Hollow microneedles for ocular drug delivery.

Microneedles (MNs) are micron-sized needles, typically <2 mm in length, arranged either as an array or as single needle. These MNs offer a minimally invasive approach to ocular drug delivery due to their micron size (reducing tissue damage compared to that of hypodermic needles) and overcoming significant barriers in drug administration. While various types of MNs have been extensively researched, significant progress has been made in the use of hollow MNs (HMNs) for ocular drug delivery, specifically through suprachoroidal injections. The suprachoroidal space, situated between the sclera and choroid, has been targeted using optical coherence tomography-guided injections of HMNs for the treatment of uveitis. Unlike other MNs, HMNs can deliver larger volumes of formulations to the eye. This review primarily focuses on the use of HMNs in ocular drug delivery and explores their ocular anatomy and the distribution of formulations following potential HMN administration routes. Additionally, this review focuses on the influence of formulation characteristics (e.g., solution viscosity, particle size), HMN properties (e.g., bore or lumen diameter, MN length), and routes of administration (e.g., periocular transscleral, suprachoroidal, intravitreal) on the ocular distribution of drugs. Overall, this paper highlights the distinctive properties of HMNs, which make them a promising technology for improving drug delivery efficiency, precision, and patient outcomes in the treatment of ocular diseases.

Microneedles for advanced ocular drug delivery.

In the field of ocular drug delivery, topical delivery remains the most common treatment option for managing anterior segment diseases, whileintraocular injectionsare the current gold standard treatment option for treating posterior segment diseases. Nonetheless, topical eye drops are associated with low bioavailability (<5%), and theintravitreal administration procedure is highly invasive, yielding poor patient acceptability. In both cases, frequent administration is currently required. As a result, there is a clear unmet need for sustained drug delivery to the eye, particularly in a manner that can be localised. Microneedles, which are patches containing an array of micron-scale needles (<1 mm), have the potential to meet this need. These platforms can enable localised drug delivery to the eye while enhancing penetration of drug molecules through key ocular barriers, thereby improving overall therapeutic outcomes. Moreover, the minimally invasive manner in which microneedles are applied could provide significant advantages over traditional intravitreal injections regarding patient acceptability. Considering the benefitsofthis novel ocular delivery system, this review provides an in-depth overviewofthe microneedle systems for ocular drug delivery, including the types of microneedles used and therapeutics delivered. Notably, we outline and discuss the current challenges associated with the clinical translation of these platforms and offer opinions on factors which should be considered to improve such transition from lab to clinic.

Ocular application of electrospun materials for drug delivery and cellular therapies.

The constraints of delivering conventional drugs, biologics and cell-based therapeutics to target ocular sites necessitate the fabrication of novel drug delivery systems to treat diverse ocular diseases. Conventional ocular drug delivery approaches are prone to low bioavailability, poor penetration and degradation of therapeutics, including cell-based therapies, leading to the need for frequent topical applications or intraocular injections. However, owing to their exceptional structural properties, nanofibrous and microfibrous electrospun materials have gained significant interest in ocular drug delivery and biomaterial applications. This review covers the recent developments of electrospun fibers for the delivery of drugs, biologics, cells, growth factors and tissue regeneration in treating ocular diseases. The insights from this review can provide a thorough understanding of the selection of materials for the fabrication of nano- and/or micro-fibrous systems for ocular applications, with a particular interest in achieving controlled drug release and cell therapy. A detailed modality for fabricating different types of nano- and micro-fibers produced from electrospinning and factors influencing generation are also discussed.

Vitreous Humor: Composition, Characteristics and Implication on Intravitreal Drug Delivery.

Purpose: Intravitreal administration of drug molecules is one of the most common routes for treating posterior segment eye diseases. However, the properties of vitreous humour changes with the time. A number of ocular complications such as liquefaction of the vitreous humour, solidification of the vitreous humour in the central vitreous cavity and detachment of the limiting membrane due to the shrinking of vitreous humour are some of the factors that can drastically affect the efficacy of therapeutics delivered via intravitreal route. Although significant research has been conducted for studying the properties of vitreous humour and its changes during the ageing process, there have been limited work to understand the effect of these changes on therapeutic efficacy of intravitreal drug delivery systems. Therefore, in this review we discussed both the coomposition and characteristics of the vitreous humour, and their subsequent influence on intravitreal drug delivery.Methods: Articles were searched on Scopus, PubMed and Web of Science up to March 2022.Results: In this review, we discussed the biological composition and biomechanical properties of vitreous humour, methods to study the properties of vitreous humour and the changes in these properties and their relevance in ocular drug delivery field, with the aim to provide a useful insight into these aspects which can aid the process of development of novel intravitreal drug delivery systems.Conclusions: The composition and characteristics of the vitreous humour, and how these change during natural aging processes, directly influence intravitreal drug delivery. This review therefore highlights the importance of understanding the properties of the vitreous and identifies the need to achieve greater understanding of how changing properties of the vitreous affect the therapeutic efficacy of drugs administered for the treatment of posterior eye diseases.

Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye.

Intravitreal injections (IVT) are regarded as the gold standard for effective delivery of hydrophobic drugs to the back of the eye. However, as a highly invasive procedure, the injection itself may lead to poor patient compliance and severe complications. In this research work, a hybrid system of nanosuspensions (NS) and dissolving microneedles (MNs) was developed as an alternative to conventional hypodermic needles used in IVT for minimally invasive transscleral delivery of hydrophobic drugs. NS of a hydrophobic drug, triamcinolone acetonide (TA), were fabricated using a wet milling technique. TA NS optimised by central composite factorial design had a proven diameter of 246.65 ± 8.55 nm. After optimisation, TA NS were incorporated into MN arrays to form a bilayer structure by high-speed centrifugation. TA NS-loaded MNs were robust enough to pierce excised porcine sclera with insertion depth higher than 80% of the needle height and showed rapid dissolution (<3 min). In contrast, the plain TA-loaded MNs exhibited poor mechanical and insertion performances and took more than 8 min to be fully dissolved in the scleral tissue. Importantly, transscleral deposition studies showed that 56.46 ± 7.76 µg/mm2 of TA was deposited into the sclera after 5 min of NS-loaded MN application, which was 4.5-fold higher than plain drug-loaded MNs (12.56 ± 2.59 µg/mm2). An ex vivo distribution study revealed that MN arrays could promote the transscleral penetration of hydrophobic molecules with higher drug concentrations observed in the deep layer of the sclera. Moreover, the developed TA NS-loaded MN array was biocompatible with ocular tissues, as demonstrated using the hens egg-chorioallantoic membrane assay and cytotoxicity test. The results presented here demonstrate that the hybrid system of NS and dissolving MNs can provide a novel and promising technology to alleviate retinal diseases in a therapeutically effective and minimally invasive manner.

Injectable Depot Forming Thermoresponsive Hydrogel for Sustained Intrascleral Delivery of Sunitinib Using Hollow Microneedles.

Purpose: Age-related macular degeneration is a vision-threatening disorder affecting the posterior segment of the eye. Drug delivery to the posterior segment is challenging owing to the complex anatomical and physiological structure, necessitating monthly injections of antivascular endothelial growth factors. Thermoresponsive hydrogels provide sustained drug delivery and ease of injection, due to their sol-gel transition. Poly (N-isopropyl acrylamide) (PNIPAAm) is a widely researched thermoresponsive hydrogel; however, insufficient wet strength and a wide mesh network make it inept for the entrapment of small molecules. Methods: A novel approach of grafting PNIPAAm with chitosan is exploited. A chitosan concentration altered in 10%, 30%, and 50% compared to PNIPAAm is investigated for entrapment of a small-molecular weight, hydrophilic drug, sunitinib (SUN), a multiple tyrosine kinase receptor inhibitor. Furthermore, these hydrogels were characterized using 1H-NMR, FTIR, differential scanning calorimetry (DSC), and thermogravimetric analysis for chemical characterization and viscosity, swellability, syringeability, degradation, and In-vitro permeation using Franz-diffusion cell. Results: In-vitro drug release kinetics suggested that the release of SUN could be controlled with the percentage of chitosan grafting; however, gel strength (3%-5% w/v) of 30% Cs-g-PNIPAAm did not significantly affect percentage drug release. Sustained release of SUN was observed for 1 month. In-vitro permeation studies on porcine sclera suggested that a thermoresponsive gel of chitosan grafted PNIPAAm (Cs-g-PNIPAAm) was able to sustain the drug release by 40%, compared to SUN solution. Conclusions: The study indicates that the synthesized Cs-g-NIPAAm hydrogel has the potential to serve as a tailorable injectable platform for intrascleral drug delivery applications.

An Ex Vivo Evaluation of Moxifloxacin Nanostructured Lipid Carrier Enriched In Situ Gel for Transcorneal Permeation on Goat Cornea.

The study was designed to fabricate the moxifloxacin nanostructured lipid carriers (MOX-NLCs) loaded in situ gel for opthalmic application to improve the corneal permeation and retention and also subside the toxic effect associated with intracameral injection of moxifloxacin in endophthalmitis treatment. Initially, Box-Behnken design was used to optimize the various factors significantly affecting the final formulation attributes. MOX-NLCs with particle size 232.1 ± 9.2 nm, polydispersity index 0.247 ± 0.031, zeta potential -16.3 ± 1.6 mV, entrapment efficiency 63.1 ± 2.4%, and spherical shape was achieved. The optimized MOX-NLCs demonstrated the Higuchi release kinetics with highest regression coefficient. Besides this, FTIR, differential scanning calorimetry, and X-ray diffraction results suggested that MOX had excellent compatibility with excipients. Furthermore, the results of ex-vivo permeation study demonstrated 2-fold higher permeation (208.7 ± 17.6 µg), retention (37.26 ± 2.83 µg), and flux (9.57 ± 0.73 µg/cm2 h) compared with free MOX in situ gel. In addition, MOX-NLCs exhibited normal corneal hydration and did not show any sign of structural damage to the corneal tissue as confirmed by histology. Therefore, the findings strongly suggest that MOX-NLCs in situ gel with higher permeation and retention can be a better alternative strategy to prevent and treat the endophthalmitis infection.

Alginate lyase immobilized chitosan nanoparticles of ciprofloxacin for the improved antimicrobial activity against the biofilm associated mucoid P. aeruginosa infection in cystic fibrosis.

Dense colonization of mucoid Pseudomonas aeruginosa within the self-secreted extracellular matrix (mainly alginate), called biofilm, is a principal reason for the failure of antimicrobial therapy in cystic fibrotic patients. Alginate is a key component in the biofilm of mucoid P. aeruginosa and responsible for surface adhesion and stabilization of biofilm. To overcome this problem, alginate lyase functionalized chitosan nanoparticles of ciprofloxacin were developed for the effective treatment of P. aeruginosa infection in cystic fibrosis patients. The developed nanoparticles were found to have desired quality attributes and demonstrated sustained release following the Higuchi release kinetics. Drug compatibility with the chitosan was confirmed by FTIR while powder X-ray diffraction analysis confirmed the entrapment of drug within the nanoparticle matrix. Lactose adsorbed NPs showed promising aerodynamic property. Nanoparticles showed prolonged MIC and significant reduction in biofilm aggregation and formation in planktonic bacterial suspension. Nanoparticles exhibited significantly higher inhibitory effect against biofilm of P. aeruginosa and reduced the biomass, thickness and density confirmed by confocal microscopy. Furthermore, developed nanoparticles were haemocompatible and did not exhibit any toxicity in vitro MTT assay and in vivo on lungs male Wistar rats. The data in hand collectively suggest the proposed strategy a better alternative for the effective treatment of cystic fibrosis infections.