Nano- and Microscale Drug Delivery Systems: Design and Fabrication
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Nano- and Microscale Drug Delivery Systems: Design and Fabrication presents the developments that have taken place in recent years in the field of micro- and nanoscale drug delivery systems. Particular attention is assigned to the fabrication and design of drug delivery systems in order to i) reduce the side effects of therapeutic agents, ii) increase their pharmacological effect, and iii) improve aqueous solubility and chemical stability of different therapeutic agents.
This book is designed to offer a cogent, concise overview of current scholarship in this important area of research through its focus on the characterization and fabrication of a variety of nanomaterials for drug delivery applications. It is an invaluable reference source for both biomaterials scientists and biomedical engineers who want to learn more about how nanomaterials are engineered and used in the design of drug delivery nanosystems.
- Shows how micro- and nanomaterials can be engineered to create more effective drug delivery systems
- Summarizes current nanotechnology research in the field of drug delivery systems
- Explores the pros and cons of using particular nanomaterials as therapeutic agents
- Serves as a valuable reference for both biomaterials scientists and biomedical engineers who want to learn more about how nanomaterials are engineered and used in the design of drug delivery nanosystems
Alexandru Mihai Grumezescu
Dr. Grumezescu is Assistant Professor at the Department of Science and Engineering of Oxide Materials and Nanomaterials, in the Faculty of Applied Chemistry and Materials Science, with a second affiliation to the Faculty of Medical Engineering, at the Politehnica University of Bucharest in Romania. He is an experienced and oft-published researcher and editor in the field of nano and biomaterials, and he is the Editor-in-Chief of three journals: Biointerface Research in Applied Chemistry, Letters and Applied NanoBioScience, and Biomaterials and Tissue Engineering Bulletin. He also serves as editor or guest editor for several notable journals. Dr. Grumezescu has published 150 peer-reviewed papers, 20 book chapters, 6 co-authored books and 11 edited books.
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Nano- and Microscale Drug Delivery Systems - Alexandru Mihai Grumezescu
Nano- and Microscale Drug Delivery Systems
Design and Fabrication
Edited by
Alexandru Mihai Grumezescu
University Politehnica of Bucharest, Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, Bucharest, Romania
Table of Contents
Cover
Title page
Copyright
List of Contributors
Foreword
Preface
Chapter 1: Microscale Drug Delivery Systems: Current Perspectives and Novel Approaches
Abstract
1. Introduction
2. Microscale Drug Delivery Systems
3. Conclusions
Acknowledgment
Chapter 2: Sustainable Delivery Systems Through Green Nanotechnology
Abstract
1. History and Development of Nanotechnology
2. Different Forms of Nanostructures
3. Synthesis of Gold Nanoparticles (AuNP)
4. Transition Toward Green Nanotechnology
5. Green Synthesis of Gold Nanoparticles From Plant Extracts
6. Sustainable Gold Nanoparticles
7. Summary
Chapter 3: Polymer Therapeutics: Design, Application, and Pharmacokinetics
Abstract
1. Introduction
2. Polymeric Therapeutics for Treatment of Cancer
3. Polymeric Therapeutics for Treatment of Viral Infections
4. Polymeric Therapeutics for Treatment of Diabetes
5. Polymeric Therapeutics for Treatment of Osteoporosis
6. Polymer Therapeutics for Treatment of Digestive Tract Diseases
7. Polymeric Therapeutics for Wound Dressing and Tissue Regeneration
8. Polymeric Therapeutics for Treatment of Sepsis
9. Polymer Therapeutics for Treatment of Bacterial Infections
10. Polymer Therapeutics for Treatment of Fungal Infections
11. Polymer Therapeutics for Treatment of Malaria
12. Polymer Therapeutics for Treatment of Inflammation
13. Polymer Therapeutics for Treatment of Ocular Diseases
14. Polymer Therapeutics for Treatment of Leishmaniasis
15. Polymer Therapeutics for Treatment of Hypertension
16. Conclusions
17. Websites
Chapter 4: Fibonacci Nanostructures for Novel Nanotherapeutical Approach
Abstract
1. Introduction
2. Motivation
3. Biomolecular Signaling and Fibonacci Nanostructures
4. Fibonacci Nanostructures/C60
5. Conclusions
Acknowledgments
Chapter 5: Dendrimers and Dendrimers-Grafted Superparamagnetic Iron Oxide Nanoparticles: Synthesis, Characterization, Functionalization, and Biological Applications in Drug Delivery Systems
Abstract
1. Introduction
2. Dendrimers as Nanoscale Containers
3. Dendrimers in Gene Transfection
4. Dendrimers in Drug Delivery
5. Dendrimers Modified Magnetic Nanoparticles in Drug Delivery
6. Conclusions
Chapter 6: Nanotechnology and the New Frontiers of Drug Delivery in Cerebral Gliomas
Abstract
1. Introduction
2. Glioma
3. Nanoparticles: New Therapeutic Potentials
4. Nanotoxicology
5. Applications in Brain Tumors
6. Conclusion
Chapter 7: Nanoparticles: A Novel Approach to Target Tumors
Abstract
1. Introduction
2. Types of Nanoformulations for Therapeutic Delivery
3. Modern Trends in Therapeutic Nanoformulations
4. Polymers and Methods Concerned in Nanodrug Delivery Systems
5. Challenges in the Fabrication of Nanoparticles as Targeted Delivery
6. Toxicity Control Process During Fabrication of Nanoparticles
7. Future Prospects
8. Conclusions
Chapter 8: Therapeutic Nanostructures for Dermal and Transdermal Drug Delivery
Abstract
1. Introduction
2. Nanocarriers in Skin Delivery
3. Nanoparticles in Skin Delivery
4. Conclusions
Chapter 9: Electrospun Nanofibrous Scaffold as a Potential Carrier of Antimicrobial Therapeutics for Diabetic Wound Healing and Tissue Regeneration
Abstract
1. Introduction
2. Materials for the Fabrication of Antimicrobial Nanofibrous Scaffolds
3. Methods of Fabrication of Nanofibrous Scaffolds
4. Antimicrobial Applications of Nanofibrous Scaffolds
5. Physicochemical Characterization of Antimicrobial Nanofibrous Scaffolds
6. Detecting Resistance to Antimicrobial Agents
7. Evaluation of Antimicrobial Efficacy of Antimicrobial Nanofibrous Scaffolds
8. Strategies for the Incorporation of Antimicrobial Compounds on Nanofibrous Scaffolds
9. Conclusions
Acknowledgment
Chapter 10: Nanosized Drug Carriers for Oral Delivery of Anticancer Compounds and the Importance of the Chromatographic Techniques
Abstract
1. Introduction
2. Nanocarrier-Based Approaches for Oral Delivery of Anticancer Compounds
3. The Place of Chromatographic Techniques in Cancer Drugs
4. Conclusions
Chapter 11: Promising Novel Nanopharmaceuticals for Improving Topical Antifungal Drug Delivery
Abstract
1. Introduction
2. Skin Structure and Penetration Route
3. Topical Drug Delivery System and Skin
4. Topical Antifungal Drugs and Available Dosage Forms
5. Need for Novel Nanopharmaceuticals for Topical Delivery
6. Conclusions
Chapter 12: Nanoconstructs Based on Cyclodextrins for Antimicrobial Applications
Abstract
1. Cyclodextrins and Their Nanoconstructs
2. CD-Ns and Antibacterial/Antibiotic Drugs
3. CD-Ns and Antiviral Agents
4. CD-Ns and Antifungal Agents
5. CD-Ns, Disinfectants, and Antiseptics
6. Photodynamic Antimicrobial Chemotherapy by Using CD-Ns
7. CD-Capped AgNPs for Antimicrobial Applications
8. Conclusions and Perspectives
Acknowledgments
Chapter 13: Nanoemulsions: A Novel Antimicrobial Delivery System
Abstract
1. Introduction
2. Definitions
3. Preparation Techniques
4. Fundamental Concepts on the Formation of Nanoemulsions
5. Thermo Dynamical Concept
6. Applications of Nanoemulsions in Pharmaceuticals
7. Pharmaceutical Applications
8. Mechanism of Antimicrobial Action of Nanoemulsions
9. Anticancer Nanoemulsions
10. Food Applications of Nanoemulsions
11. Microbial Food Spoilage
12. Microbial Products as Preservative
13. Food-Borne Diseases
14. Microbial Fermented Foods
15. Nanoemulsions as Food Preservative
16. Nanoemulsions as a Food Antimicrobial Delivery System
17. Food Marketing
18. Cosmetics
19. Conclusions
Chapter 14: Nanodrug Delivery Systems for Dermal and Transdermal Photosensitizer Drugs
Abstract
1. Dermal and Transdermal Drug Delivery Systems: Concepts and Classification
2. Photosensitizer Drugs and Drug Delivery Systems
3. Biological Studies of Dermal and Transdermal Photosensitized Nanomaterials
4. Tissue Engineering and Dermal/Transdermal Photosensitized Nanomaterials
5. Conclusion and Future Directions
Chapter 15: Recent Advances in the Delivery of Chemotherapeutic Agents
Abstract
1. Background
2. Overview of New Generation Cancer Chemotherapeutics
3. Targeted Therapies
4. Cancer Vaccine
5. Chemoprevention
6. Patent Information
7. Conclusions
Chapter 16: Polyurethane Nanostructures for Drug Delivery Applications
Abstract
1. Introduction
2. Biocompatibility
3. Processing of Polyurethanes
4. Drug Delivery Applications of Polyurethanes
5. Conclusions
Chapter 17: Nanoemulsion as a Valuable Nanostructure Platform for Pharmaceutical Drug Delivery
Abstract
1. Introduction
2. Nanoemulsion for Pharmaceutical Drug Delivery
3. Research in Nanoemulsion in the 21st Century
4. Conclusions
Conflicts of Interest
List of Abbreviations
Acknowledgment
Chapter 18: The Supramolecular Complex of Sertraline With Cyclodextrins: Physicochemical and Pharmacological Properties
Abstract
1. Introduction
2. Sertraline and β-Cyclodextrin Supramolecular Complex: Thermodynamic Parameters
3. Cyclodextrins as Drug Carriers
4. Cyclodextrins as Hypodlycemic Agents
5. Sertraline as a Hypoglycemic Agent
6. The Efficacy of the HPβCD: Sertraline Complex in Prevention of Alloxan-Induced Diabetic Lesions in Rats
7. Conclusions
Chapter 19: Pharmacokinetic and Pharmacodynamic Modulations of Therapeutically Active Constituents From Orally Administered Nanocarriers Along With a Glimpse of Their Advantages and Limitations
Abstract
1. Introduction
2. Nanocarriers in Oral Drug Delivery
3. Various Types of Oral Nanocarrier Systems
4. Major Obstacles in Successful Oral Delivery of Nanocarriers
5. Transport Across the Intestinal Epithelium
6. PK/PD Modulation of Orally Administered Drugs Loaded in Nanocarriers Based on Recent Research Findings
7. Critical Factors Affecting the PK/PD and Fate of Orally Administered Nanocarriers
8. Some Strategies to Enhance Bioavailability of Oral Nanocarriers
9. Challenges in Clinical Feasibility of Oral Nanocarriers
10. Conclusions and Future Prospects
Chapter 20: Nanostructured Propolis as Therapeutic Systems With Antimicrobial Activity
Abstract
1. Introduction
2. Terminology and Identification
3. Historical and Current Uses of Propolis
4. Botanical Origin and Composition
5. Therapeutic Activity and Biological Properties
6. Micro/Nanotherapeutic Systems Containing Propolis
7. Strategies to Release Propolis
8. Conclusions and Remarks
Chapter 21: Nanostructures for Curcumin Delivery: Possibilities and Challenges
Abstract
1. Introduction and Background of Curcumin
2. Photophysical and Photochemical Properties of Curcumin
3. Antimicrobial Properties of Curcumin
4. Bioavailability of Curcumin
5. Nanostructures for the Delivery of Curcumin
6. Conclusions
Acknowledgments
Chapter 22: Nanostructures for Improved Antimonial Therapy of Leishmaniasis
Abstract
1. Introduction
2. Chemistry and Pharmacology of Pentavalent Antimonials
3. Injectable Liposomal Formulations of Antimonial Drugs
4. Injectable Nonlipid-Based Nanocarriers for Antimonial Drugs
5. Oral Formulations for Antimonial Drugs
6. Topical Formulations of Antimonial Drugs for Cutaneous Leishmaniasis
7. Conclusions
Acknowledgments
Chapter 23: Nanoarchitectures for Neglected Tropical Protozoal Diseases: Challenges and State of the Art
Abstract
1. Neglected Protozoal Diseases: A Treatment Challenge
2. Nanoarchitectures and Classification
3. Chagas Disease (American Trypanosomiasis)
4. Leishmaniasis
5. African Trypanosomiasis and Nanodelivery of Trypanocidal Agents
6. Concluding Remarks
Index
Copyright
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List of Contributors
Blessing A. Aderibigbe, University of Fort Hare, Eastern Cape, South Africa
Atousa Aliahmadi, Shahid Beheshti University, Tehran, Iran
Afshan Ardalan, Shahid Beheshti University, Tehran, Iran
Erly G. Azevedo, Juiz de Fora Federal University (UFJF), Governador Valadares and Juiz de Fora, Minas Gerais, Brazil
Leila Azharshekoufeh Bahari, Biotechnology Research Center and Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, East Azerbaijan, Iran
Silwia Belica-Pacha, University of Lodz, Lodz, Poland
Sanchari Bhattacharya, Jadavpur University, Kolkata, West Bengal, India
Marcos L. Bruschi, State University of Maringá, Maringá, Paraná, Brazil
Vyacheslav Buko
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus
School of Medical Sciences, Bialystok, Poland
Maria Caffo, University of Messina School of Medicine, Messina, Italy
Gerardo Caruso, University of Messina School of Medicine, Messina, Italy
Rhitabrita Chakraborty, Jadavpur University, Kolkata, West Bengal, India
Nagendra S. Chauhan, Drugs Testing Laboratory Avam Anusandhan Kendra, Raipur, Chhattisgarh, India
Murthy Chavali
Vignan’s Foundation for Science, Technology, and Research University (VFSTRU; Vignan’s University)
Centre of Excellence in Advanced Materials, Manufacturing, Processing and Characterization (CoExAMMPC), Vignan’s Foundation for Science, Technology, and Research University (VFSTRU; Vignan’s University), Guntur, Andhra Pradesh, India
Sydnei M. Da Silva, Federal University of Uberlândia (UFU), Institute of Biomedical Sciences, Uberlândia, Minas Gerais, Brazil
Lizziane M.B. de Francisco, State University of Maringá, Maringá, Paraná, Brazil
Marigilson P. de Siqueira Moura, College of Pharmaceutical Sciences, Federal University of Sao Francisco Valley—UNIVASF, Petrolina, Pernambuco, Brazil
Lucas de A.S. de Toledo, State University of Maringá, Maringá, Paraná, Brazil
Cynthia Demicheli, Federal University of Minas Gerais (UFMG), Institute of Exact Sciences, Belo Horizonte, Minas Gerais, Brazil
Gabriela Dorcioman, National Institute for Lasers, Plasma and Radiation Physics, Magurele, Ilfov, Romania
Charu Dwivedi
Jacob School of Biotechnology and Bioengineering, Sam Higginbottom Institute of Agriculture, Technology and Sciences
Nanotechnology Application Centre, University of Allahabad, Allahabad, Uttar Pradesh, India
Frédéric Frézard, Federal University of Minas Gerais (UFMG), Institute of Biological Sciences, Belo Horizonte, Minas Gerais, Brazil
Aravinthan Gopanna
Royal Commission Yanbu-Colleges and Institutes, Yanbu Al-Sinaiyah, Kingdom of Saudi Arabia
Vignan’s Foundation for Science, Technology, and Research University (VFSTRU; Vignan’s University), Guntur, Andhra Pradesh, India
Giovanni Grassi, University of Messina, Messina, Italy
Valentina Grumezescu
National Institute for Lasers, Plasma and Radiation Physics, Magurele, Ilfov
University Politehnica of Bucharest, Bucharest, Romania
Mehmet Gumustas
Ankara University, Ankara
Hitit University, Çorum, Turkey
Madhu Gupta, Center for Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, New Delhi, Delhi, India
Mojdeh Hakemi-Vala, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
Yousef Javadzadeh, Biotechnology Research Center and Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, East Azerbaijan, Iran
Gunjan Jeswani, Shri Shankaracharya Group of Institutions, SSTC, Bhilai, Chhattisgarh, India
Amita Joshi, B.V. Patel PERD Centre, Ahmedabad, Gujarat, India
Djuro Koruga
University of Belgrade
European Center for Peace and Development (ECPD), United Nations-Mandated University for Peace, Belgrade, Serbia
Kiruba Krishnaswamy, McGill University, Sainte-Anne-de-Bellevue, QC, Canada
Veeranjaneya R. Lebaka, Yogi Vemana University, Kadapa, Andhra Pradesh, India
Lidija Matija, University of Belgrade, Belgrade, Serbia
Antonino Mazzaglia, CNR-ISMN Istituto per lo Studio dei Materiali Nanostrutturati c/o University of Messina, Messina, Italy
Lucia Merlo, University of Messina School of Medicine, Messina, Italy
Ivana Mileusnic, University of Belgrade, Belgrade, Serbia
Shanti Bhushan Mishra, United Institute of Pharmacy, Allahabad, Uttar Pradesh, India
Vimal P. Mishra, Jadavpur University, Kolkata, West Bengal, India
Hembe E. Mukaya, University of Johannesburg, Johannesburg, South Africa
Biswajit Mukherjee, Jadavpur University, Kolkata, West Bengal, India
Jelena Muncan, University of Belgrade, Belgrade, Serbia
Venkata Ramireddy Narala, Yogi Vemana University, Kadapa, Andhra Pradesh, India
Irina Negut
National Institute for Lasers, Plasma and Radiation Physics
University of Bucharest, Magurele, Ilfov, Romania
Valérie Orsat, McGill University, Sainte-Anne-de-Bellevue, QC, Canada
Sibel A. Ozkan, Ankara University, Ankara, Turkey
Bartlomiej Palecz, University of Lodz, Lodz, Poland
Kalpana Panati, Government College for Men, Kadapa, Andhra Pradesh, India
Avinash C. Pandey, Nanotechnology Application Centre, University of Allahabad, Allahabad, Uttar Pradesh, India
Himanshu Pandey
Sam Higginbottom Institute of Agriculture, Technology and Sciences
Nanotechnology Application Centre, University of Allahabad, Allahabad, Uttar Pradesh, India
Ishan Pandey, Sam Higginbottom Institute of Agriculture, Technology and Sciences, Allahabad, Uttar Pradesh, India
Bharat G. Patel, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Gujarat, India
Mrunali R. Patel, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Gujarat, India
Rashmin B. Patel, A.R. College of Pharmacy and G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar, Gujarat, India
Sandip Patil, Indian Institute of Technology, Kanpur, Uttar Pradesh, India
Swarnali D. Paul, Shri Shankaracharya Group of Institutions, SSTC, Bhilai, Chhattisgarh, India
Raphaela R. de A. Pereira, State University of Maringá, Maringá, Paraná, Brazil
Cinzia Pignataro, University of Messina School of Medicine, Messina, Italy
Anna Piperno, University of Messina, Messina, Italy
Fernando L. Primo, São Paulo State University, (UNESP), School of Pharmaceutical Sciences, Araraquara, São Paulo, Brazil
Swati Pund, Indian Institute of Technology-Bombay, Powai, Mumbai, Maharashtra, India
Hassan Rafati, Shahid Beheshti University, Tehran, Iran
Manasa D. Rajagopalan, East West College of Pharmacy, Bangalore, Karnataka, India
Krishna P. Rajan
Yanbu Industrial College, Yanbu Al-Sinaiyah, Kingdom of Saudi Arabia
Vignan’s Foundation for Science, Technology, and Research University (VFSTRU; Vignan’s University)
Centre of Excellence in Advanced Materials, Manufacturing, Processing and Characterization (CoExAMMPC), Vignan’s Foundation for Science, Technology, and Research University (VFSTRU; Vignan’s University), Guntur, Andhra Pradesh, India
Pramod W. Ramteke, Jacob School of Biotechnology and Bioengineering, Sam Higginbottom Institute of Agriculture, Technology and Sciences, Allahabad, Uttar Pradesh, India
Dharaneeswara D. Reddy, Micco Laboratories Private Limited, Tirupati, Andhra Pradesh, India
Raul R. Ribeiro, Juiz de Fora Federal University (UFJF), Governador Valadares and Juiz de Fora, Minas Gerais, Brazil
Hélen C. Rosseto, State University of Maringá, Maringá, Paraná, Brazil
Bhabani S. Satapathy, Jadavpur University, Kolkata, West Bengal, India
Angela Scala, University of Messina, Messina, Italy
Luigi M. Scolaro
University of Messina
C.I.R.C.M.S.B., Unit of Messina
CNR-ISMN Istituto per lo Studio dei Materiali Nanostrutturati c/o University of Messina, Messina, Italy
Ceyda T. Sengel-Turk, Ankara University, Ankara, Turkey
Vikas Sharma, Shri Rawatpura Sarkar Institute of Pharmacy, Datia, Madhya Pradesh, India
Hamidreza Shirzadfar, Sheikhbahaee University, Baharestan, Isfahan, Iran
Gabriel Socol, National Institute for Lasers, Plasma and Radiation Physics, Magurele, Ilfov, Romania
Katta A. Sridhar, East West College of Pharmacy, Bangalore, Karnataka, India
Parasuraman A. Subramani
Yogi Vemana University, Kadapa, Andhra Pradesh
Center for Fish Immunology, Vels Institute for Science, Technology and Advanced Studies (VISTAS), Chennai, Tamil Nadu, India
Asghar Taheri-Kafrani, University of Isfahan, Isfahan, Iran
Elham Tavassoli-Kafrani, College of Agriculture, Isfahan University of Technology, Isfahan, Iran
Antonio C. Tedesco, Center of Nanotechnology and Tissue Engineers, University of Sao Paulo—USP, Ribeirão Preto, São Paulo, Brazil
Shivam D. Thakore, A.R. College of Pharmacy and G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar, Gujarat, India
Selvin P. Thomas
Yanbu Industrial College
Royal Commission Yanbu-Colleges and Institutes, Yanbu Al-Sinaiyah, Kingdom of Saudi Arabia
Ema Tot, University of Messina School of Medicine, Messina, Italy
Bengi Uslu, Ankara University, Ankara, Turkey
Rajashekar Valluru, East West College of Pharmacy, Bangalore, Karnataka, India
Gaurav Verma
Dr SS Bhatnagar University Institute of Chemical Engineering & Technology
Centre for Nanoscience and Nanotechnology, U.I.E.A.S.T, Panjab University, Chandigarh, Punjab, India
Ilya Zavodnik
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences
Yanka Kupala Grodno State University, Grodno, Belarus
Foreword
Modern therapeutics aims to design efficient targeting systems able to deliver a particular drug at the site of an injury while not affecting healthy tissue. Nowadays, the science of materials engineering allows the development of nano- and microscale elements able to specifically transfer potentially any drug to a given site and cure diseases. Progress made in the biomedical field led to the emergence of nanostructured drug delivery systems, which proved their utility in the therapy and diagnosis of difficult-to-treat diseases, such as cancer and infections. The design of such a magic bullet
of reduced sizes is a concept intensively investigated and expected to make a significant difference in future therapeutics.
This book is an impressive collection of up-to-date knowledge regarding the progress of drug delivery systems in nano- and microscale. Although approaching a very modern field, the book is composed in a concise and accessible manner and is clearly illustrated, so that a wide audience can benefit from its content.
The editor has mixed traditional information regarding the synthesis and characterization of nanobiomaterials designed for drug delivery with recently described technologies that allow obtaining improved nano- and microscale material for personalized medicine. Information regarding the most modern approaches in the production of nanosized drug delivery systems is conveyed with their main applications, properties, and perspectives in the management of severe diseases. Readers can discover here the perspectives to an improved drug delivery approach that is more specific, faster, and with reduced side effects. Also, both advantages and risks of modern nano- and microscale technologies applied in drug design are revealed and dissected in this work. With this information, the reader is encouraged to develop a realistic and extensive idea on the impact of delivery systems of very small size in the field of novel and personalized therapy.
The book is a useful tool of methods, techniques, and modern approaches in drug design by implementing nano- and microscale elements that may improve or even change the therapeutic effect of classical drugs. The most ambitious approaches rely on obtaining highly specific therapeutic alternatives to limit side effects of the drugs, which are most of the time responsible for altered results and sometimes, even for the failure of the therapy.
Alina M. Holban
University Politehnica of Bucharest, Bucharest, Romania
Monica C. Gestal
College of Veterinary Medicine, University of Georgia, Athens, GA, United States
Preface
In the past decade diagnosis and therapy have made impressive advances in terms of innovation and efficiency. This progress has led to the knowledge that we have to treat individual patients, not general diseases. Although numerous therapeutic approaches have emerged, the specific targeting of a particular health condition is still under investigation. The development of micro- and nanoscale materials has offered an important tool in the design of highly specialized systems for drug delivery and targeting. These minuscule warriors are able to specifically target the diseased tissue or even individual cells and to avoid injuring surrounding healthy tissue. Drug delivery systems in nanoscale are considered the best invention of the century, and their applications range widely, from cancer therapy to the targeting of severe infections. In this book, general approaches of the most recent innovations in the field of medical micro- and nanoscale materials are revealed. Also, this work brings together the most investigated applications and results of nanostructured drug delivery systems, exposing their advantages and risks while discussing future perspectives. The book contains 23 chapters, prepared by outstanding international researchers from Romania, Canada, South Africa, Serbia, Iran, Italy, India, Turkey, Brazil, Belarus, Poland, and Saudi Arabia.
Chapter 1, entitled Microscale Drug Delivery Systems: Current Perspectives and Novel Approaches,
prepared by Irina Negut et al., reviews recent progress in the design, fabrication, and characterization of microscale drug delivery devices in the form of microneedles and microparticles. Different forms of pharmaceutical substances (antibiotics, vaccines, antiinflammatory agents, and anticancer drugs for various forms of cancer) are linked with metals, ceramics, or biopolymers to form microsystems in order to be more effective in disease management than traditional procedures.
Kiruba Krishnaswamy and Valérie Orsat, in Chapter 2, entitled Sustainable Delivery Systems Through Green Nanotechnology,
present the progressive transition toward green nanotechnology and highlight the state of current regulatory rules and standardizations related to nanotechnology and nanostructures for delivery systems. Also, the authors focus on the development of nanostructures and synthesis of gold nanoparticles using green nanotechnology.
Chapter 3, prepared by Blessing A. Aderibigbe and Hembe E. Mukaya, entitled Polymer Therapeutics: Design, Application, and Pharmacokinetics,
focuses on the progress and up-to-date design, application, and pharmacokinetics of polymer therapeutics.
Lidija Matija et al., in Chapter 4, entitled Fibonacci Nanostructures for Novel Nanotherapeutical Approach,
present an investigation about a new type of nanomaterial, nanoharmonized substance (NHS), whose composition of matter follows a harmonized form (Fibonacci law: Φ/φ). Conducting its vibrations to water molecules in near surroundings could force biomolecules to recover its natural vibration mode.
Chapter 5, entitled Dendrimers and Dendrimers-Grafted Superparamagnetic Iron Oxide Nanoparticles: Synthesis, Characterization, Functionalization, and Biological Applications in Drug Delivery Systems,
prepared by Asghar Taheri-Kafrani et al., presents the developments made in dendrimer fabrication and dendrimers-based magnetic nanoparticles with varied surface structures and their contributions to theranostics.
Gerardo Caruso et al., in Chapter 6, entitled Nanotechnology and the New Frontiers of Drug Delivery in Cerebral Gliomas,
focus on the different types of nanoparticle compounds studied for the treatment of brain tumors. Also, the authors present various preclinical and/or clinical studies in brain tumor treatment.
Chapter 7, prepared by Gaurav Verma et al., entitled Nanoparticles: A Novel Approach to Target Tumors,
offers extensive ideas about materials, methods applied for the production of nanoparticles to target various diseases, and also how to deal with toxicity management in nanolaboratories.
Chapter 8, entitled Therapeutic Nanostructures for Dermal and Transdermal Drug Delivery,
prepared by Yousef Javadzadeh and Leila Azharshekoufeh Bahari, is a review of nanostructure systems (liposomes, transfersomes, ethosomes, niosomes, dendrimers, lipid and polymer nanoparticles, and nanoemulsions) used for drug delivery to dermal and transdermal targets. Their fabrication, advantages, and disadvantages are also discussed.
Charu Dwivedi et al., in Chapter 9, entitled Electrospun Nanofibrous Scaffold as a Potential Carrier of Antimicrobial Therapeutics for Diabetic Wound Healing and Tissue Regeneration,
give an up-to-date overview about recent developments in the fabrication of electrospun nanofibers for elimination of microbial infections from chronic wounds to accelerate wound healing.
Chapter 10, prepared by Ceyda T. Sengel-Turk et al., Nanosized Drug Carriers for Oral Delivery of Anticancer Compounds and the Place of the Chromatographic Techniques,
describes the importance of lipid- and polymer-based nanoscale drug delivery technologies of the anticancer molecules, and summarizes the effect and type of nanostructures, characterization parameters, analysis parameters, such as column types and mobile phase compositions, and validation parameters.
Madhu Gupta et al., in Chapter 11, entitled Promising Novel Nanopharmaceuticals for Improving Topical Antifungal Drug Delivery,
summarize emerging efforts for progression of nanoconstructs as a newer tool to overcome the challenges in treating cutaneous infectious disorders.
Chapter 12, prepared by Angela Scala et al., entitled Nanoconstructs Based on Cyclodextrins for Antimicrobial Applications,
gives an up-to-date overview about photo-independent/dependent strategies based on the use of cyclodextrin (CD) nanocarriers in delivering antibiotics/antibacterials, antivirals, antifungals, disinfectants, and antiseptics. Also, the authors present details about nanophototherapeutics based on CDs as antibacterials in photo-antimicrobial chemotherapy with their in vitro and/or in vivo applications.
Mojdeh Hakemi-Vala et al., in Chapter 13, entitled Nanoemulsions: A Novel Antimicrobial Delivery System,
give an overview of nanoemulsion systems with or without bioactive compounds with a wide range of applications. Furthermore, the latest developments in nanoemulsion delivery systems for food, drug, and cosmetic applications are presented in this chapter.
Chapter 14, entitled Nanodrug Delivery Systems for Dermal and Transdermal Photosensitizers Drugs,
prepared by Antonio C. Tedesco et al., provides a comprehensive overview of the different types of drug delivery systems, their main characteristics, mechanisms of action in skin penetration, some applications already in use, and future prospects of nanosystems for dermal and transdermal drug delivery.
Gunjan Jeswani and Swarnali D. Paul, in Chapter 15, entitled Recent Advances in the Delivery of Chemotherapeutic Agents,
describe recent drug delivery approaches such as targeted therapy including small molecule drugs, monoclonal antibodies, and cancer vaccines, which are explored to achieve tumor-directed release of active agents with minimal adverse effects. Newer strategies, such as chemoprevention (different types, clinical trial methods, and approved drugs) are also discussed.
Chapter 16, entitled Polyurethane Nanostructures for Drug Delivery Applications,
prepared by Krishna P. Rajan et al., gives a comprehensive review of therapeutic nanostructures of polyurethane (PU) for drug delivery applications. PU technology and its emergence in biomedical and pharmaceutical applications are briefly touched upon. Developments in the nanostructures of PU and recent developments in controlled drug delivery applications are described in detail.
Rashmin B. Patel et al., in Chapter 17, entitled Nanoemulsion as a Valuable Nanostructure Platform for Pharmaceutical Drug Delivery,
describe the prevalence of nanotechnology as the most promising platform for pharmaceutical drug delivery. This chapter highlights the basics of nanoemulsion, its fantastic characteristics, and its remarkable acceptance in pharmaceutical sector.
Chapter 18, entitled The Supramolecular Complex of Sertraline With Cyclodextrins: Physicochemical and Pharmacological Properties,
prepared by Vyacheslav Buko et al., describes and discusses how the pharmacological effect of sertraline can be improved, due to enhanced drug bioavailability.
Chapter 19, prepared by Biswajit Mukherjee et al., entitled Pharmacokinetic and Pharmacodynamic Modulations of Therapeutically Active Constituents From Orally Administered Nanocarriers Along With a Glimpse of Their Advantages and Limitations,
focuses on advancements in the oral delivery of drug nanocarriers, highlighting pharmacokinetic and pharmacodynamic modulations, their advantages along with fundamental limitations, and the future perspective based on recent findings in the field.
Marcos L. Bruschi et al., in Chapter 20, entitled Nanostructured Propolis as Therapeutic Systems With Antimicrobial Activity,
highlight the therapeutic potential of nanostructured systems containing propolis that may add safety and effectiveness in the antimicrobial arsenal.
Chapter 21, prepared by Parasuraman A. Subramani et al., entitled Nanostructures for Curcumin Delivery: Possibilities and Challenges,
reviews the potential antimicrobial activity of curcumin, its oral bioavailability challenges, and the efforts undertaken by researchers so far to overcome this problem. Also, the authors give important details about strategies required in future to make curcumin a marketable drug using current advances in nanotechnology.
Chapter 22, entitled Nanostructures for Improved Antimonial Therapy of Leishmaniasis,
prepared by Frédéric Frézard et al., covers the progress achieved toward pharmaceutically acceptable nanostructured formulations for the improved delivery of antimonial drugs. The most promising nanosystems comprise liposomes for visceral leishmaniasis and micelle-like nanostructures for the oral delivery of antimony.
Swati Pund and Amita Joshi, in Chapter 23, entitled Nanoarchitectures for Neglected Tropical Protozoal Diseases: Challenges and State of the Art,
focus on the biological and biopharmaceutical concerns in the design of nanodelivery systems of antiprotozoal drugs. The role of the various nanocarriers in overcoming the challenges for effective therapy of parasitic infections is emphasized with the help of state-of-the-art developments to date. Applications of phytonanocarriers for the treatment of neglected parasitic infections are also discussed.
Alexandru Mihai Grumezescu
University Politehnica of Bucharest, Bucharest, Romania
http://grumezescu.com/
Chapter 1
Microscale Drug Delivery Systems: Current Perspectives and Novel Approaches
Irina Negut*,**
Valentina Grumezescu*,†
Gabriela Dorcioman*
Gabriel Socol*
* National Institute for Lasers, Plasma and Radiation Physics, Magurele, Ilfov, Romania
** University of Bucharest, Magurele, Ilfov, Romania
† University Politehnica of Bucharest, Bucharest, Romania
Abstract
Drug delivery (DD), in general, represents a method of administering therapeutic complexes to biological systems. DD microstructures control and regulate various processes of liberation, absorption, dispersal, and elimination of biomedical entities. The routes by which drugs can be delivered or taken into the body are numerous. Conventionally, these administration routes include oral, transdermal, transmucosal, pulmonary, and intravenous injection. Subsequently, new therapeutic agents, such as peptides, proteins, and DNA-based therapeutics are prone to enzymatic decomposition; the paths of conventional administration may alter drugs in terms of treatment time duration and efficiency in targeting the area affected by the disease.
Keywords
drug delivery
microscale
microneedle
microparticle
microparticulate
polymerization
emulsion
Chapter Outline
1 Introduction
2 Microscale Drug Delivery Systems
2.1 Microneedles Drug Delivery Systems
2.2 Microparticulate Drug Delivery Systems
3 Conclusions
References
1. Introduction
Drug delivery (DD), in general, represents a method of administering therapeutic complexes to biological systems. DD microstructures control and regulate various processes of liberation, absorption, dispersal, and elimination of biomedical entities. The routes by which drugs can be delivered or taken into the body are numerous. Conventionally, these administration routes include oral, transdermal, transmucosal, pulmonary, and intravenous injection (Dollery et al., 1971). Subsequently, new therapeutic agents, such as peptides, proteins, and DNA-based therapeutics are prone to enzymatic decomposition; the paths of conventional administration may alter drugs in terms of treatment time duration and efficiency in targeting the area affected by the disease (Illum, 2003; Torchilin and Lukyanov, 2003).
This chapter outlines and discusses recent developments on microscale DD systems for cellular, tissue, and organism scales.
Progress on applying micro- and nanosystems for drug administration comprises an assorted collection of novel materials and methods. These novel methodologies embrace the current principles in DD, such as biodistribution and dosing efficacy coupled with innovative nanostructured smart
surfaces and materials (Lavan et al., 2003). Therapeutic drugs have advanced from single- to multiconstituent formulations, such as tablets, anisotropic particles, or microneedles. An ideal DD device must be both multifunctional and smart. DD vehicles must discharge drugs at specific anatomical sites at definite time periods and with negligible side effects. Polymeric DD transporters can link to cells or be fragmented by biochemical means.
New concepts of shape-shifting DD systems inspired by cells profile changes (Käpylä et al., 2016) and robotics (Alici, 2015) are now in different stages of progress, ranging from research curiosity to clinical interest. Shape modification suggests novel options for self-directed, environmentally receptive multistate functionality.
DD systems can be classified based on their shape into microneedles (MNs) and microparticles (MPs). The two categories will be further discussed in terms of fabrication procedures, types, and limitations.
2. Microscale Drug Delivery Systems
Miniaturization of a device can result in the creation of portable, transferable, or implantable devices, which are appropriate for DD uses. As a result of their sizes, microdevices usually require less than a microliter of drug for examination or other procedures. Another benefit is represented by the integration process of a microfabricated device with electronic components, which allows for enhanced device operation and control. This facilitates the advance of complex devices that can offer new and/or upgraded prevailing functions or processes.
Microfabricated devices that allow for the therapeutic delivery of agents with combined structural, mechanical, and possibly microelectronic features may overcome challenges connected with conventional DD systems.
2.1. Microneedles Drug Delivery Systems
Macromolecular drug supply through the skin is mostly facilitated by using hypodermic needles, which have more than a few shortcomings, such as unintended needle-sticks, discomfort, pain, and needle phobia. These unpleasant problems that patients face have led toward research advances for discovering substitute techniques for drug and vaccine delivery across the skin. Thus, the resulting engineered therapeutic microdelivery needles offer many clinical advantages. Furthermore, the benefit of a pain-free application makes microneedles ideal approaches for vaccination (McAllister et al., 2000).
MNs represent minimally invasive microscale needles that can be applied for transdermal vaccination, gene therapy, and DD (Reed and Lye, 2004). They are capable of delivering both low and high molecular weight substances into the systemic circulation by penetrating the stratum corneum, which is the main barrier for intradermal DD. Since the stratum corneum has no nerve endings, MNs with adequate dimensions do not excite nerves existing in the deeper tissue and have the possibility of making transdermal delivery, which is a painless and a more viable procedure. MNs have the possibility to relieve patients from multiple injections and to develop immunization (Trimmer et al., 1995).
2.1.1. Microneedles Fabrication Procedures
MNs are designed with needle groups and exhibit heights from approximately 25–2000 μm (Donnelly et al., 2010).
Up to now, MNs have been fabricated from a variety of materials, such as metals, polymers, glass, and ceramics with different tip shapes and tip intervals, being attached to a base support. Based on their designs and tip shapes, different types of MNs have been prepared. Numerous designs of MNs, such as spike, spear, square, cylindrical, and hexagonal have been reported (Ashraf et al., 2010a,b). Additionally, certain MNs can be applied to the skin as a roller (Doddaballapur, 2009; Doraiswamy et al., 2006).
Conventional MN fabrication techniques are centered on hot embossing (Oh et al., 2008), photolithography (Dardano et al., 2015), surface and laser micromachining (Chandrasekaran et al., 2003; Vinayakumar et al., 2016), micropipette pulling (Jiang et al., 2009), micromolding (Loizidou et al., 2016), lithography, electroplating, molding (LIGA) (Shewale and Bhole, 2015), laser beam patterning and ablation (Ita, 2015; Tu and Chung, 2015), ICP etching (Moon and Lee, 2005), deep reactive ion etching (DRIE) (Chen et al., 2010b). Thus, the resulted engineered therapeutic microdelivery needles offer many clinical advantages (McAllister et al., 2000).
2.1.2. Microneedles Classification
Based on their properties and depending on the delivery mechanism, MNs can be classified into four different categories: (1) solid MNs that puncture the skin to increase skin permeability (Hoang et al., 2015), (2) MNs coated with drugs or vaccines (Arya and Prausnitz, 2016; Ma et al., 2015; Uddin et al., 2015; Vrdoljak et al., 2012), (3) polymeric skin-solvable MNs that encapsulate drugs for rapid or controlled release (Sullivan et al., 2010), and (4) hollow MNs for drug injection (Liu et al., 2014; Matriano et al., 2002) (Fig. 1.1).
Figure 1.1 Mechanisms of different microneedles to deliver drugs.
(A) Solid microneedles; (B) coated microneedles; (C) dissolving microneedles; and (D) hollow microneedles.
2.1.2.1. Solid Microneedles
The basic requirements of solid MNs are mechanical strength achieved by selecting proper materials, tip geometry, and the applied force on the skin for drilling microholes. After the needle is removed from the site, a drug formulation then can be applied on the penetrated skin (Haq et al., 2009). The most used materials for manufacturing solid MNs are metals (Tawde et al., 2016; Vinayakumar et al., 2016), silicon (Vučen et al., 2013), polymers (Park et al., 2005), and ceramics (Olhero et al., 2016).
Hoang et al. used stainless steel microneedle rollers of 500 μm to assist the transdermal delivery of antiparkinson’s-disease-specific drugs, namely amantadine hydrochloride and pramipexole dihydrochloride. They conducted tests on the drug release rates and in vitro assessments across a porcine ear after the creation of microchannels (Hoang et al., 2015).
A novel motorized metal-based MN device for transdermal provision of plasmid DNA that encoded green fluorescent protein (EGFP) and firefly luciferase (pEGFP-Luc) was evaluated by Yan et al. The authors also took into account different approaches for the delivery of DNA into the skin. When compared with passive diffusion and intradermal injection methods, the motorized My-M microneedle device manufactured by Bomtech Electronics Co. turned out to be more effective than the other two methods in equivalent conditions. Their results showed that the average skin gene expression at a duration of 60 s was 3 times that of the other methods (Yan et al., 2014).
2.1.2.2. Coated Microneedles
By using coated MNs, the two-step application required for applying solid MNs can be avoided. Coated MNs are solid MNs encrusted with drug molecules or other formulations, and they can be applied directly to the desired area for instant DD, after which they can be removed (Andrianov et al., 2011). Coatings containing the drug of interest are usually applied to solid MNs using a variety of techniques: (1) layer-by-layer (van der Maaden et al., 2015), (2) dip coating (Kusamori et al., 2016), or (3) spraying. Viruses (Choi et al., 2015; Hiraishi et al., 2011; Kines et al., 2015), proteins (Witting et al., 2015), medicines (Ma et al., 2015), nanoparticles (Gill and Prausnitz, 2007a; Ma et al., 2015), DNA (Gill et al., 2010; Pearton et al., 2012; Saurer et al., 2010), and even analgesics (Zhang et al., 2012) can be glazed on MN surfaces.
Uddin et al. successfully inject-printed surfaces of solid stainless steel MNs with a copolymer and three anticancer drugs—5-fluororacil, curcumin, and cisplatin. Drug release rates were evaluated in vitro using diffusion cells. The results demonstrated that drug liberation rates were dependent on the drug–Soluplus polymer ratios as well as on the drug lipophilicity and porcine skin thickness (Uddin et al., 2015). Matriano et al. (2002) revealed that by coating Macroflux MN structures with ovalbumin, a 50-fold higher immune reaction was induced, compared with intramuscular administration of the same dosages (at 1 and 5 μg) into the skin of guinea pigs at an average depth of 100 μm.
Coated MNs have also been used for injury healing. Kim et al. used coated MNs to locally deliver the bevacizumab protein in the intrastromal space of the cornea in order to treat injury-induced neovascularization in eyes of New Zealand white rabbits. MNs of 400 μm length were covered with bevacizumab using a fast-dissolving preparation. The bevacizumab supply (∼1.1 μg single bolus) was compared to topical eyedrops and subconjunctival injection at different time intervals. These coated MNs proved to be more effective in suppressing neovascularization after suture-induced wounds at a much lower dosage (Kim et al., 2012a).
2.1.2.3. Dissolving Microneedles
Dissolving MNs are prepared from mixtures of complex materials combined with drugs that are progressively dissolved after insertion into the skin (Jiruedee et al., 2015; Ochoa et al., 2015). Consequently, the ejection of MNs from patients’ skin is not mandatory. An important class of materials appropriate to produce dissolving MNs includes dissolvable polymers like polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(l-lactic acid) (PLA) (Park et al., 2005). Unfortunately, these polymers are very expensive. Other materials, like silk (Jiruedee et al., 2015), sugars (e.g., maltose and sucrose) (Gill and Prausnitz, 2007b; Miyano et al., 2005), dextran, and carboxymethyl cellulose (CMC) (Kim et al., 2012c), have also been used to formulate these types of MNs. Dissolving MNs have bigger drug cargo capacity compared with coated MNs. The drug release kinetics depends on the MN constituents’ dissolution rates. Thus, the manufacturing of controllable DD is possible by adaptating the composition of MNs or by adjusting the MN fabrication processes (Donnelly et al., 2010). Dissolving MNs offer many advantages: low cost, good material performance, and facile fabrication process (Donnelly et al., 2012).
Dissolvable MNs have also been used for vaccination and/or immunization. Sullivan et al. introduced dissolvable polymeric MNs patches for influenza immunization. Disabled influenza viruses were entrapped in the polymeric MN’s body for insertion and dissolution into the skin. The MN’s drug-encapsulated matrix produced resilient antibody and cellular immune reactions in tested mice challenged with live homologous virus, even after 4 days. MNs immunization led to a safe lung virus clearance and enhanced cellular recall reactions compared with conventional intramuscular injection.
The results found in literature suggest that dissolving MNs patches are the new pillars for simpler vaccination with improved immunogenicity (Sullivan et al., 2010).
2.1.2.4. Hollow Microneedles
Hollow MNs used to inoculate a vaccine into the skin can further promote intensification in the vaccine bioavailability, since the whole amount of the drug ends up in the skin or body fluid sampling. Drug formulas are freed from MNs at the desired site by applying pressure or electrically driven flow. When short MNs are used, the probability of leaking onto the skin’s surface is expected to be significant (Bal et al., 2010). Hollow MNs ensure the supply of a specific treatment into the skin through the inoculation of a fluid preparation. These MNs are capable of dispensing larger amounts of drugs in contrast to solid, coated, and dissolving MNs (Roxhed et al., 2007). The most preferred materials for hollow MN fabrication are silicon (Zhang et al., 2009), metals (Chandrasekaran et al., 2003; Roxhed et al., 2007), glass (Martanto et al., 2006b), polymers (Sammoura et al., 2007), and ceramics (Ovsianikov et al., 2007).
Hollow MNs were effectively used to distribute drugs to different parts of the body, such as eyes (Patel et al., 2011) and skin (Lyon et al., 2014). For example, cylindrical hollow out-of-plane silicon MNs with pointed tips have been manufactured for the treatment of cardiovascular or hemodynamic disorders. The fabrication of silicon hollow MNs was based on a succession of isotropic and anisotropic etching processes, namely inductively coupled plasma-etching technologies. The flow rate through MNs was investigated in coupled field using multiple code connection methods (Ashraf et al., 2010a,b).
2.1.3. Limitations of Producing MNs
Although MNs have been proved to be operative and useful carriers for drugs and other curative substances into the skin, many problems still remain unknown and require efforts to be solved.
Solid MNs are mainly fabricated from silicon, which has raised various concerns about its biocompatibility (Braybrook, 1996). In the same time, solid, uncoated MNs involve a two-step application procedure, which is unattractive (Haq et al., 2009).
The coating of MNs could be limited only to tips, and covering materials could reduce the penetration of the skin. If the thickness and surface tension of the used material disturb the uniform coating of MNs, then the DD at the targeted area could be ineffective. The main limitation of coated MNs remains the coating capacity of assemblies’ surface area. For that reason, accurately coating of MN is still difficult to perform, and the obtained microneedle–drug complex can deliver only a very small amount (<1 mg) of medicine as a bolus (Coulman et al., 2011; Kim et al., 2012c).
Dissolving MNs are mainly formulated from biodegradable polymers, and their decomposition products after insertion into the skin have a potential issue for in vivo biocompatibility. The release kinetics of dissolving MNs are dependent on the internal structure of the polymer from which they are commonly composed. Some MNs construction processes involve high temperatures for polymer melting, which are critical for delicate compounds (e.g., proteins, nucleic acids). An additional concern is related to the fact that the filling of drugs could affect the needles’ mechanical performances (Kim et al., 2012b). Dissolving MNs prepared from sugars are fragile and easy to liquefy in moist environments (Miyano et al., 2005). Besides these, the combination of dissolving MNs with nanoparticulates could be an appropriate method to overcome intracellular barriers (Kumar et al., 2012; McCaffrey et al., 2015). As these types of MNs necessitate body areas that are easy to penetrate, their application is limited to arms, hands, and abdomen, and the duration of application is critical for the dissolving rate (Lee et al., 2011).
In case of hollow MNs, there is a risk of clogging needle tips with tissue due to the compressed dermal tissue surrounding MNs upon puncturing and the flow resistance (Gardeniers et al., 2003; Martanto et al., 2006a). This can be overcome by means of different designs able to detect the exposed bore at the side of the MN’s tip (Griss and Stemme, 2003). Another prospect is fractional needle retraction subsequent to insertion, which can improve fluid relaxation of the tissue around the tip (Wang et al., 2006).
2.2. Microparticulate Drug Delivery Systems
There are many procedures for supplying an active substance to a target site in an unrelenting controlled release approach. For in vivo uses, smart carriers (Lavan et al., 2003) capable of delivery and release of correct drug doses to unhealthy tissues have attracted significant attention in the research community. These smart carrier complexes can be categorized into (1) microparticles (Siepmann and Siepmann, 2006), (2) biocapsules (Desai et al., 1998; Leoni and Desai, 2004; Tao and Desai, 2003), and (3) nanoparticles (Singh and Lillard, 2009).
Microparticulate systems are capable of providing sustained and controlled DD for long time periods. They are small solid particles or liquid droplets having diameters of 0.1–200 μm, fenced with barriers of natural and/or synthetic polymer thin films of variable thickness (Collnot et al., 2012; Vasir et al., 2003; Wise, 2000).
2.2.1. Methods for Microparticles Preparation
When preparing controlled release MPs, the choice of the optimum technique has crucial importance for the efficient entrapment of drugs.
Depending on the preparation method, the drug is entrapped, dissolved, and/or encapsulated into MPs’ environment. These structures are considered trustworthy means for the delivery and sustaining of desired drug concentrations to specific targets without inconvenient effects. Hydrophilic or lipophilic drugs can accommodate only a selection of MPs and are dependent on unhealthy conditions as well (Padalkar et al., 2011). A variety of highly potent drug complexes for sustained and controlled release have been microencapsulated and transported, as shown in Table 1.1. The material used for the halo can be chosen from a wide range of polymers with respect with the material to be entrapped and the desired features (Chen et al., 2010a; Wu et al., 2013).
Table 1.1
Exemplification From Literature of Microparticle Drug Delivery Systems
In addition, MPs embrace a diversity of prospects like defense, screening of delicate complexes prior to and after administration, and spatial aiming of components, while enabling specific transport of small amounts of active drugs (Madhav and Kala, 2011).
There are various techniques applied for the preparation of MPs, as described next.
2.2.1.1. Spray Drying
Spray drying involves the dispersing of an insoluble core material in a coating solution. The obtained matrix is then atomized in an air stream, causing the solvent to be eliminated from the coating solution and resulting in the microcapsule formation. MP sizes are dependent on atomizing conditions. The main drawback of this technique is the loss of significant quantities of products, caused by the highly adherence of MPs to inner walls of the spray-dryer (Jalil and Nixon, 1992).
2.2.1.2. Phase Separation
The phase separation method involves a stage separation of a polymer by adding an organic nonsolvent under uninterrupted stirring for solidification of the polymer. Drug particles are first distributed or dissolved in the polymeric solution, and, by adding to the matrix of a newer polymer, the first phase separates and encapsulates the drug. The features of obtained MPs are determined by the molecular weight of the polymer and viscosity of the nonsolvent; the polymer determines the particles’ sizes and their distribution (Dowding et al., 2005; Mallardé et al., 2003).
2.2.1.3. Polymerization
Polymerization methods generally used for the preparation of MPs include bulk, emulsion, suspension, and interfacial polymerization. In the case of the bulk polymerization technique, one or more monomers are heated to induce polymerization in the presence of a catalyst. The obtained polymer can be prepared and/or fragmented to become microspheres, and drug surrounding may occur during the polymerization process (Surini et al., 2009). The suspension polymerization is similar to the bulk one, but the polymerization process occurs at lower temperatures. Drugs are found in the form of droplets distributed in an aqueous phase. Emulsion polymerization is characterized by the use of an aqueous phase catalyst, which diffuses to the surface of MPs. Interfacial polymerization occurs in the presence of two monomers, one oil-soluble and the other water-soluble, dissolved and dispersed separately. A thin polymeric film is created at the interface between the two solutions (Whateley, 1996).
2.2.1.4. Single Emulsion
In the single-emulsion procedure, the drug is dissolved in an aqueous dispersed phase before being released into an oil continuous phase. Consequently, a sole emulsion is created, which will be stabilized by means of heat or by the addition of ligand agents. This process is frequently applied for the encapsulation of lipophilic drugs (Rosca et al., 2004).
2.2.1.5. Double Emulsion
The double-emulsion or multiple-emulsion procedure is mostly used for integrating hydrophilic drugs, proteins, enzymes, vaccines, vitamins, and other macromolecular elements. This method is suitable for both natural and synthetic polymers. In this technique, polymers are dissolved in an organic solvent and emulsified into an aqueous phase to form a water-in-oil emulsion. As a result, two emulsions are made. The primary emulsion is subjected to homogenization and dropped into an aqueous solution. The organic phase represents a barrier between the aqueous parts, avoiding the dispersion of active materials to the external aqueous phase (Baena-Aristizábal et al., 2016; Ramazani et al., 2016).
2.2.2. Microparticle Types
These systems are distinctive in terms of their sizes and materials from which they are constructed. MPs can be supplementary, classified into two subcategories: microcapsules and microspheres (Komatsu et al., 1983). Regardless of these subgroups, the literature uses these terms interchangeably. Microcapsules apply to microparticulate reservoir systems composed of a solid, liquid, or gaseous core encircled by a material that is different from that of the core (Arshady, 1991). Microspheres are typically free-flowing precipitates consisting of proteins and biocompatible and biodegradable polymers with diameters in the range of 1–200 μm (Collnot et al., 2012). Thus, depending on the material from which they are composed and their functionality, MPs can be classified as the following types.
2.2.2.1. Bioadhesive Microparticles
Bioadhesion can be defined as the capability of a synthetic or biological macromolecule to bind to biological tissues (e.g., buccal, nasal, ocular, transdermal, and rectal) for extended time periods. This capability contributes to an adjacent and sustained connection at the site of administration, resulting in an amplified controlled and absorption drug release, and reducing the frequency of administration (Ahuja et al., 1997; Roy and Prabhakar, 2010; Tao and Desai, 2003). Deutel et al. developed novel efficient MPs for the systemic circulation of insulin via the nasal route. The resulting microsized particles of poly(vinyl pyrrolidone) (PVP), poly(acrylic acid) (PAA), or poly(acrylic acid)-cysteine (PAA-Cys)-insulin loaded were physicochemically and morphologically tested. The insulin release and the effect on ciliary beat frequency was evaluated in vitro on human nasal epithelial cells (Deutel et al., 2016).
2.2.2.2. Magnetic Microparticles
Owing to their sizes, magnetic MPs can travel through capillaries without causing embolic constriction. Their ferromagnetic properties allow them to be captured and dragged in microvessels or into tissues by magnetic fields (Chopra and Singla, 1994). Such MPs usually comprise an iron oxide core surrounded by a polymeric covering layer (Pamme and Manz, 2004). These magnetic microcarriers are regularly used for therapeutic and diagnostic purposes in many medical applications (Driscoll et al., 1984; Liu et al., 2015; Pouponneau et al., 2011; Pulfer and Gallo, 1998; Rudge et al., 2000; Zhu et al., 2015). Medicines, proteins, and even peptides can be also targeted by these microstructures (Kakar et al., 2013). They can also be used for metastases imaging and to distinguish other abnormal biological structures (Kim et al., 2016). Applying an externally magnetic field, one can direct these magnetic DD particles to a specific body site (Qiu et al., 2016). A typical magnetic microparticle equipped with necessary agents in DD is represented in Fig. 1.2.
Figure 1.2 Schematic of a typical functionalized magnetic microparticle.
Using particular experimental systems, a range of magnetic encapsulated MPs for the delivery of different drugs has been produced. Wang et al. reported the fabrication of magnetic microplatforms for the simultaneous delivery of dual-anticancer drugs, doxorubicin (DOX) and curcumin (Cur). These microspheres demonstrated that the saturated magnetization was of ∼27.9 emu/g (Wang et al., 2016).
In another study, Grumezescu et al. prepared by a precipitation method magnetic hollow silica microspheres for antibiotic delivery and/or controlled release. Three antibiotics, penicillin, amoxicillin and norfloxacin (Fluka) were tested against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 reference bacterial strains. The antimicrobial susceptibility assay on the S. aureus strain to penicillin and norfloxacin in solution compared with microspheres that were antibiotic loaded showed an improvement of the bactericidal activity when the hollow silica DD system was used. In contrast, no enhancement of the antimicrobial efficiency was observed on E. coli (Grumezescu et al., 2013).
Chifiriuc et al. shaped by chemical precipitation multifunctional magnetic chitosan microspheres for the delivery of second-, third-, and fourth-generation cephalosporins. The integration of cephalosporins in chitosan considerably improved the antimicrobial action of antibiotics, as confirmed by the diminution of the minimal inhibitory concentration from 2 to 7.8 times, both on E. coli and on S. aureus strains. In addition, the obtained microspheres proved to be biocompatible. Their results validated the prospect of integrating commonly used antibiotics in active forms into chitosan arrays (Chifiriuc et al., 2012).
An innovative approach to overcome the resistance of individuals to biofilm-associated microbial infections was proposed by Grumezescu et al. The authors manufactured by laser means a novel surface coated with magnetite-eugenol and (3-hidroxybutyric acid-co-3-hidroxyvaleric acid)–polyvinyl alcohol microspheres [P(3HB-3HV)–PVA–Fe3O4@E microspheres]. The composite microspheres were prepared by a solvent evaporation. A suspension of 1% (weight/volume) P(3HB-3HV)–PVA–Fe3O4@E microspheres in dimethyl sulfoxide was frozen in liquid nitrogen and then used as a target for laser depositions on different substrates. In an in vitro study monitored for 24, 48, and 72 h of incubation, the viability of endothelial cells on the coated surfaces was maintained. Moreover, fluorescence imaging analysis confirmed the viability of endothelial cells even after 5 days. The antimicrobial biofilm assay exposed a great antimicrobial efficacy of the coatings against S. aureus and P. aeruginosa (Grumezescu et al., 2014).
2.2.2.3. Polymeric Microparticles
The polymers used in controlled MP drug release structures could be biodegradable or nonbiodegradable.
Biodegradable polymers have the ability to be reabsorbed within the body as an effect of in vivo biological processes and to produce biocompatible or nontoxic products. Therefore, the need to remove a DD system can be avoided after the release of the active agent (Arshady, 1991; Jeong and Kim, 1986; Nair and Laurencin, 2007; Ramazani et al., 2016). Biodegradable polymers can intensify the residence time when in connection with mucous membrane due to their degree of swelling with aqueous medium, subsequent with gel creation.
Chitosan is a commonly used biopolymer for MPs formulation (Gelfuso et al., 2011; Ko et al., 2002; Sonia and Sharma, 2011). The particle sizes of some chitosan MPs cross-linked with tripolyphosphate were found to be in the range of 500–710 μm (Ko et al., 2002). Other natural polymers, such as gelatine (Phromsopha and Baimark, 2014), albumin (Aganyants et al., 2016), and collagen (Jiménez et al., 2015) were also used for the preparation of MPs.
Innumerable intramuscular or subcutaneous controlled DD delivery microdevices in forms of MPs have been advanced using biodegradable polyesters like poly(lactic acid) (PLA) (Tyler et al., 2016) and poly(lactide-co-glycolide) (PLGA) (Jiang et al., 2005).
PLGA is the most used polymer for developing microparticulate DD systems (Singh et al., 2004). Owing to the hydrophobicity expressed by PLGA, hydrophilic drugs can be captured in the hydrophilic core of these MPs while hydrophobic drugs are disposed to dispense in the hydrophobic shell (Kakizawa et al., 2010; Ramazani et al., 2016). Each MP represents a matrix of drug distributed in the polymer from which discharge happens by a first-order process (Ramazani et al., 2016).
Other materials of interest that are very often used in the pharmacology domain are nondegradable polymeric MPs. Their properties recommend them as embolic particles (Laurent, 2007), DD vehicles (Varde and Pack, 2004), and fillers and bulking agents (Broder and Cohen, 2006; Kusin and Lippitz, 2009), and they have proved to be biocompatible and durable during in vivo applications. These nondegradable polymers for creating proper DD microscale systems include polyurethanes (Iskakov et al., 2016) and poly(methyl methacrylate) (PMMA) (Ferreira et al., 2015), polystyrene (Tamilvanan and Sa, 2000), and poly(vinyl alcohol) (Singh et al., 2016).
2.2.2.4. Floating Microparticles
Floating microspheres are, in a strict sense, empty sphere-shaped particles deprived of a core (Mukund et al., 2012). The terminologies used for defining floating MPs can denote hollow microspheres (Huang et al., 2016), microballoons (Choudhary et al., 2016), or floating microspheres (Zhang et al., 2016). Floating MPs are mostly used as gastroabsorbent DD systems concentrated on a noneffervescent approach (Arora et al., 2005).
When floating MPs are in connection with the gastric fluid, the composition materials (i.e., polysaccharides and polymers) begin to hydrate. After the hydration process, a colloidal gel is created and acts as a screen that controls the degree of fluid infiltration into the MPs and the drug release. The air confined in swollen polymers together with a minimal gastric content confers buoyancy to MPs, allowing them to remain in the stomach for prolonged time periods (Mukund et al., 2012).
Colon-specific diclofenac sodium DD vehicles were prepared by Dang et al. by using a solvent evaporation method. The pH-responsive matrix-type MPs formulated with synthetic polymers—ethyl cellulose (EC), cellulose acetate phthalate (CAP), and Eudragit L 100—were assessed for drug content, particle size, bulk density, and angle of repose. The in vitro drug release studies of microspheres having a diclofenac sodium:EC:CAP ratio of 1:2:1 indicate good flow properties and highest drug content and release for treating colorectal cancer (Dang et al., 2015). Floating MPs can achieve an encapsulation efficiency of up to 100% by changing constituents ratios or polymer amounts (Streubel et al., 2002).
2.2.3. Limitations
The shortcomings of existing MPs are that they entail composite fabrication techniques or combinations of techniques (Dowding et al., 2005; Jalil and Nixon, 1992; Ramazani et al., 2016; Rosca et al., 2004; Surini et al., 2009) and use numerous components (Grumezescu et al., 2013).
Polymeric MPs have the tendency to travel away from inoculation sites, leading to embolism and further to organ damage. Other problems encountered in the use of polymeric MPs are complex drug charging efficiency, medication discharge control, and variability of dose liberation and stability evaluation (Lee et al., 2010; Nguyen et al., 2015; Tran et al., 2011).
Magnetic targeting is expensive and has the need of a dedicated fabrication and quality control system together with a magnet for directing, systems for monitoring, and a qualified staff to execute the procedure. In order to prevent local overdosing with drugs, magnets must have constant gradients. Another limitation is that a large proportion of the magnetic substance, which was entrapped in the DD transporter, is agglomerated permanently in targeted tissues (Patil et al., 2016).
3. Conclusions
Despite the development of micro- and nanotechnologies and their involvement in people’s lives, their health remains the most important domain where the efforts and determination of specialists must be as perpetuum mobile.
Maintaining the population in a healthy status or alleviating various diseases became the primary concern of many interdisciplinary research teams consisting of biologists, medical doctors, pharmacists, chemists, physicists, and even specialists in materials science. In this respect, during the past decades a lot of attention has been paid to the research related to the production of drugs, injections, and vaccines. Nowadays, there is a strong demand concerning these types of medical treatment procedures: to be able to counteract various diseases and ailments considering targeted administration and controlled delivery of active medical substances, to minimize pain and discomfort, to be efficient in order to decrease the duration of treatment, and to be cost-effective.
This work is an overview about the two types of DD systems at the microscale level: microneedles and microparticulates. It is obvious that the research conducted for development of new and specified DD systems is permanently updated. Different classes of active medical substances (antibiotics, vaccines, antiinflammatory agents, drugs for various forms of cancers) are combined with metals, ceramics, or biopolymers in microstructures systems with the declared role to be more efficient in disease treatment than are classical procedures. Depending on the disease and on the locale of the affected area, DD systems could be concentrated on simple particles or on smart particles and devices with programmable functions. For example, DD systems based on microspheres were greatly studied both for long-duration release and for targeting of anticancer drugs direct to the tumor. Also, microspheres have the potential to be used for diseased cell sorting, diagnostics establishment, gene and genetic materials recognition, and more applications.
Among the DD microstructures, MNs have proven their availability and suitability for minimally invasive uses in transdermal vaccination, gene therapy, and DD.
In conclusion, further developments regarding the shape and dimensions of microstructures, the physicochemical properties, biological behavior, and in vivo testing are mandatory in order to find viable solutions to many medical problems.
Acknowledgment
The work has been funded by the Romanian National Authority for Scientific Research, CNCS-UEFISCDI, project number PN-II-RU-TE-2014-4-1590 TE 188/2015.
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