Drug Delivery and Translational Research最新文献

Hydrogel-forming microneedle (MN) arrays are minimally-invasive devices that can penetrate the stratum corneum, the main barrier to topical drug application, without causing pain. However, drug delivery using hydrogel-forming MN arrays tends to be relatively slow compared to rapid drug delivery using conventional needles and syringes. Therefore, in this work, for the first time, different physical and chemical delivery enhancement methods were employed in combination with PVA-based hydrogel-forming MN arrays. Using a model drug, ibuprofen (IBU) sodium, the designed systems were assessed in terms of the extent of transdermal delivery. Iontophoresis (ITP) and heat-assisted drug delivery technology were investigated as physical permeation enhancement techniques. Ex vivo studies demonstrated that the ITP (0.5 mA/cm²)-mediated combination strategy significantly enhanced the transdermal permeation of IBU sodium over the first 6 h (~ 5.11 mg) when compared to MN alone (~ 1.63 mg) (p < 0.05). In contrast, heat-assisted technology showed almost no promoting effect on transdermal delivery. Furthermore, IBU sodium-containing rapidly dissolving lyophilised and effervescent reservoirs, classified as chemical modification methods, were prepared. Both strategies achieved rapid and effective ex vivo IBU sodium permeation, equating to ~ 78% (30.66 mg) and ~ 71% (28.43 mg) from lyophilised and effervescent reservoirs, respectively. Moreover, in vivo pharmacokinetic studies showed that the IBU sodium plasma concentration within lyophilised and effervescent groups reached a maximum concentration (C_max) at 4 h (~ 282.15 µg/mL) and 6 h (~ 140.81 µg/mL), respectively. These strategies not only provided rapid achievement of therapeutic levels (10-15 µg/ml), but also resulted in sustained release of IBU sodium for at least 48 h, which could effectively reduce the frequency of administration, thereby improving patient compliance and reducing side effects of IBU sodium.

While pharmaceutical Cocrystals have long been acknowledged as a promising method of enhancing a drugs bioavailability, they have not yet experienced widespread industrial adoption on the same scale as other multi-component drugs, such as salts and amorphous solid dispersions. This is partly due to the lack of a being no definitive screening strategy to identify suitable coformers, with the most cocrystal screening strategies heavily relying on trial and error approaches, or through utilizing a multiple and often conflicting, computational screening techniques combined with high material consumption experimental techniques. From the perspective of industry, this can often lead to high material waste and increased costs, encouraging the prioritization of more traditional bioenhancement techniques. Here we present a strategy for the selection of multicomponent systems involving computational modelling for screening of drug- former pairs based on a combination of molecular complementarity and H-bond propensity screening. Jet dispensing printing technology is co-opted as a mechanism for High-Throughput Screening (HTS) of different stoichiometric ratios, as a low material consumption screening strategy. This strategy is presented herein as a Quality by Design (QbD) crystal engineering approach, combined with experimental screening methods to produce cocrystals of a novel 5-Lipoxygenase (5-LO) inhibitor, PF-04191834 (PF4). Through this methodology, three new cocrystals were indicated for PF4, confirmed via DSC and XRPD, from less than 50 mg of original testing material. Part B of this study will demonstrate the scalability of this technique continuous extrusion.

Microneedle technology has emerged as an advanced method for transdermal drug delivery, which focuses on diverse fabrication techniques to develop microneedles with various models and geometries. This study explores the application of Computer Numerical Control (CNC) milling technology to create microneedle master molds with extremely sharp tips. We examined the effects of two key machining parameters, feed rate and ramp angle, on the tip sharpness of the microneedles. Our results showed that increasing both the feed rate and ramp angle could significantly reduce machining time. However, a higher feed rate also led to larger tip diameters and notable tip defects. Conversely, changes in the ramp angle at a constant feed rate had minimal impact on tip size. We identified an optimal condition balancing cutting time and tip sharpness at a feed rate of 100 mm/min and a ramp angle of 1.5°. Additionally, we assessed the CNC's capability to produce needles with different tip angles. The findings confirm that needles with varying tip angles maintained tip diameters below 10 μm, with needles having a 50° tip angle exhibiting the sharpest tips at approximately 3.3 μm. Further compression, insertion and diffusion tests were conducted to evaluate the performance of needles with different geometries.

Despite its established anti-diabetic activity, Metformin hydrochloride (MET) has been repurposed for the management of hepatocellular carcinoma (HCC). Owing to MET high aqueous solubility and poor oral permeability, a novel nanoplatform is sought to overcome the current challenges of traditional formulations. In this study, we developed MET-bridged nanocochleates (MET-CO) using a direct bridging method followed by optimization and assessment using various in-vitro and in-vivo pharmacokinetic methods. The optimized nanocochleates MET-CO_DCP 19, containing dicetyl phosphate (DCP), displayed uniform snail-shaped nano-rolls measuring 136.41 ± 2.11 nm with a PDI of 0.241 ± 0.005 and a highly negative ζ-potential of -61.93 ± 2.57 mV. With an impressive MET encochleation efficiency (> 75%), MET-CO_DCP 19 exhibited a controlled biphasic release profile, with minimal initial burst followed by prolonged release for 24 h. Importantly, they showed significant MET permeation in both in-vitro Caco-2 and ex-vivo intestinal models compared to non-DCP containing formula or MET solution. The in-vivo oral bioavailability study demonstrated pronounced improvements in the pharmacokinetic parameters with a 5.5 relative bioavailability compared to MET solution. Notably, a significant reduction in IC₅₀ values in HepG2 cells after 24 h of treatment was observed. Furthermore, the optimized formulation showed a significant downregulation of anti-apoptotic and cancer stemness genes, with 12- and 2-fold lower expression compared to MET solution. These promising results highlight the efficacy of the novel MET-bridged nanocochleates as a stable nanoplatform for enhancing the oral bioavailability of MET and boosting its anticancer potential against HCC.

Inflammatory bowel disease (IBD) affects over 7 million people worldwide and significant side effects are associated with current therapies such as tofacitinib citrate (TFC), which is linked to increased risks of malignancy and congestive heart issues. To mitigate these systemic adverse effects, localised drug delivery via nano-sized carriers to inflamed gut tissues represents a promising approach. Herein, we aimed to optimise the synthesis of nanoparticles (NPs) using a low molecular weight grade of Poly(lactic-co-glycolic acid) (PLGA) 50:50 loaded with TFC. This approach leverages the dual anti-inflammatory action of TFC and the local production of anti-inflammatory short-chain fatty acids from the degradation of PLGA by colonic gut microbiota. NPs were produced by nanoprecipitation and characterised for their drug release profile in vitro. The efficacy of the enhanced PLGA-TFC NPs was then tested in a C57BL/6 DSS colitis mouse model. The release profile of TFC from the enhanced PLGA NPs showed a 40% burst release within the first hour, followed by up to 80% drug release in the colonic environment. Notably, the degradation of PLGA by colonic gut microbiota did not significantly influence TFC release. In the mouse model, neither PLGA NPs alone nor TFC alone showed significant effects on weight loss compared to the TFC-loaded PLGA NPs, emphasising the enhanced efficacy potential of the combined formulation. Altogether, these results suggest a promising role of NP delivery systems in enhancing TFC efficacy, marking a significant step towards reducing dosage and associated side effects in IBD treatment. This study underscores the potential of PLGA-TFC NPs in providing targeted and effective therapy for IBD.

Oral diseases rank among the most widespread ailments worldwide posing significant global health and economic challenges affecting around 3.5 billion people, impacting the quality of life for affected individuals. Dental caries, periodontal disease, bacterial and fungal infections, tooth loss and oral malignancies are among the most prevalent global clinical disorders contributing to oral health burden. Traditional treatments for oral diseases often face challenges such as poor drug bioavailability, breakdown of medication in saliva, inconsistent antibiotic levels at the site of periodontal infection as well as higher side effects. However, the emergence of nanoemulgel (NEG) as an innovative drug delivery system offers promising solutions where NEG combines the advantages of both nanoemulsions (NEs) and hydrogels providing improved drug solubility, stability, and targeted delivery. Due to their minuscule size and ability to control drug release, NEGs hold promise for improving treatment of oral diseases, where versatility of these delivery systems makes them suitable for various applications, including topical delivery in dentistry. This review concisely outlines the anatomy of the oral environment and investigates the therapeutic potential of NE-based gels in oral disorder treatment. It thoroughly examines the challenges of drug delivery in the oral cavity and proposes strategies to improve therapeutic efficacy, drawing attention to previous research reports for comparison. Through comprehensive analysis, the review highlights the promising role of NEGs as a novel therapeutic approach for oral health management via research advancements and their clinical translation. Additionally, it provides valuable insights into future research directions and development opportunities in this area.

Conventional zolmitriptan (ZOL) has limited oral bioavailability, many adverse effects, and poor membrane penetrability that negatively influences its accessibility to its 5-HT_1B/1D receptor binding pocket, located transmemberanous. This work aimed at preparing transdermal ZOL-nanoformulation (niosomes) to surpass these limitations and to explore novel antimigraine mechanisms for ZOL via modulation of the epigenetically-altered chronification genes (RAMP-1, NPTX-2) or microRNAs and affecting the endocannabinoid CB-1/MAPK pathway. The prepared ZOL niosomes (F_sp60/6-1:1) exhibited %EE of 57.28%, PS of 472.3 nm, PDI of 0.366, and ZP of -26 mV were cast into patch with content uniformity of 93.12%, maintained endurance after 200-times folding, no interaction between its components (FT-IR), a biphasic release pattern and good stability after storage at 4 °C for 6 months. In-vivo ZOL-patch application in rats with nitroglycerin-induced migraine showed significant management of migraine pain symptoms and photophobia assessed behaviorally, decreased brain levels of the trigeminal neuronal activation marker (c-fos), the migraine pain neurotransmitter (CGRP) and the serum levels of different migraine pain markers (substance P, nitric-oxide, and TNF-α). It also significantly decreased RAMP-1, NPTX-2, miR-382-5p, and CB-1/MAPK gene expression reflecting improved efficacy and brain receptors delivery to a much greater extent than conventional ZOL has done. Additionally, this nanoformulation significantly opposed migraine-induced platelet activation and hypercoagulable status in both central and peripheral circulations as evidenced by the significant decrease in adenosine diphosphate, thrombin, factor X, CD41, and Von-Willebrand factor levels assessed peripherally and centrally. TPF_sp60/6-1:1 significantly improved ZOL efficacy and accessibility to brain-receptors to a much greater extent than conventional ZOL-solution.KeywordsEndocannabinoid receptors; Epigenetically-altered genes; Hemostatic pathways; Niosomal patch; Transdermal; Zolmitriptan.

This investigation aims to fabricate, characterize, and optimize organogel containing andrographolide nanosuspension to enhance transdermal drug delivery into and across the skin in vitro. We identified the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of andrographolide nanosuspension using a systematic quality-by-design approach. We prepared andrographolide nanosuspension using the wet milling technique and evaluated various properties of the formulations. The CMAs were types and concentrations of polymers, types and concentrations of surfactants, drug concentration, and lipid concentration. The CPPs were volume of milling media and milling duration. Mean particle size, polydispersity index, encapsulation efficiency, and drug loading capacity as critical quality attributes were selected in the design for the evaluation and optimization of the formulations. Furthermore, we developed and evaluated organogel formulation to carry andrographolide nanosuspension 0.05% w/w. Drug release and permeation studies were conducted to assess the drug release kinetics and transdermal delivery of andrographolide. We presented the alteration in the average particle size, polydispersity index, encapsulation efficiency, drug-loading capacity, and drug release among various formulations to select the optimal parameters. The permeation study indicated that organogel delivered markedly more drug into the receptor fluid and skin tissue than DMSO gel (n = 3, p < 0.05). This enhancement in transdermal drug delivery was demonstrated by cumulative drug permeation after 24 h, steady-state flux, permeability coefficient, and predicted steady-state plasma concentration. Drug quantity in skin layers, total delivery, delivery efficiency, and topical selectivity were also reported. Conclusively, andrographolide nanosuspension-loaded organogel significantly increased transdermal drug delivery in vitro.