Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-10-10
2004-05-18
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S434000, C424S078040, C424S094620, C424S094630, C424S094640
Reexamination Certificate
active
06737075
ABSTRACT:
FIELD OF THE INVENTION
The invention disclosed herein relates to biochemical methods for the elimination of corneal scars, opacification and haze.
BACKGROUND OF THE INVENTION
The cornea is the transparent dome on the front of the eye through which light passes. About eighty percent of the focus, or refracting, power of the eye is in the cornea. 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.
The global prevalence of eyes with severe corneal opacities is estimated at more than three million, with over 200,000 new cases being added to this pool every year. The current treatment for corneal opacity associated with significant visual impairment is a form of corneal transplantation, called penetrating or lamellar keratoplasty (PKP, LKP), using tissue from corneal donors. While this surgical technique is generally regarded as safe and effective, associated risks include graft failure or rejection, and infections transmitted through the donor cornea (e.g., rabies, HIV, etc.) or the surgical procedure (e.g., HIV, staph infections, etc.) Notwithstanding the various side-effects, the number of corneal transplant surgeries that can be performed is limited by the number of corneas available for transplantation. To date, the availability of donor corneal tissue suitable for transplant has failed to meet the needs of the patient population.
Present methods of correcting refractive errors of the eye, such as eye glasses, contact lenses, radial keratotomy, photorefractive keratotomy or laser in-situ keratomileusis are not useful in the elimination of corneal opacification. Preliminary evidence suggests that radial keratotomy, photorefractive keratotomy, and laser in-situ keratomileusis may cause corneal haze in some patients.
What is needed to treat the loss of corneal transparency is a biochemical, non-surgical method of treatment that produces a cornea with increase transparency. The methods and compositions taught herein satisfy this long-felt need.
SUMMARY OF THE INVENTION
The invention disclosed herein relates to biochemical methods for the elimination of corneal collagen fiber disorganization to improve vision. Disorganization of corneal collagen fibers is seen in corneal scars, corneal opacification and corneal haze. In addition, the invention relates to biochemical methods for the elimination of corneal collagen fiber disorganization resulting from accidental traumatic injury to the cornea or from refractive surgery for such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK) so as to improve visual acuity and quality of vision.
DETAILED OF DESCRIPTION OF THE INVENTION
The invention disclosed herein relates to improving corneal clarity using non-surgical, biochemical compositions and methods. The biochemical methods for eliminating corneal scars, corneal opacification, and optical aberrations including corneal haze in the eye of a subject mammal without corneal surgery are achieved by treating the source of the corneal distortion. The compositions and methods of the disclosed invention relate to reducing corneal collagen disorganization by biochemical modification of corneal stromal glycoproteins and proteoglycans.
The cornea is a transparent, multi-component structure of the eye through which light passes to reach the retina. The transparency of the cornea to light results from the unique extracellular matrix of the corneal stroma. The stroma is a tissue layer organized into collagenous lamellae of tightly packed parallel collagen fibers embedded in a hydrated matrix of glycoproteins and proteoglycans. The size, regularity, and precise spacing of the fibrillar structures are the physical characteristics essential for corneal transparency (Maurice, 1957).
The role of corneal glycoproteins and proteoglycans in the establishment and maintenance of corneal transparency is not well understood. Stromal proteoglycans have been hypothesized to play a role in the regulation of collagen fiber spacing. (Hassell et al., 1983). Although the precise role of proteoglycans is still unclear, they are thought to influence the hydration, thickness and clarity of the cornea. (Borcheding et al., 1975). The functional significance of hyaluronan in the cornea, except during development (Toole and Trelstad, 1971) and in some corneal abnormalities (Fitzsimmons et al., 1994) is still unknown.
In some opaque human corneal scars, the scars have been found to contain collagen fibrils with abnormally large diameter and irregular interfibrillar spacing. (Schwarz and Keyserlingk, 1969). However, during wound healing of rabbit corneas, the early opaque scars contain collagen fibrils of generally normal diameter that are irregularly spaced within the tissue. The collagen fibril diameter does not markedly change after a year of healing, but the spacing between the fibrils returns to normal and there is a concomitant decrease in the opacity of the scar. (Cintron & Kublin, 1977 and Cintron et al., 1978).
A 1983 paper authored by Hassell et al., showed that opaque scars that contained large interfibrillar spaces also contained unusually large chondroitin sulfate proteoglycans with glycosaminoglycan side chains of normal size. These opaque scars also lacked the keratan sulfate proteoglycan but did contain hyaluronic acid. The biochemical analysis of proteoglycans in rabbit corneal scars in corneal wounds compared to normal cornea adjacent to the scar demonstrates that the areas synthesize proteoglycans measurably different from one another. (Cintron et al., 1990).
Hassell et al. (1980) 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.
As discussed above, various traumas to the cornea result in the formation of corneal scars or opacification. The opacity of the scar tissue itself results from corneal collagen fibers that have grown during the healing process and lack the same level of organization found in undamaged corneal tissue. Penetrating keratoplasty, which uses corneal tissue from donor corneas in the form of corneal graft is the only surgical technique presently available to eliminate corneal scars or opacification. The challenges associated with penetrating keratoplasty are: (a) availability of human donor corneas for surgery; (b) compatibility of donor corneas and probability of graft survival; (c) donor cornea graft rejection; (d) donor cornea infection. The compositions and methods of the disclosed invention offer a non-surgical alternative to penetrating keratoplasty.
The transparency of the cornea may be altered in a manner more subtle than that seen in the corneal traumas described above. In certain situations the appearance of optical, monochromatic aberrations may decrease the visual acuity (VA) of a subject's eye. On the basis of the mosaic structures of the retina, the visual acuity of the human eye could be 20/10 or better; however, such good acuity is rarely obtained. Two optical conditions accounting for the sub-optimal level of visual acuity are: diffraction due to pupil size and monochromatic aberrations. (Campbell, et al., 1974). The limitations of visual acuity caused by diffraction decreases with increasing pupil diameter and may play an important role only for pupils smaller than 2 mm. The optical errors of higher order (aberrations) of the human eye, however, demonstrates an opposite behavior and may increase with larger pupil diameter.
The shape of the human cornea and lens is naturally designed in a way that
Azpuru Carlos A.
Ista Pharmaceuticals, Inc.
Knobbe Martens Olson & Bear LLP
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