A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery

Abstract

Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%. There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation, and the formulation reliably switched between thixotropy and temperature-dependent rheopexy when it was tested in a rheometer under conditions that simulate the ocular surface, including blinking. These properties should ensure that the formulation coats the cornea through blinking of the eyelid and facilitate application of the medication as an eye drop immediately prior to the patient’s bedtime. We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. This work paves the way for the introduction of novel products targeting ocular diseases to the market.

Noble Metals and Soft Bio-Inspired Nanoparticles in Retinal Diseases Treatment: A Perspective

“…The most commonly used are poly(hydroxyethyl methacrylate) (PHEMA), poly(ethylene oxide) (PEO, also called poly(ethyleneglycol) (PEG)), polyvinylpyrrolidone (PVP), poly(acrylic acid)(PAA), polyacrylamide (PAM), and poly(vinyl alcohol) (PVA) [143]. These polymers are all used in several ophthalmic applications with good results [144][145][146][147].…”

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy

“…Kabiri and collaborators (2018) developed a nanoparticle-based product able to improve the transport of the bioactive compound across the cornea and to obtain a sustained-release system, by extending the time when the drug concentration reaches therapeutic levels [110]. This research consists of preparation of a stimulus-responsive hydrogel, loaded with nanoparticles, forming in situ, as a controlled delivery system of cannabinoids inside the aqueous humor of the eye.…”

“…The product was evaluated both in a rheometer under conditions simulating the ophthalmic surface and in vivo on porcine eyeballs, showing an increase in transcorneal penetration greater than 300% against control formulation. Additionally, the nanoparticle loading hydrogel can also be formulated as a liquid, with multiple benefits, including facile dosing [110].…”

Harnessing emerging paradigms in chemical engineering to accelerate the development of pharmaceutical products

“…[49] We then employed the toolkit of synthetic biology to genetically engineer a strain of Escherichia coli to synthesize CBGA and also co-developed a stimulus-responsive, in situ forming, nanoparticle-laden hydrogel comprising hyaluronic acid (HA) and methylcellulose (MC) as the vehicle for delivering the molecule through the cornea and into the aqueous humour of the eye. [50] Current formulations for topical delivery of cannabinoids into the eye are prepared using either mineral oil [51] or cyclodextrins, [52][53][54][55] both of which are irritants to the eye. [56] HA is an anionic polysaccharide and MC is a water-soluble, hydrophobic derivative of cellulose, and both polymers have been classified by the FDA as biocompatible and safe.…”