3D printing technology is characterized by highly personalized, small batch production, and excellent reproducibility. These features enable it to address the limitations of traditional dose-dividing methods currently employed in medical institutions, thereby fulfilling the diverse dosing requirements of patients. In this study, we developed two individual dosing strategies for formulating 3D printing pharmaceutical formulations (3DPF) and 3D printing divided-dose tablets (3DPDT). Specifically, 3DPF were prepared using a gel ink containing propranolol hydrochloride as the active pharmaceutical ingredient, while 3DPDT were fabricated using a paste ink incorporating powdered commercial tablets. We investigated the rheological properties of the gel and paste ink, and assessed the mechanical properties, assay, and dissolution profile of tablets. The results indicate that the appearance, mechanical properties, drug content, content uniformity and drug dissolution rate of 3DPF and 3DPDT meet the United States Pharmacopoeia-National Formulary 2024 (USP-NF 2024) requirements. These strategies demonstrate highly reproducible and high-quality tablet preparation capabilities, which are applicable in drug development and pharmacy services. Furthermore, these approaches effectively resolve the issue of fixed dosages in commercially available drugs failing to meet the personalized medication needs of special populations. They provide a novel and promotable individual dosing solution tailored to the medication requirements of various patient groups.

As an emerging technology, 3D printing facilitates the fabrication of complex preparations and enables controlled drug release. This study integrated semi-solid extrusion (SSE) and fused deposition modeling (FDM) to develop core-shell structured sustained-release tablets (CSRT) with varying release profiles, exploring how structural design influences release behavior. Propranolol hydrochloride was selected as the model drug. Drug-loaded cores with different filling rates were prepared using SSE and characterized for appearance, hardness, XRD, and release properties. Shells with varying release windows were fabricated using FDM. Subsequently, shells and cores were assembled. Micro-CT was employed for microstructural characterization, while drug assay and release properties were assessed. The results indicated that cores exhibited a good appearance, and the SSE process had no effect on the crystal type. Adjusting the filling rate allowed for slight modulation of drug release while the shell structure effectively prolonged drug release. The CSRT displayed no significant internal defects, and the assay met the United States Pharmacopoeia-National Formulary 2024 (USP-NF 2024) requirements. Adjusting release windows resulted in a sustained release ranging from 8 to 24 h, with the release profile conforming to first-order kinetics (R2 values ranging from 0.961 to 0.999). These findings provide practical strategies for controlling drug release rates.

Mucosal vaccination plays a crucial role in activating frontline immune responses, preventing infection and transmission of respiratory pathogens. However, the development of effective mRNA mucosal vaccines faces multiple challenges, including mucosal barriers, suboptimal immune cell targeting, and limited induction of mucosal immunity. In this study, we develop a dual-functional mRNA-LNP-CS+Man vaccine by utilizing DMG-PEG2000-Chitosan and DMG-PEG2000-Mannose, capable of penetrating the pulmonary mucosal barrier and targeting immune cells in the lungs. The results show that, following intratracheal administration, mRNA-LNP-CS+Man exhibits prolonged retention in the lungs for up to 72 h, with widespread distribution across the entire lung and achieving high mRNA transfection throughout the lung, particularly in immune cells. After two immunizations, the vaccine induces strong systemic and mucosal immune responses compared to the unmodified LNP, including efficient production of IgG and IgG2a in serum, IgG and SIgA in bronchoalveolar lavage fluid, and Th1-type cytokines. Significant activation of lung germinal center B (GC B) cells and tissue-resident memory T (TRM) cells were observed, alongside the establishment of effective immune memory. The vaccine demonstrates strong protective efficacy against SARS-CoV-2 D614G pseudovirus in the lungs, offering a novel strategy for mRNA mucosal vaccine development.

Natural toxins pose a substantial threat to human health worldwide, with millions of individuals suffering from toxin poisoning annually. Rapid detection and efficient neutralization of these toxins are crucial to ensure human health. Nanobodies (Nbs) are a unique antibody type comprising only variable region fragments of the heavy chain. With properties such as small size, high stability, superior tissue penetration, and ease of production and modification, making Nbs are particularly advantageous in the diagnosis and treatment of natural toxin poisoning. This review outlines the current advancements in the modification of Nbs and highlights the research progress in addressing the diagnosis and treatment of poisoning caused by certain natural toxins. It underscores the potential of Nbs in this field, while also examining their benefits and associated challenges. By doing so, the study lays a robust groundwork for the future application of Nbs in combating natural toxin poisoning. Nbs could play an increasingly important role in diagnosing and treating natural toxin poisoning, contributing to the development of precision medicine.

This study aims to develop an alternative and effective drug delivery system through inhalation therapy to address the limitations of polymyxin B (PMB) intravenous treatment for pneumonia. PMB dry powder inhalers (DPIs) were prepared and characterized. The in vitro lung deposition and antibacterial efficacy were also assessed. To compare the systemic exposure following changes in administration routes, blood concentration measurements were conducted for different routes of administration spherical PMB particles, measuring 3 microns in diameter, achieved the highest fine particle fraction (FPF) of 53%. When particles transition from regular shapes to irregular blocks, a decrease of 1 micron in particle size resulted in an approximate 20% increase in FPF. Moreover, the FPF of PMB particles combined with smooth-surfaced lactose was approximately 10% less than that of PMB particles combined with rough-surfaced mannitol. The bioavailability of PMB DPI reached a peak of 77.46% within 10 min. In a murine model of acute lung infection, treatment with PMB DPI significantly reduced the bacterial load in lung tissues compared to the control group with intravenous PMB administration. In summary, particles with reduced size and increased sphericity displayed a greater FPF led to enhanced therapeutic efficacy and safety.

The management of the acute bacterial infections in the traumatic skin remains a significant challenge in clinical. The application of antibiotics on wounds is typically avoided due to antimicrobial resistance risks. Antisense therapeutics, like antisense oligonucleotides (ASOs), present a selective, low-resistance alternative, but effective bacterial uptake is still a major obstacle. In this work, we developed a novel microneedle-based delivery system (MNDS) distinguished by its distinctive multifunctional hydrogels and a "Tripartite Delivery" mechanism. The MNDS was designed with a bionic mushroom-shaped multilayered structure. Upon application, the MNDS enabled an initial rapid release and sustained release of the encapsulated nanocomplexes (ASO@GP-SiNPs). The needle body layer hydrogels can respond to hyaluronidase and continuously release hyaluronic acid and epsilon-polylysine for several days. These ASO@GP-SiNPs were effectively uptaken by E. coli (46.4 %) and S. aureus (37.1 %), subsequently releasing ASOs that target the acpP and ftsZ genes to effectively eliminate bacteria. The system exhibits significant antibacterial activity and effectively inhibits biofilm formation, while also inducing the polarization of macrophages toward an M2-like phenotype. Additionally, the system demonstrates excellent biocompatibility. In conclusion, this paper presents a novel strategy for addressing the challenges of acute bacterial infections in traumatic skin by utilizing the advanced functionalities of MNDS.

Background/Objectives: Omicron, the predominant variant of SARS-CoV-2, exhibits strong immune-evasive properties, leading to the reduced efficacy of existing vaccines. Consequently, the development of versatile vaccines is imperative. Intranasal mRNA vaccines offer convenient administration and have the potential to enhance mucosal immunity. However, delivering vaccines via the nasal mucosa requires overcoming complex physiological barriers. The aim of this study is to modify PEGylated lipids to enhance the mucosal immune efficacy of the vaccine. Methods: The PEGylated lipid component of lipid nanoparticle (LNP) delivery vectors was modified with chitosan or mannose to generate novel LNPs that enhance vaccine adhesion or targeting on mucosal surfaces. The impact of the mRNA encoding the receptor-binding domain of Omicron BA.4/BA.5 on the immune response was examined. Results: Compared to the unmodified LNP group, the IgG and IgA titers in the chitosan or mannose-modified LNP groups showed an increasing trend. The chitosan-modified group showed better effects. Notably, the PEGylated lipid with 1.5 mol% of chitosan modification produced high levels of IgG1 and IgG2a antibodies, promoting Th1/Th2 responses while also generating high levels of IgA, which can induce stronger cellular immunity, humoral immunity, and mucosal immunity. Conclusions: The 1.5 mol% of chitosan-modified LNPs (mRNA-LNP-1.5CS) can serve as a safe and effective carrier for intranasal mRNA vaccines, offering a promising strategy for combating the Omicron variant.

Curcumin has diverse biological functions, especially antioxidant and anti-inflammatory properties, but clinical trials have been hindered by its low bioavailability and pharmacokinetic properties. To achieve therapeutic efficacy, understanding curcumin’s in vivo metabolism is crucial. We reviewed current research on curcumin metabolism in PubMed, Google Scholar, and CNKI. This article outlines curcumin’s metabolic processes in the body via oral and intravenous injection. It suggests that upon entering the human body, curcumin may undergo oxidation, reduction, binding, and microbial community influence.

Vaccination is among the most effective ways to prevent infectious diseases. Subunit vaccines are safe but usually require multiple booster shots, which may lead to immunity loss and economic consume. In this study, a self-boosting vaccine is developed based on the pulsatile release of antigen from the core-shell microparticle after single-injection immunization. Self-healing technology applied to form an "antigen core" can avoid organic solvents from destroying the spatial structure of the antigen. The "antigen shell" is built-up by self-assemble of the antigen with the opposite charged polypeptide. Primary immunization occurs with the self-assembled film disintegration, and the booster comes with the microparticle degradation. The changing of antigen-specific antibodies after immunization with the core-shell microparticle vaccine is consistent with that caused by the two shots of immunization. The immune effect and safety evaluation results support the translational potential of this self-boosting core-shell microparticle vaccine.

全氟化碳是一种具有良好生物相容性的化学惰性物质,已广泛应用于超声造影、器官移植、预防组织器官缺血和再灌注损伤等.全氟化碳纳米乳剂具有高携氧能力,是人工氧载体研究关注的焦点,但因全氟化碳易挥发、不易溶解、乳化后稳定性差等,其纳米乳剂研发成功者极少.本文对全氟化碳纳米乳剂的研究进展进行综述,对影响乳剂稳定性的因素进行分析探讨并提出可能对策,为获得稳定的全氟化碳人工氧载体提供借鉴和参考.

The quality of active pharmaceutical ingredients (APIs) is an important factor which can affect the safety and efficacy of pharmaceuticals. This study was designed to investigate the nature of paliperidone palmitate (PP) obtained by different crystallization processes, then compare the characteristics between test formulations which prepared PP of different crystallization and reference formulations (Invega Sustenna®) in vitro and in vivo. Two different PPs, namely PP-1 and PP-2, were prepared by different crystallization methods. Contact angle, morphology, and crystallinity of the PPs were characterized. Taking the particle sizes and distribution of Invega Sustenna® as reference, test formulations were prepared by the wet milling method using either a PP-1 or PP-2 sample. Their release behavior, stability in vitro, and pharmacokinetics in vivo were subsequently investigated. The results indicated that PP-2 had a higher surface free energy (SFE). More small particles were attached to the PP-1 surface under the influence of crystallization temperature. Different crystallization processes did not change the crystal of PP, but changed the crystallinity of PP. There was no obvious difference in in vitro releases between test formulations. However, the stability and state of formulation containing PP-2 were better compared to formulations containing PP-1, indicated by differences in crystallinity and SFE. Meanwhile, pharmacokinetic in vivo results demonstrated that the pharmacokinetic profiles and parameters of formulation containing PP-2 and Invega Sustenna® tended to be consistent, but those of formulations containing PP-1 were significantly different from those of formulations containing PP-2 or Invega Sustenna®, and there was burst release phenomenon of formulations containing PP-1 in rats. PP made by different crystallization processes could induce changes in appearance, SFE, and crystallinity, and further affect the stability, state, and pharmacokinetic in vivo formulation.

The demand for personalized medicine has received extensive attention, especially in pediatric preparations. An emerging technology, extrusion-based 3D printing, is highly attractive in the field of personalized medicine. In this study, we prepared propranolol hydrochloride (PR) gummy chewable tablets tailored for children by semisolid extrusion (SSE) 3D printing technology to meet personalized medicine needs in pediatrics. In this study, the effects of critical formulation variables on the rheological properties and printability of gum materials were investigated by constructing a full-factorial design. In addition, the masticatory properties, thermal stability, and disintegration time of the preparations were evaluated. Bitterness inhibitors were used to mask the bitterness of the preparations. The results of the full-factorial design showed that the amount of gelatin and carrageenan were the key factors in the formulation. Gelatin can improve printability and masticatory properties, carrageenan can improve thermal stability, and accelerate the disintegration of preparations; therefore, a reasonable combination of both could satisfactorily meet the demand for high-quality 3D printing. γ-Aminobutyric acid can reduce the bitterness of gummy chewable tablets to improve medication compliance and the determined formulation (F7) met the quality requirements. In conclusion, the gum material has excellent potential as an extrusion material for 3D printing. The dosage can be adjusted flexibly by the model shape and size. 3D printing has broad prospects in pediatric preparations.

目的:通过星点设计-效应面法(central composite design-response surface methodology,CCD-RSM)优化姜黄素非离子表面活性剂囊泡(curcumin niosomes,Cur-Nio)的制备工艺和处方,并进行质量评价.方法:采用薄膜分散-超声法以硬脂山梨坦(Span 60)和胆固醇作为载体材料制备Cur-Nio,以包封率、载药量、平均粒径为考察指标,以总评"归一值"为评价指标优化制备处方.以CCD-RSM选取最佳处方,用二项式进行拟合预测分析,按优化出的处方制备Cur-Nio,考察测定Cur-Nio粒径、PDI和Zeta电位,透射电镜观察Cur-Nio 形态,差式扫描热及X-射线衍射分析结构特征及晶型是否有变化,并对其稳定性及体外释放进行考察.结果:Cur-Nio 的制备最佳处方及工艺条件为Span 60 与胆固醇的质量比值为3.096:1、水化时间为65 min、水化体积为19.45 mL;优化后的处方制备出的Cur-Nio的平均粒径是(151.70±2.003)nm,PDI为0.21±0.013,Zeta电位为(-45.10±1.40)mV,包封率为(82.91±0.59)％;透射电镜观察Cur-Nio外观圆整;长期存放4℃具有一定稳定性;差式扫描热及X-射线衍射结果表明Cur以无定型或分子状态包裹在囊泡中;体外释放结果表明,与游离姜黄素溶液相比,具有明显缓释效果.结论:通过CCD-RSM优化后的Cur-Nio,制备工艺简单,外观圆整,粒径均匀,具有缓释作用,符合优化试验结果.有效提高了姜黄素的生物活性,可用于进一步研究.

随着生物制药技术的发展,越来越多的多肽类药物在医药领域得到应用.但由于这类药物稳定性不佳、口服易被酶解等问题,临床多采用注射途径给药.鼻腔给药不仅能够克服口服给药的首过效应、注射给药的顺应性差等问题,而且具有脑靶向、低剂量高活性的优点.本文主要就多肽类药物的鼻腔给药进行综述,系统地介绍了鼻腔的组织构造,药物本身性质、制剂的特性和鼻腔内环境对药物鼻腔吸收的影响,以及通过添加吸收促进剂、酶抑制剂和设计成不同药物载体等方法改善药物鼻腔吸收,并叙述了鼻腔给药的研究热点-鼻脑传递,为后续相关制剂研发提供参考.

The molecular motors are protein molecules which can be teamed up to form the active mobile nanomachine with special functions. As a new type of therapeutic target different from normal enzymes or receptors, molecular motor plays a unique role in the transportation of intracellular substances, mitosis, and the construction of cytoskeleton. It has also been reported that molecular motors were capable of regulate the tumor cells' proliferation, related to the occurrence of neurodegenerative diseases, and can be used as a nano carrier to deliver drugs. Molecular motors could be divided into linear and rotary molecular motors according to their different forms of motion. The former includes dynein, kinesin, and myosin, and the latter includes ATP synthase and flagellar motors. In addition, there are also some chemically or biologically modified molecular motors to expand or enhance their therapeutic applications. In this review, after the introduction of the classification, structures, main functions and motion mechanism of molecular motors in detail, the application progress of molecular motors in recent years is summarized. Finally, the current problems and future prospect are also discussed in this paper.

3D printing is a promising technology used in the fabrication of complex oral dosage delivery pharmaceuticals. This study first reports an innovative color jet 3D printing (CJ-3DP) technology to produce colorful cartoon levetiracetam pediatric preparations with high accuracy and reproducibility. For this study, the ideal printing ink consisted of 40% (v/v) isopropanol aqueous solution containing 0.05% (w/w) polyvinylpyrrolidone and 4% (w/w) glycerin, which was satisfied with scale-up of the production. The external and internal spatial structures of the tablets were designed to control the appearance and release, and cartoon tablets with admirable appearances and immediate release characteristics were printed. The dosage model showed a good linear relationship between the model volume and the tablet strength (r > 0.999), which proved the potential of personalized administration. The surface roughness indicated that the appearance of the CJ-3DP tablets was significantly better than the first listed 3D printed drug (SpritamⓇ). Moreover, the scanning electron microscopy and porosity results further showed that the tablets have a structure of loose interior and tight exterior, which could ensure good mechanical properties and rapid dispersion characteristics simultaneously. In conclusion, the innovative CJ-3DP technology can be used to fabricate personalized pediatric preparations for improved compliance. Due to the stable formulation and fabrication process, this technology has the potential in scale-up production.

阴道环(intravaginal ring,IVR)给药系统是一种柔软的、环形的、具有弹性的药物输送装置,可向阴道提供长期、持续、控制的物质释放,实现局部给药或全身给药.其已经用于类固醇避孕和雌激素替代疗法,近几年发现将其应用于预防人类免疫缺陷病毒(human immunodeficiency virus,HIV)的杀微生物剂的递送具有很好的疗效,多种杀微生物剂的阴道环目前正在进行临床研究中.自从1970年有关阴道环的专利申请之后,很多的阴道环产品已经上市,例如Estring(R)、Nuvaring(R)、Progering(R)、Annovera(R)等,另外还有很多阴道环正在临床研究中.在2002年上市的Nuvaring(R)阴道环出现之前制备阴道环的载体材料只局限于硅橡胶(silicone,也叫硅酮),然而由聚乙烯醋酸乙烯酯(ethylene vinyl acetate,EVA)制备的Nuvaring(R)阴道环的出现给人们以启示,热塑性材料应用于阴道环的制备也表现出巨大的潜力,如今热塑性弹性体聚氨酯(polyurethane,PU)也已经用于阴道环的制备.

Poly(lactic-co-glycolic acid) (PLGA) has garnered increasing attention as a candidate drug delivery polymer owing to its favorable properties, including its excellent biocompatibility, biodegradability, non-toxicity, non-immunogenicity, and mechanical strength. PLAG are specifically used as microspheres for the sustained/controlled and targeted delivery of hydrophilic or hydrophobic drugs, as well as biological therapeutic macromolecules, including peptide and protein drugs. PLGAs with different molecular weights, lactic acid (LA)/glycolic acid (GA) ratios, and end groups exhibit unique release characteristics, which is beneficial for obtaining diverse therapeutic effects. This review aims to analyze the composition of PLGA microspheres, and understand the manufacturing process involved in their production, from a quality by design perspective. Additionally, the key factors affecting PLGA microsphere development are explored as well as the principles involved in the synthesis and degradation of PLGA and its interaction with active drugs. Further, the effects elicited by microcosmic conditions on PLGA macroscopic properties, are analyzed. These conditions include variations in the organic phase (organic solvent, PLGA, and drug concentration), continuous phase (emulsifying ability), emulsifying stage (organic phase and continuous phase interaction, homogenization parameters), and solidification process (relationship between solvent volatilization rate and curing conditions). The challenges in achieving consistency between batches during manufacturing are addressed, and continuous production is discussed as a potential solution. Finally, potential critical quality attributes are introduced, which may facilitate the optimization of process parameters.

注射用乳酸-羟基乙酸共聚物(polylactide-polyglycolide,PLGA)微球作为一种储库型释药系统,自1989年第1个产品Lupron depot获准在美国上市起,已成功用于多种疾病的治疗,具备在体内几天到几个月长时间释药的能力,可显著改善用药安全性,提升患者顺应性.体内外相关性(invitro-in vivo correlation,IVIVC)研究给微球制剂的发展带来更多可能.IVIVC可以通过微球的体外释放行为阐述体内释药的动态信息,在表征微球性能的同时减轻各阶段的工作量,对药物的研发、生产变更和监督管理等具有指导或支持作用.本文将注射用PLGA微球的释放机制、体内外释放测定涉及的常用方法和理论进行归纳总结,重点讨论了IVIVC尤其是A级IVIVC在微球制剂领域的建立及应用,为进一步的微球体内外相关性研究提供参考.