Drug Delivery and Translational Research最新文献

Additive manufacturing offers unprecedented opportunities for personalized medicine, but most pharmaceutical printing platforms are optimized for milligram-range doses, limiting their suitability for microdosing. This work introduces a novel liquid deposition approach using a modified technical pen integrated into a pharmaceutical printer. The gravity-driven mechanism enabled precise microscale dispensing without external thermal, pneumatic, or electrical inputs, which have been associated with molecular stress in other printing technologies. Desmopressin, a potent synthetic hormone indicated for diabetes insipidus and requiring ultra-low doses, was selected as a model compound. Oral films (2 × 4 cm) containing therapeutically relevant doses (33-134 µg) were produced by depositing up to four layers of pharmaceutical ink. A custom-developed software interface allowed precise control of key process parameters, supporting reproducibility and automated workflows. The system achieved ~ 100% dose accuracy, with a strong correlation between drug content and layer number. Films exhibited rapid disintegration and immediate release. Stability testing showed no drug degradation over one month. Unlike more complex printing platforms, the technical printhead architecture offered straightforward manipulation and rapid setup. Given the constant ink flow rate and low, consistent, deposition volumes, only 1 mL of formulation is sufficient to produce up to 238 single-layer 2 × 4 cm films. These findings position the technical pen-based printhead as a promising, precise, and cost-effective addition to the additive manufacturing landscape, with strong potential for low-dose personalized pharmaceutical applications, including biologics. Moreover, its performance underscores the potential for further optimization and broader application.

Glioblastoma recurrence after surgery is a major contributor to its high mortality, primarily occurring near the original tumour margin. Various hydrogels have been developed to fill the post-surgical cavity and deliver drugs to the surrounding brain tissue to eliminate residual cells. However, the impact of tissue, hydrogel, and drug properties on delivery outcomes remains unclear. Here, a parametric study is conducted to investigate these effects using mathematical modelling. The results show that post-surgical oedema strongly influences delivery: longer duration or delayed onset of oedema can homogenise drug distribution, with delayed onset yielding a larger and more sustained therapeutic drug volume. Hydrogels with higher permeability or lower drug affinity enhance early concentration and distribution but decline faster over time. Drugs with lower intracellular partitioning improve early efficacy, whereas those with stronger binding to cellular or extracellular components sustain delivery longer. Lower transvascular permeability and slower elimination further enhance outcomes, while extracellular diffusivity must be optimised to maximise drug concentration and distribution. These findings provide guidance for optimising hydrogel-based drug delivery systems to prevent glioblastoma recurrence.

Three-dimensional printing of medicines is moving from feasibility to practice across hospital point-of-care manufacture, community-pharmacy compounding and industrial production. Recent signals include a point-of-care printed oral solid dosage form that met bioequivalence in healthy adults, automated capsule preparation with embedded checks in pharmacies and the first approved industrial product. These advances suggest that 3D printing can deliver clinically acceptable quality when responsibilities, verification and documentation are in place. This review integrates evidence across all three settings and offers a critical appraisal of what is required for safe adoption. We examine how regulatory responsibilities should be allocated across distributed sites, how non-destructive testing and chemometric models can be validated for small batches and which digital systems are essential for traceability and oversight. We analyse where economics break even compared with conventional compounding and identify use cases where 3D printing is comparatively advantaged, including low-dose titration, paediatric formats and rapid design iteration. We also outline risks that must be managed, including training and competency, cleaning validation, cross-contamination control and pharmacovigilance across networks. Finally, we propose a near-term agenda that includes standardised conduct of point-of-care trials, multi-site cost and quality benchmarking, explicit guidance on recalls and labelling and deeper industrial-clinical partnerships to turn pilots into routine practice.

Inclusion of physiologically relevant clearance mechanisms into organ-on-a-chip models is essential to reproduce tissue exposure and predict therapeutic efficacy, especially for local therapies and drug delivery applications that are already common in the clinic for ocular and cancer treatments. There remains a need for clearance-enabled organ-on-a-chips amenable to high throughput screening, especially with the emerging trend to expedite formulation and drug delivery vehicle (DDV) design with machine learning. To address this gap, we developed a microfluidic platform that incorporates continuous, pressure-driven clearance through interconnected microchannels and three-dimensional (3D) systems, enabling translational evaluation of local therapies and DDVs, such as injectable hydrogels, that aim to reduce systemic toxicity and enhance efficacy by prolonging drug residence at disease sites. In this study, fluorescent 4 and 65 kDa dextrans were used to confirm that pressure gradients across the platform promote efficient clearance versus passive diffusion. The pressure gradients were then applied to breast cancer spheroids co-cultured with macrophages in a fibrin hydrogel to evaluate the therapeutic efficacy of an interferon gamma (IFN-γ)-releasing agarose hydrogel in combination with anti-human epidermal growth factor receptor 2 (anti-HER2). Fluorescent imaging of spheroid area revealed increased cancer cell viability, lower drug efficacy, when continuous clearance was present, highlighting the impact of drug clearance. This study establishes the clearance-enabled microfluidic platform as a translationally relevant in vitro model for evaluating local therapies under continuous clearance, thereby bridging the gap between traditional static platforms and in vivo models for evaluating local pharmacokinetics and pharmacodynamics.

Nanostructured lipid carriers (NLCs) decorated with sulfhydryl-modified surfactants have recently gained attention for delivering BCS Class IV drugs. However, the impact of the chain-length of these surfactants on the permeation and bioavailability properties of NLCs is still unknown. Therefore, this study investigates the effect of surfactant chain-length on the mucoadhesive, permeation, and bioavailability properties of NLCs. For this purpose, short- and long-chain sulfhydryl-modified polyethoxylated surfactants were generated to develop mucoadhesive NLCs and loaded with the model drug aprepitant (APT). NLCs were characterized and assessed for comprehensive physicochemical and biological evaluations. Moreover, in-vivo studies were performed for proof-of-concept to show enhanced oral drug bioavailability. NLCs showed particle size under 200 nm with 6.9 and 6.7% drug loading and 85 and 84% drug entrapment for short- and long-chain surfactants, respectively. The drug-loaded NLCs were safe and stable, and short- and long-chain surfactants containing NLCs exhibited 11.6- and 9.6-fold enhanced mucoadhesion, respectively. Moreover, in comparison to long-chain sulfhydryl-modified surfactant, short-chain surfactant is transported into deeper segments of mucus due to less interaction with the mucus. Similarly, short-chain sulfhydryl-modified surfactants showed significantly enhanced cellular permeation across Caco-2 cell lines. Furthermore, the long-chain sulfhydryl-modified surfactants showed 4.38-fold enhanced C_max, whereas due to better diffusion and mucoadhesion properties, the short-chain surfactants exhibited 5.38-fold enhanced C_max. Similarly, 34.8% relative bioavailability was attained for short-chain surfactants and 24.8% for long-chain surfactants. These results suggest short-chain sulfhydryl surfactants are promising candidates for improving the oral delivery of poorly soluble drugs and warrant further investigation for clinical translation.

Inflammatory bowel diseases (IBD) affect millions of people worldwide. The use of anti-TNF-α for the treatment of moderate-to-severe IBD faces primary non-response, loss of response during treatment or intolerance issues. As an alternative, a strategy consisting of oral administration of TNF-α siRNA was evaluated in the present study for the local treatment of IBD. TNF-α siRNA entrapped in lipid nanoparticles (LNPs) was microencapsulated in gastroresistant alginate particles using an original process. The encapsulation yield of both siRNA and LNPs in microparticles (MPs) was at least 90%. Oral administration of MPs significantly reduced both clinical score and therapeutic index in a TNBS-induced colitis model in mice. Near complete removal of tissue damage, including edema, ulceration and necrosis, was observed in colon sections from treated mice. Reduced variation in gene sets involved in the global inflammatory response and the TNF-α/NF-κB signaling pathway was detected in the colon compared to untreated mice, demonstrating the anti-inflammatory activity of MPs. Finally, biodistribution studies showed the targeting of the inflamed colon by MPs and the colocalization of LNPs and MPs at the site of action. These MPs may represent a promising siRNA delivery platform for the oral treatment of IBD.

Autoinjectors with dual-chamber cartridges (AIDCs) are single-use, self-administrable injection devices that facilitate automated reconstitution and injection of lyophilized products. We report the development and application of a physics-based model to understand and optimize AIDC behavior, predicting its response as a function of formulation properties and injection device parameters. Our model is based on the equations of motion for the AIDC's dual stoppers, as well as the ideal gas law and an experimentally derived stopper friction vs. glide speed relationship. Our model provides estimates for some of the key essential performance requirements that yield good device performance, including injection time, stopper trajectories, and the maximum diluent volume. We validated our model using experimental injection time data demonstrating good agreement for a range of diluent volumes, reconstituted solution viscosities, and stopper positions. The model allows different device and formulation configurations to be tested virtually without requiring the physical device and formulation, reducing the need for extensive experimental testing and ensuring the robustness of the injector performance for successful drug delivery. The modeling framework applies to a broad class of spring-driven AIDCs for lyophilized drug and vaccine delivery and enables informed device selection through simulation-led technical due diligence.

Glaucoma, a leading cause of irreversible blindness, is marked by elevated intraocular pressure (IOP) and retinal ganglion cell death. Traditional IOP-lowering eye drops often fail to penetrate the ocular barrier, leading to suboptimal outcomes. Microneedles (MN), offer a promising minimally invasive and localized alternative. Our study aimed to formulate a naturally-derived nanodelivery system using Luteolin-loaded colostrum-derived exosomes (LUT-EX) and propolis in MN arrays for better ocular delivery. The isolated exosomes were uniform, averaging 50.83 nm in size, with a zeta potential of -21.89 mV. LUT-EX showed a 48-h sustained release and high safety with an IC50 of 356.3 µg/mL. Integrating LUT-EX and propolis into MN arrays achieved optimal dissolution in over one minute and maintained mechanical strength under 30 N compression. LUT-EX@MN increased LUT permeation through scleral tissues 2.6-fold compared to gel matrix formulations. It also showed a sustained IOP-lowering effect reaching the normal IOP level in the first 3h and sustained over 7 days. The integrated system significantly reversed glaucoma-induced changes in TNF-α, IL-8, MYOC, NRF2, TIMP1, and IL-1β levels, resembling those of the healthy group. It also boosted antioxidant activity, increasing glutathione peroxidase by 1.6-fold compared to glaucomatous rabbits. Thus, our study highlighted that the integration of LUT-EX into microneedle arrays presents a groundbreaking dropless approach for localized glaucoma treatment, offering enhanced therapeutic efficacy. This platform could revolutionize glaucoma management, paving the way for more effective and targeted ocular therapies.

The global coenzyme Q10 (CoQ10) market is expanding, driven by the increasing prevalence of chronic diseases, particularly cardiovascular disorders. Forecasts project a compound annual growth rate of 9.68% from 2025 to 2034. Despite its critical role in cellular energy metabolism and antioxidant defense, CoQ10's clinical potential is constrained by poor water solubility and low oral bioavailability. This review delivers a critical and translational comparison of lipid-based and water-based encapsulation strategies, offering novel insights into their mechanistic advantages, formulation challenges, and clinical applicability for enhanced CoQ10 delivery. Lipid-based systems, such as self-emulsifying drug delivery systems (SEDDS), liposomes, and nanoemulsions, improve solubility and gastrointestinal absorption, protect CoQ10 from degradation, and promote lymphatic transport. However, they often require high excipient content and exhibit stability concerns, such as susceptibility to oxidation. Water-based approaches, including β-cyclodextrin complexation, polymeric nanoparticles, solid dispersions, and CoQ10-nicotinamide cocrystals, enhance aqueous solubility and absorption while offering better chemical stability and lower formulation cost. This review highlights the mechanistic differences, benefits, and limitations of each strategy, providing critical insights for the rational design of CoQ10 delivery systems. The findings support formulation optimization to improve therapeutic efficacy and inform manufacturing decisions for clinical and commercial applications. Looking ahead, future directions may include nano-enabled personalized medicine strategies based on individual metabolic profiles and the development of intranasal CoQ10 delivery platforms that leverage nanoscale lipid or water-based carriers for direct nose-to-brain transport in neurological disease therapy.