Abstract
The aim of this study was to develop and evaluate the effects of chitosan inserts for sustained release of the angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), in experimental glaucoma. Monolayer DIZE loaded inserts (D+I) were prepared and characterized through swelling, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC) and in vitro drug release. Functionally, the effects of D+I were tested in glaucomatous rats. Glaucoma was induced by weekly injections of hyaluronic acid (HA) into the anterior chamber and intraocular pressure (IOP) measurements were performed. Retinal ganglion cells (RGC) and optic nerve head cupping were evaluated in histological sections. Biodistribution of the drug was accessed by scintigraphic images and ex vivo radiation counting. We found that DIZE increased the swelling index of the inserts. Also, it was molecularly dispersed and interspersed in the polymeric matrix as a freebase. DIZE did not lose its chemical integrity and activity when loaded in the inserts. The functional evaluation demonstrated that D+I decreased the IOP and maintained the IOP lowered for up to one month (last week: 11.0±0.7 mmHg). This effect of D+I prevented the loss of RGC and degeneration of the optic nerve. No toxic effects in the eyes related to application of the inserts were observed. Moreover, biodistribution studies showed that D+I prolonged the retention of DIZE in the corneal site. We concluded that D+I provided sustained DIZE delivery in vivo, thereby evidencing the potential application of polymeric-based DIZE inserts for glaucoma management.
Highlights
Glaucoma is an ocular disorder, with multi-factorial etiology, characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness [1, 2]
This study was designed to develop and characterize a new drug delivery system, a chitosan-based device containing an activator of intrinsic angiotensin-converting enzyme 2 (ACE2) (DIZE), for sustained release in eyes
Our main findings were that topical inserts loaded with diminazene aceturate (DIZE) were very efficient as a controlled drug delivery system, lowering the intraocular pressure (IOP) by over a month after a single application and promoting neuroprotection by preserving Retinal ganglion cells (RGC)
Summary
Glaucoma is an ocular disorder, with multi-factorial etiology, characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness [1, 2]. Only 1% to 7% of the administered drugs reach the aqueous humor [5,6,7]. The inefficiency of this route is mainly attributed to the precorneal tear clearance mechanism, the highly selective anterior corneal epithelial barrier and the patient compliance, a factor that is quite unpredictable and difficult to control. The development of new vehicles and drug formulations that enhance bioavailability and, reduce the number of administered doses requiring less patient efforts, represents an important aspect to control glaucoma progression [7]
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