Nanopharmaceutical Advanced Delivery Systems E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
The book provides a single volume covering detailed descriptions about various delivery systems, their principles and how these are put in use for the treatment of multiple diseases. It is divided into four sections where the first section deals with the introduction and importance of novel drug delivery system. The second section deals with the most advanced drug delivery systems like microbubbles, dendrimers, lipid-based nanoparticles, nanofibers, microemulsions etc., describing the major principles and techniques of the preparations of the drug delivery systems. The third section elaborates on the treatments of diverse diseases like cancer, topical diseases, tuberculosis etc. The fourth and final section provides a brief informative description about the regulatory aspects of novel drug delivery system that is followed in various countries.
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Seitenzahl: 896
Veröffentlichungsjahr: 2020
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Table of Contents
Cover
Title page
Copyright
Preface
Part 1: INTRODUCTION TO THE FUNDAMENTALS
1 Lipid-Based Nanocarriers as Drug Delivery System and Its Applications
List of Abbreviation
1.1 Introduction
1.2 An Overview on Nanocarriers
1.3 Types of Nanocarriers
1.4 Methods of Preparation of Lipid Nanocarriers
1.5 Challenges and Hurdles
1.6 Characterization Techniques for Lipid Nanocarriers
1.7 Application of Lipid-Based Nanocarriers
1.8 Conclusion
References
2 Nanoparticulate Carriers—Versatile Delivery Systems
List of Abbreviations
2.1 Introduction
2.2 Classification of Nanoparticulate Carriers
2.3 Various Applications of Nanoparticulate Carriers
2.4 Modes of Transport of Nanoparticulate Carriers
2.5 Conclusion
References
3 Nanotools in Customized Drug Delivery System
List of Abbreviations
3.1 Introduction
3.2 Concept of Personalized Medicines
3.3 Customized Nanotools and Their Benefits
3.4 Applications of Nanotechnology in Personalized Medicine
3.5 Future Perceptions
3.6 Conclusion
References
Part 2: NOVEL AND MODERNIZED NANOSCALE DELIVERY SYSTEMS: REVOLUTIONARY PROGRESS IN THE FIELD OF PHARMACY
4 Dendrimers: Role in Novel Drug Delivery
List of Abbreviations
4.1 Introduction
4.2 Components of Dendrimers
4.3 Synthesis of Dendrimers
4.4 Classification of Dendrimers
4.5 Properties of Dendrimers
4.6 Mechanism of Drug Entrapment in Dendrimers
4.7 Dendrimers as Delivery Agents
4.8 Conclusion
References
5 Nanofibers in Drug Delivery
List of Abbreviations
5.1 Introduction
5.2 Nanofiber as Oral Drug Delivery System
5.3 Nanofiber as Topical Drug Delivery System
5.4 Nanofiber as Parenteral Drug Delivery System
5.5 Nanofiber as Multimodal Drug Delivery System
5.6 Challenges and Future Perspective
5.7 Conclusion
References
6 Microbubbles used for Drug Delivery System
List of Abbreviations
6.1 Introduction
6.2 Structural Components of Microbubble
6.3 Methods of Preparation Microbubbles
6.4 Acoustic Nature of Microbubble
6.5 Characterizations of Microbubbles
6.6 Applications of Microbubbles
6.7 Conclusions and Future Prospective
References
7 Virosomes: A Viral Envelope System Having a Promising Application in Vaccination and Drug Delivery System
List of Abbreviations
7.1 Introduction
7.2 What are Virosomes?
7.3 Comparison of Virosomes With Liposomes
7.4 Methods of Preparation of Virosomes
7.5 Characterization of Virosomes
7.6 Applications of Virosomal Technology
7.7 Conclusion
References
8 Nanocarriers: A Tool for Effective Gene Delivery
List of Abbreviations
8.1 Introduction
8.2 Key Steps in Gene Delivery
8.3 Success and Existing Challenges for Gene Delivery
8.4
In Vitro
and
In Vivo
Barriers Towards Successful Gene Transfer
8.5 Genetic Material That can be Delivered in Gene Therapy
8.6 Role of Nanocarriers in a Nucleic Acid Delivery
8.7 Nanocarriers used for Delivering Gene
8.8 Cellular Uptake of Nanocarriers and Their Fate Inside the Cell
8.9 Physicochemical Properties of Nanoparticles Affecting Their Uptake
8.10 Targeted Delivery of Genes Using Nanocarriers
8.11 Virosomes
8.12 Exosomes
8.13 Diseases Cured by Gene Therapy
8.14 Clinical Trials
8.15 Current Trends and Approved Products
8.16 Concluding Remarks
References
9 Phytosomes—Nanoarchitectures’ Promising Clinical Applications and Therapeutics
List of Abbreviations
9.1 Introduction
9.2 Structure of Phytosomes
9.3 Components of Phytosomes
9.4 Synthesis of Phytosomes
9.5 Characterization of Phytosomes
9.6 Absorption Mechanism of Phytosomes
9.7 Applications of Phytosomes
9.8 Recent Trends and Advancements in Phytosomal Delivery
9.9 Future Perspectives
9.10 Conclusion
References
10 Saponin Stabilized Emulsion as Sustainable Drug Delivery System: Current Status and Future Prospects
List of Abbreviations
10.1 Introduction
10.2 Saponins as Surfactant
10.3 Pharmaceutical Advantages
10.4 Conclusion and Future Prospects
References
11 Mono and Multi-Stimuli Responsive Polymers: Application as Intelligent Nano-Drug Delivery Systems
List of Abbreviations
11.1 Introduction
11.2 Smart or Stimuli-Responsive Polymers for Drug Delivery
11.3 Dual and Multi-Stimuli Responsive Drug Delivery Systems
11.4 Conclusion
References
12 An Insight into Nanosomes: Potential Nanopharmaceutical Delivery System
List of Abbreviations
12.1 Introduction
12.2 General Methods of Preparation of Nanosomes and Drug Loading
12.3 Trafficking Mechanism in the Body
12.4 Sterilization of Nanosomes
12.5 Evaluation Parameters
12.6 Applications
12.7 Conclusion
References
13 Nano-Structures as Bioelectronics for Controlled Drug Delivery
List of Abbreviations
13.1 Introduction
13.2 Electroactive Biopolymer
13.3 Electrochemical Desorption From Micro and Nanostructures of Conductive Polymers
13.4 Electrochemical Desorption From Micro and Nano-Composites of Conductive Polymers
13.5 Electrochemical Desorption of Self-Assembled Monolayer From a Gold Surface
13.6 Electrochemically Actuated Release of Biochemicals
13.7 Biochemical Release Controlled by Electrochemical Erosion of Electrolyte Hydrogel and Nanofilm
13.8 Biochemical Release by Electrochemical and Electrothermal Erosion of Metallic Sealing Membranes
13.9 Release of Biochemicals by Fluidic Nano-Pumps and Rotating Nano-Motors Powered by Electric Fields
13.10 Conclusion and Future Aspects
References
14 Bioadhesive Nanoparticulate Drug Delivery System
List of Abbreviations
14.1 Introduction
14.2 Mucous Membrane
14.3 Mucoadhesive Forces
14.4 Theories of Mucoadhesion
14.5 Mechanism of Mucoadhesion
14.6 Polymers Used to Prepare Mucoadhesive Nanoparticles
14.7 Ideal Properties of Mucoadhesive Polymers
14.8 Mucoadhesion of Nanoparticles
14.9 Preparation Methods of Mucoadhesive Polymeric Nanoparticles
14.10 Evaluation of Mucoadhesive Systems
14.11 Evaluation Tests of Mucoadhesive Nanoparticulate Systems
14.12 Applications
14.13 Conclusion
References
Part 3: UNDERSTANDING TARGETED DELIVERY SYSTEMS
15 Nanopharmaceuticals: An Approach for Effective Management of Breast Cancer
List of Abbreviations
15.1 Introduction
15.2 Stages of Breast Cancer
15.3 Main Types of Breast Cancer
15.4 Drawbacks in Conventional Treatment
15.5 Nanoparticulate Approach for Effective Management of Breast Cancer
15.6 Systematic Drug Delivery System Approaches
15.7 Nanoparticles Targeted Drug Delivery
15.8 Various Ligands used for Targeting Cancer Cells
15.9 New Innovative Pharmaceutical Entities and Targeting Moieties
15.10 Future of Cancer Treatment in Nanotechnology
15.11 Conclusion
References
16 Vaginal Nano-Based Drug Delivery System
List of Abbreviations
16.1 Introduction
16.2 Vaginal Anatomy Physiology and Diseases of Vagina
16.3 Advantages of Vaginal Drug Delivery
16.4 Drawbacks of Conventional Vaginal Formulation
16.5 Need of Nanocarriers for Vaginal Delivery
16.6 Different Types of Nanoparticles for Vaginal Therapy
16.7 Vaginal Patents
16.8 Nanotoxicity: Future Prospective
16.9 Conclusion
References
17 Recent Advances in Polymer-Modified Liposomes for Cancer Treatment
List of Abbreviations
17.1 Introduction
17.2 Liposomes
17.3 Future Challenges Associated With Cancer Therapy
17.4 Conclusion
References
18 Role of Nanomedicines in Neglected Tropical Diseases
List of Abbreviations
18.1 Introduction
18.2 Diseases
18.3 Conclusion
Acknowledgement
References
Part 4: OVERVIEW OF REGULATORY AFFAIRS
19 Current Framework, Ethical Consideration and Future Challenges of Regulatory Approach for Nano-Based Products
List of Abbreviations
19.1 Introduction
19.2 Issues in Aspect of Regulation of Drug Delivery System
19.3 Regulation of Nano-Based Products in Global Realms of the World
19.4 Regulatory Challenges and Solutions in DDS Development
19.5 Regulatory Education and its Involvement in Pharmaceutical Industry for the Development of Novel Drug Delivery Systems
19.6 Current Framework and Future Challenges
19.7 Conclusion
References
Index
End User License Agreement
List of Illustrations
Chapter 1
Figure 1.1 Types of liposomes. (a) Unilamellar vesicle, (b) multilamellar vesicl...
Figure 1.2 A graphical representation of solid lipid nanoparticle.
Figure 1.3 Type of the nanostructured lipid carrier.
Chapter 2
Figure 2.1 Diagrammatic representation of various nanoparticulate carriers: (a) ...
Figure 2.2a Mechanism of transport of nanocarriers across various biological bar...
Figure 2.2b Mechanism of drug delivery in tuberculosis. (i) Delivery of nanopart...
Chapter 3
Figure 3.1 Basic personalized drug delivery approach.
Figure 3.2 Response rates of patients to a major drug for a selected group of th...
Figure 3.3 Basic structure of liposomes.
Figure 3.4 Solid lipid nanoparticles (SLNs).
Figure 3.5 Carbon nanotubes.
Figure 3.6 Polymer-based nanoparticles.
Figure 3.7 Polymer-based micelle formation.
Figure 3.8 Dendrimers.
Figure 3.9 PEG coated gold nanospheres.
Figure 3.10 Nanodiamond particles with surface functional groups.
Chapter 4
Figure 4.1 Structure of dendrimers.
Figure 4.2 Mechanism of cancer targeting via dendrimers.
Chapter 5
Figure 5.1 Advances in electrospinning process to accommodate industrial hurdles...
Figure 5.2 Nanofiber successful applications for different modes of administrati...
Chapter 6
Figure 6.1 A. Floating tablet. B. Swelling dosages form. C. Sedimentation in the...
Figure 6.2 Different coating materials for microbubble preparations. (a) Protein...
Figure 6.3 Preparation of microbubble by sonication technique.
Figure 6.4 Preparation of micro-bubbles by cross-linked polymer technique.
Figure 6.5 Preparation of microbubbles by emulsion solvent evaporation technique...
Figure 6.6 Preparation of microbubbles by atomization and reconstitution techniq...
Figure 6.7 Shows behavior of polymer-coated microbubble under the influence of d...
Chapter 7
Figure 7.1 Structure of virosome.
Figure 7.2 Class I MHC and class II MHC virosomal antigen processing and present...
Figure 7.3 Mechansim of action of virosomes as adjuvants and virosomes complexed...
Figure 7.4 Virosomes for cancer immunotherapy.
Chapter 8
Figure 8.1 Mechanism of targeted gene delivery by nanocarriers.
Figure 8.2 Common diseases for which gene transfer trials are approved.
Chapter 9
Figure 9.1 Structural differences between Liposome and Phytosome.
Figure 9.2 Chemical Structure of some polyphenols—(a) ECGC, (b) Hesperidin, (c) ...
Figure 9.3 Schematic representation of synthesis of Phytomes.
Figure 9.4 Mechanism of absorption of drug–phospholipid complex.
Chapter 10
Figure 10.1 A representative oleanane saponin highlighting hydrophilic and lipop...
Figure 10.2 A representative orientation of saponins in the form of a micelle in...
Figure 10.3a Structure of selected saponins reported from Q. saponaria.
Figure 10.3b Structure of a saponin reported from Q. saponaria displaying a fatt...
Figure 10.4 Structure of selected saponins reported from S. mukorossi.
Figure 10.5 Structure of glycyrrhizic acid.
Figure 10.6 Structures of the aglycone present in different ginsenoside (R, R
1
, ...
Figure 10.7 Structures of the aglycone (R
1
–R
6
different sugar and other group at...
Figure 10.8 Structure of selected saponins reported from A. hippocastanum.
Figure 10.9 Structures of the aglycone spirostane and furostane (R
1
–R
4
different...
Figure 10.10 Structure of selected saponins reported from V. nigrum.
Figure 10.11 Structure of a saponin reported from S. officinalis.
Chapter 11
Figure 11.1 The pH-responsive swelling behavior of anionic and cationic hydrogel...
Figure 11.2 Representation of LCST and UCST concepts of temperature responsive p...
Figure 11.3 Representation of role of dual and multi-responsive polymeric nanopa...
Figure 11.4 An overview of site specific drug delivery from thermo and pH dual r...
Chapter 12
Figure 12.1 Diagrammatic representation of nanosomes.
Figure 12.2 Stages of delivery of nanosomes at various levels.
Chapter 13
Figure 13.1 Schematic representation of signal conduction through neuron. 1. Pre...
Figure 13.2 Schematic representation of band gap or energy gaps in insulator, se...
Figure 13.3 Schematic representation of conjugated chain of an intrinsically con...
Figure 13.4 Schematic representation of strategy for controlled release of macro...
Figure 13.5 Electrically stimulated controlled delivery of ATP from Nano Storage...
Figure 13.6 Schematic representation of electronically stimulated drug release f...
Figure 13.7 Schematic representation of electrochemical desorption of self-assem...
Figure 13.8 Schematic representation of a microchip.
Figure 13.9 Schematic representation of a nanopump showing sandwich assembly and...
Figure 13.10 Schematic representation of nanomotor.
Chapter 14
Figure 14.1 Representation of mechanism of mucoadhesion.
Figure 14.2 Mucoadhesive behavior of colloidal particulate systems following ora...
Figure 14.3 Nanoprecipitation method for nanoparticle preparation.
Figure 14.4 Scheme of emulsion polymerization.
Figure 14.5 Methods used for the evaluation of different properties of mucoadhes...
Figure 14.6 Falling liquid film method to measure mucoadhesion.
Figure 14.7 Atomic force microscopy force–distance curve.
Chapter 15
Figure 15.1 Multistep carcinogenesis [73].
Figure 15.2 Different types of nanosystems with their benefits [71].
Figure 15.3 Conventional chemotherapy versus targeted chemotherapy. Black color ...
Figure 15.4 Various methods used for active and passive targeting brain metastas...
Figure 15.5 Summary of various aptamer applications [75].
Figure 15.6 Schematic diagram of aptamer conformational recognition of targets t...
Chapter 16
Figure 16.1 Vaginal anatomy and physiology.
Figure 16.2 Advantages of vaginal delivery.
Figure 16.3 Comparison of convention vaginal formulation and nano-based vaginal ...
Figure 16.4 Vaginal formulation consideration.
Figure 16.5 Different types of nanoparticles for vaginal delivery.
Chapter 17
Figure 17.1 Diagrammatic representation of liposome structure.
Figure 17.2 Schematic representation of active loading of a drug into liposome.
Figure 17.3 Diagrammatic representation of passive loading of a drug into liposo...
Figure 17.4 Liposome mediated active targeting of cancer cells.
Figure 17.5 Liposome mediated passive targeting of cancer cells.
Chapter 19
Figure 19.1 Sub disciplines of nanomedicines. The red circles indicate five majo...
Figure 19.2 Stake holders involved in the relocation of nanomedicines from lab t...
List of Tables
Chapter 1
Table 1.1 Types of NLCs classified based on structure.
Table 1.2 Differences between SMEDDS, SEDDS, and SNEDDS.
Table 1.3 Different types of techniques used in the preparation of lipid nanocar...
Table 1.4 List of the drug as lipid nanocarriers under clinical investigation.
Table 1.5 Lipid carrier system used for the delivery of different peptides/prote...
Chapter 2
Table 2.1a Classification of nanoparticulate carrier systems.
Table 2.1b Targeted treatment of tuberculosis using various nano-carrier-based d...
Table 2.2 Schematic representation of classification of polymer based on their o...
Chapter 3
Table 3.1 An overview of the nanotools.
Chapter 4
Table 4.1 Properties of dendrimers.
Table 4.2 Mechanism of bonding of various anticancer drugs with dendrimers.
Table 4.3 Description of research on dendrimers.
Chapter 5
Table 5.1 Composition, characterization, and application of recent nanofiber for...
Table 5.2 Advantages of different biodegradable polymers used in the fabrication...
Chapter 6
Table 6.1 Clinically approved microbubbles.
Table 6.2 List of preclinical studies of brain tumor targeting by microbubbles.
Chapter 7
Table 7.1 Various techniques used for characterisation of virosomes.
Chapter 8
Table 8.1 Properties of commonly used polymers as nanocarriers.
Table 8.2 Approved gene therapy products [45, 46].
Chapter 9
Table 9.1 List of Phyto-phospholipid complexes fabricated by employing various p...
Table 9.2 Marketed Phytosomal Preparations along with their indications.
Chapter 11
Table 11.1 pH variations in several tissues and cellular regions.
Table 11.2 Types of pH responsive polymers and their applications in drug delive...
Table 11.3 List of temperature responsive polymeric nano-formulations.
Table 11.4 The different stimuli-responsive polymeric systems and their drug rel...
Table 11.5 List of dual and multi responsive polymeric systems.
Chapter 12
Table 12.1 List of some drugs formulated as nanosomal formulations.
Chapter 14
Table 14.1 Types of forces and their attributes in mucoadhesive systems.
Table 14.2 Theories of mucoadhesion.
Table 14.3 Classification of mucoadhesive polymers.
Table 14.4 Influence of polymer properties on mucoadhesion.
Table 14.5 Modified mucoadhesive polymers.
Chapter 15
Table 15.1 Prevalence, Prognosis, and various alternative therapies [4, 5].
Chapter 16
Table 16.1 List of nano-based vaginal formulations.
Table 16.2 Patents on vaginal delivery.
Chapter 17
Table 17.1 List of recently USFDA-approved drugs for the treatment of cancer.
Table 17.2 List of liposomal drugs currently present in clinical trials for the ...
Table 17.3 Liposomes functionalized with targeting ligands through surface engin...
Table 17.4 Liposomes functionalized with stimuli for improved delivery of antica...
Table 17.5 Recent drug polymeric nanocarriers used in drug delivery for treatmen...
Table 17.6 Recent polymer modified liposomes for treatment of cancer.
Chapter 18
Table 18.1 Dose of streptomycin, rifampicin and clarithromycin according to body...
Table 18.2 Classification of severity of Chagas disease according to New York He...
Table 18.3 Various chemotherapeutic agents used for various conditions in cystic...
Table 18.4 Various agents used for various conditions in dengue fever.
Table 18.5 Available medication for symptomatic relief in case of Dracunculosis.
Table 18.6 Medication prescribed for treatment of Fascioliasis.
Table 18.7 Medication according to parasitic infection and recommended dose for ...
Table 18.8 Treatment for specific stages and parasite involved in Human African ...
Table 18.9 Various drugs used in treatment of leishmaniasis and their route for ...
Table 18.10 Various antibiotics for different type of leprosy in treatment of le...
Table 18.11 Class of drug available for lymphatic filariasis with duration of th...
Table 18.12 Drugs used for various organisms in case of Mycetoma treatment.
Table 18.13 Drugs used for treatment of CBM.
Table 18.14 Class of compounds used for treatment of other deep mycoses.
Table 18.15 Available drugs for treatment of Onchocerciasis.
Table 18.16 Treatment for Schistosomiasis along with dosage regimen in special g...
Table 18.17 Therapeutics available for soil transmitted helminthiases [159].
Table 18.18 Treatment available for Trachoma [112].
Table 18.19 Antibiotics employed for treatment of Yaws.
Table 18.20 Design and development of nanomedicines for neglected diseases.
Chapter 19
Table 19.1 Regulatory approach in different reteams of world at a glance.
Guide
Cover
Table of Contents
Title page
Copyright
Preface
Begin Reading
Index
End User License Agreement
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Scrivener Publishing
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Publishers at Scrivener
Martin Scrivener ([email protected])
Phillip Carmical ([email protected])
Nanopharmaceutical Advanced Delivery Systems
Edited by
Vivek Dave
Nikita Gupta
Srija Sur
This edition first published 2021 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA
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Preface
Our intent in writing Nanopharmaceutical Advanced Delivery Systems was to provide a systematic understanding of various novel drug delivery systems and their preparation, characterization and impressive range of applications. These novel drug delivery systems demand a wide range of detailed knowledge of various drug delivery systems and their composition. Moreover, it is important to understand the properties of the various constituents of a nanoformulation that determine the preparative methods of the delivery systems and broadly ensure their properties. With this in mind, this book covers a wide range of pharmaceutical topics required to appropriately perform and evaluate the biological and biopharmaceutical impact of nanopharmaceuticals in living systems.
Historically, there have been many conventional dosage forms available on the market for the treatment of various diseases that are administered in particular doses at particular frequency. The biggest disadvantage of these dosage forms is the increased chance of missing a dose of short half-life drugs because they need to be frequently administered. The need for novel drug delivery systems began with the realization that new, better and safer drugs with longer half-lives have a large therapeutic index. Since conventional pharmaceutical dosage forms are incapable of controlling the rate of drug delivery to the target site, there is also an unnecessary distribution of the drug in non-target sites of the body. This is the main reason why conventional dosage forms need to be given in higher therapeutic doses, which in turn is responsible for certain severe adverse effects during or after treatment. Novel drug delivery systems play a very significant role in addressing this problem as they maintain the concentration of the drug in the therapeutic range for a longer period of time and are also capable of delivering the drug to the required site. Therefore, to overcome the shortcomings of conventional dosage forms, sustained and controlled-release dosage forms have come into existence.
The aim of this book is to provide a single volume which includes a detailed description of various delivery systems, their principles and how they are used for the treatment of specific diseases. The book is divided into four sections. The first section discusses the importance of novel drug delivery systems whereas the second section presents a detailed overview of the most advanced drug delivery systems such as microbubbles, dendrimers, lipid-based nanoparticles, nanofibers, microemulsions, etc. This section describes the major principles and techniques involved in the preparation of drug delivery systems in great detail and provides recently updated coverage of the important principles involved in the underlying science behind these therapeutic delivery systems. In this section, renowned authors focus on providing complete insight into the novel delivery systems along with their practical applications in the fields of health, medicine and therapeutics. The third section mainly elaborates on the current evocative treatments of diverse diseases like cancer, topical diseases, tuberculosis, etc. Finally, the fourth section of the book provides a brief informative description of the regulatory aspects of novel drug delivery systems that are followed in various countries.
This book was designed for both dedicated scientists and those new to scientific research who work in the fields of health and medicine. The fresh insights in this book will enhance the knowledge of the innovative young minds of those in the field by delivering detailed informative descriptions of the latest novel modern pharmaceutical dosage forms and drug delivery systems, which will in turn be a benefit to society.
Vivek DaveSrija SurNikita Gupta
Part 1INTRODUCTION TO THE FUNDAMENTALS
1Lipid-Based Nanocarriers as Drug Delivery System and Its Applications
Vikas Jain*, Hitesh Kumar, Pallavi Chand, Sourabh Jain and Preethi S
Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
Abstract
Various nanotechnology platforms have received notable attention in the field of medical biology, including diagnostics and therapy. In addition, research and development of engineered multifunctional nanoparticles as drug carriers has stimulated exponential development of applications in medicine. Lipid nanocarriers have been a very promising tool for the delivery of various drugs/therapeutic agents associated with solubility-, bioavailability-, and stability-related issues. Lipid nanocarriers including liposomes, solid lipid-based systems, self-emulsifying drug delivery system, nanoemulsions, nanostructured lipid carriers, cubosomes and hexosomes, etc. are being very promising lipidic carriers to deliver several drugs, therapeutics nucleic acids, antibodies, proteins/peptides, or ligand targeted agents. Lipids-based nanocarriers have the benefit of having exciting physicochemical behaviors such as higher bioavailability, least toxicity, higher drug loading, greater drug solubility, improved targeting effect of drug, etc. compared to others nanocarriers. This chapter includes the challenges and hurdles in lipid nano-formulations and their application in drug delivery in various diseases. The chapter provides a brief description of advantage, types of lipid nanocarriers, their preparation method, characteristic properties, and characterization/evaluation methods including instrumentations and application in the nanopharmaceutical field.
Keywords: Crystalline mesophases, drug delivery system, liposome, lipid nanocarriers, nanostructured lipid carriers, nanoemulsions, self-emulsifying drug delivery system, solid lipid nanoparticles
List of Abbreviations
SLNs
Solid lipid nanoparticles (SLNs)
NLCs
Nanostructured lipid carriers
SEDDS
Self-emulsifying drug delivery system
LDC
Lipid drug conjugate hydrophilic
HLB
Lipophilic balance (HLB)
SMEDDS
Self-Micro Emulsifying Drug Delivery System
SNEDDS
Self-Nano Emulsifying Drug Delivery System
FT-IR
Fourier-transform infrared spectroscopy
NMR
Nuclear magnetic resonance
MS
Mass spectrometry
XRD
X-ray diffraction
TGA
Thermal gravimetrical analysis
DSC
Differential scanning calorimetry
DLS
Dynamic light scattering
PCS
Photon correlation spectroscopy
SEM
Scanning electro-microscopy
TEM
Transmission electron microscopy
PLM
Polarized light microscopy
AFM
Atomic Force Microscopy
1.1 Introduction
Evolution and application of the nanotechnology in pharmaceutical field have brought the development of microscopic drug delivery systems, which have marked the birth of “micro age” drug delivery systems [1]. The beginning of the nano period can be dated back to the late 1970s as a result of the introduction of several nano tools known as nanoscaled medicine systems. A wide variety of colloidal drug carriers including polymer nanosphere and nano-capsules, lipid nanoparticles, liposomes, and micelles are involved in nanoscaled drug delivery systems.
Presently, the development of drugs in the industry is more difficult and challenging because of an increasing number of poorly soluble drug(s) and the lack of targeted therapies. More than 90% of the recorded compounds have water insolubilities and/or are poorly soluble, often due to low bioavailability and a wide intra- and intersubject variation and lack of dosage efficacy [2, 3]. To address these issues, drug formulators need to look for new methods and novel formulation strategies and to ensure effective treatments for vulnerable patients.
Various nanotechnology platforms have received notable attention in the field of medical biology, including diagnostics and therapy. In addition, multifunction nanoparticles as drug carriers have stimulated rapid development of medical applications. Nanoparticles also have superiorities such as increasing drug stability and preventing adverse reactions by prolonged drug release behaviors [4, 5].
Formulating drug delivery system of active compounds with poor aqueous solubility using lipid-based systems is one of the promising strategies. Lipid provides a better alternative for the delivery of various drugs that suffer from solubility-, bioavailability-, and stability-related issues. In many studies, lipid formulations have been tried to increase bioavailability and dissolution of drugs, which are water insoluble [6]. The spontaneous emulsification in aqueous media is one of the major benefits by imparting such carriers to promote delivery of poorly soluble drugs.
Various literatures reported the characteristics and essential properties, design and development, utilization, and potential applications of various lipid-based nanocarriers in drug delivery [7, 8]. The current chapter discusses various lipid-based nanocarriers such as solid-lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), vesicular nanocarriers including liposomes, nanoemulsions, self-emulsifying drug delivery system (SEDDS), and crystalline mesophases in various application pharmaceutical fields. The information on the formulation components and processing aspects has also been discussed in detail.
1.2 An Overview on Nanocarriers
In the early 1990s, solid polymers in nanoparticles consisting of non-biodegradable and biodegradable polymers having size from 10 to 1000 nm with site-specific delivery feature and regulated drug release were developed. However, the major problem encountered was the higher cytotoxicity associated with these polymers [9-11]. Therefore, lipid-derived carriers emerged as a keystone for novel formulations because of its low cytotoxicity.
In the past two decades, the development of lipid-based drug carriers has received greater attention. Lipid nanoparticles offer several potential uses in the fields of drugs delivery, clinical medicine, research, and other varied sciences. Due to their unusual dimensional dependency, lipid nanoparticles provide the opportunity to develop new therapeutics. A new prototype in drug delivery for secondary and tertiary targeting can be made possible by incorporating the drug into these nanocarriers [12].
The first liposomes were introduced by Dior in 1986 to the cosmetic market. After several years, liposomes in the form of pharmaceutical products appeared in the market. As a novel carrier, liposomes were not only technically advanced but also have gained wide public interest. There are several other concepts of formulation; for example, microemulsions, nanoemulsions, and solid particles (such as microsponge) were also explored in the last two decades. Nevertheless, these nanocarriers have not been found in wide applications and have not gained any attention like liposomes.
SLNs have certain benefits in contrast to liposomes and emulsion, e.g., protecting the active compounds from chemical oxidation and offering greater versatility in amplifying compound release [12, 13]. Furthermore, lipid nanoparticles made of solid lipid and liquid lipid were explored by different research groups, which were used on a variety of routes such as parenteral, oral, dermal, ocular, or rectal and were thoroughly characterized [14, 15]. Nowadays, modified SLNs were known as nanostructured lipid carriers (NLCs) and nanoparticles lipid drug conjugates (LDCs) [13, 16, 17]. These carrier systems were able to resolve the issues observed with conventional SLNs.
A lipid nanocarrier system provides the drug with smaller droplet sizes in solubilized form offering a large surface area, which increases the activity of pancreatic lipases for the hydrolysis of triglycerides, and this will enable the faster release of the drug. Neoral® (cyclosporin A) is a commercial product that is an excellent example of the utilization of these systems [18]. This carrier system has another advantage in that it can be used for clinical purposes because organic solvents can be avoided during the preparation process. A further advantage is that it is easy and cost-effective to produce.
1.3 Types of Nanocarriers
1.3.1 Liposomes
The most popular and well-researched nanocarriers are liposomes, which are synthetic phospholipid vesicles with a size of about 50–1,000 nm that can be loaded with a variety of drugs including hydrophilic and hydrophobic drugs. Figure 1.1 depicts it all [19]. Originally liposomes referred to as smectic mesophase are monolamellar or multilamellar spherical vesicles that include phospholipids either of animal or plant origin. Liposomes were first discovered by AD Bangham and later on described by Allison and Gregoriad [20, 21]. Liposomes are spherical vesicles composed of bilayer lipids. They can encapsulate hydrophilic drugs within bilayer lipids due to their unique structure, and in the central aqueous core, hydrophilic agents typically protect the agents against degradation. Liposomes promote pharmacokinetics of loaded pharmaceutical active agents and provide higher loading efficacy, higher biological stability, controlled release, biological compatibility, and many others; the basic structural components of liposomes, i.e., phospholipids, are amphiphilic in nature [22]. These amphiphilic lipids get dissolved with an aqueous medium, and liposomes were aggregated by increased process entropy over certain concentration [23, 24]. In early days, liposomes were described as not containing surface modifiers, but later they were modified to differ in rigidity, size, and other properties by altering the composition of the lipid [25]. The next-generation liposomes were offered with molecular targeting capabilities through the attachment of unique ligands to their surface [26]. In addition, different ligands and functional molecules are easy to incorporate, thereby offering practical applications for the delivery of labile drugs and genetic materials. Liposomes also suffer from certain drawback, like other carrier systems. The development costs and all other aspects should be considered while developing a formulation to enhance drug therapeutic efficacy. The uses of sophisticated explants and tedious manufacturing process increase the cost of production of liposomes [27, 28].
Figure 1.1 Types of liposomes. (a) Unilamellar vesicle, (b) multilamellar vesicle, (c) immunoliposome, and (d) stealth liposomes.
1.3.2 Solid Lipid Nanoparticles
Solid lipid nanoparticles (SLNs) were introduced in 1991, which are the most conventional carrier system compared to other lipid carrier systems. Although some polymer-based nanoparticles were developed, still they have certain disadvantages such as toxicity, residual organic solvents, and processing complication [29, 30]. SLNs were incorporated into an inert solid lipid that offers sufficient stability and protection to encapsulated drugs as shown in Figure 1.2 [31, 32]. SLNs also offer unique features of a small size range micro-colloidal carrier between 50 and 1000 nm, larger surface area, higher drug loading, and potential for delivering drugs across various barriers [33-36].
By definition, SLNs are submicron size nanoparticles composed of biocompatible and biodegradable solid lipids and are dispersed in aqueous surfactant solution; these mixtures are capable of providing a stable product for both lipophilic and hydrophilic drugs. For many years, they have become a promising platform for therapeutic drug delivery [37, 38] because they are simple, flexible, and stable for long term, have high drug loading efficacy, have potential for targeted responses [30, 31], have increased bioavailability, and do not require any special solvent and application versatility [33, 34]. SLNs for various routes of administrations such as dermal, parenteral, ocular, and rectal routes have been extensively studied and developed [39].
1.3.3 Nanostructured Lipid Carriers System
Nanostructured lipid carriers (NLCs) are a smart second-generation carrier system consisting of solid and liquid lipids. As we know, SLNs are the first-generation lipid nanoparticle that caused issue such as decreased drug encapsulation and storage instability. Later research turned towards the modification of SLNs that lead to the development of NLCs. This system consists of biodegradable and biocompatible lipids (solid and liquid); surfactants are approved for use in different drug delivery systems by regulatory authorities [16, 40]. NLCs have a whole range of unique benefits as compared to other systems such as higher drug loading capacity, more appropriate drug delivery system for various routes (topical, nasal, lung, ophthalmic, and parenteral), flexibility to modulate drug release, potential drug carrier in the future [41], minimal use of surfactants, etc. The usual diameter of NLCs range from 10 to 1000 nm. The amount of liquid lipid generally increases in such a way that nanoparticles evolve in the development of unusual shape, a non-perfect lattice, and create an amorphous structure. The solubility of the drug improves with the increase in the liquid lipid [42-45]. Nanorepair Q10 Serum (Dr. Rempler, Wedemark, Germany) and Nanorepair Q10 Cream (Dr. Rempler, Wedemark, Germany) were the first two marketed products of NLCs introduced by Muller in 1999/2009 and took 5 years to launch. More than 30 products are available in the market over the decades. The scientific community is also interested in the development of NLCs as an innovative drug delivery system. They are generally divided into three types and are described in Table 1.1 and shown in Figure 1.3.
Figure 1.2 A graphical representation of solid lipid nanoparticle.
Table 1.1 Types of NLCs classified based on structure.
S. No.
Types
Description
1
.
Imperfect type
Disordered structure.The lipid arrangement between the crystal and the liquid lipid is unordered, which enhances the drug’s capacity to penetrate.
2.
Amorphous type
Lack of crystalline structure, which prevents/decreases drug leakage.
3.
Multiple type
Provides higher levels of liquid lipid than other systems.Achieves slow drug release and high drug loading capacity, thereby avoiding decomposition of solid lipid.Similar to w/o/w microemulsion.
Figure 1.3 Type of the nanostructured lipid carrier.
1.3.4 Nanoemulsion
Nanoemulsion is an o/w type of emulsion with an average droplet diameter of 50–500 nm. The term “nanoemulsion” is used to define the dispersions of water and oil that are two immiscible liquids to form a thermodynamically stable and isotropically transparent system along with surface molecules involved in interfacial film formation. In addition, it should have an inner core of water or oil as an o/w or w/o emulsion. Nanoemulsion is composed of ingredients that are generally recognized as safe (GRAS) by FDA, approved surfactants for human use. The nanoemulsions consist of water-immiscible oil phase prepared under high shear pressure, or by mechanical extrusion system available throughout the world. Large-scale production of emulsion is easy. The use of nanoemulsion across various routes is favored due to their large surface area; thus, it is used for efficient drug delivery throughout the body [46]. Nanoemulsions are stable and have the ability to dissolve an increased amount of lipophilic drug along with certain vectors that prevent their enzyme degradation and hydrolysis [47, 48]. Reducing the size of droplets to nanoscale results in several fascinating physical properties such as visual transparency and peculiar elastic behavior. They are very promising in the non-material sector, as they are useful for the dispersion of deformable nanoscale droplets from fluid to highly solid and deformation of optical characteristic from opaque to nearly transparent [49].
Preparation of nanoemulsion contains oil and aqueous phase along with drug as well as surfactants/co-surfactant and additives. The physical and chemical characteristics of these components play an important role in formulation stability and their performances. The choice of surfactant must also be taken into account as per the hydrophilic lipophilic balance (HLB) and critical factor. Strong HLB (8-18) surfactants are used in nanoemulsion preparation, while surfactant with low HLB (3 to 6) can be used in w/o nanoemulsion preparation. The right combination of high and low HLB surfactants results in the formation of stable nanoemulsion.
The hybrid nanoemulsion preparation process combines low-energy emulsifying and high-energy emulsifying applications. Due to their drug solubilizing capacity in oil core without premature leakage, they are particularly preferred as the drug delivery system. The interactions between the lipid droplets on administration routes also reveal their targeting properties such as oral drug delivery, parental drug delivery, transdermal drug delivery, anticancer drug delivery, and vaccine drug delivery. Nanoemulsion can be used for both local and systematic targeting effectively, e.g., delivery through skin, lungs, brain, and ligand mediated drug targeting.
1.3.5 SMEDDS, SEDDS, and SNEDDS
Various techniques are used to increase the oral bioavailability of poor soluble drugs [50-52]. As it gives high degree of patient tolerance, the oral route is the main route in the chronic treatment of various kinds of diseases. Nonetheless, 50% of drugs are mainly obstructed by oral delivery due to their high lipophilicity [53]. In recent years, various types of lipid-based carrier system such as self-micro emulsifying drug delivery system (SMEDDS), self-emulsifying drug delivery system (SEDDS), and self-nano emulsifying drug delivery system (SNEDDS) are the most promising approaches for improving bioavailability of drugs that are in insoluble lipophilic phase [54]. SMEDDS often provides a different feature. SMEDDS is defined as isotropic formulation of fine oil-in water (o/w) microemulsion formed by surfactants, co-surfactants, or drug and lipid mixtures, when combined with gentle stirring in aqueous media. These systems are important in improving oral bioavailability and are of primary interest to researchers, as a result of being a potential drug delivery through the incorporation of a wide range of drug molecules inside the vehicle. SMEEDS produce clear microemulsions of less than 50 nm of oil concentration and surfactant with HLB>12. SEDDS have been used to enhance the absorption of the drug via oral route [55-59]. Such formulations form fine oils rapidly in water emulsion or micro-emulsions when diluted in water [60], which are responsible for a negative free energy demand for forming emulsion [61]. Therefore, SEDDS are quickly dispersed throughout the GI tract and offer the agitation required for emulsification due to stomach and small intestine motility. SEDDS comprise the combination of oil, surfactant, and other chemicals and drugs. The selection of the lipid and the surfactant is done with their maximum ratio for optimum self-emulsifying property for the formulation [62-65]. In addition, it has been often shown that surfactant blending has superior emulsifying properties in comparison with the use of one single hydrophilicity–lipophilicity balance (HLB)-containing surfactant to attain the HLB quality, essential in emulsification process. The smooth mixing of aqueous media produces emulsion in the range of 10–100 nm with a droplet size. Droplets of emulsion were then spread into the gastrointestinal tract to meet the absorption point in SEDDS by emulsifying into the stomach [62]. SNEDDS is thermodynamically stable and the isotropic mixture of natural or synthetic oil, surfactant, and co-surfactant ability to form non-ionized (o/w) or (w/o) nanoemulsion dispersion under moderate agitation with particle diameter of 200 nm [66-67]. SNEDDS is important for oral absorption when formulating with medium-chain glyceride oils and non-ionic surfactants. In order to offer a large interfacial region between the oil and the aqueous phase, SNEDDs are of stable nanoemulsion. It enhances drug dissolution rate and increases drug formulation bioavailability. The formulation is usually incorporated into gelatin (soft/hard) or hydroxypropylmethyl cellulose capsules, which provides patient enforcement and is used commercially. The important factor in formulating liquid soft gelatin capsule is that the volume should be 1 g maximum [68].
Similarly, the differences between the three lipid-based carrier systems are given in Table 1.2 [69].
1.3.6 Crystalline Mesophases
Most of the drugs present in the market have prevalent problems such as poor solubility, low bioavailability, drug development cost, and time taken into consideration for developing and formulating a novel drug delivery system. One of the primary methods of preparation of crystalline mesophases was selected based upon the shape, state, and form of drug molecules. Current procedures for preparing liquid crystalline mesophases have been extensively considered for over a couple of decades for improving solubility and controlled drug release rate. Crystalline mesophases are also categorized into liquid crystals, plastic crystals, and confirmatively dispersed crystals according to their transcription, orientation, and concordances that constitute a specific condensation state [70]. Disordering solids typically associated with amorphous substances have received a major focus on pharmaceutical products. The practical benefits of CMs including increased solubility in nanoparticles and greater stability for protein drugs obtained by mixing protein can be significant in amorphous condition. On the other hand, thermodynamically less stable amorphous compounds than the corresponding crystalline state can undergo physical and chemical modifications and therefore decrease the shelf life. Chemical reactivity levels of amorphous vs. crystalline materials are known for many structures, where the rates of degradation are significantly higher with amorphous materials [71-73]. CMs are mainly classified into lyotropic and thermotropic. Thermotropic liquid crystals show mesophase formation when temperature affects the transition, while the change in solvent in a mixture of components at a particular temperature forms lyotropic crystals. The availability of fluid crystals as medicines is a broad area for research. The demand for the application of drug delivery nanoparticles (cubosomes and hexosomes), in particular lyotropic crystal, has been high in the last few years. Drug delivery based on nanoparticles promises the choice of drugs to be effective, regulated, and targeted [74].
Table 1.2 Differences between SMEDDS, SEDDS, and SNEDDS.
S. No.
Property
SMEDDS
SEDDS
SNEDDS
1.
Size
<250 nm
>300 nm
<100 nm
2.
Appearance
Optically clear
Turbid
Optically clear
3.
Hydrophilic–lipophilic balance (HLB) value
>12
<12
>12
4.
Classification of lipid-based drug delivery system
Type IIIB
Type II
Type IIIB
5.
Concentration of oil
>20%
40-80%
>20%
6.
Concentration of surfactant
40-80%
30-40%
40-80%
7.
Material
Oil, surfactant, and co-solvents (both water soluble and insoluble excipients)
Oil water insoluble surfactant
Oils without surfactants (e.g., tri-, di-, and monoglycerides)
8.
Characteristics
SMEDDS create with aqueous soluble elements
SEDDS create without aqueous soluble elements
Nondispersing requires digestion
9.
Advantages
Clear dispersion, absorption of drug without digestion
Improbable loss of solvent, capacity on dispersion
Good solvent capacity for many drug formulations.
10.
Disadvantages
Less easily digested
Turbid o/w dispersion
Poor solvent capacity until drug is lipophilic
Cubosomes and hexosomes have generated great attention as they are the first to have molecular, multilevel, mesophasic, and nanoparticle observed structural compounds. They can be administrated through various routes thus providing versatility in the administration of various drugs. Internal structure defined before dispersion by liquid crystal mesophases of amphiphiles offers complex topologies; they can carry a higher volume of drug with long-term release [75]. Size ranges vary in the nanometer range, which allows similar surfactant to uniformly distribute and prevent aggregation. Since it possesses the curvature in the internal structure of crystalline mesophases, large volume of the drug can be loaded, which increases the potential for drug targeting [76, 77]. Due to the amphiphilic nature of liquid crystal forming lipid (polar head and lipophilic tail), they arrange themselves into a cubic or hexagonal phase, which is thermodynamically stable. Therapeutic applications of liquid crystal nanoparticles (cubosomes and hexagonal) are associated with the drug, route of delivery, formulation, and physiochemical properties such as increased molecular weight, the different polarity of drug molecule, compatibility issue, enzymatic degradation, and reduced toxicity.
1.4 Methods of Preparation of Lipid Nanocarriers
There are various high energy input and low energy input methods available for the preparation of lipid-based nanocarriers. The methods presented here include physical ones like homogenization and chemical ones like co-acervation. The choice of methods and energy input depends on the thermal stability of lipid molecules as well as drug molecule. Several important methods utilized for the preparation of lipid nanocarriers are given in Table 1.3.
1.5 Challenges and Hurdles
1.5.1 Scale Up and Stability Issues
The development of the lipid-based nanocarrier system can easily be scaled using the reported approach for preparation. Several issues of stability can, however, be associated with lipid carriers and can be a hurdle in the process of the scale-up. Polymorphism must first be taken into account. The colloidal size and particularly their high volume-to-surface ratio can result in the decrease in melting points. This effect may also be caused by impurities, agents, and stabilizers [86, 87]. For example, the co-acervation and hot homogenization method of fatty acids and triglycerides results in polymorphism [88]. Due to rapid solvent evaporation, polymorphic forms have been obtained during spray drying.
Table 1.3 Different types of techniques used in the preparation of lipid nanocarriers.
Preparation techniques
Description
References
High-pressure homogenizationPressure: 100–2000 bar
Hot homogenization
Drug melted in hot lipid Pressure: 500–1500 bar Production of nanoemulsion
[78, 79]
Cold homogenization
Suitable for thermosensitive drug.Formulation rapidly cooled in dry ice.
Ultrasonication
Probe ultrasonication
Use for oral drug delivery systems.Diameter range: 80–800 nmReduce shear stress.
[80]
Bath ultrasonication
Solvent emulsification–diffusion method
Lipid dissolved in organic solvents (chloroform, ethyl acetate, methylene chloride, cyclohexane).Use for hydrophilic drug (w/o/w emulsion).Diameter range: 30–100 nm.
[81]
Supercritical fluid method
Lipophilic substances dissolved in organic solvent.Nanoparticle range 25 nm.Solvent removal by evaporation (pressure 40–60 mbar).
[82]
Microemulsion-based method
Two-phase system inner and outer (o/w microemulsion)Lower mechanical energy.Increased drug loading capacity, range of 200–250 nm.
[82]
Spray drying method
Use for lipid with melting point more than 70°C.Alternative technique to lyophilization process.
[83]
Double emulsion method
w/o/w two-step microemulsion technique.Drug is encapsulated with stabilizer to prevent leakage of drug.
[82]
Precipitation technique
Glycerides dissolved in an organic solvent.Solution is emulsified in aqueous phase.
[84]
Film-ultrasound dispersion
Form uniform size nanoparticles.Drug and lipid put in suitable organic solvent.
[82, 85]
Furthermore, sterilization is an important stability parameter in lipid nanocarrier system production [89]. Irradiation is an existing technique of sterilization for pharmaceuticals. However, during irradiation, the chemical degradation of the lipids can occur: therefore, ionizing radiation is not allowed, or at least more tests are required before it is accepted as a safe and effective technique of sterilization. Diverse studies have preferred an autoclave approach because it doesn’t change the Zeta potential and mean particle size, although this is paradoxical considering the effect that temperature may influence the stability of nanoparticles.
Another significant cause for instability is phase separation [88] because of the formation of reversible or irreversible particles (coalescence, sedimentation); also during storage, gelling may occur. Adequate surfactants can be used to address these problems: they can stabilize LNP suspension by an electrostatic repulsion, which improves Zeta potential, or they can serve as steric (non-ionic surfactants) stabilizers. Surface stability, particularly electrostatic stabilization and Zeta potential, is highly sensitive to pH and eventually exists at the external phase, which may cause suspension destabilization.
The acquisition of solid water forms is an effective strategy for overcoming the problems concerning lipid nanocarrier storage stability. This can be achieved through spray drying or lyophilization of suspension.
Instability may occur in gastrointestinal fluids following enzymatic degradations of the particles or lipid matrix. Particle accumulation can be accomplished by improving the surfactant combination owing to ionic strength and acidic stomach pH. Stability conditions in combination with steric stabilization have been set at minimum 8–9 mV Zeta Potential [89].
Lipid nanocarriers have recently been investigated for their interaction with the major circulatory protein serum and albumin. Several groups of researchers also focused more and more on improving their body fluid stability through coating lipid nanocarriers with hydrophilic molecules like poly(ethylene)glycol (PEG) derivatives. Coating lipid nanocarriers with PEG improves stability and plasma half-life to suppress phagocytic uptake, thus improving drug bioavailability [90].
1.5.2 In Vivo Elimination of Nanocarriers
In order to deliver several drugs and activities for different objectives, lipid nanocarriers were developed. Still, the in vivo fate of such carriers remains questionable. Although majority of the lipids undergo biotransformation and deemed to be eliminated by common elimination pathways, researchers need to ensure their complete eradication after the drug has been completely released from such carriers. Nonetheless, several obstacles for lipid nanocarriers are still a hot topic for drug therapy among the most interesting and recent assignments for lipid nanocarriers. Cancer treatment, blood-brain barrier (BBB) elimination, and protein and gene delivery are fields of study where a healthy and reliable carrier of drug is essential, and lipid nanocarriers for such purposes are suggested and investigated.
1.6 Characterization Techniques for Lipid Nanocarriers
1.6.1 Size and Morphology
During parenteral administration, a significant factor in safety of biological systems is the particle size of the carrier system. Dynamic light scattering (DLS) is a method most often used for calculating particle size in solutions and conducting distribution-size study. Quasielastic light scattering or photon correlation spectroscopy (PCS) is the other term used instead of DLS. The method is based on Brownian movement of particle in dispersion. When laser light hits objects, it is scattered by Brown’s particle movement [91]. The motion of the particles depends on the size of the particle. The light intensity of laser light with a defined wavelength fluctuates the particles, which fluctuate the scattered light after striking with dispersed particles. By measuring the frequency of the scattered light fluctuation, the intensity of the Doppler shift can be determined by the use of a photon detector, depending on time and fluctuation. Fluctuations in light intensity are greatly affected by the viscosity of the solution and the temperature; hence, the particle size of dispersion can vary [91, 92–94].
Scanning electro-microscopy (SEM) and transmission electron microscopy (TEM) are the most needed tools to analyze morphological characteristics [95]. SEM and TEM characterization of nanoparticles provides shapes and surface facets, and it determines the accurate particle size of a particular particle in dispersion [96]. The morphological shape details can be taken from the SEM image for a large nanocrystal with a normal design. SEM works on the basis of scattered electrons and provides particulate morphology. The shape of a small nanocrystal cannot be analyzed by SEM because of its restricted resolution. Although TEM analysis is able to represent the morphology of such particles that are not suitable for SEM by passing electrons through in resultant, it differentiates the chemical entities on the basis of electron density [97].
Polarized light microscopy (PLM) is usually used to observed lyotropic liquid crystalline structures [98]. It can be used to confirm the presence of liposomes and similar structures in parenteral dispersion systems. The coordinated structure of the phospholipid surfaces results in anisotropical properties. Anisotropic systems deviate polarized light in the plane, which helps in imaging and gives a standard black and white or colored image using a λ-plate [98, 99].
SEM imaging only analyzes the samples in 2-D, that is, x- and y-axes, but cannot measure the z-axis to provide 3-D morphological information of a particle surface. Atomic force microscopy (AFM) overcomes this problem by analyzing the surface on the z-axis along with the x- and y-axes using deflection of a fine leaf spring. AFM is widely used for crystallinity studies of a sample. The technique uses fixed wavelengths to provide information on the molecular organization of crystals. In AFM imaging, with resolution up to 0.01 nm, the force between the surface of the material and the sensor tip is used [100]. Silicon wafers are usually used for sample fixation. The sample surface should be extra smooth for AFM imaging [101–106].
1.6.2 Surface Charge
Zeta potential is an essential characteristic of particles that can be easily calculated with a zetasizer tool [92]. It is an important aspect to understand particle stability. In drug delivery applications, the particle charge is an important factor. “Zeta potential is the potential differentiation between the surface and the stationary fluid layer connected to the dispersed sample.” The particle surface is surrounded by ions charged opposite to each other, which generates the thin stern layer adsorbing non-hydrated co-ions and counter ions at the surface. The next layer consists of the hydrated/partially hydrated counter ions, and the last layer consists of co-ions; this layer is known as the diffuse layer. This layer is attached to the slip plane, an imaginary plane that separates mobile ions from immovable ions on the surface. A stable dispersion has zeta potential ideally from -30 to +30 mV. Repulsion occurs between particles with a strong positive or negative surface charge; it results in reduced stability span of dispersion through flocculation or aggregation by particles [107]. The pH of the dispersion is the factor that mostly affects the zeta potential [108].
