Advances in Ocular Drug Delivery

The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA (LPvHiHA), commercial LP (cLP), and diluted LP (dLP)) and after instilling the eye drops, the aqueous humor (AH) was collected at 0.5, 1, 2, 4, and 6 h to measure the LP concentration using an enzyme-linked immunosorbent assay (ELISA). Although the LP concentration in the LPvHiHA eye drop formulation was 3.57 times lower than in the commercial eye drops used (cLP), the LP concentration in the AH following LPvHiHA administration reached a value close to that of cLP. The cLP was diluted to the same concentration of LP as in the LPvHiHA eye drops for the dLP group, but the LP concentration in the AH of these animals was lower than that of the LPvHiHA rats at all time points. The higher LP concentration in the AH of the LPvHiHA rats suggests that vHiHA may aid the transport of LP across the ocular surface epithelium. Full article

Local chemotherapy using polymer drug delivery systems has the potential to treat some cancers, including intraocular retinoblastoma, which is difficult to treat with systemically delivered drugs. Well-designed carriers can provide the required drug concentration at the target site over a prolonged time, reduce the overall drug dose needed, and suppress severe side effects. Herein, nanofibrous carriers of the anticancer agent topotecan (TPT) with a multilayered structure composed of a TPT-loaded inner layer of poly(vinyl alcohol) (PVA) and outer covering layers of polyurethane (PUR) are proposed. Scanning electron microscopy showed homogeneous incorporation of TPT into the PVA nanofibers. HPLC-FLD proved the good loading efficiency of TPT (≥85%) with a content of the pharmacologically active lactone TPT of more than 97%. In vitro release experiments demonstrated that the PUR cover layers effectively reduced the initial burst release of hydrophilic TPT. In a 3-round experiment with human retinoblastoma cells (Y-79), TPT showed prolonged release from the sandwich-structured nanofibers compared with that from a PVA monolayer, with significantly enhanced cytotoxic effects as a result of an increase in the PUR layer thickness. The presented PUR-PVA/TPT-PUR nanofibers appear to be promising carriers of active TPT lactone that could be useful for local cancer therapy. Full article

Improvement of the efficiency of drug penetration into the eye tissues is still an actual problem in ophthalmology. One of the most promising solutions is drug encapsulation in carriers capable of overcoming the cornea/sclera tissue barrier. Formulations on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), and an inhibitor of angiotensin-converting enzyme, enalaprilat, were prepared by simultaneous inclusion of both drugs into calcium phosphate (CaP) particles in situ with subsequent covering of the particles with 5 kDa chitosan. The formulations obtained were characterized by dynamic light scattering and scanning electron microscopy. Hybrid CaP-chitosan particles co-loaded with SOD1 and enalaprilat had a mean hydrodynamic diameter of 120–160 nm and ζ-potential +20 ± 1 mV. The percentage of the inclusion of SOD1 and enalaprilat in hybrid particles was 30% and 56%, respectively. The ability of SOD1 and enalaprilat to reduce intraocular pressure (IOP) was examined in vivo in normotensive Chinchilla rabbits. It was shown that topical instillations of SOD1/enalaprilat co-loaded hybrid particles were much more effective in decreasing IOP compared to free enzyme or free enalaprilat and even to the same particles that contained a single drug. Thus, the proposed formulations demonstrate potential as prospective therapeutic agents for the treatment of glaucoma. Full article

Fungal keratitis, a disease in which the cornea becomes inflamed due to an invasive fungal infection, remains difficult to treat due in part to limited choices of available treatments. Topical eye drops are first-line treatment, but can be ineffective as low levels of drug reach the target site due to precorneal losses and the impenetrability of the cornea. The aim of this study was to determine the corneal delivery of econazole using a novel topical enhancement approach using a composite delivery system based upon cyclodextrins and soft hydrogel contact lenses. Excess econazole nitrate was added to hydroxypropyl-α-cyclodextrin (HP-α-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions, and the solubility determined using HPLC. Proprietary soft hydrogel contact lenses were then impregnated with saturated solutions and applied to freshly enucleated porcine eyeballs. Econazole nitrate ‘eye drops’ at the same concentrations served as the control. After 6 h, the corneas were excised and drug-extracted, prior to quantification using HPLC. Molecular dynamic simulations were performed to examine econazole–HP-β-CD inclusion complexation and dissociation. The minimum inhibitory concentration (MIC) of econazole was determined against four fungal species associated with keratitis, and these data were then related to the amount of drug delivered to the cornea, using an average corneal volume of 0.19 mL. The solubility of econazole increased greatly in the presence of HP-β-CD and more so with HP-α-CD (p < 0.001), with ratios >> 2. Hydrogel contact lenses delivered ×2.8 more drug across the corneas in comparison to eye drops alone, and ×5 more drug delivered to the cornea when cyclodextrin was present. Molecular graphics demonstrated dynamic econazole release, which would create transient enhanced drug concentration at the cornea surface. The solution-only drops achieved the least satisfactory result, producing sub-MIC levels with factors of ×0.81 for both Fusarium semitectum and Fusarium solani and ×0.40 for both Scolecobasidium tshawytschae and Bipolaris hawaiiensis. All other treatments delivered econazole at > MIC for all four fungal species. The efficacies of the delivery platforms evaluated were ranked: HP-α-CD contact lens > HP-β-CD contact lens > contact lens = HP-α-CD drops > HP-β-CD drops > solution-only drops. In summary, the results in this study have demonstrated that a composite drug delivery system based upon econazole–HP-β-CD inclusion complexes loaded into contact lenses can achieve significantly greater corneal drug delivery with the potential for improved clinical responses. Full article

Nanofibers are frequently encountered in daily life as a modern material with a wide range of applications. The important advantages of production techniques, such as being easy, cost effective, and industrially applicable are important factors in the preference for nanofibers. Nanofibers, which have a broad scope of use in the field of health, are preferred both in drug delivery systems and tissue engineering. Due to the biocompatible materials used in their construction, they are also frequently preferred in ocular applications. The fact that they have a long drug release time as a drug delivery system and have been used in corneal tissue studies, which have been successfully developed in tissue engineering, stand out as important advantages of nanofibers. This review examines nanofibers, their production techniques and general information, nanofiber-based ocular drug delivery systems, and tissue engineering concepts in detail. Full article

Sjögren’s syndrome is a chronic and insidious autoimmune disease characterized by lymphocyte infiltration of exocrine glands. Patients typically present with dry eye, dry mouth, and other systemic manifestations. Currently, the available molecules and drug-delivery systems for the treatment of Sjögren’s syndrome dry eye (SSDE) have limited efficacy since they are not specific to SSDE but to dry eye disease (DED) in general. The current treatment modalities are based on a trial-and-error approach using primarily topical agents. However, this approach gives time for the vicious cycle of DED to develop which eventually causes permanent damage to the lacrimal functional unit. Thus, there is a need for more individualized, specific, and effective treatment modalities for SSDE. The purpose of this article is to describe the current conventional SSDE treatment modalities and to expose new advances in ocular drug delivery for treating SSDE. A literature review of the pre-clinical and clinical studies published between 2016 and 2022 was conducted. Our current understanding of SSDE pathophysiology combined with advances in ocular drug delivery and novel therapeutics will allow the translation of innovative molecular therapeutics from the bench to the bedside. Full article