International Journal of Pharmaceutics最新文献

Pulmonary drug delivery is crucial for treating respiratory diseases, requiring precise particle engineering for optimal therapeutic efficacy. This study demonstrates a novel integration of 3D-printed microfluidic micromixers with spray drying technology to produce inhalable azithromycin (AZM) microparticles targeting lung delivery. The formulation demonstrated effective deep lung deposition at both 30 L/min and 60 L/min flow rates. At 30 L/min, AZM-loaded microparticles achieved enhanced performance with 1.2-fold higher Fine Particle Fraction (FPF) < 5 µm and 1.4-fold higher FPF < 3 µm compared to 60 L/min. Microparticles (25 mg) can deliver an efficacious dose of AZM to the lung, exceeding the reported epidemiological cut-off for Haemophilus influenzae (4 mg/L) by approximately five-fold while maintaining high human bronchial epithelial cell viability (> 94 %). The antibacterial efficacy against H. influenzae was confirmed, demonstrating the therapeutic potential against lung pathogens. The successful deep lung deposition at both air flow rates reflects the robustness of the formulation design, making it suitable for diverse patient populations with varying inspiratory capabilities, including children and elderly patients.

Feline infectious peritonitis virus (FIPV) caused by feline coronavirus (FCoV) infection leads to a high mortality rate when untreated. GS-441524, an antiviral agent effective against FIPV, is orally administered twice daily or through daily subcutaneous injections for approximately 12 weeks. While the short treatment period recuses concerns about adherence, frequent administrations may cause handling-related stress in cats. Therefore, it is essential to develop a long-acting formulation that requires only a single administration. In this study, we used polylactide-co-glycolide (PLGA) as a carrier, which was used to effectively encapsulate GS-441524 with sustained-release functionality and GS-441524-loaded PLGA nanoparticles (GS-PLGA NP) were prepared. The particle size of GS-PLGA NP was 216 nm, the encapsulation efficiency was 78 %, and the 7-day release was 92 %. When GS-PLGA NP was injected at 22 mg/kg in cats, higher systemic exposure can be expected compared to injecting GS-441524 at 4 mg/kg for one week (relative bioavailability, 152 %). As well as GS-PLGA NP showed lower toxicity, improved cellular uptake, and enhanced antiviral efficacy against FCoV compared to the pure GS-441524.

Poly(lactic-co-glycolic acid) (PLGA) is an FDA-approved, biodegradable, and biocompatible polymer, which makes it a promising starting material for the development of nanoparticles. However, in vivo studies have revealed a short biological half-life due to recognition and consequently internalization of these nanoparticles by cells of the mononuclear phagocyte system, resulting in their accumulation in the liver and spleen. In this study, we analyzed the adsorption pattern of proteins on PLGA nanoparticles after incubation with human plasma and human serum. For this analysis, different nanoparticle stabilizer systems were manufactured, and the adsorbed protein amounts were determined after incubation. Additionally, the adsorbed proteins were identified and enrichment and depletion processes of specific proteins that take place during protein incubation were measured via LC-MS/MS. The results showed a high enrichment of several opsonins on the nanoparticle surface and a depletion of most dysopsonins. Therefore, we hypothesize that an explanation for the unfavorable in vivo behavior of PLGA nanoparticles could be the formation of a biomolecular corona with a preferential adsorption of opsonins. Furthermore, we aimed to analyze whether different stabilizers, located on the surface of PLGA nanoparticles, were able to modify the protein adsorption pattern. Our findings suggest that the use of different stabilizers can influence the amount of total bound proteins on the nanoparticle surface. However, the change of stabilizers has only a minor impact on the composition of the biomolecular corona.

Diabetes is a common disease worldwide, and its treatment has been continuously explored. In order to solve a series of problems associated with insulin injection, many researchers have been exploring carriers for oral insulin administration. To realize the absorption of insulin, it is necessary that the drug delivery carrier can overcome the complex internal environment. Smart hydrogels are applied in various fields of biomedicine because it can respond to external stimuli. There are feasible examples in the experiment of oral insulin administration by researchers using smart hydrogels. In this study, the obstacles in oral insulin delivery, the application of different types of smart hydrogels in oral insulin delivery and other insulin delivery methods, the application of smart response materials with different hydrogel matrices in the biomedical field, and the synthesis methods of smart hydrogels are reviewed.

Effective management of posterior ocular segment disorders necessitates sustained retinal drug delivery and rational therapeutic selection. Despite significant advances, developing drug delivery systems that simultaneously achieve deep tissue penetration and prolonged ocular surface retention remains challenging. To bridge this gap, we engineered a borneol- decorated baicalein nanoemulsion in-situ gel (Bor/Bai-N@GEL) ophthalmic formulation for dry age-related macular degeneration (d-AMD). The system integrates a borneol-decorated baicalein nanoemulsion with an ion- sensitive hydrogel. Comparative analysis revealed Bor/Bai-N@GEL's superior therapeutic performance, attributable to the prolonged ocular residence time and enhanced transcorneal permeability. Pharmacodynamic profiling demonstrated marked attenuation of inflammatory cytokines, oxidative markers, and apoptotic signaling in murine d-AMD models. In summary, our work provided a meaningful delivery strategy and research basis to treat fundus diseases. This approach offers the potential to conveniently treat early-stage d-AMD at home, improving patient adherence and overall treatment outcomes.

We have previously described a model using porcine ear skin ex vivo for longitudinal studies into the disposition of macromolecules after subcutaneous injection. Since porcine skin cannot fully mimic biological responses in human skin, we now describe an ex vivo system using "full thickness" human skin. Spongiosis and epidermal detachment were the primary endpoints to evaluate skin structural integrity over a 9-day culture period. Epidermal barrier function and basal cell proliferation were monitored using expression of claudin-1 and Ki-67, respectively. Immunofluorescent staining of type I and type III procollagens and elastin after subcutaneous injection of TGF-β3, a cross-linked hyaluronic acid hydrogel, and saline solution and "no treatment" controls, showed that the model enabled visualization of changes in extracellular matrix proteins. Semi-quantitative, automated image analysis methods using multiple ROIs were evaluated to assess signal intensity and expression area of type I procollagen but displayed high inter-regional variability due to skin sample heterogeneity. Absolute quantitative methods, e.g. RT-qPCR or ELISA, which enable determination of biomarkers at either the mRNA level or the amounts of protein expressed in the sample, could be a better reporting tool. In conclusion, we successfully developed an ex vivo "full thickness" human skin model that retained viability over 9 days and which could be deployed in combination with qualitative/quantitative methods to evaluate local biological effects of subcutaneously injected biomacromolecules.

Lipid nanoparticles (LNPs) are used to encapsulate messenger ribonucleic acids (mRNAs) and enhance mRNA vaccine efficacy by producing inflammatory mediators. However, the overproduction of inflammatory mediators via LNP injection causes severe side effects, presenting a potential limitation. To resolve this issue, we developed pH-responsive dipeptide-conjugated lipid (DPL)-based LNPs (DPL-LNPs) for efficient small interfering RNA delivery with excellent biocompatibility. In detail, we optimized the dipeptide sequence and lipid-tail length of DPL, the helper-lipid compositions, and the molecular weight and lipid-tail length of the polyethylene glycol (PEG)-lipid to achieve highly efficient and safe mRNA delivery. Our results revealed that the LNPs prepared using glutamic acid (E)- and arginine (R)-conjugated DPL (DPL-ER) displayed higher protein-expression efficacy than DPL-threonine-R- and DPL-aspartic acid-R-based LNPs. Additionally, the lipid-tail length of the C22-bearing DPL-ER (DPL-ER-C22)-based LNPs displayed higher protein-expression efficacies than their C18 (DPL-ER-C18)- and C24 (DPL-ER-C24)-based LNPs. Moreover, the DPL-ER-C22-based LNPs incorporating low-lipid-tail-length phospholipids and PEG-lipids exhibited efficient protein expression. Most importantly, the injection of optimized DPL-LNPs exhibited comparable antigen-specific antibody production levels, with significantly lower inflammatory-mediator production compared with those of the commercially available LNPs. These results indicate that DPL-based LNPs (DPL-LNPs) can be deployed as highly efficient, safe carriers for mRNA delivery for developing mRNA vaccine formulations.

Given their unique phagocytic function, inflammatory site tropism, and ability to penetrate deep into the lesion sites, macrophages are considered to have promising application potential in the field of living-cell drug delivery. The methods of drug delivery using macrophages primarily include intracellular phagocytic and extracellular drug loading. Comparatively, extracellular drug loading is potential less cytotoxicity and has minimal effects on the motility and orientation of cells. In this review, we provide an overview of the methods of extracellular drug loading, and examine the effects of the different properties of nanoformulations on extracellular drug-loaded delivery systems. In addition, we assess the prospects and challenges of a self-propelled macrophage-based drug delivery system. We hope this research contributes to optimizing the design of these drug delivery systems.

The long-acting hydromorphone loaded poly-lactic-co-glycolic acid (HM-PLGA) microspheres for chronic pain management were developed and prepared using an automatic and scalable microfluidic process system in this study. The system consists of a novel designed micro-mixer for particle generation, syringe and HPLC pumps for continuous dosing, a process Raman spectrometer as process analytical technology (PAT) tool and an automation system for programmable automatic control. With the benefits of the automation and digitalization of the system, a wide range of formulation parameters was investigated for its impact on the properties of the microspheres. The particle size of the HM-PLGA microspheres was tunable with the automatic microfluidic process system. The long-acting injectable homogeneous HM-PLGA microspheres were successfully prepared with maximum drug-loading capacity of 7.71 % and drug encapsulation efficiency of 69.40 %. The physical and chemical properties were characterized using various analytical technologies. Pharmacokinetic experiments in female ICR mice confirmed prolonged exposure in plasma compared to the HM hydrochloride injection. In vivo studies in beagle dogs showed that the HM-PLGA microspheres provided sustained drug release for over 11 days. The results demonstrated the potential of the novel automatic microfluidic process system in the development and continuous manufacturing of the particle size-controllable drug loaded microspheres.