There is no cure for diabetic retinopathy (DR) and current treatments, such as anti-VEGF injections for chronic treatment for diabetic macular edema (DME) and DR and panretinal laser therapy, provide only temporary relief. Kato Pharmaceuticals is developing a first-in-class treatment for DR using urea as the active pharmaceutical ingredient (API) for intravitreal injection. Urea acts to disrupt the hydrogen bonds between the vitreous and the retina, inducing a total posterior vitreous detachment (PVD) that inhibits the progression of retinal damage due to DR and other age-related pathologies of the eye. By using this therapeutic, patients suffering from these pathologies may avoid invasive surgery and preserve vision.
Because the volume of drugs that can be delivered to the eye is limited by the size of the organ, and because ophthalmic formulations dissipate relatively quickly once introduced into the vitreous, delivering and maintaining therapeutic doses of drugs to the macula and adjacent tissues has been a great challenge for ophthalmic drug developers and clinicians. There exists a need for ophthalmic drug formulations that can deliver a therapeutically effective dose to the back of the eye over an extended period of time for the treatment of chronic diseases, such as AMD, DME, and DR, among others.
Liposomes represent a promising injectable delivery system for intravitreal administration as they are a biodegradable, biocompatible carrier that can provide sustained release for prolonged periods. By controlling their size and structure, one can tailor the intravitreal elimination kinetics of the liposome carrier and the encapsulated API. This will optimize liposome formulations to be used in delivering a sustained release of urea to the vitreoretinal interface to cause a total PVD within the clinically acceptable duration (30-60 days)
Extended Release Formulation
In-Vitro Release Rate – ResolvER™ 40% Encapsulated Urea
Release Rate – ResolvER™ 40% Encapsualted Urea in Retina Tissue
Release Rate – Resolv ER™ 40% Encapsulated Urea
Urea in concentrations of 10 molar or greater acts as a powerful protein denaturant. Vitreous collagen fiber networks anchor the vitreous and retina by binding onto proteins, laminin, and fibronectin, found in the internal limiting membrane (ILM) of the retina. Resolv ER™ acts at the back of the eye to denature collagen fibrils by disrupting the water network which acts to stabilize the collagen strands by hydrogen bonding. By delivering concentrated Urea at the vitreoretinal border region, Resolv ER™ acts to disrupt the hydrogen bonds within the triple helix structure of the collagen strands and cause the strands to unravel. The denatured collagen fibers are no longer able to bind to the fibronectin and laminin on the ILM. As a result, a posterior vitreous detachment (PVD) is induced once the collagen networks of fibrils separate from the ILM of the retina.
The junction between the vitreous and the retina is formed by a chemical mechanism and anchoring. At the vitreoretinal border region, vitreous fibrils (contains collagen) insert and anchor into the ILM. Just as in other basement membranes, the ILM has three structures: the fusing points of the anchoring vitreous fibrils, the lamina densa, and the lamina lucida. Among the mass of type IV collagen, there is type I collagen, LN, FN, and proteoglycans. The FN (Fibronectin) and LN (laminin) can connect collagen between the posterior vitreous cortex and the ILM. Furthermore, FN has a high affinity with hyaluronic acid and type II collagen.
The posterior hyaloid membrane is a true basement membrane enveloping the posterior hyaloid surface. Because this membranous structure is observed only after posterior vitreous detachment, the results of this study indicate that it forms part of the internal limiting membrane when the vitreous is in its attached state….collagen fibrils of the posterior vitreous cortex are firmly adherent to the internal limiting membrane of the retina by proteoglycans, including laminin and fibronectin….The generally accepted consensus regarding the definition and diagnosis of a posterior vitreous detachment is that there is a separation of the condensed outer layers of type II collagen fibrils of the vitreous, known as the posterior vitreous cortex, from the internal limiting membrane of the retina.
Direct urea interactions consisted of hydrogen bonding to the polar moieties of the protein, particularly peptide groups, leading to a screening of intramolecular hydrogen bonds. Solvation of the hydrophobic core proceeded via the influx of water molecules, then urea. Urea also promoted protein unfolding in an indirect manner by altering water structure and dynamics, as also occurs on the introduction of nonpolar groups to water, thereby diminishing the hydrophobic effect and facilitating the exposure of the hydrophobic core residues. Overall, urea-induced effects on water indirectly contributed to unfolding by encouraging hydrophobic solvation, whereas direct interactions provided the pathway.
The purpose was to study the relation between posterior vitreous detachment (PVD) and progression of diabetic retinopathy (DR), based on our observation that proliferative DR is rare in patients with complete PVD. The medical records of 403 patients with diabetes were reviewed for the relation between progressive DR and the status of PVD and HbA(1c) over 3 years. There was no progression of DR over 3 years of eyes with complete PVD with collapse. Complete PVD is a strong negative risk factor for DR. The PVD status in patients with diabetes should be evaluated.
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