Subconjunctival therapy by cubic liquid crystalline nanoparticles to deliver Triamcinolone acetonide for the management of diabetic Retinopathy: In vivo evidences.

The expression of inflammatory markers and vascular endothelial growth factor (VEGF) was found to be upregulated in various posterior ocular disorders, including diabetic retinopathy (DR). Effective delivery of therapeutic agents to the retina poses a significant challenge in ophthalmic drug delivery due to biological ocular barriers. Triamcinolone acetonide (TA) was selected as the model corticosteroid drug targeting cytokines and VEGF in DR. However, despite TA's low molecular weight and hydrophobicity, which enable it to bypass the conjunctival epithelial barrier, it doesn't efficiently exert its effect at the target site. Nanocarriers have emerged as a solution to enhance drug delivery to the retina and improve bioavailability. This study aimed to compare the effects of Triamcinolone-loaded cubic liquid crystalline nanoparticles (TA-cubic LCNPs) and TA-Suspension in an experimental DR model administered via the subconjunctival (SCJ) route. The results demonstrated that TA-cubic LCNPs enhanced TA periocular delivery efficacy by reducing inflammatory and VEGF markers through the advanced glycation end products (AGE)/protein kinase C pathway. They were identified as promising nano-carriers, exhibiting potential for targeted delivery to the retina.

A Review on Development and Characterization of a Cost-effective Targeted Quality-driven Antimalarial Product with an Emphasis on Phytosomes.

Malaria, a protozoan disease, led to numerous deaths and several new million cases raised due to the development of resistance as per the WHO malaria report 2019. This can be overcome by the development of an effective targeted plant-based delivery system through phytosomes that are effective in permeation and bioavailability to treat infected RBCs (parasitic cells). This review article explained the development of targeted Nanophytosomes to overcome resistance, to improve efficacy. This review paper also emphasized various quality-driven developmental approaches in developing an antimalarial product at a reasonable cost. By implementing molecular modeling techniques in development, a significant phytoconstituent with the capability of acting at the target (receptor or enzymes) of the parasite and the one with the capability to overcome drug resistance against resistant strains of parasites can be identified. Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies information provide a route to the design and formulation of a potent antimalarial agent. Efficient, targeted Nanophytosomal formulations can be formulated by functionalizing or conjugating with suitable targets to direct the phytoconstituent to the infected RBCs thereby achieving complete parasitic eradication. Artificial Neural Network technology (ANN), Quality by Design (QbD), molecular dynamics, and simulation studies implementation improves quality and reduces the cost of the product, as these malarial products are much utilized in low-income countries. Hence it can be concluded that targeted developmental quality-driven approaches implementation is essential for effective malarial treatment.

Stimuli-responsive and cellular targeted nanoplatforms for multimodal therapy of skin cancer.

Interdisciplinary applications of nanopharmaceutical sciences have tremendous potential for enhancing pharmacokinetics, efficacy and safety of cancer therapy. The limitations of conventional therapeutic platforms used for skin cancer therapy have been largely overcome by the use of nanoplatforms. This review discusses various nanotechnological approaches experimented for the treatment of skin cancer. The review describes various polymeric, lipidic and inorganic nanoplatforms for efficient therapy of skin cancer. The stimuli-responsive nanoplatforms such as pH-responsive as well as temperature-responsive platforms have also been reviewed. Different strategies for potentiating the nanoparticles application for cancer therapy such as surface engineering, conjugation with drugs, stimulus-responsive and multimodal effect have also been discussed and compared with the available conventional treatments. Although, nanopharmaceuticals face challenges such as toxicity, cost and scale-up, efforts put-in to improve these drawbacks with continuous research would deliver exciting and promising results in coming days.

Brinzolamide Dimethyl Sulfoxide In Situ Gelling Ophthalmic Solution: Formulation Optimisation and In Vitro and In Vivo Evaluation.

In the present work, a cost-effective, stable and sustained release ophthalmic solution formulation of brinzolamide (BRZ) was developed for the treatment of glaucoma. The prototype formulation undergoes 'in situ gelling' when administered in the eye, thereby providing longer residence (16-24 h). As a result, the same therapeutic endpoint is achieved with once daily dosing vis-à-vis the commercially available product Azopt® (brinzolamide 1.0% w/v, Alcon Laboratories, USA) that requires 3-4 times instillations per day. The prototype formulations were prepared using dimethyl sulfoxide, polyoxyl 35 castor oil and polysorbate 80. Gellan gum was used as the in situ gelling agent. Formulation variables like (i) concentration of the drug, dimethyl sulfoxide and in situ gelling agent and (ii) type and concentration of solubiliser showed a significant effect on the solubility of brinzolamide, in vitro gelling time, in vitro drug release and in situ gel stability. Prototype formulations were evaluated in New Zealand white rabbits for ocular toxicity and efficacy study. The tested formulations were well tolerated and reduced intraocular pressure (IOP) from 25-28 to 12-14 mmHg compared to saline and placebo control samples. Additionally, a significant increase in the area under change in IOP from baseline (ΔIOP) vs. time curve and a longer mean residence time (MRT) were also observed for the test formulations (7.4 to 17.7 h) compared to the commercially available suspension of Azopt® (4.9 h) (p < 0.0001). Thus, 'in situ gelling' formulation strategy described in this work can work as a viable option for ocular delivery of brinzolamide for the treatment of glaucoma.

Design, optimisation and evaluation of in situ gelling nanoemulsion formulations of brinzolamide.

The present research work summarises the development of an in situ gelling ophthalmic nanoemulsion of brinzolamide providing sustained release and prolonged therapeutic effect for the treatment of glaucoma. Nanoemulsions were prepared using castor oil, polyoxyl 35 castor oil and polysorbate 80 and with gellan gum as the in situ gelling agent. Formulations were screened based on globule size, Zeta potential, in vitro drug release and stability towards phase separation and sol to gel conversion upon storage. Selected formulations exhibiting a low mean globule diameter (< 160 nm), narrow size distribution (polydispersity index < 0.3), quick in vitro gelling time (< 15 s) and stability for at least 6 months at 25 °C/40% RH and 40 °C/25% RH were evaluated for intraocular pressure (IOP)-lowering efficacy studies using glaucomatous rabbits. Tested nanoemulsion formulations were well tolerated and significantly decreased IOP relative to saline and placebo controls (p < 0.005). Furthermore, an appreciable increase in the area under change in IOP from baseline (ΔIOP) vs. time curve and a longer mean residence time (MRT) was also observed for the test formulations compared with commercially available suspension of brinzolamide (Azopt, Alcon Laboratories, USA). Thus, nanoemulsion formulations containing in situ gelling polymer may serve as improved drug delivery system providing superior therapeutic efficacy and better patient compliance for the treatment of glaucoma. . Graphical abstract.

Levofloxacin Hemihydrate In Situ Gelling Ophthalmic Solution: Formulation Optimization and In Vitro and In Vivo Evaluation.

Bacterial conjunctivitis is a leading cause of ocular infections requiring short-term therapeutic treatment with frequent administration of drugs on daily basis. Topical dosage forms available in the market for the treatment of bacterial conjunctivitis such as simple drug solutions and suspensions are rapidly eliminated from the precorneal space upon instillation due to tear turn over and nasolacrimal drainage, limiting intraocular bioavailability of drug to less than 10% of the administered dose. To overcome issues related to conventional drop, an effort was made to design and evaluate prolong release ophthalmic solution of levofloxacin hemihydrate (LFH) using ion-sensitive in situ gelling polymer. Gellan gum was used as the in situ gelling agent. Formulations were screened based on in vitro gelation time, in vitro drug release, and stability towards sol to gel conversion upon storage. The prototype formulations exhibiting quick in vitro gelling time (< 15 s), prolonged in vitro drug release (18-24 h), and stability for at least 6 months at 25°C/40% relative humidity (RH) and 40°C/25% RH were evaluated for pharmacokinetic studies using healthy New Zealand white rabbits. Tested formulations were found to be well-tolerated and showed significant increase in AUC0-24 (22,660.39 h ng/mL) and mean residence time (MRT 12 h) as compared with commercially available solution Levotop PF® (Ajanta Pharma Ltd., India)(AUC0-24 6414.63 h ng/mL and MRT 4 h). Thus, solution formulations containing in situ gelling polymer may serve as improved drug delivery system providing superior therapeutic efficacy and better patient compliance for the treatment of bacterial conjunctivitis.

A top-down technique to improve the solubility and bioavailability of aceclofenac: in vitro and in vivo studies.

The aim of the present work was to tackle the solubility issue of a biopharmaceutics classification system (BCS)-II drug, aceclofenac. Although a number of attempts to increase the aqueous solubility have been made, none of the methods were taken up for scale-up. Hence size reduction technique by a top-down approach using wet milling process was utilized to improve the solubility and, consequently, the dissolution velocity of aceclofenac. The quality of the final product was ensured by Quality by Design approach wherein the effects of critical material attributes and critical process parameters were assessed on the critical quality attributes (CQAs) of nanocrystals. Box-Behnken design was applied to evaluate these effects on critical quality attributes. The optimized nanocrystals had a particle size of 484.7±54.12 nm with a polydispersity index (PDI) of 0.108±0.009. The solid state characterization of the formulation revealed that the crystalline nature of the drug was slightly reduced after the milling process. With the reduced particle size, the solubility of the nanocrystals was found to increase in both water and 0.1 N HCl when compared with that of unmilled pure aceclofenac. These results were further supported by in vitro release studies of nanocrystals where an appreciable dissolution velocity with 100.07%±2.38% release was observed for aceclofenac nanocrystals compared with 47.66%±4.53% release for pure unmilled aceclofenac at the end of 2 h. The in vivo pharmacokinetic data generated showed a statistically significant increase in the Cmax for aceclofenac nanocrystals of 3.75±0.28 µg/mL (for pure unmilled aceclofenac Cmax was 1.96±0.17 µg/mL). The results obtained indicated that the developed nanocrystals of aceclofenac were successful in improving the solubility, thus the absorption and bioavailability of the drug. Hence, it may be a viable and cost-effective alternative to the current therapy.