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.

During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.

Individuals with special needs, such as children, the elderly, and the visually impaired, encounter significant hurdles in the field of personalized pharmacotherapy due to their distinctive medication needs. 3D printing technology, a novel approach for preparing drug products with intricate personalized designs, has shown considerable promise in improving the safety and adherence to patient medication regimens. This study chose acetaminophen, a commonly employed antipyretic analgesic, as the model drug and employed binder jetting 3D printing (BJ-3DP) to manufacture oral disintegrating tablets (ODTs) with multiple specifications and complex structures. The study initiated with an assessment of the printable properties of powder and ink formulations, proceeding to craft ODTs with individualized dosages and surfaces embedded in QR codes, cartoon figures, textual information, and raised braille. These tablets are internally designed with spaces that do not eject ink, resulting in a loose powder structure. The results of tests including porosity, surface roughness, Micro CT scanning, mechanical properties, and in vitro drug release of the printed product indicate that the personalized ODTs with complex structures designed in this study can offer treatment solutions for specific populations.

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.

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.

Compared with conventional transdermal drug delivery systems, dissolving microneedles significantly enhance drug bioavailability by penetrating the stratum corneum barrier and achieving intradermal drug delivery. In order to improve the transdermal bioavailability of dexmedetomidine hydrochloride, in this study, a novel microneedle delivery system was developed for dexmedetomidine hydrochloride based on 3D printing combined with micro-molding. By systematically optimizing the microneedle geometrical parameters, array arrangement, and preparation process parameters, we determined the optimal ratio of drug-carrying matrix as 15% PVP (polyvinyl pyrrolidone) K90. The microneedles exhibited significant drug loading gradients, with mean content of (209.99±27.56) μg/patch, (405.31±30.31) μg/patch, and (621.61±34.43) μg/patch. They showed a regular pyramidal structure under SEM and handheld electron microscopy, and their mechanical strength allowed effective penetration into the stratum corneum. The surface contact angles were all < 90°, indicating excellent hydrophilicity. The microneedles dissolved completely within 10 min after skin insertion, achieving a cumulative release rate of 90% (Higuchi model, r=0.996) during 2 hours of in vitro transdermal permeation. The cytotoxicity test and hemolysis test verified good biocompatibility. Pharmacodynamic evaluation showed that the microneedle group demonstrated pain-relieving effect within 15 min, with the pain threshold at the time point of 60 min being 3 times that in the transdermal cream group. The microneedle system developed in this study not only offers an efficient drug delivery option for patients but also establishes an innovative platform for rapid percutaneous delivery of hydrophilic drugs, demonstrating significant potential in perioperative pain management.

Lipid nanoparticles (LNP) have emerged at the forefront of the delivery of RNA molecules during the COVID-19 pandemic, leading to a giant leap in RNA therapies. Despite their great success, the long-term storage and transportation of mRNA vaccines without ultra-low temperatures is still challenging due to their poor stability. Here, we demonstrated that LNP-mRNA could be lyophilized via a simple freeze‒drying process. This process produced a dry powder formulation that could maintain the physicochemical properties of LNP-mRNA after storage at 4 °C for at least two months. However, the shear forces generated during the lyophilization process may disrupt the structure of the LNP, affecting the efficacy of the vaccine. Therefore, a cholesterol analogue, β-sitosterol, and a type of phospholipid, DOPE, were utilized instead of cholesterol and DSPC to improve the transfection efficiency after freeze-drying. The optimized formulation of LNP exhibited an enhanced transfection effect both in vitro and in vivo. Additionally, intratracheal administration of reconstituted lyophilized LNPs could induce innate cellular, humoral and mucosal immunity in vivo, indicating that our LNP-mRNA may serve as an effective vaccine against COVID-19. In summary, our study revealed that lyophilization of LNPs could increase their stability and maintain their ability to be transfected both in vitro and in vivo, inducing strong immune responses.

Mucosal vaccines can prevent viruses from infecting the respiratory mucosa, rather than only curtailing infection and protecting against the development of disease symptoms. The SARS-CoV-2 spike receptor-binding domain (RBD) is a compelling vaccine target but is undermined by suboptimal mucosal immunogenicity. Here, we report a SARS-CoV-2-mimetic extracellular-vesicle vaccine developed using genetic engineering and dendritic cell membrane budding. After mucosal immunization, the vaccine recruits antigen-presenting cells rapidly initiating a strong innate immune response. Notably, it obviates the need for adjuvants and can induce germinal center formation through both intramuscular and intratracheal vaccination. It not only elicits high levels of RBD-specific antibodies but also stimulates extensive cellular immunity in the respiratory mucosa. A sequential immunization strategy, starting with an intramuscular injection followed by an intratracheal booster, significantly bolsters mucosal immunity with high levels of IgA and tissue-resident memory T cell responses, thereby establishing a formidable defense against pseudovirus infection.

Microneedles (MNs) penetrate the stratum corneum and reach the epidermis, bypassing nerve fibers and providing a precise and controlling pathway for the delivery small molecule drugs, proteins, and nucleic acid drugs. This approach minimizes pain and tissue damage during penetration, facilitating autonomous administration. Emerging 3D micro-nano printing technologies offer innovative fabrication strategies for MNs. In addition to enhanced printing resolution, 3D printing allows flexibility in prototype design and manufacturing methods, enabling the fabrication of complex structure MNs or polydimethylsiloxane (PDMS) molds with excellent repeatability and effectiveness. Recently, several micro-nanoscale 3D printing technologies, such as projection micro stereolithography (PμSL) and two-photon polymerization (TPP), have been integrated into various stages of MNs manufacturing. This review aims to provide a comprehensive overview of diverse strategies for drug release and delivery modes using MNs, and a specific focus on analyzing advancements in 3D micro-nano printing technologies. It emphasizes the pivotal role played by 3D printing in the field of MNs and specifically discusses future research directions and emerging trends in this domain.

After decades of development, hot melt extrusion (HME) technology has matured as a well-established pharmaceutical methodology. Through the process of extruding both drug and carrier materials in a molten state under specific conditions of pressure, velocity, and screw design, this technology facilitates the dispersion of the drug within the carrier in various states such as molecular, amorphous, or sub-stable, thereby significantly improving the solubility and bioavailability of challenging drugs. Currently, over 20 drugs have obtained FDA approval for production and formulation via hot-melt extrusion, underscoring the demonstrated effectiveness and dependability of this technique. This review aims to offer an in-depth examination of the principles, benefits, and applications of hot-melt extrusion in pharmaceutical science, with a particular focus on the key determinants that impact the success of hot-melt extrusion. Additionally, it aims to explore the future applications and potential developmental opportunities of this technology, with an emphasis on its utility for continuous manufacturing (CM) and personalized drug delivery.

微针是一种新型的透皮给药方式,因具有无痛、生物利用度高及易给药等特点而被广泛关注.介绍了微针的分类和释药机制、光固化3D打印微针技术的原理和优缺点及其应用,重点分析了光固化3D打印微针在皮肤疾病治疗、胰岛素递送、癌症治疗和美容医疗方面应用的研究进展,阐述了光固化3D打印微针具有可以显著提高药物经皮渗透率、提高给药精确性、减少全身副作用的独特优势.最后,对光固化3D打印微针当前面临的材料生物相容性差、载药量低和现行法规不完善等问题进行探讨,并对其发展前景进行了展望.

Atherosclerosis (AS) is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation and lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect of a single therapeutic method is limited. It is suggested that a combination of these two strategies could help prevent lipid accumulation caused by inflammation and oxidative stress, and also promote lipid efflux from atherosclerotic plaque, to normalize arteries to the maximum extent. Hence, a strategy involving a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate (EGCG) and a lipid-efflux-promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide a protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28 ± 2.28 nm characterized by DLS), making it easier to target AS lesions, which have smaller vascular endothelial spaces. After being efficiently internalized into the cells, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1β, and MCP-1), which was due to the effect of EGCG. Besides, the lipid-efflux-promoting protein ABCA1 was upregulated when treated with lip@EGCG/miR-223. Through the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which are a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in the heart and aorta compared to that in the kidney was significantly increased when compared with free drugs (the ratio was 6.27% for the free miR-223-treated group, which increased to 66.10% for the lip@EGCG/miR-223-treated group). By decreasing the inflammation level and lipid accumulation, the arterial vessels in AS were normalized, with less macrophages and micro-angiogenesis, when treated with lip@EGCG/miR-223. Overall, this study demonstrated that lip@EGCG/miR-223 could be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory, and lipid-efflux-promoting effects, which provides a novel strategy for the safe and efficient management of atherosclerosis.

Three-dimensional printing technology, also called additive manufacturing technology, is used to prepare personalized 3D-printed drugs through computer-aided model design. In recent years, the use of 3D printing technology in the pharmaceutical field has become increasingly sophisticated. In addition to the successful commercialization of Spritam® in 2015, there has been a succession of Triastek’s 3D-printed drug applications that have received investigational new drug (IND) approval from the Food and Drug Administration (FDA). Compared with traditional drug preparation processes, 3D printing technology has significant advantages in personalized drug manufacturing, allowing easy manufacturing of preparations with complex structures or drug release behaviors and rapid manufacturing of small batches of drugs. This review summaries the mechanisms of the most commonly used 3D printing technologies, describes their characteristics, advantages, disadvantages, and applications in the pharmaceutical industry, analyzes the progress of global commercialization of 3D printed drugs and their problems and challenges, reflects the development trends of the 3D printed drug industry, and guides researchers engaged in 3D printed drugs.

Three-dimensional (3D) printing is an additive manufacturing technique that creates objects under computer control. Owing to the rapid advancement of science and technology, 3D printing technology has been widely utilized in processing and manufacturing but rarely used in the pharmaceutical field. The first commercial form of Spritam® immediate-release tablet was approved by FDA in 2015, which promoted the advancement of 3D printing technology in pharmaceutical development. Three-dimensional printing technology is able to meet individual treatment demands with customized size, shape, and release rate, which overcomes the difficulties of traditional pharmaceutical technology. This paper intends to discuss the critical process parameters of binder jet 3D printing technology, list its application in pharmaceutical manufacturing in recent years, summarize the still-open questions, and demonstrate its great potential in the pharmaceutical industry.

PURPOSE:Proper taste-masking formulation design is a critical issue for instant-dissolving tablets (IDTs). The purpose of this study is to use the electronic tongue to design the additives of the 3D printed IDTs to improve palatability. METHODS:A binder jet 3D printer was used to prepare IDTs of levetiracetam. A texture analyzer and dissolution apparatus were used to predict the oral dispersion time and in vitro drug release of IDTs, respectively. The palatability of different formulations was investigated using the ASTREE electronic tongue in combination with the design of experiment and a model for masking bitter taste. Human gustatory sensation tests were conducted to further evaluate the credibility of the results. RESULTS:The 3D printed tablets exhibited rapid dispersion (<30 s) and drug release (2.5 min > 90%). The electronic tongue had an excellent ability of taste discrimination, and levetiracetam had a good linear sensing performance based on a partial least square regression analysis. The principal component analysis was used to analyze the signal intensities of different formulations and showed that 2% sucralose and 0.5% spearmint flavoring masked the bitterness well and resembled the taste of corresponding placebo. The results of human gustatory sensation test were consistent with the trend of the electronic tongue evaluation. CONCLUSIONS:Owing to its objectivity and reproducibility, this technique is suitable for the design and evaluation of palatability in 3D printed IDT development.

α-Conotoxin GeXIVA[1,2] is a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype. It has the advantages of strong efficacy, no tolerance, and no effect on motor function, which has been expected help patients with neuropathic pain. However, drug development for clinical use is severely limited owing to its instability. Lyophilization is applied as the most preferred method to solve this problem. The prepared lyophilized powder is characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR). Molecular simulation is also used to explore the internal distribution and forces formed in the system. The analgesic effect on paclitaxel-induced neuropathic pain following single and 14-day repeated administrations are evaluated by the von Frey test and the tail-flick test. Trehalose combined with mannitol in a ratio of 1:1 is employed as the excipients in the determined formulation, where trehalose acts as the stabilizer and mannitol acts as the bulking agent, according to the results of DSC, PXRD, and FTIR. Both GeXIVA[1,2] (API) and GeXIVA[1,2] lyophilized powder (formulation) could produce stable analgesic effect. These results indicated that GeXIVA[1,2] lyophilized powder could improve the stability and provide an effective strategy to push it into clinical use as a new analgesic drug.

Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups.

打印液开发是黏结剂喷射型3D打印制剂的重点和难点,直接决定了打印产品的质量.本研究运用质量源于设计理念,采用3个中心点的23全因子实验设计(Design of Experiment,DoE),对左乙拉西坦3D打印分散片的打印液组成进行优化.使用40％ (v/v)异丙醇水溶液作为基础溶剂,以聚乙烯吡咯烷酮K30、甘油及聚山梨酯20用量作为自变量,分析其对打印片剂重量差异、硬度、脆碎度及分散均匀性等关键质量属性的影响.通过DoE模型分析获得了打印液处方的设计空间,并通过响应优化器获得了最优的打印液处方:含有0.1％ (w/w)聚乙烯吡咯烷酮K30和4.0％ (w/w)甘油的异丙醇水溶液.对打印液的喷射机制和润湿性进行分析,并制备和表征了不同规格的3D打印个性化制剂,验证了打印液处方的合理性,为黏结剂喷射型3D打印制剂中打印液的研究提供了参考和依据.

将药物高效且安全地透过生物膜递送到治疗部位一直是药物递送领域的研究难点和热点.近年来,由于烷基糖苷类化合物(alkyl polyglycoside,APG)高效的促透性能、良好的安全性和生物降解性,成为药物递送系统的理想促透剂,引起了国内外研究者的广泛关注.本文将对APG的理化性质、特点、作用机制及在药物递送系统中的应用进行全面的综述,并对其在药物递送系统中的应用前景进行展望.