Drug Delivery Letters - Volume 13, Issue 3, 2023

This review aims to provide historical, present, and future drug deliveries for treating inner ear disorders. Systemic delivery, such as antibiotics and steroids for the inner ear, was the basis on which current drug delivery systems and devices have been researched and developed. Researchers and clinicians had to develop and deliver drugs locally due to adverse effects caused by drugs systemically. Intratympanic method of antibiotics and steroid delivery has been common; however, newer techniques such as microcatheter implantation, hydrogels, nanoparticles, and intracochlear implants are being investigated successfully. Recently advances in microfluidic and microsystems technology have applied medications directly into the inner ear. This technology will also be adopted to deliver gene therapy, RNA interference technology, and stem cell therapy by clinicians in the future.

Background: This study aims to assess the suitability of in vitro drug release methods, dialysis and paddle methods for predicting in vivo behaviour of Aceclofenac (ACE) proniosomes. Methods: ACE proniosomes are prepared using different carriers: glucose, maltodextrin and mannitol by the slurry method. The release studies of ACE proniosomes formulations were performed using the paddle, and dialysis methods while in vivo studies were performed in albino rats. Graphical presentation, model-dependent and model-independent approaches were applied to compare two dissolution methods. Results: More than 70% of the drug was released from ACE proniosomes over 60 min by paddle method while not more than 5% was released in the same period by dialysis method. The paddle method provides a reproducible and faster release, whereas poor drug release occurred with the dialysis method. For the paddle method, lower values of similarity factor (f2) and greater differences in the dissolution efficiency (DE) amongst different formulations and in comparison, to that of the pure drug indicates that it is a more discriminative method compared to dialysis. The paddle method also illustrated high regression coefficients (r²) of 0.81, 0.998 and 0.975 for FN1, FN2, and FN3, respectively for level A IVIVC, while poor or no relation (r² 0.1) was detected in the case of dialysis method. Conclusion: Based on the results, the paddle method is concluded to be the more suitable method compared to the dialysis method for in vitro drug release studies of a novel dosage form such as proniosomes.

Background: Dexamethasone (DEX) is a glucocorticosteroid used in the treatment of steroid-responsive inflammatory conditions of the eye. The currently marketed formulations pose several issues, like poor drug residence time, resulting in frequent administration of the formulation, making them less effective. Objective: The present study aims to provide comprehensive data encompassing the designing, optimization, development, and characterization of DEX nanoemulsion (DEX NE) for treating inflammatory conditions of the anterior segment of the eye by employing the Quality by Design (QbD) approach. Methods: A Plackett-Burman Design (PBD) was employed to screen seven independent variables, such as oil concentration, surfactant concentration, polymer concentration, homogenization speed and time, microfluidization pressure and cycles, and their influence on critical quality attributes (CQAs), such as globule size, zeta potential, and viscosity, was evaluated. Furthermore, the Box- Behnken Design (BBD) was employed for optimization, and design space was generated to obtain the optimized DEX NE. Results: The experimental results after DEX NE characterization reveal a globule size of 181 ± 90 nm with a zeta potential of -21.03 ± 1.68 mV and a viscosity of 19.99 cp. Furthermore, the drug release study of simulated tear fluid demonstrated prolonged and steady release for up to 48 hr. Cytotoxicity assay of DEX NE exhibited good cell viability. Conclusion: All these findings pave the way for a better understanding of developing a robust, safe, and non-toxic formulation for ocular drug delivery.

Background: Cinacalcet hydrochloride (CINH) is a BCS class IV drug. It is mainly used for the treatment of chronic renal disease and parathyroid cancer. It exhibits poor oral bioavailability of less than 25%. Objectives: The main objective is to improve the bioavailability of CINH by formulating the nanostructure lipid carrier (NLC). Methods: In this research, glyceryl monostearate (GMS), labrasol, and tween 20 were the main excipients selected for the formulation of NLC. Hot high-speed homogenization and ultra-sonication method was used for the NLC formulation of CINH. The characterization of the NLCs was done as per standard procedures. Optimization of the formulated NLC was carried out by applying Box- Behnken Design (BBD) with the help of the Design Expert software. The pharmacokinetic study was conducted to determine the improvement in the bioavailability of the CINH. The cytotoxicity study was performed by using the MTT assay method to know the cell viability. Results: The optimized NLC formulation exhibited high drug content with a particle size of less than 200nm. A pharmacokinetic study showed 4 fold increase in oral bioavailability for the optimized NLC in comparison to the aqueous suspension of CINH. Minimum viability was determined as 94%, which indicates the safety of the incubated formulations. Conclusion: NLC formulation has the potential to improve oral bioavailability with high drug loading and cell viability for CINH.

Aim: The goal of this research was to formulate and optimize a cost-effective selfemulsifying drug delivery system (SEDDS) of cilnidipine to increase its dissolution rate. Cilnidipine is a BCS class II active pharmaceutical ingredient, which limits its use. Methods: Cilnidipine's solubility in various oils, surfactants, and cosurfactants, has been investigated. To determine if there is any interaction between cilnidipine and certain excipients, drug compatibility tests were carried out. Based on phase solubility and compatibility studies, two combinations (Canola oil, Tween 80, and PEG 300; Peanut oil, Cremophor EL, and PEG 200) were prepared to create ternary phase diagrams for selecting the best combination with higher microemulsion region and to identify the range of concentration of excipients. Cilnidipine-loaded-SEDDS formulation was prepared by incorporating Canola oil, Tween 80, and PEG 300. For achieving the best formulation, D-optimal mixture design was used. The optimized SEDDS formulation was evaluated for globule size, zeta potential, drug release, drug content, self-emulsification time, and stability studies. Results: The zeta potential (Y1) and globule size (Y2) of the optimized SEDDS formulation were found to be -36mV and 124.3nm, respectively. The optimized SEDDS formulation showed more than 98% drug release within 15 min in 10% ethanolic 0.1N HCl media, which was significantly higher than that of the pure drug (7.5%) and marketed tablet (~21%). The optimized formulation's self-emulsification time, drug content, and cloud point were 55s, 99.97 ± 1.57 %, and 75.6°, respectively. After stability studies, there was no evidence of phase separation, colour change, and change in globule size. Conclusion: A significant improvement in in vitro drug release was observed from cilnidipineloaded- SEDDS.

Background: Anti-sclerostin antibodies are among the most efficient drugs for the treatment of osteoporosis, and have been also expected for the treatment of local bone disorders. We have previously developed porous microparticles of hydroxyapatite and chondroitin sulfate loading anti-sclerostin antibodies formulated with zinc cations. However, the biological behavior and concentration dependence of anti-sclerostin antibodies in vitro released from the microparticles remain unclear. Objective: Bolus administration and the subsequent release of anti-sclerostin antibodies from the microparticles formulated with or without zinc cations were investigated; bone-resorptive inhibitory effects on mouse MC3T3-E1 osteoblast function were revealed by cell culture using a cell culture insert plate. Methods: Differentiation induction culture of osteoblasts was performed after maintaining the concentrations of anti-sclerostin antibodies and sclerostin at previously reported concentrations of 5.0 and 1.0 μg/mL for the first 3 days. Subsequently, the medium was replaced with fresh medium that did not contain anti-sclerostin antibodies but microparticles loading anti-sclerostin antibodies (20 or 80 μg/mg) with or without zinc cations in the cell culture insert. After 11 days of incubation, the bioactivity of the osteoblasts was evaluated using the polymerase chain reaction method. Results: The formulation using zinc cations showed an increase of anti-sclerostin antibodies released from the microparticles, which increased the expression of receptor activator of the nuclear factor kappa-B ligand in the osteoblasts on day 14. This result indicates the inhibition of sclerostinmediated bone resorption. However, the increase of loading amounts of anti-sclerostin antibodies extremely enhanced the subsequent release of anti-sclerostin antibodies, which decreased the inhibition of bone resorption contrary to expectations. Conclusion: The moderately sustained release of anti-sclerostin antibodies from the microparticles can promote the inhibition of bone resorption in osteoblasts, supporting the potential of this formulation for the treatment of localized bone disorders.