Preocular Surface Research Articles

How does Spix's yellow-toothed cavy (Galea spixii Wagler, 1831) face the thermal challenges of the Brazilian tropical dry forest?

The aim of this work was to investigate the thermal biology of the Spix's yellow-toothed cavy (Galea spixii) from the hot and dry environment of the Brazilian Caatinga by infrared thermography and biophysical equations. We monitored the rectal temperature, as well as the non-evaporative (radiative and convective pathways) and evaporative heat exchanges of males and females. The mean rectal temperature of females and males was 37.58±0.02 and 37.47±0.02°C, respectively. We identified thermal windows by infrared thermography. The surface temperatures and the long-wave radiation heat exchanges were higher in the periocular, preocular, pinnae and vibrissae regions, in that order. The surface temperature of the periocular and preocular regions correlated positively with rectal temperature. Convective heat exchange was insignificant for thermoregulation by G. spixii. Evaporative heat loss increased when the thermal environment inhibited the radiative pathway. Females showed higher evaporative thermolysis than males at times of greater thermal challenge, suggesting a lower tolerance to heat stress. Therefore, infrared thermography identified the thermal windows, which represented the first line of defense against overheating in G. spixii. The periocular and preocular surface temperatures could be used as predictors of the thermal state of G. spixii.

Dry Tablet Formulation of PLGA Nanoparticles with a Preocular Applicator for Topical Drug Delivery to the Eye.

To enhance ocular drug bioavailability, a rapidly dissolving dry tablet containing alginate and drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles was proposed. For hygienic and easy administration of an accurate drug-dose with this tablet, the use of a preocular applicator was suggested. Herein, a dry tablet was prepared by embedding dexamethasone-loaded PLGA nanoparticles in alginate, which was deposited on the tip of the applicator. The nanoparticles were loaded with 85.45 μg/mg drug and exhibited sustained drug release for 10 h. To evaluate in vivo efficacy, dexamethasone concentration in the aqueous humor was measured after topical administration of the dry tablet, with the applicator, to rabbit eyes and was compared to that achieved with Maxidex®, a commercially-available dexamethasone eye drops. When applied with the preocular applicator, the dry tablet containing alginate could be fully detached and delivered to the eye surface. In fact, it showed up to 2 h of nanoparticle retention on the preocular surface due to tear viscosity enhancement, causing an estimated 2.6-fold increase in ocular drug bioavailability compared to Maxidex®. Therefore, the preocular applicator combined with a dry alginate tablet containing PLGA nanoparticles can be a promising system for aseptically delivering an accurate dose of ophthalmic drug with enhanced bioavailability.

Designing Minimally Invasive Preocular Contact Tips for Potential Application in Tear Collection.

Basal tear fluid has drawn great attention as a medium for many disease markers and, hence, for its potential to be used in self-diagnosis. However, collection of basal tear fluid is difficult because a conventional tear collector, such as a glass capillary tube, may inflict irritation or damage on the sensitive ocular surface. Therefore, we sought to design a tip for contact with the preocular surface [a preocular contact tip (PCT)] that minimizes damage to the ocular surface. We designed the shape of the tip to have rounded boundaries and no sharp edges. We then tested different tip areas, each of which was contacted with the inferior palpebral conjunctiva of rabbit eyes at varying depths to demonstrate their feasibility in vivo. The area of damaged tissue and the time required for tissue recovery were monitored according to the pressure applied through the tips. Our findings revealed that a contact area of the PCT greater than 2.36 mm caused relatively little damage to the inferior palpebral conjunctival tissue, which could recover within 4 hours after contact at all pressing depths. In contrast, a glass capillary tube caused relatively severe damage, which did not recover for more than 8 hours. The PCT (3.14 mm) was embedded with a microchannel as a prototype tear collector, which could collect 0.3 μL of tears with minimal tissue damage. The PCT proposed in this study can be a promising tool for minimally invasive collection of basal tears from the inferior palpebral conjunctiva.

Mathematical modelling of brimonidine absorption via topical delivery of microparticle formulations to the eye

We developed a mathematical model to elucidate the absorption profile of an ocular drug, brimonidine, into the aqueous humour (AH) after its topical administration to the eye via microparticle formulations. For this, a compartment model with three distinct compartments of tear, cornea, and AH was proposed. The parameters were estimated, employing the experimental data of in vitro drug release, in vivo preocular retention, and drug concentration in the AH, which were obtained with four distinct microparticle types: (1) spherical microparticles without mucoadhesion, (2) spherical microparticles with mucoadhesion, (3) nanostructured microparticles without mucoadhesion, and (4) nanostructured microparticles with mucoadhesion. Our results showed that, for all microparticle types, the simulated and experimental profiles of drug concentration in the AH were in good agreement, as were the overall pharmacokinetic parameters, implying that the model is reliable. With this validated model, we predicted the drug concentration profile in the tear, where nanostructured, mucoadhesive microparticles showed greater than 1.9-fold increase in drug bioavailability, compared with the other microparticle types. This improvement at the preocular surface was reflected in the enhanced drug bioavailability in the AH: greater than 1.5-fold increase compared with the other microparticle types.

Thermosensitive hexanoyl glycol chitosan-based ocular delivery system for glaucoma therapy

Conventional eye drops quickly move away from the surface of the eye; as a result, ocular bioavailability is very limited. To overcome this issue, we developed a thermosensitive hexanoyl glycol chitosan (HGC) as a carrier for topical drug delivery to the eye. Here, we modulated the degree of N-hexanoylation to control the thermogelling behavior and prepared a new ocular formulation of HGC for glaucoma therapy. The viscosity of the aqueous formulation sharply and significantly increases at body temperature. The results from cytotoxicity evaluation showed that HGC is non-toxic at up to 1.25wt.%. In vivo experiments demonstrated that HGC is maintained on the preocular surface for a comparatively longer period of time due to its enhanced viscosity at body temperature. As a result, when brimonidine was loaded, the formulation exhibited attractive bioavailability properties as well as more prolonged period of lowered intra-ocular pressure (14h) compared with Alphagan P, the marketed medication for brimonidine treatment. Statement of SignificanceIn this manuscript, hexanoyl glycol chitosan (HGC) was synthesized by the N-hexanoylation of glycol chitosan. We have observed that an aqueous solution of HGC exhibited a dramatic increase in viscosity as the temperature increased. The HGC-based formulation showed prolonged retention on the preocular surface and enhanced drug availability and efficacy.

Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug

Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion-wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine.

Nanostructured mucoadhesive microparticles for enhanced preocular retention

We describe nanostructured microparticles (NMs) containing a mucoadhesive polymer for enhanced preocular retention and consider them as potential carriers of drugs to the eye. These NMs are each composed of entangled nanofibers to give an enlarged specific surface area, and thus can better adhere to the preocular mucus surface. This physical design allows the microparticles still to be composed mainly of a wall material, poly(lactic-co-glycolic acid), as required for controlled drug delivery, while the effects of an additive, mucoadhesive material, polyethylene glycol, can be synergistically improved via the nanostructured morphology. Thus, when formulated in a dry tablet dosage form, the NMs in this work show more than a 10-fold increase in preocular retention in vivo compared to conventional spherical microparticles. Therefore, we conclude that these mucoadhesive NMs can reside on the preocular surface for a prolonged period, and thus appear to be a promising system for topical drug delivery to the eye.

Mucoadhesive Microparticles in a Rapidly Dissolving Tablet for Sustained Drug Delivery to the Eye

To test the hypothesis that mucoadhesive microparticles formulated in a rapidly dissolving tablet can achieve sustained drug delivery to the eye. Mucoadhesive microparticles, smaller than 5 μm were fabricated with poly(lactic-co-glycolic acid) and poly(ethylene glycol) as a core material and mucoadhesion promoter, respectively, and encapsulated pilocarpine as a model drug. These microparticles were embedded in a poly(vinyl alcohol) matrix to form a dry tablet designed to reduce rapid clearance of the microparticles on initial application to the eye. This in vitro drug release study exhibited that for all formulations, approximately 90% of pilocarpine was released during the first 10 minutes, and the remaining 10% was released slowly for 3 hours. In vivo mucoadhesion test on the rabbit eye indicated that mucoadhesive microparticles adhered significantly better to the preocular surface than other formulations. To assess the pharmacodynamics, the most prolonged pilocarpine-induced pupil constriction was observed in rabbit eyes in vivo using a tablet with mucoadhesive microparticles; it lasted up to 330 minutes. The authors conclude that mucoadhesive microparticles formulated into a dry dosage form is a promising system for sustained drug delivery to the eye.

Mucoadhesive Microdiscs Engineered for Ophthalmic Drug Delivery: Effect of Particle Geometry and Formulation on Preocular Residence Time

To test the hypothesis that mucoadhesive microdiscs formulated in a rapidly dissolving tablet can increase preocular residence time. Microparticles smaller than 10 mum in diameter were fabricated by emulsification with poly(lactic-co-glycolic acid) as a core material and, in some cases, poly(ethylene glycol) as a mucoadhesion promoter. To examine the effect of particle geometry, microparticles were also cut to have flat surfaces (i.e., microdiscs) and were compared with spherical particles (i.e., microspheres). In vitro mucoadhesion of microparticles was tested on a mucous layer under shear stress, mimicking the human blink. The resultant microparticles were also formulated in two dosage forms, an aqueous suspension and a dry tablet, to test the effect of formulation on the retention capacity of microparticles on the preocular space of rabbits in vivo. Mucoadhesive microdiscs adhered better to the simulated ocular surface than did other types of microparticles. When a dry tablet embedded with mucoadhesive microdiscs was administered in the cul-de-sac of the rabbit eye in vivo, these microdiscs exhibited longer retention than the other formulations tested in this study. More than 40% and 17% of mucoadhesive microdiscs remained on the preocular surface at 10 minutes and 30 minutes after administration, respectively. Fluorescence images from the eye surface showed that mucoadhesive microdiscs remain for at least 1 hour in the lower fornix. This study demonstrated that mucoadhesive microdiscs formulated in a dry tablet can achieve a prolonged residence time on the preocular surface and thus are a promising drug delivery system for ophthalmic applications.