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Published: 02 September 2024

An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs

Kangfan Ji 1 , 2 ,
Xiangqian Wei 1 , 2 ,
Anna R. Kahkoska 3 ,
Juan Zhang 1 , 2 ,
Yang Zhang 1 , 2 ,
Jianchang Xu 1 , 2 ,
Xinwei Wei 1 , 2 ,
Wei Liu 1 , 2 ,
Yanfang Wang 1 , 2 ,
Yuejun Yao 1 , 2 ,
Xuehui Huang 1 , 2 ,
Shaoqian Mei 1 , 2 ,
Yun Liu 1 , 2 ,
Shiqi Wang 1 , 2 ,
Zhengjie Zhao 1 , 2 ,
Ziyi Lu 1 , 2 ,
Jiahuan You 1 , 2 ,
Guangzheng Xu 1 , 2 ,
Youqing Shen ORCID: orcid.org/0000-0003-1837-7976 4 ,
John. B. Buse ORCID: orcid.org/0000-0002-9723-3876 5 ,
Jinqiang Wang ORCID: orcid.org/0000-0002-0048-838X 1 , 2 , 6 , 7 &
Zhen Gu ORCID: orcid.org/0000-0003-2947-4456 1 , 2 , 6 , 8 , 9 , 10 , 11

Nature Nanotechnology ( 2024 ) Cite this article

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Contrary to current insulin formulations, endogenous insulin has direct access to the portal vein, regulating glucose metabolism in the liver with minimal hypoglycaemia. Here we report the synthesis of an amphiphilic diblock copolymer comprising a glucose-responsive positively charged segment and polycarboxybetaine. The mixing of this polymer with insulin facilitates the formation of worm-like micelles, achieving highly efficient absorption by the gastrointestinal tract and the creation of a glucose-responsive reservoir in the liver. Under hyperglycaemic conditions, the polymer triggers a rapid release of insulin, establishing a portal-to-peripheral insulin gradient—similarly to endogenous insulin—for the safe regulation of blood glucose. This insulin formulation exhibits a dose-dependent blood-glucose-regulating effect in a streptozotocin-induced mouse model of type 1 diabetes and controls the blood glucose at normoglycaemia for one day in non-obese diabetic mice. In addition, the formulation demonstrates a blood-glucose-lowering effect for one day in a pig model of type 1 diabetes without observable hypoglycaemia, showing promise for the safe and effective management of type 1 diabetes.

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Week-long normoglycaemia in diabetic mice and minipigs via a subcutaneous dose of a glucose-responsive insulin complex

Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

Data availability.

The data that support the results of this study are available within the Article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2022YFE0202200, J.W.), JDRF (2-SRA-2021-1064-M-B, Z.G.; 2-SRA-2022-1159-M-B, J.W.), the Key Project of Science and Technology Commission of Zhejiang Province (2024C03083, Z.G.; 2024C03085, J.W.), Zhejiang University’s start-up packages and the Starry Night Science Fund at Shanghai institute for Advanced Study of Zhejiang University (SN-ZJU-SIAS-009, J.W.). A.R.K. is supported by the National Center for Advancing Translational Sciences, National Institutes of Health (KL2TR002490, J.W.). The project was supported by the Clinical and Translational Science Award program of the National Center for Advancing Translational Science, National Institutes of Health (UL1TR002489, J.W.). We appreciate the help from J. Pan and D. Wu of the Research and Service Center (College of Pharmaceutical Science, Zhejiang University) for technical support, G. Z. and Y. Zhang (Cryo-EM centre, Zhejiang University) for processing the samples for electron microscopy and D. Xu, M. Zhang, S. Xiong and D. Chen (Disease Simulation and Animal Model Platform of Liangzhu Laboratory) for taking care of the minipigs.

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State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

Kangfan Ji, Xiangqian Wei, Juan Zhang, Yang Zhang, Jianchang Xu, Xinwei Wei, Wei Liu, Yanfang Wang, Yuejun Yao, Xuehui Huang, Shaoqian Mei, Yun Liu, Shiqi Wang, Zhengjie Zhao, Ziyi Lu, Jiahuan You, Guangzheng Xu, Jinqiang Wang & Zhen Gu

Jinhua Institute of Zhejiang University, Jinhua, China

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Anna R. Kahkoska

Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China

Youqing Shen

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA

John. B. Buse

Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

Jinqiang Wang & Zhen Gu

Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

Jinqiang Wang

Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Liangzhu Laboratory, Hangzhou, China

Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, China

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China

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Z.G., J.W., Y.S. and J.B.B. conceived and designed the study. K.J., Xiangqian Wei, J.Z., J.X., Xinwei Wei, Y.Z., W.L., Y.W., Y.Y., S.M. and Y.L. conducted experiments and obtained related data. X.H., S.W., Z.Z., J.Y., G.X. and Z.L. gave experimental operation and theoretical guidance of mice experiments. K.J., Xiangqian Wei, J.Z. and J.X. conducted minipigs experiments and provided theoretical support. Z.G., J.W., Y.S., K.J., J.Z., Xiangqian Wei, A.R.K., J.B.B. and J.X. analysed the data and wrote the paper.

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Correspondence to Jinqiang Wang or Zhen Gu .

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Z.G. is the co-founder of Zenomics Inc., Zcapsule Inc. and μ Zen Inc. The other authors declare no competing interests.

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Extended data

Extended data fig. 1 bg-regulating effects in diabetic minipigs..

BG of diabetic minipigs treated with the insulin capsules (oral), the PPF-ins capsules (oral) or Lantus (s.c.). The insulin dose of oral formulations was set to 4.2 U/kg. The Lantus dose was set to 0.3 U/kg.

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Ji, K., Wei, X., Kahkoska, A.R. et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01764-5

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DOI : https://doi.org/10.1038/s41565-024-01764-5

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Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

Affiliations.

1 Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., La Jolla, California (E.K.); Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, California (A.V.K.); Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland (M.W.); Drug Metabolism, Pharmacokinetics, and Bioanalysis Department, AbbVie, Worcester, Massachusetts (E.T.); Disposition, Safety and Animal Research, Sanofi, Vitry sur Seine, France (A.D.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (R.A.I.); Departments of Drug Disposition, Development, and Commercialization, Eli Lilly and Co., Indianapolis, Indiana (A.D.-M.); Drug Metabolism and Pharmacokinetics, Celgene Corp., Summit, New Jersey (P.S.); Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (Mi.B.); Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Boston, Massachusetts (J.J.Y.); Bioanalytical Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Ware, United Kingdom (Ma.B.); Preclinical Pharmacokinetics and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Biologics Discovery Drug Metabolism and Pharmacokinetics and Bioanalytics Department, Merck Research Laboratories, Palo Alto, California (E.E.); Biologics Clinical Pharmacology, Janssen R&D, Spring House, Pennsylvania, (W.W.); Amgen Pharmacokinetics and Drug Metabolism, Thousand Oaks, California (D.A.R.); Seattle Genetics Inc., Seattle, Washington (N.V.C); and Department of Pharmaceutical Sciences, Roche Innovation Center, New York City, New York (D.J.M.) [email protected].
2 Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., La Jolla, California (E.K.); Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, California (A.V.K.); Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland (M.W.); Drug Metabolism, Pharmacokinetics, and Bioanalysis Department, AbbVie, Worcester, Massachusetts (E.T.); Disposition, Safety and Animal Research, Sanofi, Vitry sur Seine, France (A.D.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (R.A.I.); Departments of Drug Disposition, Development, and Commercialization, Eli Lilly and Co., Indianapolis, Indiana (A.D.-M.); Drug Metabolism and Pharmacokinetics, Celgene Corp., Summit, New Jersey (P.S.); Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (Mi.B.); Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Boston, Massachusetts (J.J.Y.); Bioanalytical Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Ware, United Kingdom (Ma.B.); Preclinical Pharmacokinetics and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Biologics Discovery Drug Metabolism and Pharmacokinetics and Bioanalytics Department, Merck Research Laboratories, Palo Alto, California (E.E.); Biologics Clinical Pharmacology, Janssen R&D, Spring House, Pennsylvania, (W.W.); Amgen Pharmacokinetics and Drug Metabolism, Thousand Oaks, California (D.A.R.); Seattle Genetics Inc., Seattle, Washington (N.V.C); and Department of Pharmaceutical Sciences, Roche Innovation Center, New York City, New York (D.J.M.).
PMID: 26669328
DOI: 10.1124/dmd.115.068049

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.

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Protein Absorption Alters the Cellular Targeting of Glycopolymeric Nanoparticles

22 Pages Posted: 19 Aug 2024

affiliation not provided to SSRN

Yuying Shen

University of Shanghai for Science and Technology

Jiayu Zheng

Mingliang fan.

Glycopolymeric nanoparticles are widely employed in biomedical applications due to their high targeting ability, biocompatibility, and biodegradability. The pendant saccharides serve as targeting ligands to be explicitly coordinated to receptors on cell membrane surfaces. However, proteins in the blood often absorb onto the nanoparticle surface, potentially impacting the exposure and effectiveness of the saccharide ligands for targeted delivery. To elucidate the protein absorption effects, we prepared micelles decorated with different percentages of fructose moieties and evaluated the bioactivity of nanoparticles using 2D cell culture, tumor spheroid, liver organoid, and coculture models. The 2D cell culture model did not show a significant difference in activity between protein-coated and non-coated micelles. However, a dramatic decrease in cellular uptake and penetration ability of micelles was observed in 3D tumor spheroids after protein absorption. Additionally, protein absorption notably increased micelle accumulation in liver organoids. In the coculture model, protein absorption reduced micelle accumulation in tumor spheroids while favoring accumulation in liver organoids. Our work suggests that decreasing non-specific protein absorption of glycopolymeric nanoparticles could enhance their delivery efficiency. These findings underscore the importance of understanding protein interactions in nanoparticle applications for drug delivery.

Keywords: Protein absorption, Glycopolymeric micelles, Tumor spheroids, Liver organoids

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Published: 03 September 2024

Trends and insights in dengue virus research globally: a bibliometric analysis (1995–2023)

Yumeng Liu ORCID: orcid.org/0000-0002-3124-0627 1 ,
MengMeng Wang 2 ,
Ning Yu 2 ,
Wenxin Zhao 2 ,
Peng Wang 2 ,
He Zhang 2 ,
Wenchao Sun 3 ,
Ningyi Jin 1 , 2 &
Huijun Lu 2

Journal of Translational Medicine volume 22 , Article number: 818 ( 2024 ) Cite this article

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Dengue virus (DENV) is the most widespread arbovirus. The World Health Organization (WHO) declared dengue one of the top 10 global health threats in 2019. However, it has been underrepresented in bibliometric analyses. This study employs bibliometric analysis to identify research hotspots and trends, offering a comprehensive overview of the current research dynamics in this field.

We present a report spanning from 1995 to 2023 that provides a unique longitudinal analysis of Dengue virus (DENV) research, revealing significant trends and shifts not extensively covered in previous literature. A total of 10,767 DENV-related documents were considered, with a notable increase in publications, peaking at 747 articles in 2021. Plos Neglected Tropical Diseases has become the leading journal in Dengue virus research, publishing 791 articles in this field—the highest number recorded. Our bibliometric analysis provides a comprehensive mapping of DENV research across multiple dimensions, including vector ecology, virology, and emerging therapies. The study delineates a complex network of immune response genes, including IFNA1, DDX58, IFNB1, STAT1, IRF3, and NFKB1, highlighting significant trends and emerging themes, particularly the impacts of climate change and new outbreaks on disease transmission. Our findings detail the progress and current status of key vaccine candidates, including the licensed Dengvaxia, newer vaccines such as Qdenga and TV003, and updated clinical trials. The study underscores significant advancements in antiviral therapies and vector control strategies for dengue, highlighting innovative drug candidates such as AT-752 and JNJ-1802, and the potential of drug repurposing with agents like Ribavirin, Remdesivir, and Lopinavir. Additionally, it discusses biological control methods, including the introduction of Wolbachia-infected mosquitoes and gene-editing technologies.

This bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV.

The Dengue virus (DENV) is a global public health threat transmitted primarily by mosquitoes [ 1 ]. Dengue fever manifests with symptoms including fever, headache, eye pain, muscle and joint pain, and skin rash [ 2 , 3 ]. Dengue fever is prevalent in tropical and subtropical regions, resulting in millions of infections and thousands of deaths annually. It has expanded to non-traditional areas, including the United States and Europe, with significant case surges in the Americas in 2015 and 2019 and a notable outbreak in the Western Pacific in 2013. For a comprehensive overview of global dengue cases and related deaths since 1995, see Table S1 in the supplementary materials, which includes World Health Organization data, although some information may be incomplete due to COVID-19-related disruptions [ 3 ]. Recent epidemiological trends show a concerning expansion in Dengue’s geographic and demographic scope, exacerbated by climate change and urbanization that facilitate vector breeding and shorten the viral incubation period. Studies predict an increase in the global population at risk from 53% in 2015 to 63% by 2080 [ 4 ]. First identified in Myanmar in 1943 by American virologists Albert Sabin and Robert Phillips, DENV was isolated from a patient’s blood sample, laying the foundation for subsequent research on the virus [ 5 ]. The Dengue virus, a single-stranded RNA virus of the Flavivirus genus, comprises four serotypes (DENV-1, DENV-2, DENV-3, DENV-4). Each confers lifelong immunity against itself but leaves individuals susceptible to the other serotypes, complicating prevention efforts and contributing to the severity of outbreaks [ 6 ].

Many commonly used vector control strategies, such as insecticide spraying, have failed to curb disease incidence but continue to be employed in the absence of robust evidence for their effectiveness or optimal implementation. However, advancements in understanding dengue epidemiology, immune response, and innovative control measures, including effective management, vaccines, and novel mosquito control methods, could significantly enhance dengue control efforts.

To tackle the complex challenges posed by the Dengue virus (DENV), this study employs bibliometric analysis to assess the breadth and impact of DENV-related research across various disciplines. Integrating existing studies is crucial to encapsulate the comprehensive scope of DENV research, covering aspects such as transmission dynamics, clinical manifestations, treatment options, and preventive measures. This approach is vital to identify critical research gaps and new potential areas of study, which are essential for advancing our understanding of the virus.

Data source

Data for this bibliometric analysis were retrieved from two primary databases: Web of Science (WOS) Science Citation Index Expanded (SCI-EXPANDED) and Scopus. These databases are widely recognized and extensively utilized in academic research, providing access to a broad array of high-quality academic journals. The selection of these databases enhances the comprehensiveness and credibility of our findings. The SCI-EXPANDED offers extensive coverage of scientific literature, particularly within the natural sciences, and includes high-impact journals, thereby ensuring the quality and reliability of the data. Scopus, as a multidisciplinary database, spans a wide range of subjects including science, technology, medicine, social sciences, arts, and humanities. Its broad coverage and high-quality data make it an indispensable resource for academic research. However, it is important to note that both SCI-EXPANDED and Scopus have a higher representation of English-language literature and high-impact journals, which may result in the underrepresentation of non-English literature and research published in lower-impact journals. Additionally, despite their extensive coverage, literature from certain specific fields may be underrepresented in these databases.

These databases are particularly well-suited for research on the Dengue virus (DENV) due to their reliable indexing in disciplines such as virology and public health. This study, covering the period from 1995 to 2023, focuses on the increase in Dengue-related publications and advancements in scientific databases, with an emphasis on research articles and reviews.

Research methods

In this study, we employed a variety of software tools to conduct comprehensive bibliometric analyses. VOSviewer (versions 1.6.18 and 1.6.20) and Pajek were utilized to analyze countries, institutions, journals, co-cited journals, authors, co-cited authors, and keyword co-occurrence, facilitating the construction of collaboration, co-citation, and co-occurrence networks. The visualization maps produced by VOSviewer and Scimago Graphica provided insightful visual representations of these networks. Pajek offered additional network analysis capabilities, particularly effective for handling large networks with its advanced features for detailed analysis and visualization. CiteSpace (version 6.1.R1) was employed to generate dual-map overlays of journals and to analyze references with Citation Bursts. The R package “bibliometrix” (version 3.2.1) was used to analyze thematic evolution and identify the 15 most active authors in DENV research. Microsoft Office Excel 2019 facilitated the quantitative analysis of publications. Gene visualization analysis was conducted using VOSviewer, while keyword visualization was performed using the R packages ComplexHeatmap (version 2.16.0) and circlize (version 0.4.16). Gene information was sourced from the Citexs Big Data Analysis Platform ( https://www.citexs.com ), which generated relevant visualizations to delineate the current research landscape, identify key research areas, and discern trends. The document selection and analysis process is illustrated in Fig. 1 .

Despite their powerful capabilities, tools like VOSviewer, Pajek, CiteSpace, and various R packages have limitations such as steep learning curves, complexity in data integration, and challenges in interpretation. These tools may also face performance issues with large datasets and might not fully capture the qualitative aspects of research trends. Therefore, a combination of multiple tools and methodologies is often necessary to achieve a comprehensive and accurate bibliometric analysis.

Flowchart Illustrating the Document Selection and Analysis Process for Dengue Virus Research

Global trends and collaborative dynamics in dengue virus research

Over the past 30 years, Dengue virus research has shown a significant upward trend, peaking at 747 articles in 2021. This growth can be divided into three phases: slow (1991–2002, under 120 publications annually), fast (2003–2013, 120–600 publications annually), and rapid (2014–2023, over 640 publications annually), likely influenced by global infectious disease outbreaks (Fig. 2 a). From 2021 to 2023, 45.5% of these publications were in high-impact, Q1 journals (Fig. 2 b).

Overview of Dengue Virus (DENV) Research Publication Trends and Distributions. ( a ) Temporal trends in publications from 1980 to 2020; ( b ) classification of these publications into journal quartiles from 1995 to 2023, using Journal Citation Reports (JCR) rankings; ( c ) geographical distribution of these publications by continent, categorized by the same journal quartiles. Quartiles are determined by the journal’s rank within its category, divided by the total number of journals in that category, and expressed as a percentile: Q1 (top 25%), Q2 (25–50%), Q3 (50–75%), and Q4 (bottom 25%). For journals spanning multiple WOS categories, the harmonic mean of Category Expected Citations is used to determine quality

Analysis of the top 20 corresponding authors’ countries shows variations in self-citation percentage (SCP) and most cited paper (MCP) metrics. The United States leads with the highest SCP (1281) and MCP (885), highlighting its significant contribution to the field. China and India also emerge as key players, supported by robust research infrastructures and extensive funding (Fig. 3 a). Visual maps from VOSviewer and Scimago Graphic illustrate the collaborative landscape, with the United States, China, and India leading in publications and collaborations (Fig. 3 b). This global network underscores the importance of international partnerships in advancing Dengue virus research.

Global Collaboration in Dengue Virus (DENV) Research from 1995 to 2023. ( a ) Displays the top 20 countries ranked by the number of corresponding authors in DENV research. ( b ) Showcases a VOSviewer network visualization of international co-authorship among these countries, where each country is represented as a node. The size of each node indicates the quantity of publications or the centrality in the collaborative network—larger nodes suggest higher publication outputs or more extensive collaboration. Links between nodes illustrate collaborative relationships, and node colors denote clusters of countries with frequent research collaborations in DENV

Comprehensive gene and keyword analysis in dengue virus research

Using VOSviewer 1.6.18 for gene visualization and keyword co-occurrence analysis has revealed a complex landscape in Dengue virus research, covering six main clusters: vector ecology, clinical manifestations, virology, vaccine development, immune response, diagnostic methods, and disease epidemiology (Fig. 4 a and b). This extensive range highlights the breadth of research, from molecular interactions to epidemiological patterns. Specific attention is focused on the virus’s basic properties, including replication mechanisms and immune responses, as well as disease transmission and epidemic trends, emphasizing crucial aspects such as viral transmission routes and genetic diversity.

Keyword Analyses in Dengue Virus-Related Publications from 1995 to 2023. ( a ) A co-occurrence network of 16,833 unique keywords with 58 keywords occurring more than 200 times, organized into six color-coded clusters. ( b ) An overlay visualization showing the temporal progression of keywords, with early keywords in blue and more recent ones in yellow. ( c ) A heatmap detailing the trends of keyword usage over the study period. ( d ) A co-occurrence cluster analysis focusing on genes associated with the Dengue virus

The heatmap analysis from 1995 to 2023 shows an increased focus on keywords like “Aedes” (the primary vector), “antibody”, “ADE” (antibody-dependent enhancement), “dengue vaccine”, and “antiviral agents”, indicating heightened research activity in developing prevention and treatment methods (Fig. 4 c). Emerging keywords such as “covid-19” and “zika” indicate a shift towards research on new infectious diseases, with significant regional research activity in Brazil, Thailand, and Indonesia.

The co-occurrence clustering analysis of genes including IFNA1, DDX58, IFNB1, STAT1, IRF3, and NFKB1 has identified key molecular players in the immune response to Dengue infection. This analysis reveals complex networks of gene interactions via pathways such as Toll-like and RIG-I-like receptors, essential for recognizing viral components and initiating antiviral defenses (Fig. 4 d). Genes such as IFITM3, TBK1, and STAT2 have been identified as potential therapeutic targets for their roles in modulating the host’s immune response and controlling viral load.

Journal impact and citation dynamics in dengue virus research

Over 29.76% of Dengue virus-related publications have appeared in the top 10 journals, underscoring the significant concentration of research output in high-impact periodicals. For more information on these leading journals, refer to Table S2 in the supplementary materials, which lists the top 10 global journals in the field of Dengue. Notably, Plos Neglected Tropical Diseases leads with 791 articles, followed by the American Journal of Tropical Medicine and Hygiene with 579 articles, Journal of Virology with 322 articles, and BMC Infectious Diseases with 207 articles. Predominantly classified within the Q1 and Q2 quartiles, these journals have a profound impact on the scientific community, covering areas such as virology, immunology, epidemiology, and public health. These leading journals contribute significantly to various research domains within the field. For instance, Plos Neglected Tropical Diseases and the American Journal of Tropical Medicine and Hygiene are instrumental in advancing basic research and epidemiological research. The Journal of Virology plays a critical role in disseminating virological and immunological research, while BMC Infectious Diseases provides extensive coverage of clinical studies and the public health implications of research. This interdisciplinary approach is essential for addressing the multifaceted challenges of Dengue research.

A dual-map overlay analysis provides further insights by visualizing the diversity of research topics covered in these journals and the co-citation relationships among articles in the Dengue virus research field (Fig. 5 ). This analysis highlights the interconnectedness of research activities, with molecular biology, immunology, and clinical medicine prominently featured. It also reveals extensive collaboration across research domains, underscoring the pivotal role of molecular biogenetics as a frequently cited area in Dengue virus research. This network illustrates the depth of collaborative efforts and showcases the journals’ roles in fostering a comprehensive understanding of and response to global Dengue fever challenges.

Dual Map Overlay of Journals in Dengue Virus Research. This visualization illustrates the thematic distribution and citation flows among disciplines involved in Dengue studies. It highlights key citation trajectories between journals in Molecular Biology, Genetics, and other related fields, showcasing the interconnectivity of medical, clinical, and biological research in advancing our understanding of Dengue

The inaugural bibliometric analysis of the global research landscape on the dengue virus reveals a field predominantly characterized by descriptive and observational studies. From 1995 to 2023, the number of published papers peaked in 2021, with 747 articles. This surge suggests a rapid advancement and increased interest in Dengue virus research, potentially driven by emerging challenges and advancements in the field. These pivotal moments have often been marked by disease outbreaks, policy changes, or scientific breakthroughs. For instance, severe outbreaks in the Philippines and Brazil during 2019–2021 led to an increased focus on studying transmission patterns and developing effective prevention strategies [ 7 , 8 ]. Global health organizations and national governments have implemented new policies to combat the rising threat of Dengue. The World Health Organization’s comprehensive Dengue control strategy, launched in 2020, emphasized the need for enhanced surveillance, improved diagnostics, and vaccine development. These policies spurred increased funding and research initiatives, contributing to the surge in publications. Advances in genomics, proteomics, and bioinformatics have provided new tools and methodologies for studying the Dengue virus. Breakthroughs in vaccine development, such as the approval and rollout of the Dengvaxia vaccine, and innovative diagnostic methods have accelerated research efforts to evaluate efficacy and safety, understand virus-host interactions, and explore novel therapeutic targets. These pivotal events have directed research towards specific aspects of Dengue virus biology, immunology, and epidemiology, guiding the evolution of the field [ 9 ]. Initially dominated by basic research on viral properties, replication mechanisms, and vaccine development, the field has progressively expanded to encompass broader areas such as vector ecology [ 10 ], clinical manifestations [ 11 ], diagnostic methods [ 12 ], and disease epidemiology [ 13 , 14 ].

Geographical analysis reveals significant disparities in research quality across continents. Europe leads with 59.36% of its publications in the top quartile, followed by Central America and the Caribbean (57.14%), and North America (51.17%). These disparities are influenced by several factors. Research output is disproportionately lower in regions such as Sub-Saharan Africa, parts of the Middle East, and smaller island nations in the Pacific. Despite the presence of Dengue in these areas, they contribute relatively few research publications compared to regions like Southeast Asia and Latin America. Many underrepresented regions lack the necessary infrastructure, funding, and trained personnel to conduct extensive research. Limited access to advanced technologies and laboratories hampers local research efforts. In regions burdened by multiple infectious diseases (e.g., malaria, HIV/AIDS), public health resources and research funding are often directed towards more immediate health threats, sidelining Dengue research. Variations in Dengue virus transmission dynamics and environmental conditions might influence the intensity and focus of research activities. Regions with sporadic outbreaks may not prioritize Dengue research as highly as those with continuous high transmission rates. These disparities impact global Dengue virus research and control efforts by creating gaps in knowledge and hindering the development of universally effective interventions. Underrepresentation in research limits the understanding of region-specific transmission patterns, vector behavior, and population immunity, which are crucial for designing targeted control measures.

Comparison with existing literature

Spanning from 1995 to 2023, this study provides a unique longitudinal analysis of Dengue virus research, revealing significant trends and shifts using advanced bibliometric and statistical techniques like network and trend analyses. Our findings are consistent with and build upon prior bibliometric studies on Dengue virus and related arboviruses. By integrating disciplines like epidemiology, biology, and environmental science, the study provides an in-depth view of the field’s evolution and the challenges posed by the Dengue virus. It particularly highlights the impact of global climate change on disease transmission, offering insights not extensively covered in previous literature. For instance, the study titled “Dengue,” published in The Lancet in February 2024, includes data only up until October 10, 2022 [ 15 ]. In contrast, our research incorporates updated data, extending our analysis from 1995 to 2023. This expansion enables a more comprehensive analysis and deeper insights into long-term trends that elucidate the development and impact of Dengue fever.

Hotspots and frontiers

The analysis of keywords and gene clustering patterns highlights emerging trends and research priorities in DENV research. Key research focuses include vaccine development [ 16 , 17 ], novel antiviral therapies, virus transmission and control strategies, climate change and disease distribution, epidemiology and model predictions [ 18 , 19 , 20 ], and immune responses and pathogenic mechanisms [ 21 , 22 , 23 ]. The dynamic nature of DENV research is evident, with a recent pivot toward issues such as climate change and the emergence of viruses like Zika and chikungunya [ 24 , 25 , 26 , 27 ]. Since 2019, the focus has notably shifted toward antiviral activities [ 28 , 29 ] and the exploration of neutralizing antibodies [ 30 , 31 , 32 , 33 , 34 ] as critical areas of investigation. Effective antiviral strategies are essential to control the rising prevalence of Dengue virus infection and reduce mortality. The identified trends indicate a growing reliance on interdisciplinary approaches in DENV research. To comprehensively understand the transmission mechanisms and pathological processes of the dengue virus, future studies should continue to foster collaborations across fields such as epidemiology, molecular biology, climate science, and public health. Additionally, the hotspots reveal the rapid development of new diagnostic and therapeutic technologies. Future research should further promote innovation in areas such as nanotechnology, gene editing, and vaccine development to discover more effective prevention and treatment methods. Moreover, enhancing global data sharing and applying big data analytics can enable researchers to more accurately predict dengue outbreaks and develop more effective interventions. The analysis of research trends and hotspots can also provide evidence-based support for policy-making. Understanding regional patterns of virus transmission and high-risk factors can help formulate targeted control strategies. Furthermore, public health strategies can be significantly improved by integrating community involvement and education, environmental management, and continuous monitoring. Environmental factors play a significant role in virus transmission, as indicated by hotspot analyses. Public health strategies should establish and refine monitoring systems and emergency plans to ensure swift and effective action during outbreaks.

Vaccine development

The development of an effective dengue vaccine has been hindered by the immunological complexities of its four serotypes, requiring uniform protection to prevent antibody-dependent enhancement (ADE), a significant challenge for vaccine efficacy [ 35 , 36 ]. Several vaccine candidates have emerged, targeting either the structural E protein or the non-structural protein NS1, with various stages of development currently underway [ 37 , 38 , 39 ]. Currently, three primary vaccines are in use: Sanofi Pasteur’s Dengvaxia (CYD-TDV), the first licensed vaccine; this vaccine has shown an efficacy rate of approximately 60% but has been associated with an increased risk of severe dengue in seronegative individuals. This risk led to its restricted use to those who have had a previous dengue infection. Recent studies have continued to monitor its long-term efficacy and safety, providing critical data on its performance in diverse populations. Takeda’s Qdenga (TAK-003), approved in the EU in December 2022 and in Brazil in March 2023; Qdenga has demonstrated a higher efficacy rate, with recent studies showing an 80% reduction in hospitalizations and a 90% reduction in severe dengue cases among vaccinated individuals. where the vaccine was approved for ages 4–60, corroborate these findings, showing substantial decreases in dengue-related hospitalizations and severe cases. and the NIH’s TV003 has shown promise, with phase II trials indicating strong immunogenicity and a balanced response against all four serotypes. Phase III trials are ongoing, and preliminary data suggest high efficacy across different age groups and regions [ 40 ]. This vaccine’s simpler dosing schedule and robust immune response make it a strong candidate for broad use. For a comparison of the efficacy of licensed and Phase 3 live attenuated tetravalent Dengue vaccines across targeted populations, refer to Table 1 . Additional candidates, such as attenuated live, inactivated, recombinant, and DNA vaccines, are currently under clinical or preclinical evaluation. For a comprehensive overview of these vaccine candidates, refer to Table S3 in the supplementary materials.

Novel antiviral therapies

The urgent need for effective antiviral agents against the Dengue virus is underscored by the limited efficacy of currently available treatments [ 41 , 42 ]. Substantial efforts have been invested in identifying potent antivirals, with a notable shift toward repurposing existing drugs as a viable strategy [ 43 ]. However, drugs such as balapiravir, chloroquine, lovastatin, and celgosivir have shown limited success in clinical trials, highlighting the need for a targeted approach in developing novel therapies. Many repurposed drugs were originally designed to target different pathogens or disease mechanisms, which do not align well with the unique biology of the Dengue virus. For instance, chloroquine, primarily an anti-malarial drug, failed to exhibit significant antiviral activity against Dengue in clinical settings [ 44 ]. The pharmacokinetic profiles of some repurposed drugs are not suitable for achieving effective concentrations in tissues affected by Dengue. Additionally, toxicity at the required doses for antiviral efficacy can limit their use. Balapiravir, for instance, showed hepatotoxicity in clinical trials, making it unsuitable for Dengue treatment [ 45 ]. The potential for the development of viral resistance is another concern. Drugs like lovastatin, initially considered for their antiviral properties, may induce resistance mechanisms in the virus, reducing their long-term efficacy [ 46 ]. Lessons learned for future drug development include the importance of tailoring drug design to the specific viral and host mechanisms involved in Dengue pathogenesis. Additionally, a better understanding of the pharmacokinetic and pharmacodynamic requirements for effective antiviral activity is crucial. Future efforts should focus on identifying compounds that specifically target Dengue virus replication and its interaction with host cells.

Detailed information on the most promising candidates(see Table 2 ), such as AT-752 and JNJ-1802, can shed light on the potential breakthroughs in antiviral treatments for Dengue. AT-752-This candidate has shown potent in vitro activity against all four DENV serotypes. Phase I trials have indicated favorable pharmacokinetics and safety profiles, making it a promising candidate for further development. AT-752 targets the viral RNA polymerase, inhibiting viral replication. Early clinical data suggest that AT-752 can achieve therapeutic concentrations in the blood with minimal side effects, paving the way for phase II trials to assess its efficacy in Dengue patients. JNJ-1802-An inhibitor of the DENV NS4B protein, JNJ-1802 has demonstrated robust antiviral activity in preclinical models. It disrupts the viral replication complex, effectively reducing viral load. Early-phase clinical trials have shown promising results, with significant reductions in viral RNA levels in treated individuals. The safety profile has also been favorable, with no serious adverse events reported. Ongoing trials aim to determine the optimal dosing regimen and confirm its efficacy in larger patient cohorts. Additionally, research into host-targeted therapies, such as those modulating the immune response or viral entry pathways, is ongoing, with several candidates showing promise in preclinical studies. These approaches aim to enhance the host’s ability to combat the virus or prevent the virus from entering and replicating within host cells. Continued interdisciplinary research and innovative methodologies are crucial in addressing the challenges of treating DENV infections. For detailed information on recent advances, refer to Table S4 in the supplementary materials, which outlines the development of new antiviral drugs for Dengue. The integration of novel therapeutic approaches, combined with a deeper understanding of the virus-host interactions, holds the potential for significant breakthroughs in managing Dengue virus infections.

Virus transmission and control strategies

Recent advances in biological control methods have significantly shaped strategies to mitigate dengue fever transmission via vector mosquitoes. One notable approach is infecting Aedes mosquitoes with Wolbachia, an endosymbiotic bacterium that effectively reduces the mosquitoes’ ability to transmit the dengue virus [ 47 ]. Another method is the release of sterile mosquitoes through radiation or genetic modification, which controls population numbers by preventing offspring production after mating with wild mosquitoes [ 48 ]. Additionally, the use of CRISPR-Cas9 gene editing technology is emerging as a revolutionary approach to engineer mosquitoes that either cannot survive or transmit the dengue virus, although this remains experimental [ 48 ]. The application of nanotechnology in insecticides shows promise, enhancing the delivery and effectiveness of chemical controls with minimal environmental impact by targeting specific biological pathways in mosquitoes [ 49 ]. Furthermore, smart surveillance systems utilizing IoT (Internet of Things), AI (Artificial Intelligence), and big data are improving the monitoring and predictive analysis of vector populations and dengue transmission patterns, leading to more targeted and efficient control measures [ 50 ].

Epidemiology and model predictions

Recent advancements in epidemiological modeling have significantly enhanced our understanding of disease transmission in the context of climate change. Machine learning and AI models have become essential for processing large datasets and predicting disease spread patterns with high accuracy, leveraging complex nonlinear data to forecast trends and potential outbreaks [ 51 ]. Spatial statistical models, another critical tool, use geographic and environmental data to map the potential distribution of vectors like Aedes mosquitoes and predict regions at increased risk for dengue outbreaks [ 51 ]. Dynamic simulation models, such as the Susceptible-Exposed-Infectious-Recovered (SEIR) model, simulate transmission dynamics within populations using differential equations to describe interactions between hosts, pathogens, and the environment, providing a detailed predictive framework [ 52 ]. Additionally, regression analysis identifies key factors influencing transmission, while Geographic Information Systems (GIS) assess how environmental factors, exacerbated by climate variability, affect disease patterns. Integrating GIS with epidemiological data helps guide targeted interventions and resource allocation [ 53 ].

Immune responses and pathogenic mechanisms

Gene co-occurrence analysis has highlighted critical molecular mechanisms in Dengue virus infection, pinpointing key genes such as IFNA1, DDX58, and STAT1 that play significant roles in the host immune response. IFNA1 enhances antiviral gene expression and adaptive immunity [ 54 ]. DDX58 activates innate immune signaling upon viral RNA recognition [ 55 ], and STAT1 is crucial for cytokine production and immune cell activation [ 56 , 57 ]. Dysregulation of these genes can lead to severe outcomes in Dengue fever. Other important genes in the Toll-like and RIG-I-like receptor pathways, such as TLR3, TLR7, TLR9, IFNAR1, and MAVS, have been linked to virus recognition and response mechanisms [ 58 ]. The dynamic host immune response to Dengue virus involves innate immune sensor activation, cytokine production, and adaptive immune response induction. The virus employs evasion strategies that can lead to dysregulated immune responses and severe disease manifestations such as cytokine storm and tissue damage [ 30 , 59 , 60 , 61 ]. This understanding opens avenues for targeted therapies, such as viral RNA-sensor inhibitors or cytokine blockers, which could mitigate immune-mediated damage and improve outcomes in severe Dengue cases. Insights from gene co-occurrence studies suggest potential therapeutic targets in immune signaling, viral replication, and inflammation pathways, crucial for developing novel treatments to control viral replication and modulate immune responses in Dengue virus infection [ 62 ].

Strategic initiatives for global dengue research collaboration

Future research on Dengue virus (DENV) should prioritize international collaboration and interdisciplinary cooperation to effectively address global challenges. Establishing international research consortia and networks is essential, aiming to foster partnerships among countries, institutions, and disciplines to facilitate knowledge exchange, resource sharing, and collaborative research efforts. Initiatives like joint funding programs, collaborative research projects, and researcher exchange programs are crucial for promoting cross-cultural collaborations and interdisciplinary approaches. Leveraging the strengths of diverse stakeholders, such as researchers, policymakers, public health agencies, and community organizations, is key to driving innovation and accelerating progress in understanding and combating DENV globally. Future studies should explore Dengue virus dynamics, leveraging advanced technologies and data analysis methods to predict outbreaks and identify key environmental, social, and biological factors. Collaborative efforts among epidemiologists, virologists, entomologists, climatologists, and public health experts can provide a holistic understanding of transmission mechanisms and accelerate the development of targeted interventions. Integrating real-time surveillance systems, geographic information systems (GIS), and mathematical modeling can enhance the accuracy and timeliness of outbreak predictions, optimizing resource allocation for prevention and control. Community-based interventions, such as vector control programs and health education campaigns, are crucial in reducing transmission and mitigating the impact of outbreaks. Despite advancements, challenges in rapid diagnostics, effective antiviral treatments, and developing vaccines that are efficacious across all DENV serotypes remain. Addressing these challenges through innovative diagnostic technologies, novel vaccine platforms, and interdisciplinary collaboration is vital for progress. Moreover, emerging technologies like gene editing and biotechnology hold promise for new therapeutic interventions, underscoring the importance of international and interdisciplinary efforts in advancing DENV research and developing sustainable solutions for its control and prevention.

Conclusions

This bibliometric analysis reveals key trends and research gaps in DENV studies from 1995 to 2023, highlighting the importance of interdisciplinary approaches in understanding virus behavior, vaccine development, and prevention strategies. Although notable progress has been made, our analysis identifies several underexplored areas, including the interactions between DENV and its host, the socio-economic impacts of public health interventions, and the application of advanced technologies like artificial intelligence in epidemic prediction and management. Future research requires strengthened interdisciplinary collaboration, uniting experts from molecular biology, epidemiology, data science, and other fields to address comprehensively the challenges posed by DENV. By fostering such cooperation, we can bridge existing research gaps and pioneer new directions, ultimately achieving effective control and prevention of DENV.

Supplemental materials

To further enrich the understanding of our research, we have provided detailed Supplemental Materials. These include Table S1 , which presents data on global dengue cases and related deaths since 1995; Table S2 , which lists the top 10 global journals in the field of dengue; Table S3 , which details current dengue vaccine candidates under evaluation; and Table S4 , which summarizes recent advances in dengue antiviral drug development. These materials offer additional insights and broader context to the discussions presented in this paper.

Data availability

Not applicable.

Abbreviations

Dengue virus

The World Health Organization

The Web of Science

Science Citation Index Expanded

Self-citation percentage (SCP)

Most cited paper (MCP)

Corona Virus Disease 2019

Antibody-dependent enhancement

Interferon Alpha 1

DEAD (Asp-Glu-Ala-Asp) Box Polypeptide 58

Interferon Beta 1

Signal Transducer and Activator of Transcription 1

Interferon Regulatory Factor 3

Nuclear Factor Kappa B Subunit 1

Toll-like Receptors

RIG-I-like Receptors

Interferon-Induced Transmembrane Protein 3

TANK-Binding Kinase 1

Signal Transducer and Activator of Transcription 2

National Institutes of Health

Internet of Things

Artificial Intelligence

Susceptible-Exposed-Infectious-Recovered (a compartmental model in epidemiology)

Geographic Information System

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This work was supported by the National Key Research and Development Program of China (2021YFC2301704) and CAMS Innovation Fund for Medical Sciences (2020-12 M-5-001).

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Liu, Y., Wang, M., Yu, N. et al. Trends and insights in dengue virus research globally: a bibliometric analysis (1995–2023). J Transl Med 22 , 818 (2024). https://doi.org/10.1186/s12967-024-05561-5

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Pharmaceutics

Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

Ahlam zaid alkilani.

1 School of Pharmacy, 97 Lisburn Road, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; E-Mails: [email protected] (M.T.C.M.); [email protected] (R.F.D.)

2 Faculty of Pharmacy, Zarqa University, Zarqa 132222, Jordan

Maelíosa T.C. McCrudden

Ryan f. donnelly.

The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies.

1. Introduction

The most common routes of drug delivery are the oral and parenteral routes with the majority of small molecule drugs conventionally delivered orally [ 1 , 2 ]. The oral route has the advantage of pre-determined doses, portability and patient self-administration. For these reasons, the oral route remains the most convenient means of delivering medications [ 3 , 4 ]. However, most therapeutic peptides or proteins are not delivered by the oral route, due to rapid degradation in the stomach and size-limited transport across the epithelium [ 5 ]. The primary mode of administering macromolecules is therefore via injection [ 1 , 5 , 6 ] which is not without limitations, such as the invasive nature of injections eliciting pain and lower acceptance/compliance by patients, in addition to the requirement for administration by a trained administrator [ 5 , 6 , 7 ]. Rationally, the conventional routes of medication delivery have many inherent limitations which could potentially be overcome by advanced drug delivery methodologies such as transdermal drug delivery (TDD).

2. Transdermal Drug Delivery (TDD)

TDD is a painless method of delivering drugs systemically by applying a drug formulation onto intact and healthy skin [ 2 , 5 ]. The drug initially penetrates through the stratum corneum and then passes through the deeper epidermis and dermis without drug accumulation in the dermal layer. When drug reaches the dermal layer, it becomes available for systemic absorption via the dermal microcirculation [ 8 , 9 ]. TDD has many advantages over other conventional routes of drug delivery [ 10 , 11 , 12 ]. It can provide a non-invasive alternative to parenteral routes, thus circumventing issues such as needle phobia [ 2 ]. A large surface area of skin and ease of access allows many placement options on the skin for transdermal absorption [ 5 ]. Furthermore, the pharmacokinetic profiles of drugs are more uniform with fewer peaks, thus minimizing the risk of toxic side effects [ 2 ]. It can improve patient compliance due to the reduction of dosing frequencies and is also suitable for patients who are unconscious or vomiting, or those who rely on self-administration [ 13 ]. TDD avoids pre-systemic metabolism, thus improving bioavailability [ 2 , 4 ]. With reference to the use of the skin as a novel site for vaccination strategies, this organ is known to be replete with dendritic cells in both the epidermal and dermal layers which play a central role in immune responses making TDD an attractive vaccination route for therapeutic proteins and peptides [ 3 , 14 ]. The requirement for an inexpensive and non-invasive means of vaccination, especially in the developing world [ 3 , 14 , 15 ], has given rise to substantial research focused on the development of simple, needle-free systems such as TDD for vaccination purposes. This theme will be explored further in Section 4.5.2 of this review.

3. A Brief Review of Skin Structure

Skin is the most accessible and largest organ of the body with a surface area of 1.7 m 2 , compromising 16% of the total body mass of an average person [ 16 , 17 , 18 ]. The main function of the skin is to provide a protective barrier between the body and the external environment against microorganisms, the permeation of ultraviolet (UV) radiation, chemicals, allergens and the loss of water [ 19 ]. Skin can be divided into three main regions: (1) the outermost layer, the epidermis, which contains the stratum corneum; (2) the middle layer, the dermis and (3) the inner most layer, the hypodermis ( Figure 1 ) [ 5 , 20 , 21 ].

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3.1. Epidermis

The epidermis is the outermost layer of the skin and varies in thickness with approximately 0.8 mm on the palms of the hands and soles of the feet [ 19 ]. It consists of multi-layered regions of epithelial cells and the viable epidermis is often referred to as the epidermal layers below the stratum corneum [ 8 , 19 ]. The cellular content of the epidermis consists predominantly of keratinocytes (approximately 95% of cells), with other cells of the epidermal layers including melanocytes, Langerhans cells and merkel cells [ 14 ].The stratum corneum is the most superficial layer of the epidermis [ 19 , 23 , 24 ]. It is in direct contact with the external environment and its barrier properties may be partly related to its very high density (1.4 g/cm 3 in the dry state) and its low hydration of 15%–20% [ 25 ]. The cells of the stratum corneum are composed mainly of insoluble keratins (70%) and lipid (20%) [ 25 ]. Water in the stratum corneum is associated with keratin in the corneocytes [ 19 , 26 ].

3.2. Dermis

The dermis is approximately 2–3 mm thick and consists of collagenous (70%) and elastin fibres which give strength and elasticity to the skin [ 17 ]. Blood vessels found in the dermis provide nutrients for both the dermis and epidermis. Nerves, macrophages and lymphatic vessels are also present in the dermis layer, as depicted in Figure 1 [ 23 ].

3.3. Hypodermis

The hypodermis or subcutaneous layer is the deepest layer of the skin and consists of a network of fat cells [ 17 ]. It is the contact layer between the skin and the underlying tissues of the body, such as muscles and bone. Therefore, the major functions of the hypodermis are protection against physical shock, heat insulation and support and conductance of the vascular and neural signals of the skin [ 27 ]. Hypodermis-resident fat cells account for approximately 50% of the body’s fat with the other predominant cells of the hypodermis consisting of fibroblasts and macrophages [ 28 ].

3.4. Drug Penetration Routes

There are two possible routes of drug penetration across the intact skin, namely the transepidermal and transappendegeal pathways, which have been diagrammatically presented in Figure 2 . The transepidermal pathway involves the passage of molecules through the stratum corneum, an architecturally diverse, multi-layered and multi-cellular barrier. Transepidermal penetration can be termed intra- or inter-cellular [ 29 ]. The intra-cellular route through corneocytes, terminally differentiated keratinocytes, allows the transport of hydrophilic or polar solutes. Transport via inter-cellular spaces allows diffusion of lipophilic or non-polar solutes through the continuous lipid matrix. The transappendegeal route involves the passage of molecules through sweat glands and across the hair follicles [ 5 , 30 ].

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3.5. Kinetics of TDD

An understanding of the kinetics of skin permeation is necessary for development of successful TDD systems. In order to evaluate any TDD, the assessment of percutaneous absorption of molecules is a very important step. Percutaneous absorption is the penetration of substances into various layers of skin and permeation across the skin into the systemic circulation [ 8 , 31 , 32 , 33 ]. Percutaneous absorption of molecules is a step wise process involving:

Penetration: The entry of a substance into a particular layer of the skin;
Partitioning from the stratum corneum into the aqueous viable epidermis;
Diffusion through the viable epidermis and into the upper dermis;
Permeation: The penetration of molecules from one layer into another, which is different both functionally and structurally from the first layer;
Absorption: The uptake of a substance into the systemic circulation.

In delivery systems involving transdermal patches, the drug is stored in a reservoir (reservoir type) or drug dissolved in a liquid or gel-based reservoir (matrix type).The starting point for the evaluation of the kinetics of drug release from a transdermal patch is an estimation of the drug compound’s maximum flux across the skin (flux ( J )) which is typically expressed in units of μg/cm 2 /h) (Equation 1) ( Figure 3 ). Based on Fick’s law of diffusion, the transport of therapeutic molecules across skin will be maintained until the concentration gradient ceases to exist [ 33 , 34 , 35 ].

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Object name is pharmaceutics-07-00438-g003.jpg

Description of flux across the skin from a transdermal patch where J is the molecular flux, C 2 is the concentration of the active molecule in the patch, C 1 is the concentration of the active molecule in the body, D is the diffusion coefficient; L is the cross sectional thickness of diffusion, and t is the diffusion time. The equation indicates Fick’s law of diffusion. (Reprinted from [ 33 ] with permission. Copyright 2013 Elsevier).

where D is the diffusion coefficient and d c / d t is the concentration gradient.

Conventional TDD is possible only if the drug possesses certain physiochemical properties. The rate of permeation across the skin (d Q / d t ) is given by [ 35 ]:

where C d and C r are the concentration of the skin penetrant in the donor compartment ( i.e. , on the surface of stratum corneum ) and in the receptor compartment ( i.e. , body), respectively. P is the permeability coefficient of the skin tissue to the penetrant.

where D is he diffusion coefficient obtained from the permeability coefficient, P , the solute partition coefficient, K , and L is the overall thickness of skin tissues.

From equation (2) it is clear that a constant rate of drug permeation can be obtained only when C d >> C r i.e ., the drug concentration at the surface of the stratum corneum. C d is consistently and substantially greater than the drug concentration in the body C r . The equation becomes:

The cumulative amount permeating ( Q ) the barrier with the effective surface area of permeation ( A ) at a given time ( t ) is calculated by using Equation (5) [ 35 ]:

The permeability coefficient ( P ) can be obtained from the slope of a plot of cumulative permeation of diffusant vs. time obtained from an experimental permeation study. A typical plot of permeation study is shown in Figure 4 .

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Object name is pharmaceutics-07-00438-g004.jpg

A typical plot of permeation study.

L is the swollen membrane thickness. As shown in Figure 4 , the cumulative permeation curve has two portions. The initial portion of the curve represents non-steady state diffusion and the linear portion corresponds to steady state diffusion. The non-steady portion of the curve can be described mathematically by Fick’s second law, while the linear portion can be expressed by Fick’s first law [ 35 ]. The time required to reach steady state is called the lag time ( t Lag). The lag time can be determined by extrapolating the linear portion of permeation vs. the time curve to the time axis. With lag time, Equation (6) is rewritten as (7) [ 35 ].

The lag time can be calculated by Equation (8) [ 35 ]:

Transdermal systems should be formulated to provide the maximum thermodynamic driving force for passive diffusion across the skin which is saturated with a sufficient payload of the drug to ensure delivery of drugs across the skin. The ability of approved transdermal drugs to penetrate the skin varies widely from the extremely permeable nicotine to compounds, such as buprenorphine and the progestins, which have very low predicted fluxes.

The first transdermal patch approved for systemic delivery in 1979 was a patch for the sustained, three days delivery of scopolamine in the treatment of motion sickness [ 1 , 34 ]. Transdermal delivery is currently restricted to approximately 17 drug molecules that are approved by the US Food and Drug Administration (FDA) ( Table 1 ) [ 2 , 4 ]. The limited number of drug molecules seen in s Table 1 reflects the difficulty of meeting the dual challenge of potent pharmacological activity and the correct physicochemical properties to enable skin penetration [ 34 , 36 ].These approved molecules are all of low molecular weight (MW < 500 Da), a balanced lipophilicity (log P = 1–3), and a measurable solubility both in oil and in water because TDD systems require both breaching the lipophilic stratum corneum and resorption into the aqueous central compartment of the systemic circulation [ 8 , 34 ]. Moreover, high pharmacological potency of drug molecules is required to become a feasible candidate for TDD [ 8 , 36 , 37 ]. The limited permeability of molecules is due to the outermost layer of the skin, the stratum corneum [ 38 , 39 ]. This “dead” layer of tissue has the ability to prevent the permeation of foreign compounds including drug molecules and therefore acts as a very effective barrier [ 39 , 40 ]. In order to enhance drug permeation across the skin, a number of chemical and physical methods have been devised [ 3 , 5 , 34 ].

Drug (Year of Approval)	Dose/Day (mg)	MW (Da)	Log	Cl (L/h)	(h)	F (%)	C (ng/mL)
Scopolamine (1979)	0.3	303	0.98	672	2.9	27	0.04
Glyceryl trinitrate (1981)	2.4–15	227	01.62	966	0.04	<1	0.1–5
Clonidine (1984)	0.1–0.3	230	2.42 ± 0.52	13	6–20	95	0.2–2.0
Estradiol (1986)	0.025–0.1	272	4.01	615–790	0.05	3-5	0.04–0.06
Fentanyl (1990)	0.288–2.4	337	4.05	27–75	3–12	32	1.0
Nicotine (1991)	7–21	162	1.17	78	2	30	10–30
Testosterone (1993)	0.3–5	288	3.32		0.17–1.7	<1	10–100
Estradiol & Norethisterone Acetate (1998)	0.025–0.050 0.125–0.250	272 340	4.01 3.99		2–3 6–8	3–5 64	0.04–0.07 0.8–1.1
Norelgestromin & EthinylEstradiol (2001)	0.025–0.050 0.125–0.250	327 296	3.90 ± 0.47 3.67		28 17	40	0.8 0.05
Estradiol & Levonorgestrel (2003)	0.025–0.050 0.125–0.250	272 312	4.01 3.72 ± 0.49		3 28	3-5	0.03–0.05 0.1–0.2
Oxybutynin (2003)	3.9	357	4.02 ± 0.52		2	6	1.0–5.0
Selegeline (2006)	6–12	187	2.90	84	10	10	2.0–3.0
Methylphenidate (2006)	26–80	233	2.15 ± 0.42	20	2–3	5–20	5.0–25
Rotigotine (2007)	1–3	315	4.58 ± 0.72	600	5–7	n/a	~1.0
Rivastigmine (2007)	4.6–9.5	250	2.34 ± 0.16	108	1.5	40	~10
Granisetron (2008)	3.1	312	2.55 ± 0.28	33–76 healthy 15–34 patients	4–6 healthy 9–12 patients	60	0.7–9.5
Buprenorphine (2010)	0.12–1.68	468	4.98	55	22–36	n/a	0.1–0.4

a Log{octanol-water partition coefficient ( P )}: either experimental or calculated (mean ± SD) values; b Terminal half-life post-oral or IV dosing; c Oral bioavailability; d Terminal half-life following transdermal delivery; e Pharmacologically effective plasma concentration.

Due to the aforementioned challenges associated with successful drug permeation across the skin, a number of different, innovative approaches have been explored and developed to overcome these challenges. These will be discussed in the subsequent sections of this review.

4. Techniques for Enhancement of Skin Permeabilisation

Technologies used to modify the barrier properties of the stratum corneum can be divided into passive/chemical or active/physical methodologies ( Figure 5 ). Passive methods include the influencing of drug and vehicle interactions and optimization of formulation, in order to modify the stratum corneum structure [ 29 , 41 , 42 ]. Passive methods are relatively easy to incorporate into transdermal patches such as chemical enhancers and emulsions [ 43 ]. However, the main drawback of passive methods may be a lag time in drug release incurred with obvious negative influence on rapid onset drugs, such as insulin.

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Approaches for enhancing drug transport across the skin.

One of the most widely used passive approaches is the use of chemical penetration enhancers which facilitate drug permeation across the skin by increasing drug partitioning into the barrier domain of the stratum corneum, without long-term damage to the skin [ 11 , 44 ]. Penetration enhancers have several mechanisms of action such as: increasing the fluidity of the stratum corneum lipid bilayers, interaction with intercellular proteins, disruption or extraction of intercellular lipids, increase of the drug’s thermodynamic activity and increase in stratum corneum hydration [ 11 , 44 , 45 ]. Several types of penetration enhancers are known and they can be divided into several groups based on their chemical structure, rather than their mechanism of action [ 32 , 44 ]. Most of these have mixed modes of action so it is difficult to classify them according to this characteristic. Examples of commonly investigated penetration enhancers are alcohols, sulphoxides, azone, pyrrolidones, essential oil, terpenes and terpenoids, fatty acids, water and urea [ 44 , 45 ]. However, the major limitation for penetration enhancers is that their efficacy is often closely correlated with the occurrence of skin irritation [ 32 , 45 ]. Gels have been used in TDD and recent developments in the technology have introduced new variations of semisolid vehicles such as proniosomes and microemulsion gels into the field of penetration enhancers [ 43 ]. Proniosomes are non-ionic based surfactant vesicles, they are known as ‘‘dry niosomes’’ because they may require hydration before drug release and permeation through the skin. Proniosomal gels have been used in TDD because they act as penetration enhancers that enhance the drug permeation from the skin barrier [ 43 , 46 ]. Upon hydration proniosomesare converted into niosomes which are capable of diffusing across the stratum corneum and then adhere to the cell surface which causes a high thermodynamic activity gradient of the drug at the vesicle/stratum corneum surface, thus acting as the driving force for the penetration of lipophilic drugs across the skin ( Figure 6 ) [ 43 , 46 ].

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Possible mechanisms of action of surfactant vesicles for dermal and transdermal applications: ( A ) drug molecules are released by niosomes; ( B ) niosome constituents act as penetration enhancer; ( C ) niosome adsorption and/or fusion with stratum corneum; ( D ) intact niosome penetration through the intact skin; ( E ) niosome penetration through hair follicles and/or pilosebaceous units. (Reprinted from [ 46 ] with permission. Copyright 2014 Elsevier).

Some of the limitations associated with penetration enhancers are poor efficacy and safety. They do not achieve the desired skin disruption and their ability to increase transport across the skin is low and variable [ 46 , 47 ] . Regarding safety considerations, penetration enhancers have been shown in a limited number of cases to potentially cause skin irritation including local inflammation, erythema, swelling and dermatitis [ 47 ].

The active methods for skin permeabilisation include ultrasound, electrically assisted methods (electroporation and iontophoresis), velocity based devices ( powder injection, jet injectors), thermal approaches (lasers and radio-frequency heating) and mechanical methodologies such as microneedles (MN) and tape stripping [ 2 , 48 , 49 , 50 , 51 ]. These approaches allow a broader class of drugs to be delivered into the skin. Active methods involve the use of external energy to act as a driving force for drug transport across the skin or by physically disrupting the stratum corneum [ 48 , 49 ]. These techniques greatly expand the range of drugs that can be delivered effectively across the skin. This in turn will significantly enhance the value of the transdermal delivery market and will be increasingly important over the coming years as the number of new drugs of biological origin continues to increase. In addition, active methods also offer more reproducible control over the delivery profiles of the medications, thus overcoming lag times between the application and the drug reaching the systemic circulation when compared to passive methods [ 11 , 48 ]. Some of these active methodologies will be described in detail below.

4.1. Ultrasound Devices

Ultrasound is an oscillating sound pressure wave that has long been used for many research areas including physics, chemistry, biology, engineering and others in a wide range of frequencies [ 2 , 50 ]. Ultrasound, sonophoresis, or phonophoresis can be defined as the transport of drugs across the skin by application of ultrasound perturbation at frequencies of 20 kHz–16 MHz which has a sufficient intensity to reduce the resistance of skin [ 2 , 5 ]. The use of ultrasound has resulted in the effective delivery of various different categories and classes of drugs, regardless of their electrical characteristics, by increasing skin permeability. These drugs have included hydrophilic and large molecular weight drugs [ 39 ]. However, the mechanism of action is still not clearly understood or characterized [ 50 ]. The proposed mechanisms by which ultrasound effects tissues and cells include thermal effects and cavitation effects caused by collapse and acoustic streaming which can be explained as oscillation of cavitation bubbles in the ultrasound field [ 5 ]. Ultrasound can increase the temperature of the insonated medium (the skin) by the absorption of the sound waves with a frequency greater than the upper limit of the human hearing range. Obviously, the higher the medium’s absorption coefficient, the higher the increase in temperature and thus the greater the thermal effect [ 50 ]. All recent studies point out that cavitation is believed to be the predominant mechanism in the enhancement of TDD via ultrasound treatment [ 50 ].

The concept of ultrasound for use in TDD was initially reported by Fellinger and Schmidt in 1950 for the successful treatment of polyarthritis using hydrocortisone ointment combined with sonophoresis [ 52 , 53 , 54 ]. However, the first ultrasound device for transdermal application was approved in 2004 by the FDA for the delivery of local dermal anesthesia by the Sontra Medical, SonoPrep ® ( Figure 7 ). Since that time, ultrasound has been widely used as a TDD system in the treatment of many other diseases including bone joint diseases and bursitis [ 2 ]. Many challenges must be overcome before such devices gain commercial acceptance however. Some of these challenges include: availability of easy-to-use devices; the determination of the duration of treatment required; gaining a full understanding of how the technology functions; broadening of the range of drugs that can be delivered and evaluation of the safety profiles of the devices [ 5 , 39 , 55 , 56 ]. Examples of undesirable side effects of ultrasound approaches were observed by Singer et al. (1998) when it was shown that low-intensity ultrasound caused minor skin reactions in dogs while high-intensity ultrasound was capable of inducing second-degree burns [ 56 ]. Limitations such as this must be overcome before these innovations can garner full acceptance.

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4.2. Electrical Techniques

4.2.1. electroporation.

The two major means of electrically-facilitated TDD are iontophoresis and electroporation [ 2 , 4 ]. In electroporation, cells are temporarily exposed to high intensities of electric pulses that lead to the formation of aqueous pores in the lipid bilayers of the stratum corneum, thus allowing the diffusion of drugs across skin [ 5 , 57 , 58 , 59 ]. The technique was first described by Neumann et al. in 1982 [ 59 ]. Usage of high voltage pulses (50–500 V) for short times of only one second have been shown to increase transport across the skin for different molecular weight drugs ranging from small e.g., fentanyl, timolol [ 60 , 61 ], orcalcein [ 62 ], to high molecular weight drugs such as LHRH, calcitonin, heparin or FITC–dextran with molecular weights up to 40 kDa [ 58 , 63 , 64 , 65 , 66 ]. However, the main drawbacks are the lack of quantitative delivery, cell death with high fields and potential damage to labile drugs, e.g., those of protein origin [ 57 , 67 ].

4.2.2. Iontophoresis

Iontophoresis involves the application of physiologically acceptable electrical currents (0.1–1.0 mA/cm 2 ) to drive charged permeants into the skin through electrostatic effects and make ionic drugs pass through the skin into the body by its potential gradient [ 5 , 20 , 58 , 68 , 69 , 70 , 71 ]. Unlike other transdermal enhancement methodologies, it acts mainly by involving a second driving force, the electrical potential gradient as companion to the concentration gradient across the skin since uncharged species can also be delivered through electroosmosis ( Figure 8 ) [ 5 , 70 ].

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Phoresor ® , Lidosite ® , and E-trans ® are examples of three commercially developed iontophoretic delivery systems ( Figure 9 ). The first approved commercial iontophoretic patch system was LidoSite ® , which was developed to deliver lidocaine for fast dermal anaesthesia. The system was composed of a disposable pre-filled patch, re-usable battery-powered controller and a flexible interconnect module [ 20 ]. Iontophoresis has a minor effect on skin structure over short treatment periods due to the low-voltage nature of the applied electric current, when compared to electroporation [ 5 ].

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Commercially developed iontophoretic delivery systems: ( a ) Phoresor ® and ( b ) Lidosite ® .

Several factors affect iontophoretic TDD, including pH of the donor solution, electrode type, buffer concentration, current strength and the type of current employed [ 20 , 69 , 72 , 73 ]. The molecular size of the solute/drug is an important factor in determining its feasibility for successful iontophoretic delivery. The flux of smaller and more hydrophilic ions is faster than larger ions [ 72 , 73 , 74 ]. A plethora of studies correlating flux as a function of molecular weight have been conducted and it was found that the transport of compounds decreased with increase in molecular weight (chloride > amino acid > nucleotide > tripeptide > insulin) [ 22 , 72 , 75 , 76 , 77 , 78 ]. There is a linear relationship between the current and drug flux across the skin but the current is limited to 1 mA in order to facilitate patient comfort and consider safety concerns as with increasing current, the risk of nonspecific vascular reactions (vasodilatation) also increases [ 72 ]. Furthermore, the maximum time that the devices can be applied is 3 min, in order to prevent local skin irritation or burns. The maximum physiologically acceptable iontophoretic current is 0.5 mA/cm 2 [ 79 ]. The current should be adequately high to provide a desired flux rate but it should not irritate the skin [ 80 ]. The use of continuous direct current (DC) can decrease the drugs flux due to its polarization effect on the skin [ 69 ]. In order to overcome this problem, pulsed current has been used [ 81 ]. Overall, only a limited number of studies have been carried out comparing pulsed direct current iontophoresis vs. continuous direct current iontophoresis. Recently, Kotzki et al. 2015 showed that pulsed iontophoresis of treprostinil significantly enhanced cutaneous blood flow compared with continuous iontophoresis [ 69 ]. The most common electrodes that are used in iontophoresis are aluminum foil, platinum and silver/silver chloride electrodes [ 73 ]. However, the preferred one is Ag/AgCl since it resists the changes in pH. In addition, the electrode materials used for iontophoretic delivery should be harmless to the body and flexible so as to be applied closely to the body surface [ 73 ].

The maximum molecular weight for iontophoretic delivery has not been extensively studied, although it is estimated that molecules with a molecular weight less than 12,000 Da may be successfully delivered across skin via iontophoresis [ 79 ]. In order to deliver molecules greater than 12,000 Da, an alternate means of overcoming the barrier properties of the stratum corneum must be sought. However, it was found that a small protein, cytochrome c (12.4 kDa) was delivered non-invasively across intact skin [ 82 , 83 ]. Afterwards, ribonuclease A, with isoelectric point of 8.64 (13.6 kDa), was successfully delivered across porcine and human skin [ 84 ]. More recently, it was shown that transdermal iontophoresis was also able to deliver biologically active human basic fibroblast growth factor (hbFGF; 17.4 kDa) in therapeutically relevant amounts corresponding to those used in clinical trials and animal studies [ 85 , 86 ].

The applications of iontophoresis can be classified into therapeutic and diagnostic applications. Iontophoresis has been used in various diagnostic applications e.g. diagnosing cystic fibrosis [ 87 ] and recently for monitoring blood glucose levels [ 88 ].The major advantage of iontophoresis in diagnostic applications is that there is no mechanical penetration or disruption of the skin involved in this approach [ 89 , 90 ].

4.3. Velocity Based Devices

Velocity based devices, either powder or liquid jet injections, employ a high-velocity jet with velocities ranging from 100 to 200 m/s to puncture the skin and deliver drugs using a power source (compressed gas or a spring) [ 91 ]. The concept of jet injectors for use in drug delivery was first explored in the early of 1930s by Arnold Sutermesiter [ 11 ]. Since then, interest in this method of drug delivery has expanded significantly and two types of liquid jet injectors have been developed; single-dose jet injectors (disposable cartridge jet injectors) and multi-use-nozzle jet injectors (MUNJIs) [ 91 ]. Jet injections have been used for more than 50 years for parenteral delivery of vaccines, as well as small molecules, such as anesthetics and antibiotics [ 11 ]. A jet injector is a needle free device capable of delivering electronically controlled doses of medication which result in improved consistency of delivery and reduced pain for the patient ( Figure 10 ) [ 48 , 92 ].

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Liquid-jet injectors propel liquid from a nozzle with an orifice diameter ranging from 50 to 360 μm, which is much smaller than the outer diameter of a standard hypodermic needle (810 μm for a 21G needle) [ 20 , 93 , 94 ]. The jet can deliver drug into different layers of skin e.g., intradermal (i.d.), subcutaneous (s.c.) or intramuscular (i.m.), by changing the jet velocity and orifice diameter [ 20 ]. The major advantage of using needle free devices relates to concerns regarding safe needle disposal and avoidance of accidental needle stick injuries [ 20 ]. However, the risk of cross contamination is not excluded, since splash back of interstitial liquid from the skin may contaminate the nozzle [ 95 ]. Therefore the use of multi-use nozzle jet injectors has been terminated and such devices are now only used for multi-dose drug delivery to the same individual, e.g., the Tjet ® device which delivers somatropin (human growth hormone (hGH)) ( Figure 11 ).

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Commercially available jet injector Tjet ® device.

Powder jet injectors have an advantage over liquid jet injectors of delivering solid drugs or vaccines to the skin, so the stability of the formulation will be increased and the necessity for cold storage will be avoided, which simplifies transportation and reduces associated costs. Powder jet injectors may be formulated from nano-or micro-particles containing the active or lyophilised drugs and antigens [ 20 , 96 ]. Excellent bioavailability for a number of drugs has been reported but the intermittent pain and bruising caused to patients has restricted wide acceptance of jet injectors [ 91 ]. Regarding the levels of pain experienced by volunteers, some reports state no difference in the pain recorded when comparing jet injectors to conventional needle injections [ 97 ] but others have reported higher pain scores [ 98 ].

The basic design of solid jet injectors consists of compressed gas as the power source, drug loaded compartment containing solid drug formulation, and a nozzle to direct the flow of particles towards the skin [ 99 ]. By triggering the actuation mechanism, compressed gas expands and forces drug powder through a nozzle into the skin. Upon impacting on the skin, particles create micronsized holes and deposit in the stratum corneum or viable epidermis. The most important parameters that govern particle delivery across the stratum corneum are particle properties (size, density) and impact velocity e.g., for DNA vaccination, the particle size range should be between 0.5 and 3 µm [ 11 ].

4.4. Thermal Approaches (Lasers and Radio-Frequency Heating)

Thermal ablation is a method used to deliver drugs systemically through the skin by heating the surface of the skin, which depletes the stratum corneum selectively at that site of heating only, without damaging deeper tissues [ 49 , 100 ]. Many methods could be used to cause thermal ablation such as laser [ 101 ], radiofrequency [ 49 , 102 ], in addition to electrical heating elements [ 49 ]. In order to generate the high temperatures needed to ablate the stratum corneum without damaging the underlined epidermis, the thermal exposure should be short, so the temperature gradient across the stratum corneum can be high enough to keep the skin surface extremely hot but the temperature of the viable epidermis does not experience a significant temperature rise [ 100 ].

4.4.1. Laser Thermal Ablation

Laser methodologies have been used in clinical therapies for the treatment of dermatological conditions such as pigmented lesions [ 101 , 103 , 104 ]. The main mechanism of laser thermal ablation of the skin is the selective removal of the stratum corneum without damaging deeper tissues, thus enhancing the delivery of lipophilic and hydrophilic drugs into skin layers [ 26 , 45 , 104 , 105 ]. Lasers ablate the stratum corneum by deposition of optical energy, which causes evaporation of water and formation of microchanels in the skin [ 106 ]. In addition, such approaches have been used to extract interstitial fluid for subsequent measurement of glucose levels in diabetic patients [ 49 , 101 , 103 ]. However, the degree of barrier disruption achieved is controlled by wavelength, pulse length, tissue thickness, pulse energy, tissue absorption coefficient, pulse number, duration of laser exposure and pulse repetition rate [ 48 , 58 , 107 ]. Baron et al. , 2003 demonstrated that pre-treatment with the laser followed by lidocaine cream was found to reduce the onset of lidocaine action to 3–5 min in human volunteers [ 106 ]. However, the structural changes in the skin must be assessed, especially at the higher intensities of laser employed that may be needed to enhance the transport of large molecular weight therapeutics [ 108 , 109 ].

4.4.2. Radiofrequency (RF) Thermal Ablation

Radiofrequency (RF) thermal ablation involves the placement of a thin, needle-like electrode directly into the skin and application of high frequency alternating current (~100 kHz) which produces microscopic pathways in the stratum corneum, through which drugs can permeate ( Figure 12 ) [ 49 , 100 ]. Exposure of skin cells to a high frequency (100–500 kHz) causes ionic vibrations within the tissue which attempts to localize the heating to a specific area of the skin and thus ablate the cells in that region, resulting in drug transport across the skin [ 110 ]. This technology may enable transdermal delivery of a wide variety of hydrophilic drugs and macromolecules using a low-cost, fully disposable device [ 49 ].

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Schematic diagram of drug delivery using thermal ablation: ( a ) micro-electrodes are pressed against the skin, ( b ) skin is ablated via heating due to RF energy or resistive heating in the electrodes, ( c ) after removing the ablation device, ( d ) micropores formed. (Reprinted from [ 11 ] with permission. Copyright 2008 Elsevier).

4.5. Mechanical Approaches to Mediate Skin Permeation

The use of hypodermic needles, often associated with phobia, pain and the risk of needle-stick injuries have been used to overcome some of the delivery limitations often experienced when delivering macromolecular compounds [ 111 , 112 ]. Some innovative methodologies have been explored to overcome these issues and include the use of MN and tape stripping. These concepts will be described further below.

4.5.1. Tape Stripping

Tape stripping is a simple method for removing the stratum corneum layer by repeated application of adhesive tapes [ 113 ]. The amount of stratum corenum removed by a single adhesive tape depends on many factors such as the thickness of the stratum corenum , the age of the patient, the composition and amount of lipid which varies depending on the anatomical site and finally, skin parameters such as transepidermal water loss (TEWL) and pH. In addition, other factors also affect the amount of stratum corneum removed by tape stripping, such as the force of removal of the tape from the skin and the duration of pressure on the skin [ 113 , 114 ]. Tape stripping is a robust and simple method. However, many parameters should be taken into consideration before and during the application of this procedure, such as the duration of pressure on the skin, in order to remove the stratum corneum homogeneously.

4.5.2. Microneedle (MN) Arrays

MN arrays, minimally invasive drug delivery systems, were developed to overcome some of the disadvantages commonly associated with hypodermic needle usage and in order to address and improve patient compliance. MN arrays have the potential to be used as an alternative to hypodermic and subcutaneous needle technologies ( Figure 13 ) [ 12 , 34 , 111 , 112 ]. MN technologies have been subject to intensive research and development efforts by both academic and industrial researchers with some devices currently in clinical development and others awaiting FDA approval [ 1 , 34 ]. Also the number of publications describing MN as novel minimally invasive devices for drug delivery purposes has grown exponentially in recent years [ 1 , 34 , 112 , 115 ]. As MN combine the ease of use of a transdermal patch with the effectiveness of delivery achieved using conventional hypodermic needle and syringes, they continue to elicit interest and investment [ 34 , 116 ].

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Schematic representation of the mechanism of action of a microneedle array device. The device perforates the stratum corneum (SC) providing direct access of drugs to the underlying viable epidermis, without reaching blood vessels and nerve fibres located in the dermis (Reprinted from [ 12 ] with permission. Copyright 2013 Elsevier).

MN are multiple microscopic projections typically assembled on one side of a supporting base or patch, generally ranging from 25 to 2000 μm in height [ 5 , 12 ], 50 to 250 μm in base width and 1 to 25 μm in tip diameter [ 20 , 112 , 117 , 118 ]. The needles should be of suitable length, width and shape to avoid nerve contact when inserted into skin layers [ 117 , 118 , 119 ]. They are usually designed in arrays in order to improve the surface contact with the skin and facilitate penetration of therapeutic molecules into the skin [ 112 , 120 ]. MN are designed to create transient aqueous conduits across the skin, thereby enhancing flux of the molecules ranging from small hydrophilic molecules such as alendronate [ 52 ] to macromolecules, including low molecular weight heparins [ 4 , 121 ], insulin [ 122 ] and vaccines [ 123 ], in a pain-free manner [ 112 , 124 ]. Besides the aspect of pain-free delivery, there are many other advantages of MN technologies, such as: the fact that they do not cause bleeding [ 125 ]; eliminate transdermal dosing variability of small molecules [ 45 , 126 ]; only minimal introduction of pathogens through MN-induced holes [ 124 , 127 ]; potential for self-administration [ 1 , 128 ]; the potential to overcome and reduce instances of accidental needle-sticks injuries and the risk of transmitting infections [ 12 , 112 ], in addition to the ease of MN waste disposal [ 11 , 112 ].

As conceded previously in this review, one of the most attractive applications of MN arrays is to use them in vaccination and indeed, self-vaccination strategies. The skin contains high concentrations of adaptive and innate immune cells including macrophages, Langerhans cells, and dermal dendritic cells. To date, only oral typhoid vaccine is approved for self-administration in patients’ homes [ 129 ]. Injecting vaccines into the epidermis or dermis is immunologically superior to injecting into the muscle where much lower populations of immune cells reside and this MN approach therefore offers excellent amplification potential for the desired immune response [ 21 , 130 ]. As a result, the dose required to vaccinate through the skin via MN will be much lower than that require dosing of a conventional needle and syringe injection into the muscle. Vaccine delivery via the skin offers easier and painless administration. Moreover, these MN vaccination devices can be manufactured inexpensively [ 5 , 34 , 112 ].

The first two commercially marketed MN-based products are Intanzia ® and Micronjet ® which are based on metal and silicon MN, respectively ( Figure 14 ) [ 131 ]. Intanza ® is the first influenza vaccine that targets the dermis, a highly immunogenic area. It was developed and licensed by Sanofi Pasteur MSD Limited and is being marketed in two strengths; Intanza ® 9 µg for adults aged between 18 and 59 years and Intanza ® 15 µg for adults of 60 years and above. The Intanza ® influenza vaccine system has a needle length of 1.5 mm [ 132 ]. MicronJet is a single use, MN-based device for intradermal delivery of vaccines and drugs. It was developed and licensed by NanoPass.

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Current commercial MNs-based products ( a ) Intanza ® and ( b ) MicronJet ® .

Several companies have been working towards the development of MN-based drug or vaccine products, including 3M, Clearside Biomedical, NanoPass Technologies, Corium International, TheraJect, Circassia, Radius Health, Lohmann Therapeutic Systems (LTS) and Zosano Pharma. Zosano has developed a transdermal patch consisting of an array of titanium MN coated with parathyroid hormone (PTH) (20 to 40 μg) attached to an adhesive patch and applied via a reusable applicator across the skin [ 1 , 133 ]. A second study involving the Zosano titanium MN patch system was carried out by Ameri et al. 2014 to evaluate the feasibility of titanium MN usage to deliver recombinant human growth hormone (rhGH) [ 126 ]. In this study, it was found that the bioavailability of the rhGH MNpatch and the current subcutaneous injection products (Norditropin ® ) were similar which indicates that this MN product can be used as a patient-friendly alternative to subcutaneous injection of Norditropin ® [ 126 , 133 ]. The 3M Microneedle Technologies (MTS) has developed coated MN to deliver water-soluble, polar and ionic molecules, such as lidocaine, through the skin. This system has successfully delivered drugs to the skin within seconds and provide rapid onset of local analgesia (~1 min) which facilitates routine or emergency procedures [ 51 , 134 ].

The shape and geometry of MN is critical during design and fabrication [ 22 , 135 , 136 , 137 ]. The needles must be capable of inserting into the skin without breaking and the needles should be of suitable length, width and shape to avoid nerve contact and create efficient pathways for the delivery of small drugs, macromolecules and nanoparticles, as well as for fluid extraction, depending on the objectives of each device [ 115 , 117 , 119 , 138 ]. The elastic properties of human skin may prevent effective MN penetration by twisting of the skin fibers around the needles during application, particularly in the case of blunt and short MN [ 117 ]. To date, many papers have described the fabrication of various MN from different materials using various micro-moulding processes or other methods, such as lasers [ 112 , 139 , 140 ]. Generally, there are four strategies of TDD using MN ( Figure 15 ) [ 22 , 123 ]. These are solid, coated, dissolvable and hollow MN. A novel fifth MN-type, namely hydrogel MN have garnered much interest in the recent past and are presented in Figure 16 .

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A schematic representation of four different MN application methods used to facilitate drug delivery transdermally. ( a ) Solid MNs for increasing the permeability of a drug formulation by creating micro-holes across the skin; ( b ) Coated MNs for rapid dissolution of the coated drug into the skin; ( c ) Dissolvable MNs for rapid or controlled release of the drug incorporated within the microneedles; ( d ) Hollow MNs used to puncture the skin and enable release of a liquid drug following active infusion or diffusion of the formulation through the needle bores. (Reprinted from [ 11 ] with permission. Copyright 2008 Elsevier).

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Novel hydrogel-forming MN facilitate controlled transdermal drug delivery. ( a ) An expanded view of the backing layer, drug-loaded adhesive patch and solid crosslinked hydrogel MN array which constitutes an integrated hydrogel MN patch; ( b ) Application of the integrated hydrogel MN patch to the skin surface; ( c ) Diffusion of water into the MN array leading to controlled swelling of the arrays and diffusion of drug molecules from the adhesive patch through the hydrogel conduit; ( d ) Intact hydrogel MN arrays following removal from the skin. (Reprinted from [ 12 ] with permission. Copyright 2013 Elsevier).

(1) Hollow MN are used to deliver drug solutions via the “poke and flow” method; which involves insertion of the MN into tissue and then a drug solution can be transported through the bore of the MN in similar fashion to a hypodermic needles [ 141 , 142 ] but hollow MN usually require very precise and high cost manufacturing technology [ 111 ]. Passive diffusion of the drug solution may occur through the MN, but active delivery allows for more rapid rates of delivery. Active delivery requires a driving force, a syringe can be used to drive the solution through the MN into the tissue but some studies have combined the MN systems with a pump or pressurised gas [ 143 , 144 ].

(2) “Poke and patch” mainly for solid MN by piercing the upper layers of the skin with solid MN and creating microchannels followed by application of a drug formulation (e.g., patch, gel) at that site piercing [ 5 , 112 ]. The skin pretreatment creates micro-conduits in the skin, thereby enhancing flux of the molecules through the skin.

(3) “Coat and poke” by piercing the skin with drug coated solid MN, which solve the problem of two-step application and provide extremely quick drug delivery [ 111 , 145 ]. Delivery from coated MN was found to be attractive especially for high molecular weight molecules [ 146 ]. However, drug delivery is limited due to the small dimensions of the MN shaft and tip [ 146 , 147 , 148 ].

(4) “Poke and release” for dissolving/porous/hydrogel forming MN through which drug will diffuse into systemic circulation ( Figure 16 ). The materials from which the MN are produced act as drug depots holding the drugs until the trigger for release occurs, i.e. , dissolution in the case of dissolvable MN or swelling in the case of hydrogel MN [ 22 , 131 , 149 ]. This strategy eliminates the need for sharps disposal, and the possibility of accidental reuse of MN. Moreover, dissolvable MN patches have been reported to successfully deliver both small (MW 500 Da) and macro molecules (MW 500 Da) in “poke and release” approaches [ 25 , 26 ].

A wide variety of MN types and designs have been shown to be effective for the transdermal delivery of a diverse range of molecules, both in vitro and in vivo [ 10 , 12 ] . The potential now exists to greatly expand the range and types of drugs that can be delivered effectively across the skin. This will significantly enhance the value of the transdermal delivery market and will be increasingly important over the coming years as the number of new drugs of biological origin continues to increase. Future studies will be needed to address potential regulatory concerns over the use of MN devices, as well as focusing on the design and development of processes to enable a low cost, efficient means for MN mass production. A number of other physical approaches such as sonophoresis, electroporation, ultrasound and iontophoresis have been combined with MN in order to enhance permeation of drugs. Kolli et al. , 2012 determined that the transdermal delivery of Prochlorperazine Edisylate was significantly enhanced when MN were used in conjunction with iontophoresis [ 150 ]. Moreover, the delivery of ropinirole hydrochloride by MN and iontophoresis was significantly higher compared to modulated iontophoresis alone [ 151 ].

5. MN Overcome Many of the Limitations Associated with Other TDD Methodologies

Various limitations associated with each of the outlined TDD approaches have been documented throughout this review. To this end, MN methodologies may prove an efficacious, cost-effective and patient friendly alternative in choosing a TDD system for delivery of a host of drug molecules. With this in mind, some of the advantages of MN approaches over other TDD systems are outlined below.

As a novel and minimally invasive approach, MN are capable of creating superficial pathways across the skin for small drugs, macromolecules, nanoparticles, or fluid extractions to achieve enhanced transdermal drug delivery [ 152 ].Their sharp tips are short enough to limit contact with skin nerves, thus preventing pain sensation [ 125 ] and they are narrow enough to induce minimal trauma and reduce the opportunities for infections to develop following insertion [ 127 ]. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods [ 152 , 153 ]. Moreover, MN can be manufactured using various types of material e.g., polymers, metal or silicon. Biocompatible and biodegradable polymers can be safely applied to the skin and are generally cost-effective. Various polymeric materials such as poly- l -lactic acid, poly-glycolic acid, poly-carbonate, poly-lactic- co -glycolic acid (PLGA), poly-dimethylsiloxane, a copolymer of methyl vinyl ether and maleic anhydride, carboxymethyl cellulose, maltose, dextrin and galactose have all been used to fabricate MN [ 139 ]. MN can also deliver a wide range of drugs ranging from small molecular weight e.g., ibuprofen [ 124 ] to high molecular weight e.g., ovalbumin compounds [ 131 ]. Immunization programs in developing countries via MN could be applied with minimal medical training and with lower associated costs. In addition, MN arrays have recently been used as an alternative approach in the minimally-invasive sampling of fluids from patients, without causing pain or bleeding in the advancement of novel therapeutic drug monitoring systems [ 12 ]. Although MN technologies show tremendous promise in the field of TDD, there are still relatively few FDA approved MN devices. A number of challenges which must be addressed before MN become widely available include scale up manufacture to industrial levels which will require considerable planning and standardization. In addition, MN device regulatory considerations must be established and addressed. These issues may include but are not limited to, issues surrounding product sterility; the potential for accidental reuse of certain MN modalities (e.g., solid MN), appropriate packaging and manufacturing aspects and the potential for undesired immunological effects. These must all be addressed before MN devices receive widespread approval. Moreover, the choice of appropriate biomaterials for preparation of MN is limited due to lack of mechanical strength, poor control of drug delivery, and limitation of drug loading dose [ 154 , 155 ].

6. Conclusions

In conclusion, the TDD sector continues to grow and develop with rapid expansion in fundamental knowledge feeding industrial development. In time, it is hoped that technological advancements in TDD will lead to enhanced disease prevention, diagnosis and control, with concomitant improvement in health-related quality of life for patients worldwide. To this end, this review has charted the development of numerous novel TDD methodologies, highlighting the advantages and disadvantages of each approach. Due to the exponential growth in investment and interest in MN technologies and the numerous associated advantages of this approach, particular attention was paid to this TDD system.

Author Contributions

Ahlam Zaid Alkilani and Maelíosa T.C. McCrudden conceived, researched and wrote the paper. Ryan F. Donnelly critiqued the paper.

Conflicts of Interest

The authors declare no conflict of interest.

Modulating magnetic interface layer on porous carbon heterostructures for efficient microwave absorption

Research Article
Published: 03 September 2024

Cite this article

Zirui Jia 1 , 2 na1 ,
Lifu Sun 2 , 3 na1 ,
Zhenguo Gao 2 &

Modern communication systems call for high performance electromagnetic wave absorption materials capable of mitigating microwaves over a wide frequency band. The synergistic effect of structure and component regulation on the electromagnetic wave absorption capacity of materials is considered. In this paper, a new type of three-dimensional porous carbon matrix composite is reported utilizing a reasonable design of surface impedance matching. Specifically, a thin layer of densely arranged Fe-Cr oxide particles is deposited on the surface of porous carbon via thermal reduction to prepare the Fe-Cr-O@PC composites. The effect of Cr doping on the electromagnetic wave absorption performance of the composites and the underlying attenuation mechanism have been uncovered. Consequently, outstanding electromagnetic wave absorption performance has been achieved in the composite, primarily contributed by the enhanced dielectric loss upon Cr doping. Accordingly, an effective absorption bandwidth of 4.08 GHz is achieved at a thickness of 1.4 mm, with a minimum reflection loss value of −52.71 dB. This work not only provides inspiration for the development of novel absorbers with superior performance but also holds significant potential for further advancement and practical application.

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Acknowledgements

The work is supported by the National Natural Science Foundation of China (No. 52301192), Postdoctoral Fellowship Program of CPSF (No. GZB20240327), Shandong Postdoctoral Science Foundation (No. SDCX-ZG-202400275), Qingdao Postdoctoral Application Research Project (No. QDBSH20240102023), China Postdoctoral Foundation (No. 2024M751563), Natural Science Foundation of Hubei province (No. 2024AFB460), and the Scientific Research Foundation for Ph. Ds, Hubei University of Automotive Technology (No. BK202304). Guiding Project of the State Key Laboratory of Materials Processing and Die & Mould Technology, Huazhong University of Science and Technology (No. P2021-023). The Outstanding Young Scientific & Technological Innovation Team Plan of Colleges and Universities in Hubei Province (No. T201518). The Independent Innovation Projects of the Hubei Longzhong Laboratory (No. 2022ZZ-30) and the Qingchuang Talents Induction Program of Shandong Higher Education Institution (Research and Innovation Team of Structural-Functional Polymer Composites).

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Zirui Jia and Lifu Sun contributed equally to this work .

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School of Materials Science and Engineering, Hubei University of Automotive Technology, Shiyan, 442002, China

Zirui Jia & Di Lan

College of Chemistry and Chemical Engineering, Qingdao University, Qingdao, 266071, China

Zirui Jia, Lifu Sun & Zhenguo Gao

School of Materials Science and Engineering, Yingkou Institute of Technology, Yingkou, 115014, China

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Jia, Z., Sun, L., Gao, Z. et al. Modulating magnetic interface layer on porous carbon heterostructures for efficient microwave absorption. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6939-0

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DOI : https://doi.org/10.1007/s12274-024-6939-0

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Various pathway of drug absorption
MECHANISM OF DRUG ABSORPTION MECHANISM OF DRUG ABSORPTION
Drug absorption from the GI tract
Various pathway of drug absorption
MMED3934 Drug Absorption 1
Pharmaceutical Factors affecting drug absorption

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Absorption of Drugs
Lecture 2| Unit 1| Mechanism of drug absorption

COMMENTS

Current trends in drug metabolism and pharmacokinetics
1. Introduction. Pharmacokinetics (PK) is defined as the quantitative study of drug absorption, distribution, metabolism, and excretion (ADME)—i.e., the ways the body processes a drug 1 while the drug exerts its actions in the body. The scope of PK not only covers studies on healthy subjects but also includes broad research on variations under a variety of physiologic or pathologic ...
Impact of gastrointestinal physiology on drug absorption in special
The consequence of the reduced fluid intake in the longer term, however, may be associated with the impaired drug absorption. Further research is required to generate evidence-based data to understand: (i) whether the alteration in thirst physiology is associated with changes in intestinal absorption and (ii) if it is associated, which drugs ...
Drug Absorption
Pharmacokinetics describes the study of drug absorption, distribution, metabolism, excretion, and how the body affects the drug. The application of pharmacokinetic methods to ensure patients are treated safely and effectively is known as clinical pharmacokinetics. The introduction of pharmacokinetic ….
Drug Absorption
Drug absorption, i.e., the process by which (intact) drug molecules are transferred to the bloodstream or, more precisely, into the systemic circulation, is greatly influenced by the intrinsic physicochemical and biochemical properties of the drug, as well as several pharmaceutical and anatomophysiological factors.Only free drug molecules in solution can be absorbed (at least, when ...
Drug Absorption
Pharmacokinetics describes the study of drug absorption, distribution, metabolism, excretion, and how the body affects the drug. The application of pharmacokinetic methods to ensure patients are treated safely and effectively is known as clinical pharmacokinetics. The introduction of pharmacokinetics as a discipline has facilitated the development of rational drug therapy, the understanding of ...
PDF Biopharmaceutics: Drug absorption and bioavailability
Biopharmaceutics elucidates the journey of drugs from administration to systemic circulation, shedding light on the factors that influence their absorption, distribution, metabolism, and excretion [2] The absorption of drugs represents a critical phase in their pharmacokinetic profile, dictating the rate and extent of their therapeutic action.
Drug Absorption
Definition. Absorption is a mass transfer process that involves the movement of unchanged drug molecules from the site of absorption (which often, but not always, coincides with the site of administration) to the bloodstream. We will focus on systemic absorption, that is, the movement of drug molecules into the general circulation.
An orally administered glucose-responsive polymeric complex ...
The mucus layer is one of the main barriers that hinders the absorption of drugs in the intestine 45.The multiple particle tracking technique was used to evaluate the mucus penetration capacity of ...
PDF ISSN (P): 2349-8242 Pharmacokinetics: Drug absorption, distribution
pharmacokinetics is the intricate interplay of processes governing drug Absorption, Drug absorption represents the initial step in the pharmacokinetic journey, wherein the rate and ... This research paper delves into the multifaceted mechanisms governing ADME, exploring how these processes influence drug bioavailability, efficacy, and toxicity. ...
Current Approaches for Absorption, Distribution, Metabolism, and
An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. ... Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper Drug Metab Dispos. 2016 May;44(5):617-23. doi: 10. ...
An Introduction to Drug Disposition: The Basic Principles of Absorption
A knowledge of the fate of a drug, its disposition (absorption, distribution, metabolism, and excretion, known by the acronym ADME) and pharmacokinetics (the mathematical description of the rates of these processes and of concentration-time relationships), plays a central role throughout pharmaceutical research and development.
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Herbal interactions on absorption of drugs: Mechanisms of action and clinical risk assessment. Cristiano Colalto, in Pharmacological Research, 2010. Some studies have reported cases of drug interactions as being probably due to decreased drug absorption.Richter et al. reported a decrease in the hypocholesterolemic action of lovastatin when this was associated with some dietary fiber [243].
(PDF) Routes of Drug Administration: Dosage, Design, and ...
Abstract. Systemic absorption of a drug depends on its physicochemical properties, the nature of the. dosage form on which it is included and the anatomi cal and physiological charac teristics of ...
Research paper Drug absorption sites in the gastrointestinal tract and
It is suitable for long-term continuous therapy of chronic diseases and thus is preferred clinicians and RA patients. Despite so many advantages in drug delivery, the oral route still faces the harsh conditions along with the gastrointestinal (GI) tract, which can degrade or denature active bio-therapeutics, including the average length of the segment, pH, thickness of the mucus, the residence ...
Revising Pharmacokinetics of Oral Drug Absorption: I Models ...
The oral route is the most common for drug administration. Extensive work in this field of research revealed that two basic drug properties, namely, solubility and permeability of gastrointestinal membrane determine the extent of oral drug absorption [1, 2].These scientific advances lead to the development of the biopharmaceutic classification system (BCS), the biopharmaceutic drug disposition ...
Drug Solubility: Importance and Enhancement Techniques
The precipitate so obtained is separated using whatman filter paper, and dried in vacuum oven at 40°C. ... determining step for oral absorption of the poorly water soluble drugs and solubility is the basic requirement for the absorption of the drug from GIT. The various techniques described above alone or in combination can be used to enhance ...
Drug Absorption
Definition. Absorption is a mass transfer process that involves the movement of unchanged drug molecules from the site of absorption (which often, but not always, coincides with the site of administration) to the bloodstream. We will focus on systemic absorption, i.e., the movement of the drug molecules to general circulation.
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Discover the world's research. 25+ million members; 160+ million publication pages; 2.3+ billion citations; ... facilitate the nasal absorption of drugs includes: Nasal enzyme inhibitors .
Research paper Drug absorption sites in the gastrointestinal tract and
Determination of the absorption site of drugs The absorption site of a drug along the gas- trointestinal tract may be investigated either by in situ or by in vivo methods. 2.1. In situ methods These methods include open loop techniques such as single-pass perfusion, recirculating perfu- sion and oscillating perfusion as well as closed- loop ...
Nanoparticles in Drug Delivery: From History to Therapeutic
Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. This paper reviews the various conventionally used and current used carriage system to deliver drugs. ... , thus greater drug absorption in brain parenchyma through the secondary nose ...
Protein Absorption Alters the Cellular Targeting of ...
Our work suggests that decreasing non-specific protein absorption of glycopolymeric nanoparticles could enhance their delivery efficiency. These findings underscore the importance of understanding protein interactions in nanoparticle applications for drug delivery.
Drug Absorption
Drug absorption, i.e., the process by which (intact) drug molecules are transferred to the bloodstream or, more precisely, into the systemic circulation, is greatly influenced by the intrinsic physicochemical and biochemical properties of the drug, as well as several pharmaceutical and anatomophysiological factors.Only free drug molecules in solution can be absorbed (at least, when ...
Trends and insights in dengue virus research globally: a bibliometric
Background Dengue virus (DENV) is the most widespread arbovirus. The World Health Organization (WHO) declared dengue one of the top 10 global health threats in 2019. However, it has been underrepresented in bibliometric analyses. This study employs bibliometric analysis to identify research hotspots and trends, offering a comprehensive overview of the current research dynamics in this field ...
Absorption, Distribution, Metabolism and Excretion of ...
The different arrow types for drug absorption into blood and lymph reflect the different mechanisms of drug absorption across these two barriers, being largely by passive diffusion between cells for blood, and convective flow for lymph. ... present largely in the lysosomes, degrade such drugs. Research on the elimination of monoclonal antibody ...
Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based
The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches.
Modulating magnetic interface layer on porous carbon ...
Modern communication systems call for high performance electromagnetic wave absorption materials capable of mitigating microwaves over a wide frequency band. The synergistic effect of structure and component regulation on the electromagnetic wave absorption capacity of materials is considered. In this paper, a new type of three-dimensional porous carbon matrix composite is reported utilizing a ...

An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs

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Protein Absorption Alters the Cellular Targeting of Glycopolymeric Nanoparticles

Yuying Shen

Jiayu Zheng

Mingxia Lu (Contact Author)

University of Shanghai for Science and Technology ( email )

Trends and insights in dengue virus research globally: a bibliometric analysis (1995–2023)

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Comprehensive gene and keyword analysis in dengue virus research

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Journal of Translational Medicine

Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

Maelíosa T.C. McCrudden

1. Introduction

2. Transdermal Drug Delivery (TDD)

3. A Brief Review of Skin Structure

3.1. Epidermis

3.2. Dermis

3.3. Hypodermis

3.4. Drug Penetration Routes

3.5. Kinetics of TDD

4. Techniques for Enhancement of Skin Permeabilisation

4.1. Ultrasound Devices