Abstract
Corneal penetration is a key rate limiting step in the bioavailability of topical ophthalmic formulations that incorporate poorly permeable drugs. Recent advances have greatly aided the ocular delivery of such drugs using colloidal drug delivery systems. Ribavirin, a poorly permeable BCS class-III drug, was incorporated in bioadhesive multiple W/O/W microemulsion (ME) to improve its corneal permeability. The drug-loaded ME was evaluated regarding its physical stability, droplet size, PDI, zeta potential, ultrastructure, viscosity, bioadhesion, in vitro release, transcorneal permeability, cytotoxicity, safety and ocular tolerance. Our ME possessed excellent physical stability, as it successfully passed several cycles of centrifugation and freeze–thaw tests. The formulation has a transparent appearance due to its tiny droplet size (10 nm). TEM confirmed ME droplet size and revealed its multilayered structure. In spite of the high aqueous solubility and the low permeability of ribavirin, this unique formulation was capable of sustaining its release for up to 24 h and improving its corneal permeability by 3-fold. The in vitro safety of our ME was proved by its high percentage cell viability, while its in vivo safety was confirmed by the absence of any sign of toxicity or irritation after either a single dose or 14 days of daily dosing. Our ME could serve as a vehicle for enhanced ocular delivery of drugs with different physicochemical properties, including those with low permeability.
Highlights
Unlike drug delivery to other parts of the body, ocular drug delivery has met with significant challenges due to the presence of multiple strict barriers that are inherent in ocular anatomy and physiology that help to protect this priceless organ from toxicants either from outside or inside the body [1]
Both physiological and anatomical barriers result in a very small portion of the applied dose being absorbed and reaching its site of action inside the eyeball. Physiological barriers play their role by shortening drug–corneal contact time, and the anatomical barrier is the main cause of low drug corneal penetration [1,4]
We previously demonstrated the suitability of a multiple W/O/W microemulsion formulation for controlling the corneal permeability and sustaining the drug release of pregabalin, a model Biopharmaceutical Classification System (BCS) class I drug
Summary
Unlike drug delivery to other parts of the body, ocular drug delivery has met with significant challenges due to the presence of multiple strict barriers that are inherent in ocular anatomy and physiology that help to protect this priceless organ from toxicants either from outside or inside the body [1] It is not the only way, the corneal pathway is considered the major pathway for drug entry into the eyeball after topical drug application [2]. To have the ability to pass through the cornea, the drug molecule should possess a certain degree of both hydrophilicity and lipophilicity (i.e., amphiphilic drug molecules) Both physiological and anatomical barriers result in a very small portion of the applied dose being absorbed and reaching its site of action inside the eyeball. The first is the ability of the formulation to prolong its corneal contact time, and the second is its capability to enhance the corneal penetration of the drug molecules. The use of bioadhesive polymers, such as chitosan and its derivatives [7,8,9], sodium alginate, xanthan and carrageenan [10], may help to prolong the corneal contact time
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