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Bhuimali T, Sarifuddin, Mandal PK. Modelling receptor-mediated endocytosis in hollow microneedle-based verapamil delivery through viscoelastic skin. Comput Methods Biomech Biomed Engin 2025:1-19. [PMID: 40109032 DOI: 10.1080/10255842.2025.2477223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 02/20/2025] [Accepted: 03/04/2025] [Indexed: 03/22/2025]
Abstract
Drug delivered from the microneedle (MN) tip diffuses across the viscoelastic skin before entering the blood compartment and being absorbed. Reversible uptake kinetics between the blood and tissue compartments, reversible specific saturable binding with its receptors, and endocytosis are given due attention. Simulations predict that, unlike skin thinning, skin viscoelasticity and a higher Young's modulus value, as in an older person, inhibit verapamil diffusion within the skin, and metabolism stabilises the concentrations in the blood and tissue compartments. Simultaneously, the irreversible uptake kinetics improve drug concentrations in the tissue compartment, facilitating receptor-mediated endocytosis. The results also predict that internalised verapamil increases with time at slower internalisation rates; however, at higher rates, it attains a peak value before gradually diminishing. Furthermore, as the rate of lysosomal degradation escalates, the peak value of internalised concentration diminishes and shifts upward. A comprehensive sensitivity analysis has been performed because of uncertainty about several crucial parameters. Our findings align well with the existing literature.
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Affiliation(s)
- Tanmoy Bhuimali
- Department of Mathematics, Visva-Bharati University, Santiniketan, India
| | - Sarifuddin
- Department of Mathematics, Berhampore College, Baharampur, India
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Peng T, Chen Y, Luan X, Hu W, Wu W, Guo B, Lu C, Wu C, Pan X. Microneedle technology for enhanced topical treatment of skin infections. Bioact Mater 2025; 45:274-300. [PMID: 39659727 PMCID: PMC11629152 DOI: 10.1016/j.bioactmat.2024.11.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 10/31/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024] Open
Abstract
Skin infections caused by microbes such as bacteria, fungi, and viruses often lead to aberrant skin functions and appearance, eventually evolving into a significant risk to human health. Among different drug administration paradigms for skin infections, microneedles (MNs) have demonstrated superiority mainly because of their merits in enhancing drug delivery efficiency and reducing microbial resistance. Also, integrating biosensing functionality to MNs offers point-of-care wearable medical devices for analyzing specific pathogens, disease status, and drug pharmacokinetics, thus providing personalized therapy for skin infections. Herein, we do a timely update on the development of MN technology in skin infection management, with a special focus on how to devise MNs for personalized antimicrobial therapy. Notably, the advantages of state-of-the-art MNs for treating skin infections are pointed out, which include hijacking sequential drug transport barriers to enhance drug delivery efficiency and delivering various therapeutics (e.g., antibiotics, antimicrobial peptides, photosensitizers, metals, sonosensitizers, nanoenzyme, living bacteria, poly ionic liquid, and nanomoter). In addition, the nanoenzyme-based multimodal antimicrobial therapy is highlighted in addressing intractable infectious wounds. Furthermore, the MN-based biosensors used to identify pathogen types, track disease status, and quantify antibiotic concentrations are summarized. The limitations of antimicrobial MNs toward clinical translation are offered regarding large-scale production, quality control, and policy guidance. Finally, the future development of biosensing MNs with easy-to-use and intelligent properties and MN-based wearable drug delivery for home-based therapy are prospected. We hope this review will provide valuable guidance for future development in MN-mediated topical treatment of skin infections.
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Affiliation(s)
- Tingting Peng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment/ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Yangyan Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xuanyu Luan
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Wanshan Hu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment/ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Wentao Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Bing Guo
- School of Science, Harbin Institute of Technology, Shenzhen 518055, China
| | - Chao Lu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment/ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Chuanbin Wu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment/ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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Albayati N, Talluri SR, Dholaria N, Michniak-Kohn B. AI-Driven Innovation in Skin Kinetics for Transdermal Drug Delivery: Overcoming Barriers and Enhancing Precision. Pharmaceutics 2025; 17:188. [PMID: 40006555 PMCID: PMC11859831 DOI: 10.3390/pharmaceutics17020188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/19/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin's permeability barrier, particularly the stratum corneum, and the need for optimized formulations. Factors like skin type, hydration levels, and age further complicate the development of universally effective solutions. Advances in artificial intelligence (AI) address these challenges through predictive modeling and personalized medicine approaches. Machine learning models trained on extensive molecular datasets predict skin permeability and accelerate the selection of suitable drug candidates. AI-driven algorithms optimize formulations, including penetration enhancers and advanced delivery technologies like microneedles and liposomes, while ensuring safety and efficacy. Personalized TDDS design tailors drug delivery to individual patient profiles, enhancing therapeutic precision. Innovative systems, such as sensor-integrated patches, dynamically adjust drug release based on real-time feedback, ensuring optimal outcomes. AI also streamlines the pharmaceutical process, from disease diagnosis to the prediction of drug distribution in skin layers, enabling efficient formulation development. This review highlights AI's transformative role in TDDS, including applications of models such as Deep Neural Networks (DNN), Artificial Neural Networks (ANN), BioSIM, COMSOL, K-Nearest Neighbors (KNN), and Set Covering Machine (SVM). These technologies revolutionize TDDS for both skin and non-skin diseases, demonstrating AI's potential to overcome existing barriers and improve patient care through innovative drug delivery solutions.
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Affiliation(s)
- Nubul Albayati
- Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; (N.A.); (S.R.T.); (N.D.)
- Center for Dermal Research, Rutgers-The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Sesha Rajeswari Talluri
- Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; (N.A.); (S.R.T.); (N.D.)
- Center for Dermal Research, Rutgers-The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Nirali Dholaria
- Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; (N.A.); (S.R.T.); (N.D.)
- Center for Dermal Research, Rutgers-The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Bozena Michniak-Kohn
- Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; (N.A.); (S.R.T.); (N.D.)
- Center for Dermal Research, Rutgers-The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA
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Cammarano A, Dello Iacono S, Battisti M, De Stefano L, Meglio C, Nicolais L. A systematic review of microneedles technology in drug delivery through a bibliometric and patent overview. Heliyon 2024; 10:e40658. [PMID: 39669166 PMCID: PMC11635707 DOI: 10.1016/j.heliyon.2024.e40658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/14/2024] Open
Abstract
The transdermal drug delivery (TDD) route has gathered considerable attention for its potential to improve therapeutic efficacy while minimizing systemic side effects. Among transdermal technologies, microneedle (MN) devices have proven to be a promising approach that combines the advantages of traditional needle injections and non-invasive topical applications. This review provides a comprehensive analysis of progress in transdermal drug delivery systems (TDDS) via MN from 2000 to 2023, integrating bibliometric analysis and patent landscape to present a multi-faceted perspective on the evolution of this technology. The study identifies key trends, challenges, and opportunities in the research, implementation, and commercialization of MN tools through a systematic examination of scientific literature and an extensive investigation of global patent databases. The study of bibliometric trends reveals the leading experts, organizations, companies, and countries contributing to this field, collaboration networks, and the thematic evolution of research topics. The patent analysis offers insights into innovative trajectories, key players, and geographical distribution of intellectual property. This review resumes the latest advancements in MN devices and provides a strategic outlook that can guide future research directions, promote partnerships, and inform stakeholders involved in the development of TDDS.
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Affiliation(s)
| | - Stefania Dello Iacono
- Institute of Polymers, Composites and Biomaterials (IPCB), National Research Council, P.le Enrico Fermi 1, 80055, Portici, Italy
| | - Mario Battisti
- Materias Srl, Corso N. Protopisani 50, 80146, Naples, Italy
| | - Luca De Stefano
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council, Via P. Castellino 111, Naples, 80131, Italy
| | | | - Luigi Nicolais
- Materias Srl, Corso N. Protopisani 50, 80146, Naples, Italy
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Zaid Alkilani A, Hamed R, Musleh B, Sharaire Z. Breaking boundaries: the advancements in transdermal delivery of antibiotics. Drug Deliv 2024; 31:2304251. [PMID: 38241087 PMCID: PMC10802811 DOI: 10.1080/10717544.2024.2304251] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/18/2023] [Indexed: 01/21/2024] Open
Abstract
Transdermal drug delivery systems (TDDS) for antibiotics have seen significant advances in recent years that aimed to improve the efficacy and safety of these drugs. TDDS offer many advantages over other conventional delivery systems such as non-invasiveness, controlled-release pattern, avoidance of first-pass metabolism. The objective of this review is to provide an overview on the recent advances in the TDDS of different groups of antibiotics including β-lactams, tetracyclines, macrolides, and lincosamides, utilized for their effective delivery through the skin and to explore the challenges associated with this field. The majority of antibiotics do not have favorable properties for passive transdermal delivery. Thus, novel strategies have been employed to improve the delivery of antibiotics through the skin, such as the use of nanotechnology (nanoparticles, solid-lipid nanoparticles, nanoemulsions, vesicular carriers, and liposomes) or the physical enhancement techniques like microneedles and ultrasound. In conclusion, the transdermal delivery systems could be a promising method for delivering antibiotics that have the potential to improve patient outcomes and enhance the efficacy of drugs. Further research and development are still needed to explore the potential of delivering more antibiotic drugs by using various transdermal drug delivery approaches.
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Affiliation(s)
| | - Rania Hamed
- Department of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Batool Musleh
- Department of Pharmacy, Zarqa University, Zarqa, Jordan
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Goh M, Du M, Peng WR, Saw PE, Chen Z. Advancing burn wound treatment: exploring hydrogel as a transdermal drug delivery system. Drug Deliv 2024; 31:2300945. [PMID: 38366562 PMCID: PMC10878343 DOI: 10.1080/10717544.2023.2300945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/05/2023] [Indexed: 02/18/2024] Open
Abstract
Burn injuries are prevalent and life-threatening forms that contribute significantly to mortality rates due to associated wound infections. The management of burn wounds presents substantial challenges. Hydrogel exhibits tremendous potential as an ideal alternative to traditional wound dressings such as gauze. This is primarily attributed to its three-dimensional (3D) crosslinked polymer network, which possesses a high water content, fostering a moist environment that supports effective burn wound healing. Additionally, hydrogel facilitates the penetration of loaded therapeutic agents throughout the wound surface, combating burn wound pathogens through the hydration effect and thereby enhancing the healing process. However, the presence of eschar formation on burn wounds obstructs the passive diffusion of therapeutics, impairing the efficacy of hydrogel as a wound dressing, particularly in cases of severe burns involving deeper tissue damage. This review focuses on exploring the potential of hydrogel as a carrier for transdermal drug delivery in burn wound treatment. Furthermore, strategies aimed at enhancing the transdermal delivery of therapeutic agents from hydrogel to optimize burn wound healing are also discussed.
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Affiliation(s)
- MeeiChyn Goh
- Institute of Medical Imaging, Hengyang Medical School, University of South China, Hengyang, China
| | - Meng Du
- Institute of Medical Imaging, Hengyang Medical School, University of South China, Hengyang, China
| | - Wang Rui Peng
- Institute of Medical Imaging, Hengyang Medical School, University of South China, Hengyang, China
- The Seventh Affiliated Hospital, Hunan Veterans Administration Hospital, Hengyang Medical School, University of South China, Changsha, China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, China
| | - Zhiyi Chen
- Institute of Medical Imaging, Hengyang Medical School, University of South China, Hengyang, China
- The Seventh Affiliated Hospital, Hunan Veterans Administration Hospital, Hengyang Medical School, University of South China, Changsha, China
- The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
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Ta GH, Leong MK. Mitigating Paxlovid™-induced drug‒drug interaction toxicity: an in silico insight. Front Pharmacol 2024; 15:1496630. [PMID: 39659997 PMCID: PMC11628247 DOI: 10.3389/fphar.2024.1496630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 11/15/2024] [Indexed: 12/12/2024] Open
Abstract
The clinical drug-drug interaction side-effects of Ritonavir, an ingredient in Paxlovid™, have been documented, highlighting the need to explore alternative administration methods for Nirmatrelvir, another drug in the Paxlovid™ combination. In this study, the skin permeability potential of Nirmatrelvir was assessed using various in silico models. The prediction results suggest that Nirmatrelvir could be administrated via the transdermal route, offering a promising avenue to enhance the efficacy of anti-COVID-19 agents.
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Kushwaha R, Palei NN. Transdermal Drug Delivery Systems: Different Generations and Dermatokinetic Assessment of Drug Concentration in Skin. Pharmaceut Med 2024; 38:407-427. [PMID: 39400929 DOI: 10.1007/s40290-024-00537-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 10/15/2024]
Abstract
Transdermal drug delivery systems (TDDS) are a highly appealing and innovative method of administering drugs through the skin, as it enables the drugs to achieve systemic effects. A TDDS offers patient convenience, avoids first-pass hepatic metabolism, enables local targeting, and reduces the toxic effect of drug. This review details several generations of TDDS and the advancements made in their development to address the constraints associated with skin delivery systems. Transdermal delivery methods of the first generation have been consistently growing in their clinical application for administering small, lipophilic, low-dose drugs. Second-generation TDDS, utilizing chemical enhancers and iontophoresis, have led to the development of clinical products. Third-generation delivery systems employ microneedles, thermal ablation, and electroporation to specifically target the stratum corneum, which is the skin's barrier layer. Dermatokinetics is the study of the movement of drugs and formulations applied to the skin over a period of time. It provides important information regarding the rate and extent to which drugs penetrate skin layers. Several dermatokinetic techniques, including tape stripping, microdialysis, and laser scanning microscopy, have been used to study the intricate barrier properties and clearance mechanisms of the skin. This understanding is essential for developing and improving effective TDDS.
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Affiliation(s)
- Rahul Kushwaha
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Narahari N Palei
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India.
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Govender M, Indermun S, Choonara YE. 3D bioprinted microneedles: merging drug delivery and scaffold science for tissue-specific applications. Expert Opin Drug Deliv 2024; 21:1559-1572. [PMID: 38722022 DOI: 10.1080/17425247.2024.2351928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/02/2024] [Indexed: 11/10/2024]
Abstract
INTRODUCTION Three-Dimensional (3D) microneedles have recently gained significant attention due to their versatility, biocompatibility, enhanced permeation, and predictable behavior. The incorporation of biological agents into these 3D constructs has advanced the traditional microneedle into an effective platform for wide-ranging applications. AREAS COVERED This review discusses the current state of microneedle fabrication as well as the developed 3D printed microneedles incorporating labile pharmaceutical agents and biological materials for potential biomedical applications. The mechanical and processing considerations for the preparation of microneedles and the barriers to effective 3D printing of microneedle constructs have additionally been reviewed along with their therapeutic applications and potential for tissue engineering and regenerative applications. Additionally, the regulatory considerations for microneedle approval have been discussed as well as the current clinical trial and patent landscapes. EXPERT OPINION The fields of tissue engineering and regenerative medicine are evolving at a significant pace with researchers constantly focused on incorporating advanced manufacturing techniques for the development of versatile, complex, and biologically specific platforms. 3D bioprinted microneedles, fabricated using conventional 3D printing techniques, have resultantly provided an alternative to 2D bioscaffolds through the incorporation of biological materials within 3D constructs while providing further mechanical stability, increased bioactive permeation and improved innervation into surrounding tissues. This advancement therefore potentially allows for a more effective biomimetic construct with improved tissue-specific cellular growth for the enhanced treatment of physiological conditions requiring tissue regeneration and replacement.
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Affiliation(s)
- Mershen Govender
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Sunaina Indermun
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
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Firdous SO, Sagor MMH, Arafat MT. Advances in Transdermal Delivery of Antimicrobial Peptides for Wound Management: Biomaterial-Based Approaches and Future Perspectives. ACS APPLIED BIO MATERIALS 2024; 7:4923-4943. [PMID: 37976446 DOI: 10.1021/acsabm.3c00731] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Antimicrobial peptides (AMPs), distinguished by their cationic and amphiphilic nature, represent a critical frontier in the battle against antimicrobial resistance due to their potent antimicrobial activity and a broad spectrum of action. However, the clinical translation of AMPs faces hurdles, including their susceptibility to degradation, limited bioavailability, and the need for targeted delivery. Transdermal delivery has immense potential for optimizing AMP administration for wound management. Leveraging the skin's accessibility and barrier properties, transdermal delivery offers a noninvasive approach that can circumvent systemic side effects and ensure sustained release. Biomaterial-based delivery systems, encompassing nanofibers, hydrogels, nanoparticles, and liposomes, have emerged as key players in enhancing the efficacy of transdermal AMP delivery. These biomaterial carriers not only shield AMPs from enzymatic degradation but also provide controlled release mechanisms, thereby elevating stability and bioavailability. The synergistic interaction between the transdermal approach and biomaterial-facilitated formulations presents a promising strategy to overcome the multifaceted challenges associated with AMP delivery. Integrating advanced technologies and personalized medicine, this convergence allows the reimagining of wound care. This review amalgamates insights to propose a pathway where AMPs, transdermal delivery, and biomaterial innovation harmonize for effective wound management.
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Affiliation(s)
- Syeda Omara Firdous
- Department of Biomedical Engineering, Bangladesh University of Engineering and Technology (BUET), Dhaka 1205, Bangladesh
| | - Md Mehadi Hassan Sagor
- Department of Biomedical Engineering, Bangladesh University of Engineering and Technology (BUET), Dhaka 1205, Bangladesh
| | - M Tarik Arafat
- Department of Biomedical Engineering, Bangladesh University of Engineering and Technology (BUET), Dhaka 1205, Bangladesh
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Baumann F, Paul T, Ossmann S, Enke D, Aigner A. Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin. Pharmaceutics 2024; 16:995. [PMID: 39204340 PMCID: PMC11358937 DOI: 10.3390/pharmaceutics16080995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO3H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes.
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Affiliation(s)
- Frank Baumann
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany;
| | - Theresa Paul
- Institute of Chemical Technology, Leipzig University, 04103 Leipzig, Germany;
| | - Susann Ossmann
- Leipzig Heart Center, University Department for Cardiac Surgery, 04289 Leipzig, Germany;
| | - Dirk Enke
- Institute of Chemical Technology, Leipzig University, 04103 Leipzig, Germany;
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany;
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Hou Y, Wang Z, Chen Z, Shuai L, Pei Y, Sun B, Jiang Y, Wang H. Noninvasive Transdermal Administration of mRNA Vaccines Encoding Multivalent Neoantigens Effectively Inhibits Melanoma Growth. ACS Biomater Sci Eng 2024; 10:4587-4600. [PMID: 38869192 DOI: 10.1021/acsbiomaterials.4c00426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Abstract
It is difficult to obtain specific tumor antigens, which is one of the main obstacles in the development of tumor vaccines. The vaccines containing multivalent antigens are thought to be more effective in antitumor therapy. In this study, a mRNA encoding three neoantigens of melanoma were prepared and encapsulated into the mannosylated chitosan-modified ethosomes (EthsMC) to obtain a multivalent mRNA vaccine (MmRV) for transcutaneous immunization (TCI). MmRV can effectively induce maturation of dendritic cells, with a better performance than mRNA of a single neoantigen. TCI patches (TCIPs) loading MmRV or siRNA against PDL1 (siPDL1) were prepared and applied to the skin of melanoma-bearing mice. The results showed that TCIPs significantly increase the levels of TNF-α, IFN-γ, and IL-12 in both plasma and tumor tissues, inhibit tumor growth, as well as promote infiltration of CD4+ and CD8+ T cells in the tumor tissues. Furthermore, the combination of MmRV and siPDL1 showed much better antitumor effects than either monotherapy, suggesting a synergistic effect between the vaccine and PDL1 blocker. In addition, the treatment with the TCIPs did not cause damage to the skin, blood, and vital organs of the mice, showing good biosafety. To the best of our knowledge, this work is the first to construct a noninvasive TCI system containing MmRV and siPDL1, providing a convenient and promising approach for tumor treatment.
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Affiliation(s)
- Yuting Hou
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Zhe Wang
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Zhen Chen
- Xuhui District Dental Disease Prevention and Treatment Institute, Shanghai 200030, China
| | - Lan Shuai
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Yifei Pei
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Binbin Sun
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Yuxin Jiang
- The First Hospital of Jiaxing, Jiaxing Key Laboratory of Virus-related Infectious Diseases, Jiaxing University, Jiaxing 314001, China
| | - Hongsheng Wang
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
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Ren H, Zhang Y, Huang W, Xu H, He W, Hao N, Zhang C. Tumor-targeted nanodrug FSGG/siGal-9 for transdermal photothermal immunotherapy of melanoma. Commun Biol 2024; 7:188. [PMID: 38366083 PMCID: PMC10873409 DOI: 10.1038/s42003-024-05891-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 02/06/2024] [Indexed: 02/18/2024] Open
Abstract
Photothermal therapy (PTT) is a cancer-targeted treatment approach.The occurrence of tumors may be related to microbial infections (Viruses, bacteria, fungi, etc.), which probably provokes anti-tumor immunity. However, T cells in the context of cancer become exhausted and dysfunctional. Galectin-9 (Gal-9) is highly expressed in normal tissues and associates with body immune tolerance, and was firstly evidenced with much higher expression on the primary solid tumors than CD80/86 (B7) and CD274 (PD-L1) here, which suggests that Gal-9 may be a key factor in inhibiting the anti-tumor immunity, and its receptor T cell immunoglobulin and mucin domain 3 (TIM-3) was discovered on the cytotoxic T lymphocytes (CTL) with high expression as well based on the single cell analysis. The immune checkpoint communications showed that the Gal-9/TIM-3 axis played the most vital role on negatively regulating the anti-tumor immunity of CTL for melanoma. Then, we used a novel transdermal photothermal nanosensitizer (FSGG) loading Gal-9 siRNA (FSGG/siGal-9) for knocking the tumor cells down Gal-9 to block the Gal-9/TIM-3 axis and prohibit CTL exhaustion synergizing PTT against melanoma, which evidenced good effects on inhibiting tumor growth and enhancing anti-tumor immunity, named "photothermal immunotherapy". This paper provides a new perspective for tumor prevention and treatment.
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Affiliation(s)
- Huihong Ren
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
- Drug Dispensing Department, Zibo Central Hospital, Zibo, 255000, China
| | - Yujuan Zhang
- Department of Otolaryngology, The First Dongguan Affiliated Hospital, and Nursing College, Guangdong Medical University, Dongguan, 523808, China.
| | - Wei Huang
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Haiyan Xu
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Weixiong He
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Nan Hao
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Cong Zhang
- School of Pharmacy and School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
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14
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Cammarano A, Dello Iacono S, Meglio C, Nicolais L. Advances in Transdermal Drug Delivery Systems: A Bibliometric and Patent Analysis. Pharmaceutics 2023; 15:2762. [PMID: 38140102 PMCID: PMC10747220 DOI: 10.3390/pharmaceutics15122762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/10/2023] [Indexed: 12/24/2023] Open
Abstract
Transdermal drug delivery systems have become an intriguing research topic in healthcare technology and one of the most frequently developed pharmaceutical products in the global market. In recent years, researchers and pharmaceutical companies have made significant progress in developing new solutions in the field. This study sheds light on current trends, collaboration patterns, research hotspots, and emerging frontiers of transdermal drug delivery. Herein, a bibliometric and patent analysis of data recovered from Scopus and The Lens databases, respectively, is reported over the last 20 years. From 2000 to 2022, the annual global publications increased from 131 in 2000 to 659 in 2022. Researchers in the United States, China, and India produced the highest number of publications. Likewise, most patent applications have been filed in the USA, China, and Europe. The recovered patents are 7275, grouped into 2997 patent families, of which 314 were granted. This study could support the work of decision-makers, scientific managers, or scientists to create new business opportunities or save money, time, and intellectual capital, thereby defining when a research or technology project should be a priority or not.
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Affiliation(s)
| | - Stefania Dello Iacono
- Institute of Polymers, Composites and Biomaterials (IPCB), National Research Council, P.le Enrico Fermi 1, 80055 Portici, Italy
| | | | - Luigi Nicolais
- Materias Srl, Corso N. Protopisani 50, 80146 Naples, Italy
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15
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Cai Y, Chu Y, Gong Y, Hong Y, Song F, Wang H, Zhang H, Sun X. Enhanced Transdermal Peptide-Modified Flexible Liposomes for Efficient Percutaneous Delivery of Chrysomycin A to Treat Subcutaneous Melanoma and Intradermal MRSA Infection. Adv Healthc Mater 2023; 12:e2300881. [PMID: 37267625 DOI: 10.1002/adhm.202300881] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/28/2023] [Indexed: 06/04/2023]
Abstract
Superficial skin diseases, including skin infections and tumors, are common healthcare burdens. In this study, the in vivo activity of chrysomycin A (CA) is explored, and a transdermal liposomal CA formulation is further constructed for the simultaneous treatment of cutaneous melanoma and cutaneous methicillin-resistant Staphylococcus aureus (MRSA) infection. The prepared liposomes (TD-LP-CA) display a strong antitumor effect with an IC50 value of less than 0.1 µm in B16-F10 cells, suppress the proliferation of MRSA with a minimum inhibitory concentration (MIC) of 1 µm, and eradicate established MRSA biofilms at 10× MIC in vitro. More importantly, TD-LP-CA shows enhanced stratum corneum (SC) penetration, reaching more than 500 µm beneath the skin's surface due to modification with the TD peptide, and demonstrates excellent subcutaneous tumor penetration after skin application in vivo. TD-LP-CA displays an excellent therapeutic effect against intradermal MRSA infection in mice after topical dermal administration, as well as a moderate inhibitory effect on subcutaneous melanoma with a 75% tumor inhibition rate. The liposomes prepared herein can be a promising carrier for transcutaneous CA transfer for the treatment of superficial diseases such as skin tumors and infections due to their ability to overcome the skin barrier.
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Affiliation(s)
- Yue Cai
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Yuteng Chu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Yubei Gong
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Yulu Hong
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Fuhang Song
- School of Light Industry, Beijing Technology and Business University, Beijing, 100048, China
| | - Hong Wang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
- Key Laboratory of Marine Fishery Resources Employment & Utilization of Zhejiang Province, Hangzhou, 310014, China
| | - Huawei Zhang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Xuanrong Sun
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China
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16
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Han S, Lee P, Choi HJ. Non-Invasive Vaccines: Challenges in Formulation and Vaccine Adjuvants. Pharmaceutics 2023; 15:2114. [PMID: 37631328 PMCID: PMC10458847 DOI: 10.3390/pharmaceutics15082114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Given the limitations of conventional invasive vaccines, such as the requirement for a cold chain system and trained personnel, needle-based injuries, and limited immunogenicity, non-invasive vaccines have gained significant attention. Although numerous approaches for formulating and administrating non-invasive vaccines have emerged, each of them faces its own challenges associated with vaccine bioavailability, toxicity, and other issues. To overcome such limitations, researchers have created novel supplementary materials and delivery systems. The goal of this review article is to provide vaccine formulation researchers with the most up-to-date information on vaccine formulation and the immunological mechanisms available, to identify the technical challenges associated with the commercialization of non-invasive vaccines, and to guide future research and development efforts.
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Affiliation(s)
| | | | - Hyo-Jick Choi
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada; (S.H.); (P.L.)
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17
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Chen X, Xiao H, Shi X, Zhao Q, Xu X, Fan P, Xiao D. Bibliometric analysis and visualization of transdermal drug delivery research in the last decade: global research trends and hotspots. Front Pharmacol 2023; 14:1173251. [PMID: 37397493 PMCID: PMC10313210 DOI: 10.3389/fphar.2023.1173251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/08/2023] [Indexed: 07/04/2023] Open
Abstract
Background: Transdermal delivery has become a crucial field in pharmaceutical research. There has been a proliferation of innovative methods for transdermal drug delivery. In recent years, the number of publications regarding transdermal drug delivery has been rising rapidly. To investigate the current research trends and hotspots in transdermal drug delivery, a comprehensive bibliometric analysis was performed. Methods: An extensive literature review was conducted to gather information on transdermal drug delivery that had been published between 2003 and 2022. The articles were obtained from the Web of Science (WOS) and the National Center for Biotechnology Information (NCBI) databases. Subsequently, the collected data underwent analysis and visualization using a variety of software tools. This approach enables a deeper exploration of the hotspots and emerging trends within this particular research domain. Results: The results showed that the number of articles published on transdermal delivery has increased steadily over the years, with a total of 2,555 articles being analyzed. The most frequently cited articles were related to the optimization of drug delivery and the use of nanotechnology in transdermal drug delivery. The most active countries in the field of transdermal delivery research were the China, United States, and India. Furthermore, the hotspots over the past 2 decades were identified (e.g., drug therapy, drug delivery, and pharmaceutical preparations and drug design). The shift in research focus reflects an increasing emphasis on drug delivery and control release, rather than simply absorption and penetration, and suggests a growing interest in engineering approaches to transdermal drug delivery. Conclusion: This study provided a comprehensive overview of transdermal delivery research. The research indicated that transdermal delivery would be a rapidly evolving field with many opportunities for future research and development. Moreover, this bibliometric analysis will help researchers gain insights into transdermal drug delivery research's hotspots and trends accurately and quickly.
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Affiliation(s)
- Xinghan Chen
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China
- Department of Burns and Plastic Surgery, West China Hospital Sichuan University, Chengdu, Sichuan, China
| | - Haitao Xiao
- Department of Burns and Plastic Surgery, West China Hospital Sichuan University, Chengdu, Sichuan, China
| | - Xiujun Shi
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qiao Zhao
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xuewen Xu
- Department of Burns and Plastic Surgery, West China Hospital Sichuan University, Chengdu, Sichuan, China
| | - Ping Fan
- Department of Pharmacy, West China Hospital Sichuan University, Chengdu, Sichuan, China
| | - Dongqin Xiao
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China
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18
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Al-Nimry SS, Daghmash RM. Three Dimensional Printing and Its Applications Focusing on Microneedles for Drug Delivery. Pharmaceutics 2023; 15:1597. [PMID: 37376046 DOI: 10.3390/pharmaceutics15061597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/08/2023] [Accepted: 05/16/2023] [Indexed: 06/29/2023] Open
Abstract
Microneedles (MNs) are considered to be a novel smart injection system that causes significantly low skin invasion upon puncturing, due to the micron-sized dimensions that pierce into the skin painlessly. This allows transdermal delivery of numerous therapeutic molecules, such as insulin and vaccines. The fabrication of MNs is carried out through conventional old methods such as molding, as well as through newer and more sophisticated technologies, such as three-dimensional (3D) printing, which is considered to be a superior, more accurate, and more time- and production-efficient method than conventional methods. Three-dimensional printing is becoming an innovative method that is used in education through building intricate models, as well as being employed in the synthesis of fabrics, medical devices, medical implants, and orthoses/prostheses. Moreover, it has revolutionary applications in the pharmaceutical, cosmeceutical, and medical fields. Having the capacity to design patient-tailored devices according to their dimensions, along with specified dosage forms, has allowed 3D printing to stand out in the medical field. The different techniques of 3D printing allow for the production of many types of needles with different materials, such as hollow MNs and solid MNs. This review covers the benefits and drawbacks of 3D printing, methods used in 3D printing, types of 3D-printed MNs, characterization of 3D-printed MNs, general applications of 3D printing, and transdermal delivery using 3D-printed MNs.
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Affiliation(s)
- Suhair S Al-Nimry
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
| | - Rawand M Daghmash
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
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19
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Lago B, Brito M, Almeida CMM, Ferreira I, Baptista AC. Functionalisation of Electrospun Cellulose Acetate Membranes with PEDOT and PPy for Electronic Controlled Drug Release. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:nano13091493. [PMID: 37177038 PMCID: PMC10180495 DOI: 10.3390/nano13091493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023]
Abstract
Controlled drug release via electrical stimulation from drug-impregnated fibres was studied using electrospun cellulose acetate (CA) membranes and encapsulated ibuprofen (IBU). This research outlines the influence of polypyrrole (PPy) and poly(3,4-ethylenedioxythiophene) (PEDOT)-functionalised CA membranes and their suitability for dermal electronic-controlled drug release. Micro Raman analysis confirmed polymer functionalisation of CA membranes and drug incorporation. Scanning electron microscopy (SEM) images evidenced the presence of PPy and PEDOT coatings. The kinetic of drug release was analysed, and the passive and active release was compared. In the proposed systems, the drug release is controlled by very low electrical potentials. A potential of -0.3 V applied to membranes showed the ibuprofen retention, and a positive potential of +0.3 V, +0.5 V, or +0.8 V, depending on the conductive polymer and membrane configuration, enhanced the drug release. A small adhesive patch was constructed to validate this system for cutaneous application and verified an "ON/OFF" ibuprofen release pattern from membranes.
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Affiliation(s)
- Beatriz Lago
- CENIMAT|I3N, Materials Science Department, School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal
| | - Miguel Brito
- CENIMAT|I3N, Materials Science Department, School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal
| | - Cristina M M Almeida
- Laboratory of Bromatology and Water Quality, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
- iMed.UL (Institute for Medicines and Pharmaceutical Sciences, Portugal), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
| | - Isabel Ferreira
- CENIMAT|I3N, Materials Science Department, School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal
| | - Ana Catarina Baptista
- CENIMAT|I3N, Materials Science Department, School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal
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20
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Žigrayová D, Mikušová V, Mikuš P. Advances in Antiviral Delivery Systems and Chitosan-Based Polymeric and Nanoparticulate Antivirals and Antiviral Carriers. Viruses 2023; 15:647. [PMID: 36992356 PMCID: PMC10054433 DOI: 10.3390/v15030647] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 02/24/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Current antiviral therapy research is focused on developing dosage forms that enable highly effective drug delivery, providing a selective effect in the organism, lower risk of adverse effects, a lower dose of active pharmaceutical ingredients, and minimal toxicity. In this article, antiviral drugs and the mechanisms of their action are summarized at the beginning as a prerequisite background to develop relevant drug delivery/carrier systems for them, classified and briefly discussed subsequently. Many of the recent studies aim at different types of synthetic, semisynthetic, and natural polymers serving as a favorable matrix for the antiviral drug carrier. Besides a wider view of different antiviral delivery systems, this review focuses on advances in antiviral drug delivery systems based on chitosan (CS) and derivatized CS carriers. CS and its derivatives are evaluated concerning methods of their preparation, their basic characteristics and properties, approaches to the incorporation of an antiviral drug in the CS polymer as well as CS nanoparticulate systems, and their recent biomedical applications in the context of actual antiviral therapy. The degree of development (i.e., research study, in vitro/ex vivo/in vivo preclinical testing), as well as benefits and limitations of CS polymer and CS nanoparticulate drug delivery systems, are reported for particular viral diseases and corresponding antivirotics.
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Affiliation(s)
- Dominika Žigrayová
- Department of Galenic Pharmacy, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, 83232 Bratislava, Slovakia
| | - Veronika Mikušová
- Department of Galenic Pharmacy, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, 83232 Bratislava, Slovakia
| | - Peter Mikuš
- Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, 83232 Bratislava, Slovakia
- Toxicological and Antidoping Center, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, 83232 Bratislava, Slovakia
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21
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Yilmaz EG, Ece E, Erdem Ö, Eş I, Inci F. A Sustainable Solution to Skin Diseases: Ecofriendly Transdermal Patches. Pharmaceutics 2023; 15:579. [PMID: 36839902 PMCID: PMC9960884 DOI: 10.3390/pharmaceutics15020579] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Skin is the largest epithelial surface of the human body, with a surface area of 2 m2 for the average adult human. Being an external organ, it is susceptible to more than 3000 potential skin diseases, including injury, inflammation, microbial and viral infections, and skin cancer. Due to its nature, it offers a large accessible site for administrating several medications against these diseases. The dermal and transdermal delivery of such medications are often ensured by utilizing dermal/transdermal patches or microneedles made of biocompatible and biodegradable materials. These tools provide controlled delivery of drugs to the site of action in a rapid and therapeutically effective manner with enhanced diffusivity and minimal side effects. Regrettably, they are usually fabricated using synthetic materials with possible harmful environmental effects. Manufacturing such tools using green synthesis routes and raw materials is hence essential for both ecological and economic sustainability. In this review, natural materials including chitosan/chitin, alginate, keratin, gelatin, cellulose, hyaluronic acid, pectin, and collagen utilized in designing ecofriendly patches will be explored. Their implementation in wound healing, skin cancer, inflammations, and infections will be discussed, and the significance of these studies will be evaluated with future perspectives.
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Affiliation(s)
- Eylul Gulsen Yilmaz
- UNAM—National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey
- Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey
| | - Emre Ece
- UNAM—National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey
- Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey
| | - Özgecan Erdem
- UNAM—National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey
| | - Ismail Eş
- UNAM—National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey
| | - Fatih Inci
- UNAM—National Nanotechnology Research Center, Bilkent University, Ankara 06800, Turkey
- Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey
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22
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Phatale V, Vaiphei KK, Jha S, Patil D, Agrawal M, Alexander A. Overcoming skin barriers through advanced transdermal drug delivery approaches. J Control Release 2022; 351:361-380. [PMID: 36169040 DOI: 10.1016/j.jconrel.2022.09.025] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 10/31/2022]
Abstract
Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.
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Affiliation(s)
- Vivek Phatale
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Guwahati (NIPER-G), Changsari, Guwahati 781101, India
| | - Klaudi K Vaiphei
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Guwahati (NIPER-G), Changsari, Guwahati 781101, India
| | - Shikha Jha
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Guwahati (NIPER-G), Changsari, Guwahati 781101, India
| | - Dnyaneshwar Patil
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Guwahati (NIPER-G), Changsari, Guwahati 781101, India
| | - Mukta Agrawal
- SVKM's Narsee Monjee Institute of Management Studies (NMIMS), School of Pharmacy & Technology Management, Hyderabad 509301, India
| | - Amit Alexander
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Guwahati (NIPER-G), Changsari, Guwahati 781101, India.
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23
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Drug delivery with dissolving microneedles: Skin puncture, its influencing factors and improvement strategies. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103653] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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24
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Hassan DH, Shohdy JN, El-Setouhy DA, El-Nabarawi M, Naguib MJ. Compritol-Based Nanostrucutured Lipid Carriers (NLCs) for Augmentation of Zolmitriptan Bioavailability via the Transdermal Route: In Vitro Optimization, Ex Vivo Permeation, In Vivo Pharmacokinetic Study. Pharmaceutics 2022; 14:pharmaceutics14071484. [PMID: 35890379 PMCID: PMC9315618 DOI: 10.3390/pharmaceutics14071484] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 01/14/2023] Open
Abstract
Migraine is a severe neurovascular disease manifested mainly as unilateral throbbing headaches. Triptans are agonists for serotonin receptors. Zolmitriptan (ZMP) is a biopharmaceutics classification system (BCS) class III medication with an absolute oral bioavailability of less than 40%. As a result, our research intended to increase ZMP bioavailability by developing transdermal nanostructured lipid carriers (NLCs). NLCs were prepared utilizing a combination of hot melt emulsification and high-speed stirring in a 32 full factorial design. The studied variables were liquid lipid type (X1) and surfactant type (X2). The developed NLCs were evaluated in terms of particle size (Y1, nm), polydispersity index (Y2, PDI), zeta potential (Y3, mV), entrapment efficacy (Y4, %) and amount released after 6 h (Q6h, Y5, %). At 1% Mygliol as liquid lipid component and 1% Span 20 as surfactant, the optimized formula (NLC9) showed a minimum particle size (138 ± 7.07 nm), minimum polydispersity index (0.39 ± 0.001), acceptable zeta potential (−22.1 ± 0.80), maximum entrapment efficiency (73 ± 0.10%) and maximum amount released after 6 h (83.22 ± 0.10%). The optimized formula was then incorporated into gel preparation (HPMC) to improve the system stability and ease of application. Then, the pharmacokinetic study was conducted on rabbits in a cross-over design. The calculated parameters showed a higher area under the curve (AUC0–24, AUC0–∞ (ng·h/mL)) of the developed ZMP-NLCs loaded gel, with a 1.76-fold increase in bioavailability in comparison to the orally administered marketed product (Zomig®). A histopathological examination revealed the safety of the developed nanoparticles. The declared results highlight the potential of utilizing the proposed NLCs for the transdermal delivery of ZMP to improve the drug bioavailability.
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Affiliation(s)
- Doaa H. Hassan
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), Oct. 6, Giza 12566, Egypt;
| | - Joseph N. Shohdy
- Department of Industrial Pharmacy, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), Oct. 6, Giza 12566, Egypt;
| | - Doaa Ahmed El-Setouhy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (D.A.E.-S.); (M.E.-N.)
| | - Mohamed El-Nabarawi
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (D.A.E.-S.); (M.E.-N.)
| | - Marianne J. Naguib
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (D.A.E.-S.); (M.E.-N.)
- Correspondence:
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Chavda VP, Pandya R, Apostolopoulos V. DNA vaccines for SARS-CoV-2: toward third-generation vaccination era. Expert Rev Vaccines 2021; 20:1549-1560. [PMID: 34582298 PMCID: PMC8567274 DOI: 10.1080/14760584.2021.1987223] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/24/2021] [Indexed: 12/19/2022]
Abstract
Introduction: Coronavirus outbreak 2019 (COVID-19) has affected all the corners of the globe and created chaos to human life. In order to put some control on the pandemic, vaccines are urgently required that are safe, cost effective, easy to produce, and most importantly induce appropriate immune responses and protection against viral infection. DNA vaccines possess all these features and are promising candidates for providing protection against SARS-CoV-2.Area covered: Current understanding and advances in DNA vaccines toward COVID-19, especially those under various stages of clinical trials.Expert opinion: Through DNA vaccines, host cells are momentarily transformed into factories that produce proteins of the SARS-CoV-2. The host immune system detects these proteins to develop antibodies that neutralize and prevent the infection. This vaccine platform has additional benefits compared to traditional vaccination strategies like strong cellular immune response, higher safety margin, a simple production process as per cGMP norms, lack of any infectious agent, and a robust platform for large-scale production.
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Affiliation(s)
- Vivek P Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, Gujarat, India
| | - Radhika Pandya
- Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, Gujarat, India
| | - Vasso Apostolopoulos
- Department of Immunology, Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
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Berillo D, Zharkinbekov Z, Kim Y, Raziyeva K, Temirkhanova K, Saparov A. Stimuli-Responsive Polymers for Transdermal, Transmucosal and Ocular Drug Delivery. Pharmaceutics 2021; 13:2050. [PMID: 34959332 PMCID: PMC8708789 DOI: 10.3390/pharmaceutics13122050] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Despite their conventional and widespread use, oral and intravenous routes of drug administration face several limitations. In particular, orally administered drugs undergo enzymatic degradation in the gastrointestinal tract and first-pass metabolism in the liver, which tend to decrease their bioavailability. Intravenous infusions of medications are invasive, painful and stressful for patients and carry the risk of infections, tissue damage and other adverse reactions. In order to account for these disadvantages, alternative routes of drug delivery, such as transdermal, nasal, oromucosal, ocular and others, have been considered. Moreover, drug formulations have been modified in order to improve their storage stability, solubility, absorption and safety. Recently, stimuli-responsive polymers have been shown to achieve controlled release and enhance the bioavailability of multiple drugs. In this review, we discuss the most up-to-date use of stimuli-responsive materials in order to optimize the delivery of medications that are unstable to pH or undergo primary metabolism via transdermal, nasal, oromucosal and ocular routes. Release kinetics, diffusion parameters and permeation rate of the drug via the mucosa or skin are discussed as well.
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Affiliation(s)
- Dmitriy Berillo
- Department of Pharmaceutical and Toxicological Chemistry, Pharmacognosy and Botany School of Pharmacy, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan
| | - Zharylkasyn Zharkinbekov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (Z.Z.); (Y.K.); (K.R.); (K.T.)
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (Z.Z.); (Y.K.); (K.R.); (K.T.)
| | - Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (Z.Z.); (Y.K.); (K.R.); (K.T.)
| | - Kamila Temirkhanova
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (Z.Z.); (Y.K.); (K.R.); (K.T.)
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (Z.Z.); (Y.K.); (K.R.); (K.T.)
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Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes. Pharmaceutics 2021; 13:pharmaceutics13101608. [PMID: 34683901 PMCID: PMC8538358 DOI: 10.3390/pharmaceutics13101608] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 12/26/2022] Open
Abstract
The steady improvement and optimization of transdermal permeation is a constant and challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA) nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was investigated. For this aim, different vehicles under non-buffered and buffered conditions and different skin models (human heat separated epidermis and reconstructed human epidermis equivalents) were tested. Permeation experiments were performed using static Franz diffusion cells under infinite dosing conditions. Already the presence of drug-free nanoparticles increased drug permeation across the skin. Drug permeation was even enhanced when applying drug-loaded nanoparticles. In contrast, buffered vehicles with different pH values (pH 5.4–7.4) revealed the influence of the pH on the permeation of FFA. The change of the surrounding pH of the biodegradable nanoparticulate system was demonstrated and visualized using pH-sensitive fluorescent probes. While a potential contribution of hair follicles could be ruled out, our data suggest that the enhanced permeation of FFA through human skin in the presence of PLGA nanoparticles is mediated by a locally decreased pH during hydrolytic degradation of this polymer. This hypothesis is supported by the observation that skin permeation of the weak base caffeine was not affected.
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Drug delivery for fighting infectious diseases: a global perspective. Drug Deliv Transl Res 2021; 11:1316-1322. [PMID: 34109534 PMCID: PMC8189707 DOI: 10.1007/s13346-021-01009-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 12/16/2022]
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