently pressing a 7.0 mm Hoffer trepan, a circular incision is made, centered over the pupil. When the trepan is in this place, 5-10 drops of a certain agent (for example, 0.01% -20% aqueous solution of urea) are introduced into it and left in contact with the epithelium for several minutes. The indicated agent (for example, an aqueous solution of urea) is removed with a dry sponge, and the trepan is removed from the cornea. Through the use of a blunt spatula, the epithelium remains intact. This technique is a simple way to corneal epithelialization, as a result of which the epithelial cells are not damaged. A corneal wound formed after surgery is covered with a whole piece of epithelium removed with urea. This wound is temporarily closed by the corneal epithelium, its repeated epithelization should take 1-2 days. During this period, a protracted corneal wound is less susceptible to microbial contamination and infection. Such chemical corneal epithelialization using the agent of the present invention (for example, a urea solution) can be useful as an adjunct in ophthalmic surgery for the treatment of herpetic epithelial keratitis, as well as for refractive vision correction using laser epithelial keratomileusis (LESEK).

Improved closure of the corneal interface and the formation of healing of corneal stroma with LASIK refractive correction

The present invention also provides methods for improving corneal healing after surgery using the LASEK method. According to this method, an agent selected from the group consisting of: urea, urea derivatives, non-enzyme urea proteins, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidino, guanidino, guanidino, guanidino salts of guanidine, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds that can cause non-enzymatic dissolution of proteoglycans or their possible combinations lations applied locally on the cornea after LASIK. For example, on the surface of the stroma excised by an excimer laser, a few drops of the product (for example, 0.01% -20% aqueous solution of urea) can be applied before the cut cornea of its epithelium is repositioned on this cornea. A urea solution placed at the interface between the corneal and stromal epithelium should lead to local solubility of the corneal proteoglycans and compress collagen fibril accumulations for better visual performance, but the transparency will be standard.

Successful completion of laser refractive correction (in-situ keratomileusis, LASIK) provides an accurate incision of the cornea, excision of the stroma by the excimer laser, and reposition of the resulting circular flap on the excised cornea. Normal reattachment and healing of the corneal flap are very important parameters for implementing good vision correction and fast healing. If the stroma excised by the excimer laser undergoes subcutaneous placement of a circular corneal flap cut by a microkeratome, then a gap is created at the interface between the upper and lower parts of the stroma. This gap prevents optimal vision correction, in addition, this gap will never close completely in the form of a single stroma; this shows that complete healing of the corneal wound is absent.

According to the present invention, improved closure of the corneal interface and the formation of healing of the corneal stroma during refractive correction according to LASIK technology is as follows. On the surface of the stroma excised by an excimer laser, a few drops of the agent of the present invention are applied (for example, a 0.01% -20% aqueous solution of urea) before the keratoma cut off epithelial flap is repositioned on this cornea. A urea solution placed on the interface between two epithelial flaps should lead to local solubility of the corneal proteoglycans and eliminate the interface gap, which will create optimal vision correction. In addition, the local solubility of stromal proteoglycans should lead to compression of the collagen fibril accumulation for better visual performance, but the transparency will be standard.

Softening the stroma of the cornea when applied topically or when used inside the stroma for the non-surgical refractive correction of myopia, presbyopia, hyperopia, astigmatism and staphyloma of the cornea

The present invention also provides methods for softening the stroma of the cornea by introducing into the cornea an agent selected from the group consisting of: urea, urea derivatives, non-enzyme urea proteins, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g., adenine, adenosine, cytosine, cytadine , guanine, guanitadine, guanidine, guanidine chloride, salts of guanidine, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds Nia, which are capable of causing non-enzymatic dissolution of the proteoglycans or their possible combinations. The amount of this agent is effective in order to cause temporary softening of the cornea, which can allow changing its shape from the first configuration to the target second configuration, which gives the eye a proportionate refraction (emmetropia). Said corneal softening can occur while the patient is wearing hard contact lenses that have a concave shape of a targeted second configuration that provides eye emmetropia. After that, under the action of the lenses, the cornea can take the form of a target second configuration. Since the softening of the cornea is the result of localized dissolution of proteoglycans, and not the chemical decomposition of proteoglycan molecules, it is possible that in the presence of hard cast lenses or their absence, the softening effect of this agent on the cornea will weaken much faster.

The corneal form is based on collagen stromal fibrils, which are held in parallel at a very specific distance from each other, and between these collagen fibrils there are bonding layers of mucopolysaccharides. Urea and its derivatives have the ability to dissolve mucopolysaccharides and other proteins. Therefore, the stroma softens, becomes more plastic, it is easier to give it the most desirable shape.

In one preferred embodiment, the corneal softening agent comprises urea or a derivative thereof, as well as pharmaceutically acceptable carriers and additives. Such a preparation may be applied in liquid or lyophilized form. According to the present invention, a corneal softening agent is introduced into the cornea in various ways. Typically, this agent is administered either directly in the form of eye drops, or the corneal softening agent is delivered using excipients, which may include drug delivery systems using liposomes, delayed release gels, implantable solid dosage forms, as well as contact lenses and masks , biodegradable collagen of the cornea.

Non-surgical treatment and removal of darkening and clouding of the cornea

Reduced visual acuity and blindness can occur as a result of insufficient transparency of the cornea caused by injuries of the cornea, scars on the cornea, or any other reason for its clouding. According to estimates, the number of patients whose visual acuity decreased as a result of corneal clouding is 3 million. Currently, a method for treating corneal clouding is transplantation of the cornea using a surgical technique called penetrating laminar keratoplasty (RRC); this technique uses corneal tissue from a human donor. The indicated surgical technique is considered safe and effective, however, one of the risks associated with it is graft rejection, as well as viral or bacterial infections transmitted through the corneal donor tissue. The total number of surgical transplants that can be performed is limited by the presence of a donor cornea.

The present invention provides methods for increasing the transparency of the cornea or treating corneal scars, corneal opacities, and optical aberrations (including darkening the cornea) by administering to the eye an agent selected from the group consisting of: urea, urea derivatives, nonenzymatic urea proteins, nonenzyme proteins, nucleosides, nucleotides, and derivatives thereof (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidine chloride, guanidine salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced ty okaprilic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds. This agent is administered in an amount that can cause the non-enzymatic dissolution of proteoglycans or their possible combinations, mucopolysaccharides or various other proteins and lead to the reorganization of corneal collagen. Such a reorganization should eliminate scars on the cornea, darkening of the cornea and its clouding. For example, the indicated agent (for example, an aqueous solution of urea or a urea derivative) can be administered locally or by injection in an amount that, due to chemical modification or dissolution of the corneal stroma glycoproteins and proteoglycans, will reduce the disorganization of corneal collagen.

The role of corneal glycoproteins and proteoglycans in creating and maintaining corneal transparency is not well understood. There is a hypothesis that stromal proteoglycans play a role in regulating the spatial arrangement of collagen fibers. Although the exact role of proteoglycans is still unclear, they are believed to influence the hydration, thickness and transparency of the cornea. The functional significance for the corneal hyaluronate is still unknown (with the exception of the formation of the cornea and some of its abnormalities).

It has been found that some opaque scars of the human cornea include collagen fibrils with an abnormally large diameter and an irregular distance between the fibrils. However, when wounds were healed on the rabbit’s cornea, opaque scars containing fibrils with a normal diameter, randomly distributed within this tissue, were revealed. After wound healing within a year, the diameter of collagen fibrils did not change significantly, however, the distance between the fibrils returned to normal, and at the same time, a decrease in the opacity of this scar was observed.

In 1983, by Hassell et al. it was shown that opaque scars with large distances between fibrils also contained unusually large proteoglycans of chondroitin sulfate with normal size glucosaminoglycan side chains. There was a lack of proteoglycan keratan sulfate in these opaque scars, but contained hyaluronic acid. A biochemical analysis of proteoglycans from wound scars on the rabbit cornea and from a healthy cornea bordering the scar showed that these zones synthesize significantly different proteoglycans.

Hassell et al. examined corneal samples obtained during surgery from patients with spotted corneal dystrophy. These researchers found that normal corneal cells synthesizing both proteoglycan chondroitin sulfate and keratansulfate proteoglycan are similar to cells present in the cornea of a monkey and a bull. With spotty dystrophy of the cornea, cells synthesize normal proteoglycan of chondroitin sulfate, but they do not synthesize either keratan sulfate or mature proteoglycan of keratan sulfate. Instead, these cells synthesize a glycoprotein, the side chain of which consists of abnormally large oligosaccharides.

Corneal transparency can change in a more subtle way than with the corneal injuries described above. In some cases, the visual acuity (VA) of a subject can be reduced by the appearance of optical monochromatic aberrations. Due to the mosaic structure of the retina, the visual acuity of a person can be 20/10 or even higher; however, such high visual acuity is rarely achieved. The superoptimal level of visual acuity is determined by two optical factors: diffraction caused by the size of the pupil, as well as monochromatic aberration. Limitations of visual acuity caused by a decrease in diffraction with an increase in pupil diameter can play a significant role only with a pupil size of less than 2 mm. However, optical errors of a human eye of a higher order (aberrations) demonstrate the opposite pattern, and these errors can increase with increasing pupil size.

Naturally, the shape of the human cornea and the shape of the lenses are designed so that these aberrations are minimized. As far as we know, to date, monochromatic aberrations of the human eye have not been systematically studied in large groups of subjects. Therefore, we do not have averaged data for a standard population. However, due to the emergence of surgical correction of refraction, loss of visual acuity due to optical aberrations may become clinically relevant.

Refractive surgery for cases of myopia and astigmatism such as radial keratectomy (RK), photorefractive keratectomy (PRK) and in-situ laser keratomileusis (LASIK) creates a non-physiological corneal shape with a flat central part, and an increase in optical power occurs towards the periphery. This form increases optical aberration and can lead to loss of vision; this is detected in low light and in a test for visual acuity with low contrast. These side effects of corneal refractive surgery are potential national health problems.

The wavefront distortions after photorefractive keratectomy (PRK) and in-situ laser keratomileusis (LASIK) were compared; the comparison was performed by random sampling in 22 patients with bilateral myopia, photorefractive keratectomy was performed on one eye, and in-situ laser keratomileusis (LASIK) was performed on the other. Before the surgery, the palillary area was expanded from 3 mm to 7 mm, which caused a 5-6-fold increase in total distortion. After surgery, the same expansion caused a 25-32-fold increase in overall distortion in the group receiving PRK, and 28-46-fold in the group receiving LASIK. Both photorefractive keratecotomy and in-situ laser keratomileusis significantly increased the total distortion of the wavefront, and within 12 months after these operations, these distortions did not return to their preoperative values.

In order to evaluate the healing of wounds and corneas in rabbits after LASIK, the healing process was monitored for 1, 2, and 9 months after this operation. Periodic histological examination of the cornea of rabbits revealed a disorganization of collagen fibers along the interface of the corneal flap even 9 months after LASIK. These results suggest that corneal distortions and the corneal wound healing process induced by the LASIC method continued 9 months after this operation. The methods and compositions disclosed herein of the present invention provide means by which side effects of optical aberration as a result of modern refractive surgical techniques are overcome.

Not limited to any specific mechanism of action, a theoretical assumption was made that various corneal distortions as a result of RK, PRK, LASIC, LASEK and other surgical techniques arise due to the disorganization that occurs during healing processes. For example, after the LASIK procedure and choosing the location of the flap at which the surgical site is closed, the corneal collagen will be formed in such a way as to close the resulting incision. If such collagen has formed, then it is believed that its conformation is less organized compared to collagen located in corneal areas not subjected to surgical intervention. The reorganization of this substance should lead to a reduction in optical distortion resulting from these interventions.

Therefore, the present invention provides a new chemical method for eliminating corneal distortions and disorganizing corneal collagen fibers as a result of accidental traumatic injuries of the cornea or as a result of surgical procedures using radial keratectomy (RK), photorefractive keratectomy (PRK), in-situ laser keratomileusis (LASIC) and laser epithelial keratomileusis (LASEK) performed to improve visual acuity and visual quality.

Non-surgical treatment of pterygia

The present invention provides a new method of treating corneal pterygium by introducing into the cornea an agent selected from the group consisting of: urea, urea derivatives, non-enzyme proteins of urea, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g. adenine, adenosine, cytosine, cytadine , guanine, guanitadine, guanidine, guanidine chloride, salts of guanidine, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds Which are capable of causing non-enzymatic dissolution of the proteoglycans or their possible combinations. The specified tool is administered in an amount that is effective to suppress the expression of fibroblasts MMP-1 and MMP-3. For example, to stop or slow down the expression of MMP-1 and MMP-3 fibroblasts within the cornea, a therapeutically effective amount of an aqueous solution of urea or a urea derivative can be introduced into the corneal pterygium. Urea and its derivatives have the ability to deactivate the enzymatic activity isolated by expression of MMP. It was also found and described that urea and urea derivatives, due to their ability to dissolve proteins, must change the secondary and tertiary structure of proteins, thereby inactivating them. The solubility of proteins obtained as a result of the action of urea and urea derivatives should make the corneal pterygium transparent, stop the dissolution of the Bowman membrane, stop the neovascularization of the cornea and return it to its original state.

The clinical and pathological characteristics of primary and return pterygium were determined. These include the following:

a) ultraviolet radiation (UV-B), as it turned out, is etiological for pterygium;

b) pterygium begins its growth from the epithelium;

c) a segment of the epithelium penetrates the cornea afferently, following the conjunctival epithelium;

d) a special type of corneal cells develops at the leading edge of the pterygium tissue wing;

e) under the leading edge of the wing, the pterygium dissolves the Bowman membrane;

e) in the conjunctiva bordering pterygium, vascularization occurs;

g) the recurrence rate of pterygium is high.

As in most normal resting tissues, the expression of MMP conjunctival-limbal-corneal tissue occurs in very small quantities, which are almost not detected by immunohistochemical methods. However, it was later shown that altered basal pterygium epithelial cells secrete 6 different types of MMPs that are similar to other invasive tumors. It is assumed that these MMPs are apparently the promoters of the corneal invasion of such a tumor and contribute to the dissolution of the bowman membrane. It is known that an increase in the expression of both MMP-2 and MMP-9 dissolves the components of the basement membrane (such as hemidesmosomes), leading to the migration and invasion of tumor cells. In addition, 4 different groups of fibroblasts were identified in pterygia. These fibroblasts express mainly MMP-1 and some MMP-3.

Pterygium is a tumor of altered basal cells that secrete tumor growth factor (TGF-β) and produce various types of MMPs, similar to other invasive tumors. Proteases of tumor cells destroy the components of their basement membranes, which accelerates invasion. Pterygium cells penetrate the Bowman membrane, producing more MMP-1, MMP-2 and MMP-9, which contribute to the complete dissolution of the Bowman membrane. Thanks to tumor growth factor (TGF-β) and cytokines of fibroblast growth factor (bFGF), local fibroblasts are activated, which contributes to the complete dissolution of the Bowman membrane using MMP-1.

Treatment of neovascularization of the cornea and iris

The present invention provides a new method of treating corneal pterygium by introducing into the cornea an agent selected from the group consisting of: urea, urea derivatives, non-enzyme proteins of urea, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g. adenine, adenosine, cytosine, cytadine , guanai, guanitadine, guanidine, guanidine chloride, guanidine salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thiocaprylic acid, uric acid, calcium acetylsalicylate, ammonium sulfate or other compounds Which are capable of causing non-enzymatic dissolution of the proteoglycans or their possible combinations. The specified tool is administered in an amount that is effective to suppress neovascularization of the cornea and / or iris.

With metabolic stress or damage-related stress, the cornea can be “attacked” by white blood cells and fibrocytes, the intake of nutrients and metabolic reserve can become inadequate, and this will lead to new vessels sprouting into the stroma, causing neovascularization of the cornea. The nature of the phenomenon that blood vessels tend to grow inward is associated with the loss of tissue in combination with its damage, and this causes corneal edema. However, the initial factor of new corneal vascularization is associated with the accumulation and release of pharmacologically active angiogenic compounds such as growth factors TGF-β and bFGF, which are responsible for the formation of new vessels that would satisfy the needs of the cornea. The presence of new blood vessels in the cornea makes it filled with blood vessels and interferes with the visual acuity of the patient. Similarly, with damage to the posterior chamber of the eye and a decrease in oxygen supply to the retina and optic nerve, the accumulation of angiogenic vascular endothelial growth factor (VEGF) in the vitreous becomes free. The result of this is the formation of new vessels in the iris, which causes hemorrhage and blindness.

Glaucoma Treatment

The present invention provides methods for treating glaucoma by topical application to the eye or by injection into the eye (by injection into the vitreous body, into the stroma or under the conjunctiva) of a therapeutically effective amount of an aqueous solution containing an agent selected from the group consisting of: urea, urea derivatives, non-enzymatic urea proteins, non-enzyme proteins, nucleosides, nucleotides, as well as their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidine chloride, sol guanidine, thymidine, timitadin, uradin, uracil, cysteine), recovered tiokaprilovuyu acid, uric acid, calcium acetyl salicylate, ammonium sulfate or other compounds; this agent can cause non-enzymatic dissolution of proteoglycans or their possible combinations.

The structure of the optic head is an important sign of glaucoma and its development; it can play a role in the pathogenesis of glaucoma. There are two theories of the mechanism of damage to the optic nerve in glaucoma. The first, mechanical, theory of intraocular pressure suggests that the optic nerve head exerts direct pressure on the membrane (lamina cribosa). The specified membrane is unreliably supported above and below the optic nerve head, and it is here that initial damage occurs, causing characteristic arcuate defects. Changes in the support of ganglion cells near this disk can explain the different perceptions of intraocular pressure by subjects with the same value. The second theory is the theory of the vascular mechanism of glaucoma; it postulates that changes in microcirculation in the capillaries of the disk are responsible for glaucomatous changes, but it does not explain whether such a change with respect to intraocular pressure is primary or secondary.

The present invention provides solutions containing urea (e.g., solutions that contain urea, urea derivatives (e.g., hydroxyurea) and / or mixtures thereof) that can be applied topically to the eye or injected into the eye. In addition, antimetabolites (such as mitomycin, methotrexate, thiourea, hydroxyurea, 6-mercaptopurine, thioguanine, 5-fluorouracil, cytosine, arabinose and 5-azide) may also be included in some of the urea-containing solutions that are administered topically or by injection according to the present invention. .

Solutions of urea or hydroxyurea, the pH of which is adjusted to a value of approximately 4-8, are largely non-toxic, they are well tolerated by local administration or by injection into the vitreous body, into the stroma and conjunctival; single and double dosing is used, while the injected single volume is 15-200 μl, and the doses are 0.001% -4.0% urea (doses of 0.001% -20.0% are also possible).

Examples of stable aqueous urea formulations

The following are examples of solutions that contain urea and are suitable in accordance with the present invention.

Example 1

Urea USP / NF 0.001% -4.0% Sodium Chloride USP / NF 0.1% -0.9% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 2

Urea USP / NF 0.001% -4.0% Citric Acid USP / NF 0.00007% -0.02% Sodium Chloride USP / NF 0.1-0.9% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 3

Urea USP / NF 0.001% -4.0% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 4

Urea USP / NF 0.01% -20.0% Sodium Chloride USP / NF 0.1% -0.9% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 5

Urea USP / NF 0.01% -20.0% Citric Acid USP / NF 0.00007% -0.02% Sodium Chloride USP / NF 0.1-0.9% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 6

Urea USP / NF 4.0% Potassium Dihydroorthophosphate USP / NF 5.0 mmol Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 7

Urea USP / NF 4.0% Potassium Dihydroorthophosphate USP / NF 50.0 mmol Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 8 (lyophilized powder)

Urea USP / NF 0.01% -20.0% Sorbitol USP / NF 0.10-0.50% Citric Acid USP / NF 0.00007-0.02% Sodium Chloride USP / NF 0.1-0.9% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 9

Urea USP / NF 4.0% Sorbitol USP / NF 0.10% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

An alternative use of nitrate, phosphate or other buffers is also possible in the above formulations of Examples 1-7. The use of sodium chloride, dextrose or other alternative excipients is also possible in these formulations.

Examples of aqueous urea solutions containing alcohols and block copolymer polyols

Example 10

Urea USP / NF 0.01% -20.0% Isopropyl alcohol (90%) 0.5% -20.0% Sodium Chloride USP / NF 0.1% -0.9% Citric Acid USP / NF 0.00007-0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 11

Urea USP / NF 0.01% -20.0% Isopropyl alcohol (90%) 0.5% -20.0% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 12

Urea USP / NF 0.01% -20.0% Isopropyl alcohol (90%) 0.5% -20.0% Polyethylene glycol 0.10% -50.0% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 13

Urea USP / NF 0.01% -20.0% Propylene glycol 0.10% -50.0% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 14

Urea USP / NF 0.01% -20.0% Polyethylene glycol 0.10% -50.0% Sodium Chloride USP / NF 0.10% -0.90% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Examples of aqueous hydroxyurea solutions

The following are examples of compositions containing hydroxyurea, which are suitable for use in accordance with the present invention.

Example 15

Hydroxyurea USP / NF 4.0% Sodium Chloride USP / NF 0.10% -0.90% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 16

Hydroxyurea USP / NF 4.0% Sodium Chloride USP / NF 0.10% -0.90% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 17

Hydroxyurea USP / NF 0.01% -15.0% Sodium Chloride USP / NF 0.10% -0.90% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 18

Hydroxyurea USP / NF 4.0% Potassium Dihydroorthophosphate USP / NF 5.0-50.0 mmol Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 19

Hydroxyurea USP / NF 4.0% Sorbitol USP / NF 0.10% -0.50% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Examples of aqueous antimetabolite formulations

The following are examples of formulations of antimetabolite solutions that are suitable for use in accordance with the present invention. In ophthalmic treatment of a patient with a combination of antimetabolite and urea or another agent of the present invention, said antimetabolite solutions can be combined with aqueous solutions of urea or other agent; or an antimetabolite solution can be used topically or administered separately from an aqueous solution of urea or other agents.

Example 20

Hydroxyurea USP / NF 0.01% -15.0% Sodium Chloride USP / NF 0.10% -0.90% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 21

Mitomycin c 100 mcg - 200 mcg Sodium Chloride USP / NF 0.10% -0.90% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N Hcl or 0.1 NaOH)

Example 22

Thiourea USP / NF 0.010% -10.0% Sodium Chloride USP / NF 0.10% -0.90% Citric Acid USP / NF 0.00007% -0.02% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N HC1 or 0.1 NaOH)

Example 23

Thiourea USP / NF 0.010% -10.0% Sterile Water for Injection USP Q.S. one hundred% solution pH 4.0-8.0 (the pH of the solution is regulated by 0.1 N HC1 or 0.1 NaOH)

Example 24

Topical application of urea solutions in laser surgery

goal

Determine whether the use of local solutions of urea can loosen the corneal epithelium so that it can be scraped off in one direction and undergo laser surgery, and then put the epithelium in place after laser surgery, thus avoiding the problems associated with the healing of corneal epithelium.

Materials

Solutions: a) a sterile isotonic saline solution containing 0.9% sodium chloride,

b) a 2% urea solution containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection,

c) 10% urea solution containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection,

d) 20% urea solution containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection.

Local anesthetic

16 people who underwent laser surgery to correct vision.

Ways

Scraping off the corneal epithelium in humans is a time-consuming and difficult task if you do not have the means to facilitate the separation process.

16 people were equally divided into 4 groups of 4 people each. Patients were scheduled for laser surgery to correct vision. A few drops of local anesthetic were locally injected into the patients, and 15-30 minutes after the administration of the anesthetic, the eyes of each patient were exposed for 3-5 minutes a) sterile saline solution for injection, b) 2% urea solution, c) 10% - urea solution or d) 20% urea solution.

The corneal epithelium of the eyes exposed to various solutions was scraped off with a spatula to achieve separation of the epithelium from the cornea below it.

results

Group A: When using isotonic saline, separating the corneal epithelium was difficult.

Group B: The use of a 2% urea solution made the process of scraping the corneal epithelium much easier than using isotonic saline.

Group B: Using a 10% urea solution made the process of scraping the corneal epithelium much easier than using a 2% urea saline solution.

Group D: Using a 20% urea solution made the process of scraping the corneal epithelium much easier than using a 10% urea saline solution.

findings

This study clearly showed that urea solutions made the process of scraping the corneal epithelium much easier than using isotonic saline. In addition, increasing the urea content from 2% to 20% made the scraping process very easy.

Thus, the effect of urea solutions on the corneal epithelium makes the separation of the corneal epithelium from the underlying tissue easy to achieve, and this procedure is a valuable tool in laser surgery.

Example 25

Conjunctival bleeding in humans

goal

Determine whether the use of local solutions of urea can eliminate conjunctival bleeding in humans.

Materials

Solutions: a) a sterile isotonic saline solution containing 0.9% sodium chloride,

b) a 5% solution of urea containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection,

c) 20% urea solution containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection,

12 people who had conjunctival bleeding were included in this study.

Ways

Conjunctival bleeding is common in humans, but it takes time to eliminate it, and if you ignore it, it will take a week or more.

12 people were equally divided into 3 groups of 4 people each. Patients had conjunctival bleeding in the eyes and did not have the means to eliminate the bloody appearance of the eye.

Patients in group A were given vials with sterile saline. Patients in group B were given a 5% urea solution, and patients in group B were given a 20% urea solution and were instructed to instill the solutions in the eye 3-4 times a day.

After periods of time at 24 hours, patients came to determine if the conjunctival bleeding had stopped and there were signs of disappearance of the bleeding.

results

Group A: When using isotonic saline, the changes were very weak and not very noticeable.

Group B: When using a 5% urea solution, the changes were very noticeable, and within 3-4 days conjunctival bleeding resolved, and the eyes looked normal.

Group B: When using a 20% urea solution, the changes were very noticeable, and within 3-4 days conjunctival bleeding resolved, and the eyes looked normal.

With regard to the rate of resorption of bleeding, a large difference was observed between isotonic saline and urea solutions. But between 5% and 20% urea solutions, no large differences were observed.

findings

This study clearly showed that urea solutions eliminated conjunctival bleeding in the human eye - it resolved and disappeared.

Example 26

Corneal Epithelial Healing

goal

Determine if local urea solutions can heal the corneal epithelium faster than under normal conditions.

Materials

Solutions: a) a sterile isotonic saline solution containing 0.9% sodium chloride,

b) a 5% solution of urea containing 0.9% sodium chloride, 0.007% citric acid and sterilized water for injection,

c) 5% urea solution containing 0.9% sodium chloride, 0.007% citric acid, 0.2% hyaluronic acid and sterilized water for injection.

In the experiments used 15 rabbits.

Ways

The healing of corneal epithelium after eye damage is very important to ensure the correct type of healing and, in addition to closing the wound, it is extremely important for stopping the infection of the wound with bacterial infections.

15 rabbits were equally divided into 3 groups of 5 rabbits in each. A few drops of local anesthetic were instilled into the rabbits' eyes and, using a sterile scalpel blade, an incision was made in the corneal epithelium to double the wound of the epithelium.

Immediately after performing the incisions, drops of A) sterile isotonic saline were instilled into the eyes of rabbits of the first group and repeated 4 times a day for several days, 5% urea solution was instilled into the eyes of rabbits of the second group and repeated 4 times a day for several days, a 5% solution of urea with hyaluronic acid was instilled into the eyes of rabbits of the third group and this was repeated 4 times a day for several days.

After 24 hours, the rabbits were examined to determine the healing level of the corneal epithelium and to determine whether any of the solutions accelerated healing compared to each other.

results

Group A: When using isotonic saline, the changes were very weak, and the healing of the corneal epithelium did not complete earlier than 3-4 days after the incisions were made.

Group B: When using a 5% urea solution, the changes were more noticeable, and within 2 days there were clear signs of healing of the corneal epithelium.

Group B: When using a 5% solution of urea with hyaluronic acid, the changes were very noticeable, and in this case there were clear signs of healing of the corneal epithelium within 2 days.

A large difference was noted between isotonic saline and urea solutions in relation to the healing rate of corneal epithelium. However, large differences between a 5% solution of urea and a 5% solution of urea with hyaluronic acid were not observed.

findings

The study clearly showed that urea solutions contributed to faster healing of the corneal epithelium than isotonic saline.

Claims (20)

1. A pharmaceutical composition for topical application in the eye for softening the cornea or for treating disorders in the cornea, comprising a combination of:
A) a first component containing urea or a urea derivative; and
B) the second component selected from the group comprising: citric acid, potassium phosphate dibasic, isopropyl alcohol, sorbitol, propylene glycol, polyethylene glycol, block polymer polyhydric alcohol and antimetabolites;
moreover, this composition has a pH in the range from 4.0 to 8.0. 2. The pharmaceutical composition according to claim 1, characterized in that the first component is urea or a urea derivative and the second component is citric acid. 3. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.001-4.0% Citric acid 0.00007-0.02% Sodium chloride 0.1-0.9% Sterile water for injection up to 100% 4. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.001-4.0% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 5. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Citric acid 0.00007-0.02% Sodium chloride 0.1-0.9% Sterile water for injection up to 100% 6. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 4.0% Potassium Dihydroorthophosphate 5.0 mmol Sterile water for injection up to 100% 7. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 4.0% Potassium Dihydroorthophosphate 50.0 mmol Sterile water for injection up to 100% 8. The pharmaceutical composition according to claim 1, characterized in that it contains a lyophilized composition prepared from a solution having a pH from 4.0 to 8.0 and containing:
Urea 0.01-20.0% Sorbitol 0.10-0.50% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 9. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Isopropyl alcohol (90%) 0.5-20.0% Sodium chloride 0.1-0.9% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 10. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Isopropyl alcohol (90%) 0.5-20.0% Sterile water for injection up to 100% 11. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Isopropyl alcohol (90%) 0.5-20.0% Propylene glycol 0.10-50.0% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 12. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Propylene glycol 0.10-50.0% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 13. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Urea 0.01-20.0% Polyethylene glycol 0.10-50.0% Sodium chloride 0.10-0.90% Sterile water for injection up to 100% 14. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Hydroxyurea 4.0% Sodium chloride 0.10-0.90% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 15. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Hydroxyurea 4.0% Potassium Dihydroorthophosphate 5.0-50.0 mmol Sterile water for injection up to 100% 16. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Hydroxyurea 4.0% Sorbitol 0.10-0.50% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 17. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Hydroxyurea 0.01-15.0% Sodium chloride 0.10-0.90% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 18. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Mitomycin c 100-200 mcg Sodium chloride 0.10-0.90% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 19. The pharmaceutical composition according to claim 1, characterized in that it has a pH from 4.0 to 8.0 and contains:
Thiourea 0.010-10.0% Sodium chloride 0.10-0.90% Citric acid 0.00007-0.02% Sterile water for injection up to 100% 20. A method of treating an ophthalmic disorder in a patient, comprising topical application to the eye of a pharmaceutical composition according to any one of claims 1-19.