EP1482922A1 - Agents for corneal or intrastromal administration to treat or prevent disorders of the eye - Google Patents
Agents for corneal or intrastromal administration to treat or prevent disorders of the eyeInfo
- Publication number
- EP1482922A1 EP1482922A1 EP03711552A EP03711552A EP1482922A1 EP 1482922 A1 EP1482922 A1 EP 1482922A1 EP 03711552 A EP03711552 A EP 03711552A EP 03711552 A EP03711552 A EP 03711552A EP 1482922 A1 EP1482922 A1 EP 1482922A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- urea
- corneal
- cornea
- eye
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates generally to pharmaceutical preparations and medical treatment methods, and more particularly agents (i e Urea, Urea derivatives, non-steroidal anti-inflammatory drugs and Anti-metabolite drugs) used alone or in combinations with each other (or with other agents) to treat or prevent certain disorders of the eye
- agents i e Urea, Urea derivatives, non-steroidal anti-inflammatory drugs and Anti-metabolite drugs
- the cornea is the first and most powerful refracting surface of the optical system of the eye Production of a sharp image at the retinal receptors requires that the cornea be transparent and of the appropriate refractive power
- the average corneal thickness of a normal cornea is 0 56 mm in persons under 25 years of age, this thickness slowly increases with age to become 0 57 in persons over 65 years of age
- the cornea is somewhat thicker in the periphery than the center
- the thickness of the cornea is greatest after the eyes have been closed for some time, as after sleeping, this thickness decreases slightly when the eyes are opened and exposed to the dehydrating effects of the air
- the cornea is composed of six layers a) Epithelium b) Basement membrane c) Bowman's membrane d) Stroma e) Descemet's membrane f) Endothe um a) Epithelium
- the epithelium consists of 5-6 layers of cells The most superficial cells are flat overlapping squamous cells The middle layer consists of cells that become more columnar as the deeper layers are approached The innermost layer (basal) is made up of columnar cells packed closely together All the cells are held together by a cement substance Also, the cell surfaces form processes that are fitted into corresponding indentations of adjacent cells and connected in places by attachment bodies called desmoso es The basal cells are connected to the basement membrane by hemidesmosomes The epithelium represents 10% of the total wet weight of the cornea Water in the epithelium represents 70% of the wet weight
- the epithelium consists of 5-6 layers of cells, the healthy epithelium is very strongly attached to each other by desmosomes as well as to the Basement membrane by hemidesmosomes b) Basement membrane: Between the columnar epithelial cells and Bowman's membrane is a basement membrane from 60 - 65 nm thick The basement membrane has been examined histochemically and found to be similar to other basement membranes c) Bowman's membrane: Bowman's layer is a sheet of transparent tissue about 12 ⁇ m thick, without structure as seen by light microscopy Under electron microscopy it appears to be made up of uniform fibrils, probably of collagenous material, running parallel to the surface Bowman's layer possesses little resistance to any pathologic process, and is easily destroyed and never regenerates d) Stroma: The Stroma comprises about 90% of the whole cornea The Stroma is composed of layers of lamellae, each of which runs the full length of the cornea, although the bundles interlace with one another, they are nearly parallel to the surface The cell bodies, called keratocytes
- the glucosammoglycans represent 4% to 4 5% of the dry weight of the cornea GAG are localized in the interfib ⁇ llar or interstitial space, probably attached to the collagen fibrils or to soluble proteins of the cornea
- the GAG plays a role in corneal hydration through interaction with electrolytes and water
- Three major GAG fractions are found in the corneal Stroma keratin sulfate (50%), chondroitin (25%), and chondroitin sulfate A (25%) GAG s have been implicated in the maintenance of the corneal hydration level and transparency e)
- Descemet's Membrane Is made of type IV collagen, unlike the corneal Stroma, there are no significant amounts of sulfated GAG in the Descemet's membrane The collagen in this membrane is insoluble except in strong alkali or acid and is more resistant to collagenase than corneal stroma collagen Jakus 2 has observed with the electron microscope that this membrane
- Descemet's membrane Its inner surface is bathed by the aqueous humor
- endothelium cell layer has limited, if any, reproductive capacity Aging causes cell loss, and the remaining cells enlarge and spread so that Descemet's membrane remains completely covered therefore endothelial cell density, expressed as cells per unit area, decreases with age Similarly, cell loss from trauma, inflammation, or surgery is compensated for by increased cell size and decreased cell density
- Corneal metabolism embraces a series of chemical processes by which energy is obtained and utilized for the normal functions of the cornea In the cornea, energy is needed for maintenance of its transparency and dehydration Energy in the form of ATP is generated by the breakdown of glucose into lactic acid and into carbon dioxide and water (i e , Krebs Cycle) The cornea obtains glucose mainly from the aqueous humor
- the tears and hmbal capillaries appear to contribute minimal amounts of glucose and Oxygen for corneal metabolism
- the oxygen consumption of the epithelium and endothehum can be approximately 26 times that of the stroma
- the corneal endothelium gets most of its required oxygen from the aqueous humor, while the corneal epithelium gets much of its oxygen from either the capillaries at the hmbus or from the oxygen dissolved in the pre-corneal film
- Radial keratotomy is a surgical procedure to improve myopia by changing the corneal curvature This is achieved by making several deep incisions in the cornea in a radial pattern
- the eye surgeon makes 4, 8, or 16 incisions so as to flatten the curvature of the central cornea, thus correcting the patient's vision
- the main drawbacks of RK include, a) It can only be used to correct low levels of myopia b) This surgical procedure cannot correct hyperopia c) RK procedure seriously weakens the cornea and creates corneal scars d)
- the corneal curvature changes are temporary and frequently continue to change with time
- Photorefractive keratectomy is a surgical procedure that uses the excimer laser, which is controlled by a computer With the PRK procedure, the excimer laser ablates and sculpts the corneal surface to the desired shape to correct the patient's vision
- PRK is a surgical procedure, it can result in complications Infection is the most serious complication resulting from the ablation of a large area of the corneal epithelium
- delayed corneal healing because of the absence of the corneal epithelium corneal haze, corneal scarring, over correction or under-correction and development of astigmatism are other complications of PRK These complications must be treated with medications or further surgery
- Laser in-situ keratomileusis 11 is a surgical procedure that is a variation on PRK involving an excimer laser and a precise cutting tool called a microkeratome
- the microkeratome is used to make a 150-175 micron circular flap of the cornea
- the circular flap is flipped back, as if on a hinge, to expose the stromal layer of the cornea With the flap folded back, the refractive eye surgeon now ablates the stroma and makes the refractive correction using the excimer laser
- the circular corneal flap is repositioned on the ablated cornea to complete the procedure With a precision laser treatment and normal reattachment and healing of the corneal flap the refractive results of good vision correction are very rapid There is, however, a significant list of potential complications and risks associated with LASIK procedure, failure of the microkeratome to leave a hinge on the corneal flap with the first incision, loss of the corneal flap after the operation, slipping of the flap and healing off center, first incision is too deep or
- Laser epithelial keratomileusis is a surgical procedure that is a variation on PRK involving an excimer laser that combines the advantages and eliminates the disadvantages of PRK and LASIK
- a 7 0 mm circular area of the epithelium is marked with a Hoffer trephine centered over the pupil
- the corneal epithelium is removed by using a blunt spatula, or is exposed to 20% isopropyl alcohol solution which allows the corneal epithelium to be peeled off
- the surgeon ablates and sculpts the corneal surface to the desired shape to correct the patient's vision
- the corneal epithelial flap created by the alcoholic solution is placed back onto the ablated cornea, a drop of antibiotic, a drop of non-steroidal anti-inflammatory agent and a therapeutic contact lens is applied to the corrected eye
- Orthokeratology is a non-surgical procedure designed to correct refractive errors by reshaping the cornea to the corneal curvature required to achieve emmetropia This is accomplished by applying a series of hard contact lenses that change the corneal curvature until the desired curvature is achieved However once the desired curvature has been produced, retainer hard contact lenses must be worn to stabilize the results otherwise regression will occur
- Enzyme Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia
- the system is enhanced by enzymatically softening the cornea, and reshaping is obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem
- Chemical Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia
- the system is enhanced by applying topically or by intra-stromal injection a chemical that is not an enzyme and softening the cornea, and reshaping is obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem SUMMARY OF THE INVENTION
- the present invention provides methods for treating or preventing disorders of the eye of a human or veterinary patient by administering topically onto the eye or by injection into the eye (e g intravitreal, intrastromal or sub-conjunctival injection) a therapeutically effective amount of an aqueous solution containing an agent selected from urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleo
- the agent may be administered in combination with an antimetabolite compound such as, mitomicyn, methotrexate, thiourea, hydroxyurea, 6-mercaptopur ⁇ ne, thioguanine, 5-fluorourac ⁇ l, cytosine arabinoside and 5-azacyt ⁇ d ⁇ ne
- an antimetabolite compound such as, mitomicyn, methotrexate, thiourea, hydroxyurea, 6-mercaptopur ⁇ ne, thioguanine, 5-fluorourac ⁇ l, cytosine arabinoside and 5-azacyt ⁇ d ⁇ ne
- the agent may be administered in combination with an antmeoplastic agent such as Actinomycin D, daunorubicin, doxorubicin, idarubicin, bleomycins, or phcamycin may also be used in combination with these anti-metabolites
- corneal epithelium As explained above, the corneal epithelial cells are held together by a cement substance In addition the surfaces of the cells form processes that are fitted into the corresponding indentations of the adjacent cells and connected by attachment bodies called desmosomes In addition the basal cells of the epithelium are connected to the basement membrane by hemidesmosomes When the corneal epithelium is damaged by chemical or physical means, swelling of the stroma follows Abrasion of the cornea or any condition leading to the loss of epithelium is likely to produce localized areas of corneal swelling and cloudiness and allows microbial access and bacterial infections Fortunately, the corneal epithelium regenerates rapidly, and the excessive hydration and wound closure in the absence of bacterial infections is slight and transient
- the present invention also provides methods for enhancing healing of the cornea after LASEK surgery
- an agent selected from urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme uradine, uracil, cysteme
- reduced thioctic acid uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, is applied top
- an agent of the present invention e g , 0 01 % - 20 0% aqueous urea solution
- a few drops of an agent of the present invention is placed onto the surface of the excimer laser ablated stroma before the microkeratome cut flap of the cornea is repositioned on the laser ablated cornea
- the urea solution placed at the interface of the two corneal flaps will result in the localized solubilization the stromal proteoglycans and eliminate the interface gap, thus producing optimum vision correction
- the localized solubilization of the proteoglycans of the stroma will result in the compression of the collagen fibril packing for better visual performance, but normal transparency
- the present invention also provides methods for softening the cornea by administering to the cornea an agent selected from urea, a urea derivative, nonenzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme, uradine, uracil cysteme) reduced thioctic acid, uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of
- the shape of the cornea is based on the collagen fibrils of the stroma which are held in place at a much specified distance from each other in parallel along with the mucopolysacchandes cement layers between these collagen fibrils
- the Urea and Urea derivatives have the ability of solubi zing the mucopolysacchandes as well as various proteins
- the stroma is therefore softened and becomes more pliable and easy to mold to a more desirable shape
- the cornea softening agent comprises urea or a urea derivative together with pharmaceutically acceptable carriers and additives
- the preparation may be supplied in a liquid or lyophilized form
- the cornea softening agent in accordance with the present invention is administered to the cornea in a number of ways Typically, the agent is administered either directly in the form of eye drops, or by the use of a corneal softening agent delivery vehicle, which may include special drug delivery systems including hposomes, sustained release gels and implantable solid dosage forms as well as contact lens and biodegradable corneal collagen shield Non-Surgical Treatment and Elimination of Corneal Haze and Corneal Opacification
- a reduction of visual acuity and blindness may result from a lack of corneal clarity caused by corneal traumas, corneal scars, or any other cause of corneal opacification
- Patients who have a reduction of visual acuity as a result of corneal opacities are estimated to be three million
- the current treatment for corneal opacity is corneal transplantation using a surgical procedure called penetrating lamellar keratoplasty (PKP), using human corneal donor tissue
- PGP penetrating lamellar keratoplasty
- This surgical technique is considered safe and effective, however one of the risks includes graft rejection as well as viral and bacterial infections transmitted through the donor corneal tissue
- the overall number of transplant surgical procedures that can be performed is limited by the availability of donor corneas for transplantation
- the present invention provides methods for improving corneal clarity ortreatmg corneal scars, corneal opacification, and optical aberrations including corneal haze by administering to the eye an agent selected from urea, a urea derivative, nonenzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme, uradine, uracil cysteme), reduced thioctic acid, uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, in an amount that is effective to accelerate the
- Hassell et al analyzed corneal specimens obtained during surgery from patients with macular corneal dystrophy
- Hassell et al found that cells from normal corneas synthesized both a chondroitin sulfate proteoglycan and a keratan sulfate proteoglycan similar to those present in monkey and bovine corneas
- Cells in macular corneal dystrophy synthesized a normal chondroitin sulfate proteoglycan, but did not synthesize either keratan sulfate or a mature keratan sulfate proteoglycan Instead, the cells synthesized a glycoprotein with an unusually large oligosaccharide side chain
- the transparency of the cornea may be altered in a manner more subtle than that seen in the corneal traumas described above
- the appearance of optical, monochromatic aberrations may decrease the visual acuity (VA) of a subject's eye
- VA visual acuity
- the visual acuity of the human eye could be 20/10 or better, however, such good acuity is rarely obtained
- Two optical conditions account for the sub-optimal level of visual acuity are diffraction due to pupil size and monochromatic aberrations
- the limitations of visual acuity caused by diffraction decreases with increasing pupil diameter and may play an important role only for pupils smaller than 2mm
- the optical errors of higher order (aberrations) of the human eye demonstrate an opposite behavior and may increase with larger pupil diameter
- Refractive surgery for myopia and astigmatism such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK)
- RK radial keratotomy
- PRK photorefractive keratectomy
- LASIK laser in situ keratomileusis
- the present invention provides a new chemical method for the elimination of corneal aberrations and corneal collagen fiber disorganization resulting from accidental traumatic injury to the cornea or from refractive surgery for myopia, hyperopia and astigmatism, such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK) so as to improve visual acuity and quality of vision
- RK radial keratotomy
- PRK photorefractive keratectomy
- LASIK laser in situ keratomileusis
- LASEK laser epithelial keratomileusis
- the present invention provides a new method for treating corneal ptengia by administering to the cornea an agent selected from urea, a urea derivative, nonenzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme, uradine, uracil, cysteme), reduced thioctic acid, uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, in an amount that is effective to inhibit expression of MMP-1 and MMP-3 by fibroblasts
- an agent selected from
- UV-B radiation appears to be an etiologic agent for ptengia and hmbal tumors
- Ptengia begin growing from hmbal epithelium and not conjunctival epithelium
- a segment of the mbal epithelium invades the cornea centnpetally followed by conjunctival epithelium
- a distinct type of corneal cells develops at the leading edge of the ptengia tissue
- Bowman's layer is dissolved under the leading edge of the ptengia
- Vascularization occurs in the conjunctiva adjacent to the ptengia
- Ptengia have a high recurrence rate
- Ptengia are tumors of altered hmbal basal cells that secrete TGF- ⁇ and produce various types of MMP's similar to other invasive tumors
- the tumor cell proteases degrade components of their basement membranes, which facilitate invasion
- the pterigium cells invade over the Bowman's layer producing elevated MMP-1 , MMP-2 and MMP-9 which contribute to the complete dissolution of Bowman's layer
- Local fibroblasts are activated by the TGF- ⁇ and bFGF cytokine pathways to help complete the dissolution of the Bowman's layer by MMP-1
- the present invention provides a new method for treating corneal ptengia by administering to the cornea an agent selected from urea, a urea derivative, nonenzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme, uradine, uracil, cysteme), reduced thioctic acid, uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing non enzymatic dissolution of the proteoglycans or any possible combination thereof, in an amount that is effective to inhibit neovascularization of the cornea
- an agent selected from urea,
- the cornea may be invaded by leucocytes and fibrocytes, the nutritive supply and metabolic reserves may become inadequate with the result that new vessels sprout from the hmbal plexus and grow into the stroma, thus resulting in corneal vascularization
- the nature of the stimulus to ingrowth of vessels has been associated with the loosening of the tissue associated with the injury and the resulting of corneal edema
- the primary factor of corneal new vascularization is associated with the buildup and release of pharmacologically active angiogenic compounds like VEGF and FGF that are responsible for the formation of new vessels so as to supply the needs of the cornea
- VEGF and FGF pharmacologically active angiogenic compounds like VEGF and FGF that are responsible for the formation of new vessels so as to supply the needs of the cornea
- the presence of new blood vessels in the cornea makes the cornea full of vessels and interferes with the visual acuity of the patient
- injuries in the posterior part of the eye and reduction of supply of oxygen to the retina and the optic nerve unleash
- the present invention provides methods fortreatmg glaucoma by administering topically onto the eye or by injection into the eye (e g mtravitreal, intrastromal or sub- conjunctival injection) a therapeutically effective amount of an aqueous solution containing an agent selected from urea, a urea derivative, non-enzymatic protein urea, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e g , adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidine, guanidinium chloride, guanidinium salts, thymidine, thymitadme, uradine, uracil, cysteme), reduced thioctic acid, uric acid, calcium acetyl sahcylate, ammonium sulfate or other compounds capable of causing
- the structure of the optic nerve head may play a role in the pathogenesis of glaucoma
- Two main theories exist for the mechanism of optic nerve damage in glaucoma the mechanical IOP related theory suggests that the pressure head acts directly on the lamina c ⁇ bosa The lamina c ⁇ bosa is not supported well superiorly and interiorly at the disk and it is here that the initial damage occurs to produce the characteristic arcuate defects Variations in the ganglion cell support at the disk may explain the variations between IOP susceptibilities of individuals with similar lOP's
- Second is the vascular mechanism theory, which posits that changes within the microcirculation of the disk capillaries are responsible for glaucomatous changes whether this is primarily vascular or secondary to IOP has not been elucidated
- the present invention provides urea containing solutions (e g , solutions which contain urea, a urea derivative (e g hydroxyurea) and /or mixtures thereof) that may be topically applied or are injected into the eye Additionally, some of the urea- containing topical or mjectable solutions of the present invention may further contain ant ⁇ metabohte(s) (e g mitomicyn C, methotrexate, 6-mercaptopurine, thioguanine, 5- fluorouracil, cytosine arabmoside and 5-azacyt ⁇ d ⁇ ne) Solutions of urea or hydroxyurea, which have been adjusted to a pH of approximately 4 0 to 8 0 are substantially non-toxic and well tolerated when administered topically, or by mtravitreal, intrastromal and conjunctival injection, one (1 ), two (2) or more times, in a volume of 15 to 200 microhters per application, at doses of 0 001 % to 4 0% and also
- Citrate, phosphate or other buffers may alternatively be used in the above-listed formulations of Examples of 1-7 Also, sodium chloride, dextrose or other alternative bulking agents could be used in these formulations
- Example 14 Urea USP/NF 001% -200% Polyethylene Glycol 010% -500% Sodium Chloride USP/NF 010% -090% Sterile Water for Injection USP QS 100% pH ofthe solution 40 - 80 (Adjust pH using 01 N HCI or 01 N NaOH)
- Example 16 Hydroxyurea USP/NF 40% Sodium Chloride USP/NF 010% -090% Sterile Water for Injection USP QS 100% pH of the solution 40 - 80
- Example 17 Hydroxyurea USP/NF 001% -150% Sodium Chloride USP/NF 010% -090% Sterile Water for Injection USP QS 100% pH ofthe solution 40 - 80
- Antimetabohte solutions that are usable in accordance with the present invention
- these antimetabohte soulitions may be combined with the aqueous solution of urea or other agent or the antimetabohte solution may be administered topically or injected separate from the aqueous solution of urea or other agent
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US36397902P | 2002-03-14 | 2002-03-14 | |
US363979P | 2002-03-14 | ||
PCT/US2003/007700 WO2003077898A1 (en) | 2002-03-14 | 2003-03-14 | Agents for corneal or intrastromal administration to treat or prevent disorders of the eye |
Publications (2)
Publication Number | Publication Date |
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EP1482922A1 true EP1482922A1 (en) | 2004-12-08 |
EP1482922A4 EP1482922A4 (en) | 2005-06-08 |
Family
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Application Number | Title | Priority Date | Filing Date |
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EP03711552A Withdrawn EP1482922A4 (en) | 2002-03-14 | 2003-03-14 | Agents for corneal or intrastromal administration to treat or prevent disorders of the eye |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1482922A4 (en) |
JP (1) | JP2005522464A (en) |
KR (1) | KR20040094793A (en) |
CN (1) | CN1642536A (en) |
AU (2) | AU2003213858A1 (en) |
BR (1) | BR0308403A (en) |
CA (1) | CA2478965A1 (en) |
MX (1) | MXPA04008776A (en) |
RU (1) | RU2363459C2 (en) |
WO (1) | WO2003077898A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030199574A1 (en) | 2000-03-02 | 2003-10-23 | Vitreo-Retinal Technologies, Inc. | Treatment of ophthalmic disorders using urea and urea derivatives |
CN101231121B (en) * | 2007-01-24 | 2012-06-13 | 泰州乐金电子冷机有限公司 | Pallet stretching-out device for refrigerator |
CN102859344A (en) * | 2010-03-12 | 2013-01-02 | 独立行政法人理化学研究所 | Clearing reagent for biological material, and use thereof |
US10444124B2 (en) | 2011-05-20 | 2019-10-15 | Riken | Clarifying reagent for biological materials and use thereof |
JP6433901B2 (en) | 2013-08-14 | 2018-12-05 | 国立研究開発法人理化学研究所 | Composition for preparing biological material with excellent light transmittance and use thereof |
DE102013110608A1 (en) * | 2013-09-26 | 2015-03-26 | Florian Lang | Substance for inhibiting tissue calcification, tissue fibrosis and age-associated diseases |
CN110237238A (en) * | 2019-08-02 | 2019-09-17 | 山东省眼科研究所 | MANF is promoting the application in corneal injury reparation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000051620A1 (en) * | 1999-03-02 | 2000-09-08 | Vitreo-Retinal Technologies, Inc. | Agents for intravitreal administration to treat or prevent disorders of the eye |
WO2003068166A2 (en) * | 2002-02-13 | 2003-08-21 | Vitreo-Retinal Technologies, Inc. | Treatment of ophthalmic disorders using urea and urea derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5470881A (en) * | 1993-09-09 | 1995-11-28 | West Virginia University Research Corporation | Urea ophthalmic ointment and solution |
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2003
- 2003-03-14 MX MXPA04008776A patent/MXPA04008776A/en not_active Application Discontinuation
- 2003-03-14 RU RU2004129761/14A patent/RU2363459C2/en not_active Application Discontinuation
- 2003-03-14 CA CA002478965A patent/CA2478965A1/en not_active Abandoned
- 2003-03-14 KR KR10-2004-7014329A patent/KR20040094793A/en not_active Application Discontinuation
- 2003-03-14 JP JP2003575951A patent/JP2005522464A/en active Pending
- 2003-03-14 CN CNA038059681A patent/CN1642536A/en active Pending
- 2003-03-14 WO PCT/US2003/007700 patent/WO2003077898A1/en active Application Filing
- 2003-03-14 BR BR0308403-5A patent/BR0308403A/en not_active Application Discontinuation
- 2003-03-14 EP EP03711552A patent/EP1482922A4/en not_active Withdrawn
- 2003-03-14 AU AU2003213858A patent/AU2003213858A1/en not_active Abandoned
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2009
- 2009-05-13 AU AU2009201897A patent/AU2009201897B2/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000051620A1 (en) * | 1999-03-02 | 2000-09-08 | Vitreo-Retinal Technologies, Inc. | Agents for intravitreal administration to treat or prevent disorders of the eye |
WO2003068166A2 (en) * | 2002-02-13 | 2003-08-21 | Vitreo-Retinal Technologies, Inc. | Treatment of ophthalmic disorders using urea and urea derivatives |
Non-Patent Citations (1)
Title |
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See also references of WO03077898A1 * |
Also Published As
Publication number | Publication date |
---|---|
BR0308403A (en) | 2005-01-18 |
CN1642536A (en) | 2005-07-20 |
WO2003077898A1 (en) | 2003-09-25 |
MXPA04008776A (en) | 2005-04-19 |
CA2478965A1 (en) | 2003-09-25 |
RU2004129761A (en) | 2005-06-10 |
AU2003213858A1 (en) | 2003-09-29 |
JP2005522464A (en) | 2005-07-28 |
KR20040094793A (en) | 2004-11-10 |
EP1482922A4 (en) | 2005-06-08 |
RU2363459C2 (en) | 2009-08-10 |
AU2009201897A1 (en) | 2009-06-04 |
AU2009201897B2 (en) | 2011-09-15 |
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