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17 pages, 6891 KiB

Open AccessArticle

Transferrin-Modified Triptolide Liposome Targeting Enhances Anti-Hepatocellular Carcinoma Effects

by Xiaoli Zhao, Yifan Yang, Xuerong Su, Ying Xie, Yiyao Liang, Tong Zhou, Yangqian Wu and Liuqing Di

Biomedicines 2023, 11(10), 2869; https://doi.org/10.3390/biomedicines11102869 - 23 Oct 2023

Cited by 1 | Viewed by 1155

Abstract

Triptolide (TP) is an epoxy diterpene lactone compound isolated and purified from the traditional Chinese medicinal plant Tripterygium wilfordii Hook. f., which has been shown to inhibit the proliferation of hepatocellular carcinoma. However, due to problems with solubility, bioavailability, and adverse effects, the [...] Read more.

Triptolide (TP) is an epoxy diterpene lactone compound isolated and purified from the traditional Chinese medicinal plant Tripterygium wilfordii Hook. f., which has been shown to inhibit the proliferation of hepatocellular carcinoma. However, due to problems with solubility, bioavailability, and adverse effects, the use and effectiveness of the drug are limited. In this study, a transferrin-modified TP liposome (TF-TP@LIP) was constructed for the delivery of TP. The thin-film hydration method was used to prepare TF-TP@LIP. The physicochemical properties, drug loading, particle size, polydispersity coefficient, and zeta potential of the liposomes were examined. The inhibitory effects of TF-TP@LIP on tumor cells in vitro were assessed using the HepG2 cell line. The biodistribution of TF-TP@LIP and its anti-tumor effects were investigated in tumor-bearing nude mice. The results showed that TF-TP@LIP was spherical, had a particle size of 130.33 ± 1.89 nm and zeta potential of −23.20 ± 0.90 mV, and was electronegative. Encapsulation and drug loading were 85.33 ± 0.41% and 9.96 ± 0.21%, respectively. The preparation was stable in serum over 24 h and showed biocompatibility and slow release of the drug. Flow cytometry and fluorescence microscopy showed that uptake of TF-TP@LIP was significantly higher than that of TP@LIP (p < 0.05), while MTT assays indicated mean median inhibition concentrations (IC₅₀) of TP, TP@LIP, and TF-TP@ of 90.6 nM, 56.1 nM, and 42.3 nM, respectively, in HepG2 cell treated for 48 h. Real-time fluorescence imaging indicated a significant accumulation of DiR-labeled TF-TP@LIPs at tumor sites in nude mice, in contrast to DiR-only or DiR-labeled, indicating that modification with transferrin enhanced drug targeting to the tumor tissues. Compared with the TP and TP@LIP groups, the TF-TP@LIP group had a significant inhibitory effect on tumor growth. H&E staining results showed that TF-TP@LIP inhibited tumor growth and did not induce any significant pathological changes in the heart, liver, spleen, and kidneys of nude mice, with all liver and kidney indices within the normal range, with no significant differences compared with the control group, indicating the safety of the preparation. The findings indicated that modification by transferrin significantly enhanced the tumor-targeting ability of the liposomes and improved their anti-tumor effects in vivo. Reducing its distribution in normal tissues and decreasing its toxic effects suggest that the potential of TF-TP@LIP warrants further investigation for its clinical application. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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20 pages, 6392 KiB

Open AccessArticle

Development of a Multifunctional Oral Dosage Form via Integration of Solid Dispersion Technology with a Black Seed Oil-Based Self-Nanoemulsifying Drug Delivery System

by Abdelrahman Y. Sherif and Ahmad Abdul-Wahhab Shahba

Biomedicines 2023, 11(10), 2733; https://doi.org/10.3390/biomedicines11102733 - 09 Oct 2023

Cited by 2 | Viewed by 1010

Abstract

Lansoprazole (LZP) is used to treat acid-related gastrointestinal disorders; however, its low aqueous solubility limits its oral absorption. Black seed oil (BSO) has gastroprotective effects, making it a promising addition to gastric treatment regimens. The present study aims to develop a stable multifunctional [...] Read more.

Lansoprazole (LZP) is used to treat acid-related gastrointestinal disorders; however, its low aqueous solubility limits its oral absorption. Black seed oil (BSO) has gastroprotective effects, making it a promising addition to gastric treatment regimens. The present study aims to develop a stable multifunctional formulation integrating solid dispersion (SD) technology with a bioactive self-nanoemulsifying drug delivery system (SNEDDS) based on BSO to synergistically enhance LZP delivery and therapeutic effects. The LZP-loaded SNEDDS was prepared using BSO, Transcutol P, and Kolliphor EL. SDs were produced by microwave irradiation and lyophilization using different polymers. The formulations were characterized by particle apparent hydrodynamic radius analysis, zeta potential, SEM, DSC, PXRD, and in vitro dissolution testing. Their chemical and physical stability under accelerated conditions was also examined. Physicochemical characterization revealed that the dispersed systems were in the nanosize range (<500 nm). DSC and PXRD studies revealed that lyophilization more potently disrupted LZP crystallinity versus microwave heating. The SNEDDS effectively solubilized LZP but degraded completely within 1 day. Lyophilized SDs with Pluronic F-127 demonstrated the highest LZP dissolution efficiency (3.5-fold vs. drug) and maintained chemical stability (>97%) for 1 month. SDs combined with the SNEDDS had variable effects suggesting that the synergistic benefits were dependent on the formulation and preparation method. Lyophilized LZP-Pluronic F127 SD enabled effective and stable LZP delivery alongside the bioactive effects of the BSO-based SNEDDS. This multifunctional system is a promising candidate with the potential for optimized gastrointestinal delivery of LZP and bioactive components. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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26 pages, 4055 KiB

Open AccessArticle

Drug-Delivery Silver Nanoparticles: A New Perspective for Phenindione as an Anticoagulant

by Stoyanka Nikolova, Miglena Milusheva, Vera Gledacheva, Mehran Feizi-Dehnayebi, Lidia Kaynarova, Deyana Georgieva, Vassil Delchev, Iliyana Stefanova, Yulian Tumbarski, Rositsa Mihaylova, Emiliya Cherneva, Snezhana Stoencheva and Mina Todorova

Biomedicines 2023, 11(8), 2201; https://doi.org/10.3390/biomedicines11082201 - 04 Aug 2023

Cited by 16 | Viewed by 2027

Abstract

Anticoagulants prevent the blood from developing the coagulation process, which is the primary cause of death in thromboembolic illnesses. Phenindione (PID) is a well-known anticoagulant that is rarely employed because it totally prevents coagulation, which can be a life-threatening complication. The goal of [...] Read more.

Anticoagulants prevent the blood from developing the coagulation process, which is the primary cause of death in thromboembolic illnesses. Phenindione (PID) is a well-known anticoagulant that is rarely employed because it totally prevents coagulation, which can be a life-threatening complication. The goal of the current study is to synthesize drug-loaded Ag NPs to slow down the coagulation process. Methods: A rapid synthesis and stabilization of silver nanoparticles as drug-delivery systems for phenindione (PID) were applied for the first time. Results: Several methods are used to determine the size of the resulting Ag NPs. Additionally, the drug-release capabilities of Ag NPs were established. Density functional theory (DFT) calculations were performed for the first time to indicate the nature of the interaction between PID and nanostructures. DFT findings supported that galactose-loaded nanostructure could be a proper delivery system for phenindione. The drug-loaded Ag NPs were characterized in vitro for their antimicrobial, cytotoxic, and anticoagulant activities, and ex vivo for spasmolytic activity. The obtained data confirmed the drug-release experiments. Drug-loaded Ag NPs showed that prothrombin time (PT, sec) and activated partial thromboplastin time (APTT, sec) are approximately 1.5 times longer than the normal values, while PID itself stopped coagulation at all. This can make the PID-loaded Ag NPs better therapeutic anticoagulants. PID was compared to PID-loaded Ag NPs in antimicrobial, spasmolytic activity, and cytotoxicity. All the experiments confirmed the drug-release results. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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17 pages, 4757 KiB

Open AccessArticle

Integrating Chinese Herbs and Western Medicine for New Wound Dressings through Handheld Electrospinning

by Jianfeng Zhou, Liangzhe Wang, Wenjian Gong, Bo Wang, Deng-Guang Yu and Yuanjie Zhu

Biomedicines 2023, 11(8), 2146; https://doi.org/10.3390/biomedicines11082146 - 30 Jul 2023

Cited by 20 | Viewed by 1780

Abstract

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were [...] Read more.

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were applied to the development of a new type of pharmaceutical formulation, aiming to achieve rapid hemostasis, pain relief, and antimicrobial properties. Briefly, an approach combining a electrohydrodynamic atomization (EHDA) technique and reversed-phase solvent was employed to fabricate a novel beaded nanofiber structure (BNS), consisting of micrometer-sized particles distributed on a nanoscale fiber matrix. Firstly, Zein-loaded Yunnan Baiyao (YB) particles were prepared using the solution electrospraying process. Subsequently, these particles were suspended in a co-solvent solution containing ciprofloxacin (CIP) and hydrophilic polymer polyvinylpyrrolidone (PVP) and electrospun into hybrid structural microfibers using a handheld electrospinning device, forming the EHDA product E3. The fiber-beaded composite morphology of E3 was confirmed through scanning electron microscopy (SEM) images. Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis revealed the amorphous state of CIP in the BNS membrane due to the good compatibility between CIP and PVP. The rapid dissolution experiment revealed that E3 exhibits fast disintegration properties and promotes the dissolution of CIP. Moreover, in vitro drug release study demonstrated the complete release of CIP within 1 min. Antibacterial assays showed a significant reduction in the number of adhered bacteria on the BNS, indicating excellent antibacterial performance. Compared with the traditional YB powders consisting of Chinese herbs, the BNS showed a series of advantages for potential wound dressing. These advantages include an improved antibacterial effect, a sustained release of active ingredients from YB, and a convenient wound covering application, which were resulted from the integration of Chinese herbs and Western medicine. This study provides valuable insights for the development of novel multiscale functional micro-/nano-composite materials and pioneers the developments of new types of medicines from the combination of herbal medicines and Western medicines. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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16 pages, 3305 KiB

Open AccessArticle

Application of I-Optimal Design for Modeling and Optimizing the Operational Parameters of Ibuprofen Granules in Continuous Twin-Screw Wet Granulation

by Jie Zhao, Geng Tian and Haibin Qu

Biomedicines 2023, 11(7), 2030; https://doi.org/10.3390/biomedicines11072030 - 19 Jul 2023

Viewed by 823

Abstract

The continuous twin-screw wet granulation (TSWG) process was investigated and optimized with prediction-oriented I-optimal designs. The I-optimal designs can not only obtain a precise estimation of the parameters that describe the effect of five input process parameters, including the screw speed, liquid-to-solid (L/S) [...] Read more.

The continuous twin-screw wet granulation (TSWG) process was investigated and optimized with prediction-oriented I-optimal designs. The I-optimal designs can not only obtain a precise estimation of the parameters that describe the effect of five input process parameters, including the screw speed, liquid-to-solid (L/S) ratio, TSWG feed rate, and numbers of the 30° and 60° mixing elements, on the granule quality in a TSWG process, but it can also provide a prediction of the response to determine the optimum operating conditions. Based on the constraints of the desired granule properties, a design space for the TSWG was determined, and the ranges of the operating parameters were defined. An acceptable degree of prediction was confirmed through validation experiments, demonstrating the reliability and effectiveness of using the I-optimal design method to study the TSWG process. The I-optimal design method can accelerate the screening and optimization of the TSWG process. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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12 pages, 1615 KiB

Open AccessCommunication

Delivery of Lipid Nanoparticles with ROS Probes for Improved Visualization of Hepatocellular Carcinoma

by Vera S. Shashkovskaya, Polina I. Vetosheva, Arina G. Shokhina, Ilya O. Aparin, Tatiana A. Prikazchikova, Arsen S. Mikaelyan, Yuri V. Kotelevtsev, Vsevolod V. Belousov, Timofei S. Zatsepin and Tatiana O. Abakumova

Biomedicines 2023, 11(7), 1783; https://doi.org/10.3390/biomedicines11071783 - 21 Jun 2023

Cited by 2 | Viewed by 1650

Abstract

Reactive oxygen species (ROS) are highly reactive products of the cell metabolism derived from oxygen molecules, and their abundant level is observed in many diseases, particularly tumors, such as hepatocellular carcinoma (HCC). In vivo imaging of ROS is a necessary tool in preclinical [...] Read more.

Reactive oxygen species (ROS) are highly reactive products of the cell metabolism derived from oxygen molecules, and their abundant level is observed in many diseases, particularly tumors, such as hepatocellular carcinoma (HCC). In vivo imaging of ROS is a necessary tool in preclinical research to evaluate the efficacy of drugs with antioxidant activity and for diagnosis and monitoring of diseases. However, most known sensors cannot be used for in vivo experiments due to low stability in the blood and rapid elimination from the body. In this work, we focused on the development of an effective delivery system of fluorescent probes for intravital ROS visualization using the HCC model. We have synthesized various lipid nanoparticles (LNPs) loaded with ROS-inducible hydrocyanine pro-fluorescent dye or plasmid DNA (pDNA) with genetically encoded protein sensors of hydrogen peroxide (HyPer7). LNP with an average diameter of 110 ± 12 nm, characterized by increased stability and pDNA loading efficiency (64 ± 7%), demonstrated preferable accumulation in the liver compared to 170 nm LNPs. We evaluated cytotoxicity and demonstrated the efficacy of hydrocyanine-5 and HyPer7 formulated in LNP for ROS visualization in mouse hepatocytes (AML12 cells) and in the mouse xenograft model of HCC. Our results demonstrate that obtained LNP could be a valuable tool in preclinical research for visualization ROS in liver diseases. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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16 pages, 11067 KiB

Open AccessArticle

Drug-Loaded Silver Nanoparticles—A Tool for Delivery of a Mebeverine Precursor in Inflammatory Bowel Diseases Treatment

by Mina Todorova, Miglena Milusheva, Lidia Kaynarova, Deyana Georgieva, Vassil Delchev, Stanislava Simeonova, Bissera Pilicheva and Stoyanka Nikolova

Biomedicines 2023, 11(6), 1593; https://doi.org/10.3390/biomedicines11061593 - 30 May 2023

Cited by 3 | Viewed by 1771

Abstract

Chronic, multifactorial illnesses of the gastrointestinal tract include inflammatory bowel diseases. One of the greatest methods for regulated medicine administration in a particular region of inflammation is the nanoparticle system. Silver nanoparticles (Ag NPs) have been utilized as drug delivery systems in the [...] Read more.

Chronic, multifactorial illnesses of the gastrointestinal tract include inflammatory bowel diseases. One of the greatest methods for regulated medicine administration in a particular region of inflammation is the nanoparticle system. Silver nanoparticles (Ag NPs) have been utilized as drug delivery systems in the pharmaceutical industry. The goal of the current study is to synthesize drug-loaded Ag NPs using a previously described 3-methyl-1-phenylbutan-2-amine, as a mebeverine precursor (MP). Methods: A green, galactose-assisted method for the rapid synthesis and stabilization of Ag NPs as a drug-delivery system is presented. Galactose was used as a reducing and capping agent forming a thin layer encasing the nanoparticles. Results: The structure, size distribution, zeta potential, surface charge, and the role of the capping agent of drug-loaded Ag NPs were discussed. The drug release of the MP-loaded Ag NPs was also investigated. The Ag NPs indicated a very good drug release between 80 and 85%. Based on the preliminary results, Ag NPs might be a promising medication delivery system for MP and a useful treatment option for inflammatory bowel disease. Therefore, future research into the potential medical applications of the produced Ag NPs is necessary. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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Review

Jump to: Research

20 pages, 3270 KiB

Open AccessReview

Tumor Microenvironment-Responsive Drug Delivery Based on Polymeric Micelles for Precision Cancer Therapy: Strategies and Prospects

by Zhu Jin, Majdi Al Amili and Shengrong Guo

Biomedicines 2024, 12(2), 417; https://doi.org/10.3390/biomedicines12020417 - 11 Feb 2024

Viewed by 880

Abstract

In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of [...] Read more.

In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of the pathophysiological environment at the drug target site, the design, synthesis, or modification of environmentally responsive polymeric materials has become a crucial strategy for drug-targeted delivery. In comparison to the normal physiological environment, tumors possess a unique microenvironment, characterized by a low pH, high reactive oxygen species concentration, hypoxia, and distinct enzyme systems, providing various stimuli for the environmentally responsive design of polymeric micelles. Polymeric micelles with tumor microenvironment (TME)-responsive characteristics have shown significant improvement in precision therapy for cancer treatment. This review mainly outlines the most promising strategies available for exploiting the tumor microenvironment to construct internal stimulus-responsive drug delivery micelles that target tumors and achieve enhanced antitumor efficacy. In addition, the prospects of TME-responsive polymeric micelles for gene therapy and immunotherapy, the most popular current cancer treatments, are also discussed. TME-responsive drug delivery via polymeric micelles will be an efficient and robust approach for developing clinical cancer therapies in the future. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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20 pages, 3057 KiB

Open AccessReview

Advances and Prospects for Hydrogel-Forming Microneedles in Transdermal Drug Delivery

by Xiaolin Hou, Jiaqi Li, Yongyu Hong, Hang Ruan, Meng Long, Nianping Feng and Yongtai Zhang

Biomedicines 2023, 11(8), 2119; https://doi.org/10.3390/biomedicines11082119 - 27 Jul 2023

Cited by 3 | Viewed by 2693

Abstract

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among [...] Read more.

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among them, microneedling is a relatively simple and efficient means of drug delivery. Microneedles usually consist of micron-sized needles (50–900 μm in length) in arrays that can successfully penetrate the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without touching the blood vessels and nerves in the dermis, improving patient compliance. Hydrogel-forming microneedles (HFMs) are safe and non-toxic, with no residual matrix material, high drug loading capacity, and controlled drug release, and they are suitable for long-term, multiple drug delivery. This work reviewed the characteristics of the skin structure and TDD, introduced TDD strategies based on HFMs, and summarized the characteristics of HFM TDD systems and the evaluation methods of HFMs as well as the application of HFM drug delivery systems in disease treatment. The HFM drug delivery system has a wide scope for development, but the translation to clinical application still has more challenges. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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29 pages, 3210 KiB

Open AccessReview

Cell-Penetrating Peptide-Based Delivery of Macromolecular Drugs: Development, Strategies, and Progress

by Zhe Sun, Jinhai Huang, Zvi Fishelson, Chenhui Wang and Sihe Zhang

Biomedicines 2023, 11(7), 1971; https://doi.org/10.3390/biomedicines11071971 - 12 Jul 2023

Cited by 6 | Viewed by 2604

Abstract

Cell-penetrating peptides (CPPs), developed for more than 30 years, are still being extensively studied due to their excellent delivery performance. Compared with other delivery vehicles, CPPs hold promise for delivering different types of drugs. Here, we review the development process of CPPs and [...] Read more.

Cell-penetrating peptides (CPPs), developed for more than 30 years, are still being extensively studied due to their excellent delivery performance. Compared with other delivery vehicles, CPPs hold promise for delivering different types of drugs. Here, we review the development process of CPPs and summarize the composition and classification of the CPP-based delivery systems, cellular uptake mechanisms, influencing factors, and biological barriers. We also summarize the optimization routes of CPP-based macromolecular drug delivery from stability and targeting perspectives. Strategies for enhanced endosomal escape, which prolong its half-life in blood, improved targeting efficiency and stimuli-responsive design are comprehensively summarized for CPP-based macromolecule delivery. Finally, after concluding the clinical trials of CPP-based drug delivery systems, we extracted the necessary conditions for a successful CPP-based delivery system. This review provides the latest framework for the CPP-based delivery of macromolecular drugs and summarizes the optimized strategies to improve delivery efficiency. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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16 pages, 822 KiB

Open AccessReview

Pharmaceutical Application of Process Understanding and Optimization Techniques: A Review on the Continuous Twin-Screw Wet Granulation

by Jie Zhao, Geng Tian and Haibin Qu

Biomedicines 2023, 11(7), 1923; https://doi.org/10.3390/biomedicines11071923 - 06 Jul 2023

Viewed by 1475

Abstract

Twin-screw wet granulation (TSWG) is a method of continuous pharmaceutical manufacturing and a potential alternative method to batch granulation processes. It has attracted more and more interest nowadays due to its high efficiency, robustness, and applications. To improve both the product quality and [...] Read more.

Twin-screw wet granulation (TSWG) is a method of continuous pharmaceutical manufacturing and a potential alternative method to batch granulation processes. It has attracted more and more interest nowadays due to its high efficiency, robustness, and applications. To improve both the product quality and process efficiency, the process understanding is critical. This article reviews the recent work in process understanding and optimization for TSWG. Various aspects of the progress in TSWG like process model construction, process monitoring method development, and the strategy of process control for TSWG have been thoroughly analyzed and discussed. The process modeling technique including the empirical model, the mechanistic model, and the hybrid model in the TSWG process are presented to increase the knowledge of the granulation process, and the influence of process parameters involved in granulation process on granule properties by experimental study are highlighted. The study analyzed several process monitoring tools and the associated technologies used to monitor granule attributes. In addition, control strategies based on process analytical technology (PAT) are presented as a reference to enhance product quality and ensure the applicability and capability of continuous manufacturing (CM) processes. Furthermore, this article aims to review the current research progress in an effort to make recommendations for further research in process understanding and development of TSWG. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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