Improving ocular bioavailability of hydrophilic drugs through dynamic covalent complexation.

The clinical benefits of diquafosol tetrasodium (DQS), a hydrophilic P2Y2 receptor agonist for dry eye, have been hindered by a demanding dosing regimen. Nevertheless, it is challenging to achieve sustained release of DQS with conventional drug delivery vehicles which are mainly designed for hydrophobic small molecule drugs. To address this, we developed an affinity hydrogel for DQS by taking advantage of borate-mediated dynamic covalent complexation between DQS and hydroxypropyl guar. The resultant formulation (3% DQS Gel) was characterized by sustained release, low corneal permeation, and extended ocular retention, which were desirable attributes for ocular surface drug delivery. Both in vitro and in vivo studies had been carried out to verify the biocompatibility of 3% DQS Gel. Using corneal fluorescein staining, the Schirmer's test, PAS staining, quantitative PCR and immunohistological analyses as outcome measures, the superior therapeutic effects of 3% DQS Gel over PBS, the hydrogel vehicle and free DQS were demonstrated in a mouse dry eye model. Our DQS delivery strategy reported herein is readily applicable to other hydrophilic small molecule drugs with cis-diol moieties, thus providing a general solution to improve clinical outcomes of numerous diseases.

A topical fluorometholone nanoformulation fabricated under aqueous condition for the treatment of dry eye.

Fluorometholone (FMT) is a frequently prescribed drug for the alleviation of dry eye. However, due to low aqueous solubility, it has been routinely used as an ophthalmic suspension, which is characterized by low bioavailability, inconvenience of administration, and difficulty in delivering accurate dose. Furthermore, the opaque appearance of the ophthalmic suspension is not desirable for optical purpose. In the present study, a transparent FMT nanoformulation (FMT-CD NPs) was fabricated by the cyclodextrin (CD) nanoparticle technology without organic solvents. It was demonstrated that FMT was encapsulated in an amorphous form, which was associated with increased release rate and enhanced corneal penetration efficiency. The biocompatibility of FMT-CD NPs was confirmed by the Live/Dead assay, CCK-8 assay and the wound healing assay. Most importantly, FMT-CD NPs alleviated dry eye signs more efficiently than the commercial eye drop, with one-fifth the dosage of FMT in the latter. Collectively, our study provides a promising FMT formulation for improved management of dry eye while reducing drug related side effects.

Engineering Advanced Drug Delivery Systems for Dry Eye: A Review.

Dry eye disease (DED) is a widespread and frequently reported multifactorial ocular disease that not only causes ocular discomfort but also damages the cornea and conjunctiva. At present, topical administration is the most common treatment modality for DED. Due to the existence of multiple biological barriers, instilled drugs generally exhibit short action times and poor penetration on the ocular surface. To resolve these issues, several advanced drug delivery systems have been proposed. This review discusses new dosage forms of drugs for the treatment of DED in terms of their characteristics and advantages. Innovative formulations that are currently available in the market and under clinical investigation are elaborated. Meanwhile, their deficiencies are discussed. It is envisioned that the flourishing of advanced drug delivery systems will lead to improved management of DED in the near future.

Nanomicelle-Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo.

Ocular inflammations are common diseases that may lead to serious vision-threatening obstacles. Eye drops for antiinflammation therapy need to be administered multiple times daily at a high dosage due to the rapid precorneal removal and low bioavailability of drugs. To overcome these problems, a cRGD-functionalized DSPE-PEG2000 nanomicelle (DSPE-PEG2000-cRGD) encapsulated with flurbiprofen is proposed. The tailored nanomicelles trigger specific binding to integrin receptors on the ocular surface, which leads to rapid and robust mucoadhesion, superior ocular surface retention, and transcorneal penetration behaviors of nanomicelles. Due to the enhanced drug delivery on ocular surface and in aqueous humor, the functionalized nanoformulation significantly improves ocular antiinflammation efficacy at a low dosage by blocking the synthesis of inflammatory mediators and cytokines. The present study demonstrates a promising strategy that uses a functional peptide combined with nanomicelles for targeted delivery to the eye in ophthalmologic applications.

Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes.

This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 µg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33-8.67 mmHg, whereas that of group C gradually remained at 7.55-10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation.

Biocompatibility and drug release behavior of chitosan/poly (vinyl alcohol) corneal shield in vivo.

UNLABELLED: Backgound: Chitosan/polyvinyl alcohol corneal cap has good biocompatibility and drug slow release characteristics, which provided new treatment method for anterior segment disease. Our study was to evaluate biocompatibility of poly (vinyl alcohol)/chitosan corneal shield's intraocular and investigate its feasibility to treat ocular surface disorders. METHODS: Thirty-six white rabbits were randomly divided into four groups. Slit lamp observation were conducted at 1, 3, 7 and 10 days after operation. Corneal and conjunctiva tissue harvested from the experimental groups was observed by HE staining 10 days after operation. The aqueous humor was aspirated from the anterior chamber at each designated time point (1, 3, 7 and 10 days). The cornea and conjunctive were collected at 10 days. The concentration of each tissue was analyzed by ultra-performance liquid chromatography and microscope observation. RESULTS: In all groups, mild hyperemia was observed 1 day after operation, and there was no obvious inflammatory reaction occurring on the seventh and tenth day. No corneal edema and inflammatory reaction of anterior chamber occurred till the tenth day. For histopathology, there was no obviously mild chronic and inflammatory reaction occurred, and no significant difference between the corneal shield with-in groups and with-out groups. The drug concentrations in corneal and conjunctival in group (A, B) were significantly lower than eye drops in the control group (C, D), and blank corneal cover in group C was significantly sham operation in group D. CONCLUSION: The results indicated that the proposed membrane combined with ophthalmic solution has substantial potential as ocular delivery system.

Superior biocompatibility and osteogenic efficacy of micro-arc oxidation-treated titanium implants in the canine mandible.

The aim of this paper is to test implantation outcomes and osteogenic efficacy of plasma micro-arc oxidation (MAO)-treated titanium implants in dogs. Thirty-six pure titanium implants (18 MAO-treated, 18 untreated) were inserted into the mandibles of nine adult beagles and allowed to heal under non-weight-bearing conditions. Implant stability and interface characteristics were evaluated at 4, 8 and 12 weeks post-implantation. Methods included scanning electron microscopy, mechanical testing, histological analysis and computer-quantified tissue morphology. Osseointegration was achieved in both groups, but occurred earlier and more extensively in the MAO group. Areas of direct bone/implant contact were approximately nine times higher in the MAO group than in the control group at 12 weeks (65.85% versus 7.37%, respectively; p < 0.01). Bone-implant shear strength in the MAO group (71.4, 147.2 and 266.3 MPa at weeks 4, 8 and 12, respectively) was higher than in the control group (4.3, 7.1, and 11.8 MPa at weeks 4, 8 and 12, respectively), at all assessments (all, p < 0.01). MAO treatment of titanium implants promotes more rapid formation of new bone, and increases bone-implant shear strength compared to untreated titanium implants.