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Applications of Encapsulation
and Controlled Release
 Encapsulation and Controlled Release Series
Series Editor
Dr. Munmaya K. Mishra

The field of encapsulation, especially microencapsulation, is a rapidly growing area of research and ­product
­development. The Encapsulation and Controlled Release Series covers the entire field, with its volumes
­presenting the fundamental processes involved and exploring how to use those processes for different applications
in industry. Titles are written at a level comprehensible to non-experts, each is a rich source of technical
­information, and many address current practices in research and industry.
Handbook of Encapsulation and Controlled Release
Edited by Munmaya Mishra
Applications in Encapsulation and Controlled Release
Edited by Munmaya Mishra
For more information about this series, please visit: https​://ww​w.crc​press​.com/​Encap​sulat​ion-a​nd-Co​ntrol​led-
R​eleas​e/boo​k-ser​ies/C​RCENC​CONRE​L
Applications of Encapsulation
and Controlled Release

Edited by
Munmaya K. Mishra
CRC Press
Taylor & Francis Group
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Library of Congress Cataloging‑in‑Publication Data

Names: Mishra, Munmaya K., editor.

Title: Applications of encapsulation and controlled release / [edited by]
Munmaya K. Mishra.
Description: Boca Raton : CRC Press, Taylor & Francis Group, 2019. | Includes
bibliographical references.
Identifiers: LCCN 2019021452 | ISBN 9781138118782 (hardback : alk. paper)
Subjects: LCSH: Controlled release technology. | Drug delivery systems.
Classification: LCC TP156.C64 A67 2019 | DDC 660/.28--dc23
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 To my family.

Also, to those who made and will make a difference through

polymer research for improving the quality of life!

Contents

Preface....................................................................................................................................................... ix
Editor......................................................................................................................................................... xi
Contributors.............................................................................................................................................xiii

1 Multi-Cyclodextrin Supramolecular Encapsulation Entities for Multifaceted Topical

Drug Delivery Applications.............................................................................................................. 1
P. D. Kondiah, Yahya E. Choonara, Zikhona Hayiyana, Pariksha J. Kondiah,
Thashree Marimuthu, Lisa C. du Toit, Pradeep Kumar, and Viness Pillay

2 Nanocomplexes for Topical Drug Delivery................................................................................... 19

Sougata Jana, Arijit Gandhi, and Kalyan Kumar Sen

3 Polymeric Hydrogels for Controlled Drug Delivery.................................................................... 37

Hira Ijaz, Farooq Azam, Ume Ruqia Tul-Ain, and Junaid Qureshi

4 Polymer–Drug Conjugates as Drug Delivery Systems.................................................................61

Sauraj Singh, Ruchir Priyadarshi, Bijender Kumar, Saleheen Bano, Farha Deeba,
Anurag Kulshreshtha, and Yuvraj Singh Negi

5 Cross-Linked Polymers for Drug Delivery Systems.................................................................... 77

B. A. Aderibigbe

6 Micellar Nanoparticles for Lung Cancer Drug and Gene Delivery......................................... 103
Mariana Magalhães, Francisco Veiga, Ana Figueiras, and Ana Cláudia Santos

7 Oral Delivery of Insulin by Hybrid Polymeric Hydrogel...........................................................115

Kalyani Prusty, Anuradha Biswal, Niladri Sarkar, and Sarat K. Swain

8 Biodegradable Polymers in Controlled Drug Delivery Systems................................................131

Anurakshee Verma, Prabhat Kumar, and Ufana Riaz

9 Delivery Systems for Proteins and Peptides................................................................................145

Sougata Jana, Arijit Gandhi, and Kalyan Kumar Sen

10 Controlled Release of Therapeutic Proteins................................................................................171

Arruje Hameed, Tahir Farooq, Kanwal Rehman, and Muhammad Sajid Hamid Akash

11 Polyhydroxybutyrate-Based Nanoparticles for Controlled Drug Delivery..............................191

K.V. Radha and S. Saranya

12 Smart Delivery Systems for Personal Care and Cosmetic Products........................................211

Fanwen Zeng and Nilesh Shah

13 Controlled Release of Pesticide Formulations............................................................................ 229

Dhruba Jyoti Sarkar, S. Majumder, P. Kaushik, Najam Akhtar Shakil, and Jitendra Kumar

vii
viii Contents

14 Microcapsule-Assisted Smart Coatings...................................................................................... 249

Mahendra S. Mahajan and Vikas V. Gite

15 Encapsulation Technologies for Modifying Food Performance............................................... 267

Maria Inês Ré, Maria Helena Andrade Santana, and Marcos Akira d’Ávila

16 Encapsulation of Aroma............................................................................................................... 309

Christelle Turchiuli and Elisabeth Dumoulin

17 Encapsulation of Flavors, Nutraceuticals, and Antibacterials................................................. 343

Stéphane Desobry and Frédéric Debeaufort

18 Microencapsulation of Phase Change Materials........................................................................375

Jessica Giro-Paloma, Mònica Martínez, A. Inés Fernández, and Luisa F. Cabeza

19 Encapsulation of Bioactive Compounds...................................................................................... 405

Francesco Donsì, Mariarenata Sessa, and Giovanna Ferrari

20 Cell Immobilization Technologies for Applications in Alcoholic Beverages........................... 441

Argyro Bekatorou, Stavros Plessas, and Athanasios Mallouchos
Index....................................................................................................................................................... 465
Preface

The field of encapsulation, especially microencapsulation, is a rapidly growing area of research and
product development. The first edition of the book, Handbook of Encapsulation and Controlled Release,
covered the entire field, presenting the fundamental processes involved and exploring how to use those
processes for different applications in industry. The book also laid the groundwork for further advance-
ments in encapsulation technologies and controlled release applications. As the field is evolving, espe-
cially the area of controlled release applications, there is a clear need for a source of technical information
that has sufficient broad coverage and is written at a level comprehensible to non-experts. With these
considerations in mind, the decision to publish the second edition of the book, entitled Applications of
Encapsulation and Controlled Release, was apparent.
This book is designed for scientists and engineers working in various industries, including food, con-
sumer products, pharmaceuticals, medicine, agriculture, nutraceuticals, dietary supplements, cosmet-
ics, flavors, and fragrances. It offers a broad perspective on a variety of applications and processes,
providing research information, figures, tables, illustrations, and references. Catering to professionals,
researchers, students, and general readers in academia, industry, and research institutions, Applications
of Encapsulation and Controlled Release is a much-needed reference for continued research and devel-
opment in controlled release applications.
I feel honored to undertake the important and challenging endeavor of developing the second edition
of Applications of Encapsulation and Controlled Release, which will cater to the needs of many who are
working in the field. I would like to express my sincere gratitude and appreciation to the authors for their
excellent professionalism and dedicated work. I would like to thank the entire management of the book
program of the Taylor & Francis Group (CRC Press), including Ms. Barbara Knott and Ms. Danielle
Zarfati, who made this possible.

Munmaya K. Mishra
Editor

ix
Editor

Munmaya Mishra, PhD, is a polymer scientist who has worked in the industry for more than 30 years.
He has been engaged in research, management, technology innovations, and product development.
Currently, he is the principal at Encapcr, LLC and serves as the chief consultant in the field of encapsula-
tion/controlled release and polymer applications. He held research and technical management respon-
sibility at Altria Research Center. He serves as the editor-in-chief of three renowned Taylor & Francis
polymer journals and has contributed immensely to multiple aspects of polymer applications, includ-
ing encapsulation and controlled release technologies. He has authored and coauthored hundreds of
scientific articles, is the author or editor of eight books, and holds over 75 U.S. patents, over 50 U.S.
patent-pending applications, and hundreds of world patents. He has received numerous recognitions
and awards. He is the editor-in-chief of the recently published 11-volume Encyclopedia of Biomedical
Polymers and Polymeric Biomaterials and the Encyclopedia of Polymer Applications. He founded the
International Society of Biomedical Polymers and Polymeric Biomaterials as well as a scientific meeting
titled Advanced Polymers via Macromolecular Engineering, which has gained international recognition
and is under the sponsorship of the International Union of Pure and Applied Chemistry.

xi
Contributors

B. A. Aderibigbe Marcos Akira d’Ávila

Department of Chemistry Department of Chemical Processes
University of Fort Hare, Alice Campus School of Chemical Engineering
Eastern Cape, South Arica University of Campinas—UNICAMP
Campinas, Brazil
Muhammad Sajid Hamid Akash
Department of Pharmaceutical Chemistry Frédéric Debeaufort
Government College University Faisalabad Food and Wine Physical Chemistry Lab
Faisalabad, Pakistan Université de Bourgogne Franche Comte
Dijon, France
Farooq Azam
Incharge Pharmacy Department Farha Deeba
University of Agriculture Faisalabad Department of Polymer and Process
Faisalabad, Pakistan Engineering
Indian Institute of Technology Roorkee
Saleheen Bano
Roorkee, India
Department of Polymer and Process
Engineering Stéphane Desobry
Indian Institute of Technology Roorkee Université de Lorraine
Roorkee, India ENSAIA, LIBio
Argyro Bekatorou Vandœuvre Cedex, France
Department of Chemistry
Francesco Donsì
University of Patras
Department of Industrial Engineering
Patras, Greece
University of Salerno
Anuradha Biswal Fisciano, Italy
Department of Chemistry
Veer Surendra Sai University Lisa C. du Toit
of Technology Wits Advanced Drug Delivery Platform
Burla, India Research Unit
Department of Pharmacy and Pharmacology
Luisa F. Cabeza School of Therapeutic Sciences
GREiA Research Group Faculty of Health Sciences
INSPIRES Research Centre University of the Witwatersrand
University of Lleida Johannesburg, South Africa
Lleida, Spain
Elisabeth Dumoulin
Yahya E. Choonara UMR Ingénierie Procédés Aliments
Wits Advanced Drug Delivery Platform AgroParisTech, INRA
Research Unit Université Paris-Saclay
Department of Pharmacy and Massy, France
Pharmacology
School of Therapeutic Sciences Tahir Farooq
Faculty of Health Sciences Department of Applied Chemistry
University of the Witwatersrand Government College University Faisalabad
Johannesburg, South Africa Faisalabad, Pakistan

xiii
xiv Contributors

Giovanna Ferrari A. Inés Fernández

Department of Industrial Engineering Department of Materials Science and Physical
and Chemistry
ProdAl scarl Universitat de Barcelona
University of Salerno Barcelona, Spain
Fisciano, Italy
Sougata Jana
Ana Figueiras Department of Pharmaceutics, Gupta College of
Department of Pharmaceutical Technology Technological Sciences
and Ashram More
REQUIMTE/LAQV, Group of Pharmaceutical Asansol, India
Technology and
Faculty of Pharmacy Department of Health and Family Welfare
University of Coimbra Directorate of Health Services
Coimbra, Portugal Kolkata, India

Arijit Gandhi P. Kaushik

Department of Pharmaceutics, Gupta College of ICAR-Indian Agricultural Research Institute
Technological Sciences New Delhi, India
Ashram More
Asansol, India Pariksha J. Kondiah
Wits Advanced Drug Delivery Platform
Jessica Giro-Paloma Research Unit
Department of Materials Science and Physical Department of Pharmacy and Pharmacology
Chemistry School of Therapeutic Sciences
Universitat de Barcelona Faculty of Health Sciences
Barcelona, Spain University of the Witwatersrand
Johannesburg, South Africa
Vikas V. Gite
Pierre P. D. Kondiah
Department of Polymer Chemistry
Wits Advanced Drug Delivery Platform
School of Chemical Sciences
Research Unit
Kavayitri Bahinabai Chaudhari, North
Department of Pharmacy and Pharmacology
Maharashtra University
School of Therapeutic Sciences
Jalgaon, India
Faculty of Health Sciences
University of the Witwatersrand
Arruje Hameed
Johannesburg, South Africa
Department of Biochemistry
Government College University Faisalabad Anurag Kulshreshtha
Pakistan Department of Polymer and Process Engineering
Indian Institute of Technology Roorkee
Zikhona Hayiyana Roorkee, India
Wits Advanced Drug Delivery Platform
Research Unit Bijender Kumar
Department of Pharmacy and Department of Polymer and Process Engineering
Pharmacology Indian Institute of Technology Roorkee
School of Therapeutic Sciences Roorkee, India
Faculty of Health Sciences
University of the Witwatersrand Jitendra Kumar
Johannesburg, South Africa ICAR—Indian Agricultural Research Institute
New Delhi, India
Hira Ijaz and
Faculty of Pharmacy ICAR—Institute of Pesticide Formulation
University of Sargodha Technology
Sargodha, Pakistan Gurugram, India
Contributors xv

Prabhat Kumar Yuvraj Singh Negi

Advanced Instrumentation Research Facility Department of Polymer and Process Engineering
Jawaharlal Nehru University Indian Institute of Technology Roorkee
New Delhi, India Roorkee, India

Pradeep Kumar Viness Pillay

Wits Advanced Drug Delivery Platform Wits Advanced Drug Delivery Platform
Research Unit Research Unit
Department of Pharmacy and Pharmacology Department of Pharmacy and Pharmacology
School of Therapeutic Sciences School of Therapeutic Sciences
Faculty of Health Sciences Faculty of Health Sciences
University of the Witwatersrand University of the Witwatersrand
Johannesburg, South Africa Johannesburg, South Africa
Mariana Magalhães Stavros Plessas
Department of Pharmaceutical Technology Department of Agricultural Development
and Democritus University of Thrace
REQUIMTE/LAQV, Group of Pharmaceutical Orestiada, Greece
Technology
Faculty of Pharmacy Ruchir Priyadarshi
University of Coimbra Department of Polymer and Process Engineering
Coimbra, Portugal Indian Institute of Technology Roorkee
Roorkee, India
Mahendra S. Mahajan
Department of Polymer Chemistry, School of Kalyani Prusty
Chemical Sciences Department of Chemistry
Kavayitri Bahinabai Chaudhari, North Veer Surendra Sai University of Technology
Maharashtra University Burla, India
Jalgaon, India
Junaid Qureshi
S. Majumder Department of Pharmacy
ICAR-Indian Agricultural Research Institute Bahauddin Zakariya University
New Delhi, India Multan, Pakistan
and
ICAR-Indian Institute of Vegetable Research K.V. Radha
Varanasi, India Department of Chemical Engineering, A.C.Tech.
Campus
Athanasios Mallouchos Anna University
Food Science and Human Nutrition Department Chennai, India
Agricultural University of Athens
Athens, Greece Maria Inês Ré
Université de Toulouse
Thashree Marimuthu IMT Mines d’Albi
Wits Advanced Drug Delivery Platform Albi, France
Research Unit
Department of Pharmacy and Pharmacology Kanwal Rehman
School of Therapeutic Sciences Institute of Pharmacy, Physiology and
Faculty of Health Sciences Pharmacology
University of the Witwatersrand University of Agriculture Faisalabad
Johannesburg, South Africa Faisalabad, Pakistan
Mònica Martínez Ufana Riaz
Department of Materials Science and Physical Materials Research Laboratory, Department of
Chemistry Chemistry
Universitat de Barcelona Jamia Millia Islamia
Barcelona, Spain New Delhi, India
xvi Contributors

Maria Helena Andrade Santana Najam Akhtar Shakil

Department of Biotechnological Processes ICAR-Indian Agricultural Research Institute
School of Chemical Engineering University of New Delhi, India
Campinas—UNICAMP
Campinas, Brazil Sauraj Singh
Department of Polymer and Process Engineering
Ana Cláudia Santos Indian Institute of Technology Roorkee
Department of Pharmaceutical Technology Roorkee, India
and
REQUIMTE/LAQV, Group of Pharmaceutical Sarat K. Swain
Technology Department of Chemistry
Faculty of Pharmacy Veer Surendra Sai University of Technology
University of Coimbra Burla, India
Coimbra, Portugal
Ume Ruqia Tul-Ain
S. Saranya Faculty of Pharmacy
Department of Chemical Engineering, A.C.Tech. University Of Sargodha
Campus Sargodha, Pakistan
Anna University
Chennai, India Christelle Turchiuli
UMR Ingénierie Procédés Aliments
Dhruba Jyoti Sarkar AgroParisTech, INRA
ICAR—Central Inland Fisheries Research Université Paris-Saclay
Institute Massy, France
Barrackpore, India and
and Université Paris Sud
ICAR—Indian Agricultural Research Institute IUT d’Orsay
New Delhi, India Université Paris-Saclay
Orsay, France
Niladri Sarkar
Department of Chemistry Francisco Veiga
Veer Surendra Sai University of Technology Department of Pharmaceutical Technology
Burla, India and
REQUIMTE/LAQV, Group of Pharmaceutical
Kalyan Kumar Sen Technology
Department of Pharmaceutics, Gupta College of Faculty of Pharmacy
Technological Sciences University of Coimbra
Ashram More Coimbra, Portugal
Asansol, India
Anurakshee Verma
Mariarenata Sessa Materials Research Laboratory, Department of
Department of Industrial Engineering Chemistry
University of Salerno Jamia Millia Islamia
Fisciano, Italy New Delhi, India

Nilesh Shah Fanwen Zeng

The Dow Chemical Company The Dow Chemical Company
Collegeville, Pennsylvania Collegeville, Pennsylvania
1
Multi-Cyclodextrin Supramolecular
Encapsulation Entities for Multifaceted
Topical Drug Delivery Applications

P. D. Kondiah, Yahya E. Choonara, Zikhona Hayiyana, Pariksha J. Kondiah,

Thashree Marimuthu, Lisa C. du Toit, Pradeep Kumar, and Viness Pillay

CONTENTS
1.1 Introduction....................................................................................................................................... 1
1.2 Cyclodextrin Properties That Confer Suitability in Drug Delivery Applications............................ 2
1.3 Types of Multi-Cyclodextrin Entities: Properties and Applications................................................. 3
1.3.1 Cyclodextrin-Based Polyrotaxanes...................................................................................... 3
1.3.2 Cyclodextrin-Based Nanosponges........................................................................................ 5
1.3.3 Cyclodextrin Polymers......................................................................................................... 6
1.4 Approaches to the Production of Cyclodextrins: Synthesis and Derivatives................................... 6
1.4.1 Cyclodextrin-Based Polyrotaxanes...................................................................................... 6
1.4.1.1 Threading Process................................................................................................ 6
1.4.1.2 Rotaxanation of Pseudopolyrotaxanes.................................................................. 7
1.4.2 Cyclodextrin-Based Nanosponges ....................................................................................... 7
1.5 Cyclodextrins and Multi-Cyclodextrins Applied for Topical and Targeted Drug Delivery............. 8
1.5.1 Tissue Surface Applications................................................................................................. 8
1.5.1.1 Ocular Surface Applications ................................................................................ 8
1.5.1.2 Oral Cavity and Tooth Surface Applications.......................................................11
1.5.1.3 Dermal Applications............................................................................................11
1.5.2 Mucosal Membrane Applications ..................................................................................... 12
1.5.2.1 Buccal Mucosa.................................................................................................... 12
1.5.2.2 Sublingual Mucosa ............................................................................................ 12
1.5.2.3 Nasal Mucosa...................................................................................................... 12
1.6 Conclusion....................................................................................................................................... 13
Conflict of Interest.................................................................................................................................... 13
Acknowledgments..................................................................................................................................... 13
References ................................................................................................................................................ 13

1.1 Introduction
Topical delivery systems are one of the most popular applications of controlled, encapsulated drug deliv-
ery platforms. This is due to the ease of administration and the direct application, which translates to site
specificity, enhanced therapeutic effectiveness, and elimination of systemic side effects, such as hepa-
totoxicity, through bypassing the hepatic metabolic processes (Park et al. 2017). Topical formulations
have to be compatible with the body surface at the intended area of administration, since interactions of
the formulation with the surface will affect the pharmacokinetic properties of bioactives. This includes
permeation across the biological membranes, drug release behavior, solubility, absorption, and the overall

1
2 Applications of Encapsulation and Controlled Release

pharmacological activity (Choudhury et al. 2017). Various drug delivery systems are constantly being
developed to improve the pharmacokinetics of topically delivered drug molecules (Choudhury et al 2017).
Recent researches have revealed the capability of cyclodextrins (CDs) in enhancing drug permeability,
solubility, and bioavailability without severely altering the biological barrier as well as the drug func-
tionality (Xu et al. 2018). CDs form one of the most versatile technologies that have the capability to
encapsulate a wide range of drug molecules for a variety of applications (Sherje et al. 2017). This chapter
aims to highlight the application of CDs in topical drug delivery and how their benefits can be modified
through the formulation of multi-cyclodextrin entities. The topical administration routes discussed in this
chapter are divided into three categories: surface of tissues (ocular, oral cavity, and tooth surface routes),
skin (dermal route), and mucous membranes (buccal, sublingual, and nasal). The current applications of
CDs in these routes are elaborated and the substantial benefit of multi-cyclodextrin entities proposed.

1.2 Cyclodextrin Properties That Confer Suitability

in Drug Delivery Applications
CDs are cyclic oligosaccharides composed of glucopyranose rings co-joined by the α-1, 4 glycosidic
bonds (Xiao and Grinstaff 2017). There are three common types used in drug delivery: α- (six rings),
β- (seven rings), and γ-cyclodextrins (eight rings) (Gautam et al. 2017). Cyclodextrin forms are differ-
entiated by size and diameter of the central cavity, solubility, molecular weight, and toxicity profiles. All
the configurations of cyclodextrins are water soluble with some limitations (Zhu, Yi and Chen 2016).
Important features of CDs that make them ideal for drug delivery are their amphipathic nature, with an
inner hydrophobic central cavity and a hydrophilic outer surface, and the ability to form inclusion and
non-inclusion complexes with other compounds. The lipophilicity of the central cavity is imposed by
the presence of the glycosidic oxygen bridges and hydrogen atoms, while the hydrophilicity of the outer
surface is due to the presence of numerous primary and secondary hydroxyl groups (Sherje et al. 2017).
When CDs incorporate lipophilic, low–molecular weight, and accurately sized compounds within their
central cavity through non-covalent interactions, an improvement in permeability and aqueous solubil-
ity, stability (chemical, hydrolytic, thermal, etc.), dissolution rate, site specificity, and bioavailability
is obtained (da Silva Mourão et al. 2016). Cyclodextrins are generally non-toxic; however, different
administration routes could impose certain adverse effects: for example, the parenteral route of admin-
istration causes nephrotoxicity due to renal clearance (Azzi et al. 2018). This nephrotoxicity is most
prominent on parenteral administration of α- and β-cyclodextrins (Azzi et al. 2018) and oral administra-
tion of some β-cyclodextrin derivatives (Lucio et al. 2018). Cyclodextrins have been reported to exert
hemolytic activity at high concentrations (Yang et al. 2018). The toxicity profile of cyclodextrins is
summarized in Table 1.1.
Host–guest chemistry (inclusion complex formation) is the process of incorporating a chemical agent
within another; in this case, the cyclodextrin molecule is the host, and the lipophilic compound, usually
a bioactive agent, functions as the guest (Barman and Roy 2018a). The product formed is known as an

TABLE 1.1
Characteristic Features of α, β, and γ-Cyclodextrins
Central Solubility Contraindicated
Cyclodextrin Cavity Molecular in Water Routes of
Molecule Diameter (Å) Weight (g/mol) (mg/mL) Administration Specific Toxicity
α-cyclodextrin 4.5 972 145 Intravenous Hemolysis and nephrotoxicity
Li et al. (2004), Lockwood,
O'Malley and Mosher (2003)
β-cyclodextrin 7.0 1135 18.5 Intravenous Hemolysis and nephrotoxicity
Li et al. (2004), Lockwood,
O'Malley and Mosher (2003)
γ-cyclodextrin 8.5 1297 232 N/A Hemolysis Li et al. (2004)
Multi-Cyclodextrin Supramolecular Encapsulation Entities 3

inclusion complex. Inclusion complexes are supramolecular cages composed of active molecules incor-
porated within the cyclodextrin core in a 1:1 interaction ratio (Barman and Roy 2018b), as displayed in
Figure 1.1 (Kayaci and Uyar 2011; Kida et al. 2003), with adequate water solubility and complex revers-
ibility (Cai, Huang, and Li 2017). Inclusion complex formation is best carried out in aqueous solutions,
where enthalpy-rich water molecules are released from the cyclodextrin cavity, allowing inclusion or
non-inclusion interactions with the guest compound (Tambe et al. 2018). The inclusion or non-inclusion
interaction is largely influenced by the size, molecular weight, polarity, ionic charge, solubility, and sta-
bility of the guest molecule in aqueous solutions. These properties, therefore, determine the selectivity
of cyclodextrins to include certain compounds over others (Suvarna, Gujar, and Murahari 2017). The
formation of inclusion complexes may significantly alter the biological and physicochemical parameters
of the incorporated compound (Pápay et al. 2016).
The binding of CD molecules to cholesterol and other phospholipid components of the biological
membrane after topical administration improves membrane permeability (Duchêne and Bochot 2016).
The extraction of these biological components leads to the opening up of pores, which allows greater
permeation of the formulation than would be expected in the absence of CDs (Ryzhakov et al. 2016). The
aqueous solubility of lipophilic compounds is improved due to the bonding between the hydroxyl groups
of CDs and the substituent molecules (Mayank and Rajashree 2018) as well as the presence of external
surface hydroxyl groups. Since CDs form stable complexes in certain solutions, this enables their use
as solubilizing encapsulating agents (Ol'khovich et al. 2017). In addition, the formation of an inclusion
complex improves the stability of the included compound by protecting it against chemical degrada-
tion, hydrolysis, and oxidation due to the resultant minimal interaction between the compound and the
external environment (Ho et al. 2017). The cumulative result of all these processes leads to enhanced
dissolution rate and bioavailability of the guest compound at the targeted site, followed by controlled
release (Zhang et al. 2017). These functions have been experimentally investigated within drug delivery
parameters with good outcomes. CDs have become a subject of interest in gene delivery. One of the early
used polymers in gene delivery is polyethylenimine. The limitations associated with using this com-
pound, such as high toxicity, have led to the investigation of other compounds that could serve the same
functions in more efficient ways. CDs have been tested for localized gene delivery, stabilization of labile
proteins, DNA, and RNA, and increasing the transfection efficiency of nucleic acids. CDs do not elicit
immune responses in vivo and thus have low toxicity (Biscotti et al. 2018). Bellocq et al. (2004) reported
a synthetic biocompatible cyclodextrin-based delivery system with localized and sustained delivery of
growth factors for wound healing therapy. A β-cyclodextrin–poly(ethylenimine) complex in nanopar-
ticulate form was used as the controlled delivery vehicle for nucleic acids. The overall improvement
achieved by this cyclodextrin-based carrier was high affinity of binding to the target site, as confirmed
in a study conducted by Park and co-workers (Park et al. 2006).

1.3 Types of Multi-Cyclodextrin Entities: Properties and Applications

Multi-cyclodextrin entities are amphiphilic cyclodextrin derivatives that are formed through the assem-
bly of cyclodextrin molecules. They possess unique mechanical and stimuli-responsive properties and
significant drug encapsulation and controlled release features. The multi-cyclodextrin moieties of inter-
est include cyclodextrin-based polyrotaxanes, cyclodextrin-based nanosponges, and cyclodextrin poly-
mers (Liu et al. 2018).

1.3.1 Cyclodextrin-Based Polyrotaxanes
Polyrotaxanes (PRs) are formed when the bucket-shaped cyclodextrin molecule is threaded onto a
compound with a linear geometry, such as polyethylene glycol (PEG) (Bai et al. 2018). The occur-
rence of threading is encouraged by bond formation, which takes place between the oligosaccharide
and the linear polymeric molecules as a result of non-covalent interactions. PRs can be used as host–
guest-based controlled delivery systems for drugs, peptides, proteins, and enzymes because of their
ability to form inclusion and non-inclusion complexes. They undergo spontaneous de-complexation in
4 Applications of Encapsulation and Controlled Release

FIGURE 1.1 Schematic representation of (a) inclusion complex; (b) novel cyclodextrin derivatives incorporating one
β-(1,4)-glucosidic bond, with the skeleton-modified cyclodextrin fitting the size and shape of the guest molecule. ([a]
Reprinted with permission from Kayaci, F. and T. Uyar. 2011. Solid inclusion complexes of vanillin with cyclodextrins:
their formation, characterization, and high-temperature stability. Journal of Agricultural and Food Chemistry 59, no. 21:
11772–11778. Copyright 2011 American Chemical Society. (b) From Kida, T., A. Kikuzawa, Y. Nakatsuji, and M. Akashi.
2003. A facile synthesis of novel cyclodextrin derivatives incorporating one β-(1,4)-glucosidic bond and their unique inclu-
sion ability. Chemical Communications no. 24: 3020–3021. Reproduced by permission of The Royal Society of Chemistry.)

aqueous solutions and physiological media under specified temperature conditions. PRs possess a unique
architecture, which can be ideal for use in encapsulated and targeted drug delivery (Resmerita et al.
2017). They function as stimuli-responsive supramolecular architectures by attaching to compounds
with target-associated activity, such as peptides, proteins, etc., which respond to the stimulus at spe-
cific receptor sites. Different factors can be manipulated to ensure targeted controlled drug delivery,
Multi-Cyclodextrin Supramolecular Encapsulation Entities 5

such as pH, temperature, and the attachment of antibodies to the polyrotaxane structure (Gómez et al.
2018). A prednisolone–α-cyclodextrin-star poly (ethylene glycol) poly-pseudopolyrotaxane with delayed
pH-sensitive behavior was synthesized for targeted drug delivery. Prednisolone is an anti-inflammatory
gluco-corticosteroid used for various autoimmune diseases. This class of drugs has very serious side
effects, and targeted delivery could potentially decrease the dose needed to produce the pharmacologi-
cal activity. Encapsulation of prednisolone within the pseudopolyrotaxane provides structural protection
against acid hydrolysis and could potentially reduce the dose and frequency of administration (Resmerita
et al. 2017).
Molecular recognition and self-assembly of supramolecular architectures are achieved through bind-
ing or encapsulation (Qin et al. 2017). The molecular recognition effect of PRs can be enhanced by conju-
gating other functional agent(s) (biological/chemical compounds) to the polyrotaxane structure (Adeoye
and Cabral-Marques 2017), and this also functions to impart improved water solubility. For example,
Choi and co-workers revealed that the addition of saccharide groups to cyclodextrin molecules threaded
in a polyrotaxane increased the biomolecular recognition of lectin due to the mobility of the CDs affect-
ing the intermolecular interactions (Choi et al. 2006), while in another study, a bis-(β-cyclodextrin) was
synthesized and possessed multiple binding sites and recognition abilities, whereby a hydrophobic agent
was incorporated, and the other site was determined to be suitable for metal binding (Cheng et al. 2003).

1.3.2 Cyclodextrin-Based Nanosponges
Cyclodextrin-based nanosponges (CDNS) are cyclodextrin cross-linked supramolecular architectures.
The cross-linking is stabilized by non-covalent interactions such as hydrogen bonding, van der Waal’s
forces, ionic interactions, etc. They are dichotonic, hyper-cross-linked, porous, colloidal nanosys-
tems (Caldera et al. 2017). They function as nanocarriers for a range of hydrophilic and lipophilic
compounds with marked encapsulation efficiency (Morin-Crini et al. 2018). The encapsulation effi-
ciency is markedly affected by the nature of the cross-linking agent; therefore, the fine tuning of the
cyclodextrin to cross-linker ratio can improve drug loading, solubility, and controlled release kinetics.
Nanosponges have a higher number of cyclodextrin molecules interconnected as compared with pure
cyclodextrins; this is the reason for their significant swelling in aqueous solutions and a common
mode of controlled drug release platforms (Gabr, Mortada, and Sallam 2018). They can be transported
through aqueous media and improve the aqueous solubility of compounds with high lipophilicity
(Caldera et al. 2017).
CDNS have found wide applications as novel excipients in drug delivery (Pushpalatha,
Selvamuthukumar, and Kilimozhi 2018). This is due to the availability of various forms of nanosponges
due to the cross-linking agent used, which is responsible for imparting new functional groups that pro-
vide novel structure–activity relations. Cross-linking agents such as diphenylcarbonate, pyromellitic
dianhydride, epichlorohydrin, etc. have been extensively researched in the development of innovative
nanosponge systems. These nanosponge forms are useful in numerous drug administration routes, as
explained in the following paragraphs.
Carboxylated CDNS have been synthesized and used in the oral delivery of acyclovir, an antiviral
drug used to treat herpes simplex virus (Lembo et al. 2013). The challenges that surround the delivery of
acyclovir lie in the fact that it possesses a low oral bioavailability of about 10–30% because of slow and
incomplete absorption in the gastrointestinal tract. The encapsulation of acyclovir in carboxylated CDNS
resulted in prolonged release properties of the acyclovir drug and efficient enhancement of its antiviral
efficacy in vitro on an HSV-1-based cell line. CDNS were also synthesized using diphenylcarbonate as
a cross-linker (Minelli et al. 2012). These nanosponges were further used to incorporate camptothecin,
an efficacious antitumor agent for hematological and solid tumors. This agent is highly labile in physi-
ological environments due to the presence of the lactone ring in each chemical structure, which makes it
highly susceptible to hydrolysis. Therefore, it is prone to chemical degradation and has very low aqueous
solubility. The encapsulation resulted in prolonged release of camptothecin with an increase in concen-
tration over time. The in vitro efficacy of camptothecin-loaded diphenylcarbonate CDNS was improved,
as cytotoxicity was achieved at lower concentrations compared with commercial camptothecin formula-
tions. The anti-proliferative effect and DNA damage were more pronounced, and proper stabilization
6 Applications of Encapsulation and Controlled Release

of the drug was achieved. A ternary mixture of β-cyclodextrin nanosponges, itraconazole, and copoly-
vidonum was formulated by Swaminathan and co-workers (Swaminathan et al. 2007). Itraconazole is
a biopharmaceutical classification system class II drug with dissolution rate–limited bioavailability.
Copolyvidonum is a water-soluble polymer used in this mixture to enhance the encapsulation efficiency
of the nanosponges (Swaminathan et al. 2007). The ternary mixture provided great improvement in the
solubility of itraconazole, evidenced by the phase solubility studies, and therefore overcame the chal-
lenge of low bioavailability, as expected.

1.3.3 Cyclodextrin Polymers
Cyclodextrin-based polymers were the first of the supramolecular architectures to be fabricated. They
are chemically linked cyclodextrin molecules produced using cross-linking agents such as epichlorohy-
drin or modification with other polymers (Chang et al. 2018). They can be either soluble or insoluble in
water, depending on the chemicals used for their formation, and this directly affects their applications
(Li et al. 2018). Cyclodextrin polymers have found a wide variety of applications in controlled drug
delivery due to their low toxicity profiles by numerous administration routes. Cyclodextrin polymers
are usually modified with other polymeric agents such as polyethylenimine, chitosan, hyaluronic acid,
etc. Cyclodextrin-based polymers have been used extensively in gene and drug delivery applications.
Zawko and co-workers prepared hyaluronic acid–based hydrogels functionalized with the methacryloyl
derivative of β-cyclodextrin for the delivery of hydrocortisone (Zawko, Truong, and Schmidt 2008).
Functionalization with a cyclodextrin contributes inclusion complex–forming capability to the hyal-
uronic acid hydrogel, and the system can be used in various drug delivery routes and dosage forms.
A similar study was undertaken by Das and Subuddhi, in which preformed cyclodextrin and naproxen
complexes were incorporated in a pH-responsive hydrogel made from chitosan and polyvinyl alcohol,
cross-linked with glutaraldehyde as a colon-targeted delivery system, which was successful in deliver-
ing drug only in the intestinal fluid (Das and Subuddhi 2013). Thus, this delivery system could function
well as a controlled drug-encapsulated platform intended to act specifically in the large intestine and for
localized disease treatment.

1.4 Approaches to the Production of Cyclodextrins: Synthesis

and Derivatives
Generally, cyclodextrins are produced by the enzymatic degradation of starch, specifically the amylase
component. This reaction is catalyzed by the glucosyltransferase enzyme (Zhang et al. 2017). The pro-
duction of α- and β-cyclodextrins occurs naturally in the presence of the bacterium Bacillus macerans
(Pal, Gaba, and Soni 2018).

1.4.1 Cyclodextrin-Based Polyrotaxanes
Polyrotaxanes are synthesized through the threading of cyclodextrin molecules on linear inclusion com-
pounds and/or the rotaxanation of pseudopolyrotaxanes (Li et al. 2016). The polyrotaxane yield is depen-
dent on temperature control, reaction time, type of inclusion compound, molecular weight, and solvent type.

1.4.1.1 Threading Process
Cyclodextrin molecules are threaded onto a linear polymeric inclusion compound such as polydimeth-
ylsiloxane (PDMS) in the presence of a polar aprotic solvent (dimethyl formamide [DMF], dimethyl
sulfoxide [DMSO], or acetonitrile), and the pseudopolyrotaxane (Figure 1.2a and b) precipitates are col-
lected by centrifugation, filtration, or lyophilization (Iguchi et al. 2013). The threading process is driven
by thermodynamic variations. The first reported synthesis involved the use of cyclodextrins threaded on
PEG (Poudel et al. 2018). The product obtained can be either single or multiple cyclodextrin molecules
Multi-Cyclodextrin Supramolecular Encapsulation Entities 7

FIGURE 1.2 Diagrammatic representation of the nomenclature of cyclodextrin-based pseudopolyrotaxanes (a) single
ring-like cyclodextrin molecule threaded on a linear compound, (b) multiple ring-like cyclodextrin molecules threaded on
a linear compound and polyrotaxanes, and (c, d, and e) one, two, and multiple ring-like cyclodextrin molecules threaded on
a linear compound capped with a stopper molecule to prevent de-threading.

threaded on the linear compound, as seen in Figure 1.2a and b. All this is a result of attenuation in the
reaction parameters.

1.4.1.2 Rotaxanation of Pseudopolyrotaxanes
To prevent the occurrence of de-threading of the cyclodextrins, an end-capping molecule is added at both
ends of the linear compound. This process is known as rotaxanation. The end-capping molecules should
have very concrete specificity for the linear molecule to prevent reaction with the cyclodextrin molecules
(Alvarez-Lorenzo, García-González, and Concheiro 2017). The rotaxanation of pseudopolyrotaxanes pro-
duces polyrotaxanes (Figure 1.2c–e). The difference between pseudopolyrotaxanes and polyrotaxanes is
that pseudopolyrotaxanes easily de-thread in aqueous solutions due to the absence of end-capping mole-
cules and easily separate in aqueous solutions, while polyrotaxanes remain insoluble (Higashi et al. 2017).

1.4.2 Cyclodextrin-Based Nanosponges
Nanosponges are synthesized through the cross-linking of cyclodextrins and further reduction to a
nanorange size (Singh et al. 2018). Their shapes may vary, ranging from spherical to rod-like structures.
The techniques employed in synthesis include solvent techniques and ultrasound synthesis. Solvent tech-
niques, cross-linking cyclodextrins in the presence of a polar aprotic solvent such as DMF or DMSO, and
the ultrasound-assisted method ensure the proper cross-linking of cyclodextrins (Leudjo Taka, Pillay,
and Yangkou Mbianda 2017). The products are collected and washed with water to remove the non-
reacted residues and dried in an oven at 60 ˚C, which is followed by a purification process (soxhlet extrac-
tion) using ethanol. The chemical nature of the cross-linker offers novel and peculiar properties to the
CDNS. Moreover, the controlled drug release behavior from the complex varies according to the concen-
tration of the cross-linkers employed during the synthesis. Similar reports were discussed by Caldera and
co-workers (Caldera et al. 2017), evaluating the degree of cross-linking with CD nanosponges employ-
ing the popular cross-linker pyromellitic dianhydride. Spectroscopic evaluation proved that the highest
degree of cross-linking was obtained using a molar ratio of 1:6 (CD: pyromellitic dianhydride). Higher
molar ratios showed a decrease in the degree of cross-linking, possibly due to steric hindrance from the
cross-linker linked to the CD units. Figure 1.3 thus explains the synthesis reaction, employing CDs as
controlled release nanosponges, with significant influence of the cross-linker in relation to the optimum
physico-chemical properties of the system (Caldera et al. 2017).
Cyclodextrin polymers are synthesized via various methods: cross-linking with other reagents, polym-
erization of acrylic monomers with cyclodextrins, and linking to a polymeric backbone through either
covalent bonding or physical encapsulation in a polymeric chain (Thomsen et al. 2017). The most com-
mon of these methods is cross-linking bifunctional reagents such as di-epoxides.
8 Applications of Encapsulation and Controlled Release

FIGURE 1.3 Schematic representation of cyclodextrin-based nanosponges employing a pyromellitic cross-linker for
controlled release kinetics. (From International Journal of Pharmaceutics, 531, Caldera, F., M. Tannous, R. Cavalli,
M. Zanetti, and F. Trotta, Evolution of cyclodextrin nanosponges, 470–479, Copyright (2017), with permission from Elsevier.)

1.5 Cyclodextrins and Multi-Cyclodextrins Applied

for Topical and Targeted Drug Delivery
Topical and localized drug delivery is the direct administration of pharmaceuticals for local effects. This
mode of drug delivery is advantageous due to site targeting, elimination of systemic effects, and improved
drug encapsulation efficiency. This route of drug delivery presents inherent benefits. These include
bypassing hepatic clearance, which improves drug bioavailability, limited systemic adverse events due
to toxic drug blood levels, and prevention of unwanted effects in other body organs. Cyclodextrins, after
topical administration, increase the amount of drug available at the surface of biological membranes
such as the surface of tissues, skin, and mucosal membranes. This improves the drug’s bioavailability by
ensuring that the drug is available for absorption. It has been suggested in previous work that cyclodex-
trins themselves do not penetrate biological membranes (Shelley and Babu 2018). After delivering the
drug to the membrane surface, cyclodextrins remain extracellular, as seen in Figure 1.4. This also means
that possible intracellular damage is avoided. By attaching to the membrane surface, cyclodextrins may
also improve the membrane permeability by binding with membrane components. Cyclodextrins are
non-irritant to the surfaces of tissue, skin, and mucosa.
The applications of cyclodextrins for topical drug delivery are described primarily under three clas-
sifications: the surface of tissues and the dermal and mucosal routes. According to this classification, the
tissue surface route of administration includes the eye, oral cavity, and tooth surfaces. The mucosal route
includes buccal, sublingual, and nasal. Cyclodextrin-based formulations used for application in these
routes are discussed in the following subsections.

1.5.1 Tissue Surface Applications

1.5.1.1 Ocular Surface Applications
Many ocular diseases are treated by surgery as well as administration of therapeutics by means of topi-
cal routes, intravitreal injection, or implantation. However, these administration routes are generally
accompanied by complications that could have potential detrimental effects on the eye, which could lead
Multi-Cyclodextrin Supramolecular Encapsulation Entities 9

FIGURE 1.4 Diagrammatic representation of the pathway taken by cyclodextrin complexes after topical administration
to biological membranes. Biological membranes have components such as phospholipids and cholesterol; their locations
are the primary sites of entry of the drug. The cyclodextrin extracts these components to form inclusion complexes, which
remain in the extracellular space until excretion takes place. The drug diffuses in through these new temporary pores. Drug
diffusion also occurs through membrane transport pathways.

to severe vision impairment or blindness (Loftsson and Stefánsson 2017). The challenges associated with
topical drug delivery systems for ocular diseases mainly revolve around penetration, absorption, solubili-
zation, and bioavailability limitations. These are exerted by the natural makeup of the eye as well as the
disease state. The ocular biofactors that significantly affect therapeutic effectiveness are the biological
membranes, such as the cornea, sclera, and blood–retinal barrier, by notably affecting drug perme-
ation and fluid drainage mediated through lacrimation, which may lead to premature drug elimina-
tion. The chemical degradation of drugs by ocular enzymes alters their absorption, therapeutic activity,
and bioavailability (Jóhannsdóttir et al. 2017). The ideal properties of compounds intended for topical
administration to the eyes are that they should be lipophilic enough to cross the ocular membranes and
hydrophilic enough for stability and solubility in the aqueous humor; ultimately, they should be amphi-
philic in nature. The use of cyclodextrins and multi-cyclodextrins achieves this, as they are amphiphilic
compounds with a hydrophobic central cavity and an outer hydrophilic surface. A number of lipophilic
drugs exist with applications in ocular disease treatment that have poor aqueous solubility and low bio-
availability; cyclodextrins combat this through their outer hydrophilic surface, which provides stability
in aqueous media and therefore, enhanced aqueous solubility (Jansook, Ogawa, and Loftsson 2018).
Jansook and co-workers reported that the use of γ-cyclodextrin modified with hydroxypropyl methyl-
cellulose (HPMC) for the delivery of dorzolamide produced controlled drug release and improved the
permeation and bioavailability of the drug to the posterior segment of the eye (Jansook et al. 2010). The
major drawback of this group of drugs is its side effects. The γ-cyclodextrin/HPMC system could offer the
possibility of reduced dosage with appropriate therapeutic success and delivery for drugs that can cause
extreme adverse events. Another study aimed at improving the delivery of carbonic anhydrase inhibitors
using a hydrophilic acrylic hydrogel with a built-in pendant cyclodextrin. The application of this delivery
system achieved adequate penetration and bioavailability for acetazolamide and ethoxzolamide. Ribeiro
and co-workers reported that the delivery system could be used for other antiglaucoma drugs (Ribeiro et
al. 2012). According to Tanito and co-workers, cyclodextrins were well tolerated when applied topically
to the eye. The study involved the use of cyclodextrins in a dexamethasone eye drop formulation. Clinical
10 Applications of Encapsulation and Controlled Release

FIGURE 1.5 HET-CAM test result of (a) γ-cyclodextrin: HPMC nanogel, (b) negative control (saline), and (c) posi-
tive control (0.1 N NaOH). The test gave an irritation score close to zero for the nanogel and negative control, confirm-
ing that the nanogel is non-irritant. (From International Journal of Pharmaceutics, 441, Moya-Ortega, M., T. Alves, C.
Alvarez-Lorenzo, A. Concheiro, E. Stefánsson, M. Thorsteinsdóttir, and T. Loftsson, Dexamethasone eye drops containing
γ-cyclodextrin-based nanogels, 507–515, Copyright (2013) with permission from Elsevier.)

trials demonstrated that the active component, dexamethasone, maintained its efficacy against diabetic
edema, decreased central macular thickness, and greatly enhanced visual acuity (Tanito et al. 2011).
Alvarez-Lorenzo and co-workers reported the development of γ-cyclodextrin-based drug-loaded nanogels
by cross-linking γ-cyclodextrin using an emulsification/solvent evaporation process. These aqueous con-
trolled release eye drops were specifically studied for in vivo topical administration to rabbits. Moreover,
the study revealed that the formulation showed reduced appearance and severity of side effects such as
irritation, redness, and localized lethal effects (Figure 1.5) (Moya-Ortega et al. 2013). These nanogels can
be applied to treat diseases that require an extended duration of treatment.
The use of cyclodextrin-based polyrotaxanes and nanosponges in future can offer the delivery of both
hydrophilic and lipophilic agents and macromolecules and achieve targeted and controlled drug delivery
(Sherje et al. 2017). Cyclodextrin-based polyrotaxanes can be used as transport-targeted delivery sys-
tems of prodrugs to overcome chemical degradation and can be linked to the prodrug activating agents
to ensure complete therapeutic activity at the site of action. The targeting of ion channels/transporters is
also possible. These cyclodextrin-based supramolecular architectures are amphiphilic in nature, which
is ideal for permeation of the extracellular matrix and the inner endothelium layer (Li et al. 2016). Their
physical nature bypasses melanin binding in the uvea; therefore, there is no disruption in drug phar-
macological activity, as melanin is most likely to bind to lipophilic agents, and these supramolecular
architectures have an outer hydrophilic layer. Since cyclodextrin-based supramolecular architectures can
entrap both hydrophilic and hydrophobic drugs, they can improve the delivery of these agents to both the
anterior and the posterior segments of the eye (Figure 1.6).

FIGURE 1.6 Diagrammatic representation of the mechanism of permeability enhancement exerted by cyclodextrin-based drug
delivery systems. A reversible inclusion complex of a cyclodextrin and drug molecule forms on topical administration to the eye.
The cyclodextrin extracts phospholipids and cholesterol from the biological membrane, which opens up temporary pores that
function as sites of entry for the drug molecules, while the cyclodextrins themselves are excreted through the uveoscleral pathway.
Multi-Cyclodextrin Supramolecular Encapsulation Entities 11

1.5.1.2 Oral Cavity and Tooth Surface Applications

Loftsson and co-workers investigated the effects of β-cyclodextrins and their hydrophilic deriva-
tives on silica-based triclosan toothpaste (Loftsson et al. 1999). The study found that the addition of
β-cyclodextrins enhanced triclosan solubilization. The combination of triclosan, β-cyclodextrin, and
carboxymethylcellulose increased the bioavailability, duration of action, and substantivity of triclosan.
The tooth surface is covered by tooth enamel, whose main component is hydroxyapatite (HA). Lee and
co-workers developed a biomineral-binding conjugate of alendronate–β-cyclodextrin (Liu et al. 2007).
The conjugate showed a very strong binding affinity for HA. This conjugate holds great potential as a
novel delivery system for oral cavity–localized diseases such as tooth decay, periodontitis, etc.

1.5.1.3 Dermal Applications
Skin has a prominent barrier function, and hence, the need to develop an optimized drug delivery for-
mulation that overcomes these barriers is indispensable; otherwise, the bioactives may achieve only lim-
ited bioavailability (Bianchi et al. 2018). The properties required for an appropriate skin drug delivery
chemical enhancer are: (i) it must be pharmaceutically inert, (ii) non-toxic and immediate and reversible
in action, (iii) chemically and physically compatible, and (iv) cosmetically acceptable. Excipients such
as cyclodextrins, when incorporated in pharmaceutical formulations, can extract dermal lipids, opening
pores, which improves bioactive permeation and bioavailability for better therapeutic efficiency and
efficacy (Sakulwech et al. 2018).
An attempt to overcome the challenges of dermal drug delivery using cyclodextrins has been made
with success in the past. These include an increase in absorption, dissolution and solubility, skin perme-
ability, and controlled release. Randomly methylated β-cyclodextrin (RAMEB) and 2-hydroxypropyl
β-cyclodextrin (HP-β-CD) were reported earlier to incorporate a central dopaminergic agonist, piri-
bedil, and were found to extract all the major classes of lipids, thus being able to open up more pores
for penetration. Furthermore, they enhanced the percutaneous absorption of S-9977 hydrochloride (a
cognition-enhancing drug) (Legendre et al. 1995). The combination of RAMEB with oleic acid caused
the flux of S-9977 to increase about 30-fold. This delivery system could benefit other drugs with limited
penetration. In another study, β-cyclodextrin and HP-β-CD were complexed with ketoprofen, a non-
steroidal anti-inflammatory and analgesic agent, which is insoluble in aqueous media. The complexes
were incorporated in multilamellar vesicle liposomes and are expected to positively influence drug pen-
etration enhancement and improve drug efficacy (Maestrelli et al. 2005). In a similar study performed by
Maestrelli and co-workers, the cyclodextrin complexation improved drug solubilization and entrapment
efficiency in the aqueous phase of the liposome structure with extended release kinetics (Maestrelli et
al. 2006). The effect of pH on the solubility of the drug–HP-β-CD complex was determined by using
different concentrations of the complex at varying pH values. The ionized drug complex had a 2.5-fold
increase in solubility as compared with the unionized complex and a much better intrinsic permeabil-
ity (Sridevi and Diwan 2002). Sigurðoardottir reported on the effect of polyvinylpyrrolidone on cyclo-
dextrin complexation of hydrocortisone and its diffusion through hairless mouse skin (Sigurðoardóttir
1995). The study revealed that with a gradual increase in the cyclodextrin concentration and a constant
hydrocortisone concentration, a flux of hydrocortisone was observed until all its molecules were in solu-
tion following a flux decrease, resulting in increased cyclodextrin concentration. The addition of oleic
acid to the system further enhanced the permeation capacity.
The application of multi-cyclodextrins in topical skin drug delivery would provide a more pronounced
benefit as compared with unmodified cyclodextrins. Based on the applications of multi-cyclodextrin enti-
ties for other drug administration routes, by use of appropriate concentrations and further modification,
can produce the desired mode of drug release. Multi-cyclodextrin entity based delivery systems can be
manipulated to form different dosage forms including patches which achieve controlled and prolonged
drug release. One of the challenges of dermal drug delivery is that most drugs, especially hydrophilic
drugs, do not possess a suitable partition coefficient to interact with lipids (Sakulwech et al. 2018). Hence,
the use of multi-cyclodextrin entities such as nanosponges would enable the encapsulation of these agents
and achieve enhanced and targeted drug delivery when using polyrotaxanes.
12 Applications of Encapsulation and Controlled Release

1.5.2 Mucosal Membrane Applications

The mucous membranes cover internal organs (buccal, nasal, and sublingual mucosae) and form linings
in cavities exposed to external organs. The nasal mucosa–targeting drugs are commonly formulated as
nasal sprays, allowing maximum absorption for immediate therapeutic benefits. Thus, these routes of
administration are essential for bypassing hepatic metabolism, allowing significant concentrations of
encapsulated drug to be absorbed due to the profusely rich blood supply.

1.5.2.1 Buccal Mucosa
Buccal drug delivery is advantageous due to its high patient acceptance as compared with other non-oral
drug administration routes (Mura et al. 2016). Therapeutic benefits are produced through the following
mechanisms: bypassing liver clearance, direct access to systemic circulation, and therefore, enhanced
bioavailability. The disadvantages are that the buccal membranes possess low penetrability and sur-
face area. Cyclodextrins have been proved to provide various benefits in buccal drug delivery, such as
improvement in permeation, stability, solubility, absorption, muco-adhesiveness, and the rate of dissolu-
tion. Figueiras and co-workers used methylated cyclodextrins as penetration enhancers for omeprazole,
a hydrophobic agent that is highly unstable in neutral conditions (Figueiras et al. 2009). When the drug
was complexed with pure β-cyclodextrins and methyl-β-cyclodextrins separately, both its stability and its
penetration capacity were enhanced. A successful delivery system for carvedilol was reported by using
methyl-β-cyclodextrins. The challenges in the use of carvedilol are its high metabolic clearance and poor
solubility. Methyl cyclodextrin–based buccal tablets enhanced its muco-adhesive strength, permeation,
and bioavailability (Mura et al. 2016). Another cyclodextrin derivative, HP-β-CD, has been reported for
the effective delivery of darifenacin through the buccal route. Darifenacin is a urinary antispasmodic
with significantly poor solubility and bioavailability of about 15–19% (Jagdale et al. 2013). Complexation
with cyclodextrins produced an enhanced dissolution rate as compared with the free drug powder. This
was administered using a patch dosage form, bypassing hepatic metabolism, with HP-β-CD significantly
enhancing buccal absorption.

1.5.2.2 Sublingual Mucosa
Mannila and co-workers used α-cyclodextrins and chitosan derivatives to deliver low-solubility peptides
intra-orally (sublingually) using cyclosporine, a hydrophobic agent, as the model peptide. This study
confirmed enhanced solubility of the α-cyclodextrin–cyclosporine complexes as compared with the pure
peptide agent (Mannila et al. 2009). The complexes had improved sublingual bioavailability. The addi-
tion of chitosan derivatives did not significantly affect the pharmacokinetic properties, substantiating
α-cyclodextrin as a plausible drug delivery system alone. When a formulation is applied sublingually,
it undergoes absorption due to profuse blood capillaries in the connective tissue under the epithelium.
This route of drug delivery has received great attention as a solution in the delivery of labile peptides
and proteins. As indicated, the major challenge in the delivery of hydrophobic drugs is their erratic and
insufficient oral bioavailability. Researchers have reported the use of pure and modified cyclodextrins
as mucosal membrane–localized delivery systems with improved solubility, penetration, and absorption.
Hydrophobic drugs and labile peptides and proteins also displayed enhanced bioavailability using cyclo-
dextrins (Jagdale et al. 2013).

1.5.2.3 Nasal Mucosa
The nasal route of drug delivery has been used for localized interests as well as the delivery of drugs to
other parts of the body (e.g., the circulatory system) (Yalcin et al. 2016). Methyl-β-cyclodextrin, a hydro-
philic cyclodextrin derivative, was found to act as a potent nasal absorption enhancer for peptides. This
research can be dated a while back to studies undertaken by Romeijn and co-workers (Romeijn et al.
1990). The methylated β-cyclodextrin derivative is also known to function as a paracellular permeation
enhancer, opening up the tight junctions in the nasal epithelium. Hydrophilic derivatives of cyclodextrins
Another Random Scribd Document
with Unrelated Content
good-looking, and smart dresses become me; I could perfectly well
produce a son, but then my husband is old.”
Then the word of God came to Abraham, and said, “Wherefore did
Sarah laugh? Am I, the all-powerful God, too old to create miracles?
At the appointed time Sarah shall have a son.” To Sarah, who, out of
fear, denied having laughed, the word came, “Fear not, but thou
didst laugh.”
Then Michael withdrew, for his mission was accomplished; and left
the other two, Gabriel and Raphael, with Abraham. Then God
revealed to Abraham, by Gabriel, that He was about to destroy the
cities of the plain; and by Raphael, that He would deliver Lot and his
family in the overthrow.
These cities were very guilty before God. Eliezer, having been sent
by Sarah to her brother Lot with a message, some years before,
arrived in Sodom. An acquaintance invited him to a meal. But
hospitality was a virtue abhorred in Sodom, and the news of the
invitation having got wind, Eliezer’s friend was driven out of the city.
Now it was a custom in Sodom to make every stranger arriving
within the walls rest in a certain bed; and if the bed proved too long
for him, his legs were pulled out to fit it; and if it proved too short, his
legs were pared down to its dimensions. Eliezer saw with horror
what it was that they purposed to do with him, and he had recourse
to a lie of necessity; he declined to sleep in the bed, because he had
taken an oath upon the death of his mother never to lie on a bed
again; and thus he escaped. Shortly after, having seen a Sodomite
rob a poor stranger of his garment, Eliezer attempted to interfere, but
the robber struck him over the head and made a gash, from which
he lost much blood. Both being brought before the judge, this was
the magistrate’s decision:—That Eliezer was indebted to the
Sodomite robber for having bled him. The servant of Abraham
thereupon took up a large stone, flung it at the judge’s head, which
he cut open, and said, “Now, pay me for having bled thee!” and then
he fled out of the city.
From these incidents it may be seen how wicked the city was.
Now Abraham had interceded with God to spare the cities of the
plain, for the intercession of His saints is mighty with God. And
Abraham had obtained of God that if in Zoar, the smallest of the
cities, five righteous could be found, and forty-five in all the rest of
the country, God would spare them. Then God ceased talking with
Abraham. Next morning early, Abraham arose and took his staff, and
went to the place where God had met him, to make further
intercession for the cities of the plain, but the smoke of them rose as
from a furnace, for brimstone and fire had been rained upon them
out of heaven, and they had been consumed along with their
inhabitants. Only Zoar was spared, as a place of refuge for Lot, and
Lot was kept alive and his daughters; for God remembered how he
had been true to Abraham in Egypt, and had not betrayed the truth
about Sarah when questioned by Pharaoh.
The Mussulman tradition is as follows:—
Lot, whom the Arabs call Loth, was sent by God as a prophet to
convince the inhabitants of the cities of the plain of their ungodly
deeds. But, though he preached for twenty years, he could not
convince them. And whenever he visited Abraham he complained to
him of the iniquity of the people. But Abraham urged him to patience.
At length the long-suffering of God was exhausted, and He sent the
angels Michael, Gabriel, and Azrael, armed with the sword of
destruction, against these cities.
They came to Abraham, who received them, and slaughtered a calf,
and prepared meat and set it before them. But they would not eat.
And he pressed them, and ate himself; but they would not eat, being
angels. Then Abraham’s colour went, and he was afraid, for to
refuse to eat with a man is a token that you seek his life.
Seeing him discouraged, the angels announced their mission. But
Sarah, observing her husband’s loss of colour, laughed and said in
her heart, “Why is he fearful, being surrounded with many servants
and faithful friends?”
Now the angels promised to Abraham a son in his old age, and that
they would rescue Lot in the overthrow of Sodom. Then they rose up
and went on their way, and entered into Sodom; and they met a
young maiden in the street, and asked her the way to Lot’s house.
She answered, “He is my father, and I dwell with him; but know you
not, O strangers, that it is against the laws of this city to show
hospitality?”
But they answered her, “Fear not; lead us to thy father.”
So she led them, and ran before and told Lot, “Behold three men
come seeking thee and asking shelter, and they are beautiful as the
angels of God.”
Then Lot went out to them, and told them that the city was full of
wickedness, and that hospitality was not permitted.
But they answered, “We must tarry this night in thy house.” Then he
admitted them, and he hid them. But Lot’s wife was an infidel, a
native of Sodom; and finding that he lodged these strangers, she
hastened to the chief men of the city and said, “My husband has
violated your laws, and the customs of this people; he has housed
travellers, and will feed them and show them all courtesy.”
Therefore the men of the city came tumultuously to the door of Lot’s
house, to bring forth the men that were come to him, and to cast
them out of the city, having shamefully entreated them. They would
not listen to the remonstrances of Lot, but went near to break in his
door.
Then the three angels stepped forth and passed their hands over the
faces of all who drew near, and they were struck blind, and fled from
their presence.
Now, long before the day began to break, the angels rose up and
called Lot, his wife and daughters, and bade them take their clothes
and all that they had that was most precious, and escape out of the
city. Therefore Lot and his family went forth.
And when they were escaped, the angel Gabriel went through the
cities, and passed his wing over the soil on which they were built,
and the cities were carried up into heaven; and they came so near
thereto that those on the confines of heaven could hear the crowing
of the cocks in Sodom, and the barking of the dogs in Gomorrah.
And then they were overthrown, so that their foundations were
towards the sky and their roofs towards the earth. And God rained
on them stones heated in the fire of Hell; and on each stone was
written the name of him whom it was destined to slay. Now there
were many natives of these accursed cities in other parts of the land,
and where they were, there they were sought out by the red-hot
stones, and were struck down. But some were within the sacred
enclosure of the temple at Mecca, and the stones waited for them in
the air; and at the expiration of forty days they came forth, and as
they came forth the stones whistled through the air, and smote them,
and they were slain.
Now Lot’s wife turned, as she went forth, to look back upon the city,
and a stone fell on her, and she died.[314]
It is related further of Lot that, after he had escaped, he committed in
ignorance a very great sin; and Abraham sent him to expiate his
crime to the sources of the Nile, to fetch thence three sorts of wood,
which he named to him. Abraham thought, “He will be slain by
ravenous beasts, and so will he atone for the sin that he has
committed.”
But Lot after a while returned, bringing with him the woods which
Abraham had demanded—a cypress plant, a young cedar, and a
young pine.
Abraham planted the three trees in the shape of a triangle, on a
mountain, and charged Lot with watering them every day from
Jordan. Now the mountain was twenty-four thousand paces from
Jordan, and this penance was laid on Lot to expiate his sin.
At the end of three months the trees blossomed; Lot announced this
to Abraham, who visited the spot, and saw to his surprise that the
three trees had grown together to form one trunk, but with three
distinct roots of different natures.
At the sight of this miracle he bowed his face to the ground and said,
“This tree will abolish sin.”
And by that he knew that God had pardoned Lot.
The tree grew and subsisted till the reign of Solomon, when it was
cut down, and this was the tree which the Jews employed to form the
Cross of Christ.[315]
This tradition is, of course, Christian; though Jewish in origin, it has
been adapted to the Gospel story.
 6. THE BIRTH OF ISAAC.

The country was wasted; travellers were few; those who passed by,
and accepted Abraham’s hospitality, spoke with scorn of the sin of
Lot, his nephew; and the neighbourhood became intolerable to the
patriarch, who resolved to change his place of residence for a while.
He therefore went south, between Kadesh and Sur, and dwelt in
Gerar.
Now Sarah had bloomed again as fair as in her youth, as the angel
Michael had foretold; and Abraham persuaded her to pretend again
to be his sister, though Sarah, remembering the ill-success of this
deceit before, hesitated to comply.
Abimelech, king of Gerar, hearing of Sarah’s beauty, sent for her to
his palace. He asked Abraham, “Who is this woman?” and he
answered, “She is my sister.” Then Abimelech inquired of the camels
and of the asses, and they answered the same, “She is his sister.”
But that same evening, as it grew towards dusk, as he sat on his
throne, he fell asleep; and in dream saw an angel of God approach
him with a drawn sword in his hand to slay him. The king in his
dream cried out to know why he was doomed to death; and the
angel answered, “Because thou hast received into thy house the wife
of another man, the mistress of a house.”
Abimelech excused himself, saying that Abraham had concealed the
truth from him, and had said Sarah was his sister.
“The All-Holy knows that thou hast sinned in ignorance,” said the
angel; “but is it seemly, when strangers enter thy land, to be
questioning closely into their connexions? Know that Abraham is a
prophet, and foreseeing that thy people would entreat his wife ill, he
resolved to call her his sister, and he knew, being a prophet, that
thou couldst not harm her.”[316]
That night—it was the Paschal eve,—the angel with the drawn sword
traversed all the streets of the city, and closed the wombs of those
about to bear.
Next morning early, while it was yet dark, Abimelech sent for
Abraham and Sarah, and gave Sarah back to her husband, and paid
him a thousand ounces of silver, and to Sarah he gave a costly robe,
which might conceal her from her eyes to her feet, that none might
henceforth be bewitched by her beauty. “But,” said Abimelech to
Abraham, “because thou didst deceive me, and blind my eyes with a
lie, therefore thou shalt bear a son, whose eyes shall be dim so that
he shall be deceived.” And Abraham prayed to the Lord, and all the
women that were with child in Gerar were delivered of men-children,
without the pangs of maternity, and those who were barren felt
themselves with child. The angel hosts besought the Lord to look
upon Sarah, and to remember His covenant. “O Lord of the whole
world! Thou didst hear the cry of Abraham, and grant his petitions
when he prayed for the barren women of Gerar; and his own wife,
from whom Thou didst promise him a son, is unfruitful and despised.
Does it beseem a Lord, when he prepares a fleet, to free his subjects
from pirates, but to leave the vessel of his best friend in bondage?”
Now it was the first day of the seventh month, Tischri, the day on
which, at the close of the world’s history, the Lord will come to judge
the quick and the dead, that the Lord God remembered Sarah, and
the promise He had made, and looked upon her, and she conceived
a son in her old age, one year and four months after her sojourn in
Gerar; and nine months after, say some, but, say others, six months
and two days after; at mid-day say some, others say in the evening
of the fifteenth of Nisan; or, as others affirm, on the first of Nisan she
was delivered of a son, without suffering any pains in the bringing
forth. And the same time that Sarah’s womb was blessed, God
looked upon many other barren women and blessed them also; and
on the day that the child was born they were delivered likewise; and
the blind saw, the dumb spake, the deaf heard, and the lame walked,
and the crazed recovered their senses. Also, the sun shone forty-
eight times brighter than he shines at Midsummer, even with the
splendour that he had on the day of his creation.
And when eight days were accomplished, Abraham circumcised his
son, and called him Isaac.
But many thought it was an incredible thing that Abraham and Sarah
should have a son in their old age, and they said, “This is a
foundling, or it is the child of one of the slaves, which they pass off
as their own.” Now Abraham held a great feast on the day that Isaac
was weaned, and he invited thereto all the princes and great men of
the country. And there came Abimelech, king of Gerar, and Og, king
of Basan, and all the princes of Canaan, sixty-two princes in all.
Such an assembly was not seen before, yet all these princes fell in
after-years by the hands of Joshua.[317]
Of this feast it is related that Og’s companions said to him, “Do you
believe that that old mule, Abraham, can be the father of this child?”
Og replied with scorn, “I could crack this imp with the nail of my little
finger.”
Then came there a voice from heaven, saying, “Thou despisest this
little child, but know thou that tens of thousands shall spring from his
loins, and that before them thy pride shall be humbled.”
Also, Abraham’s ancestors, Shem and Eber, and his father, Terah—
though some say he was dead—and Nahor, Abraham’s brother,
attended the feast, and the Shekinah, the glory of the Lord,
appeared to grace it.
But Satan also appeared in the form of a poor beggar-man, and he
stood at the door and asked an alms. Now Abraham and Sarah were
busy attending to their guests, so they perceived him not, but the
servants thrust him away, and Satan received nothing; therefore he
presented himself before the Most High, and laid an accusation of
inhospitality and churlishness against the Friend of God.
In the meantime Sarah had assembled, and was entertaining all the
wives of the guests of Abraham. And it happened that the women
found that they had no milk in their bosoms to give their infants, and
the babes screamed that no one could hear the voice of another.
The mothers were in despair, for the children were hungry, and they
were all dry. Then Sarah uncovered her breasts, and there spurted
from them jets of milk, and all the babes were nourished at her
bosom, and yet there was more.
Now when they saw this, the women, who had doubted that the child
was really the offspring of Sarah, doubted no more, and cried, “We
are not worthy that our little ones should be nourished at thy bosom!”
And the story goes that all those who afterwards joined themselves
to the people of Israel, and all those in every nation who in after-
times became proselytes, were descended from those who sucked
the breasts of Sarah. In allusion to this incident it is said in the Book
of Psalms: “Thou makest the barren woman to keep house, and to
be the joyful mother of (i.e. giving suck to) children.”[318]
The child Isaac was shown to every visitor, and all were astonished
at his resemblance to Abraham. Both the babe and his father were
so much alike that it was impossible to distinguish one from the
other, and all doubt as to whose it was vanished before such
evidence of likeness to the father, and before the fulness of Sarah’s
breasts. But as confusion was likely to arise through the striking
similarity between father and son, Abraham besought God to give
him wrinkles and white hair, that he might not be mistaken for the
babe Isaac, or the babe Isaac be mistaken for him.[319]
 7. THE EXPULSION OF HAGAR AND ISHMAEL.

Ishmael grew up, and became skilful with his bow; he was rough and
undisciplined, and he occasionally lapsed into idolatry, but without
his father knowing it. But Sarah was aware of his sin, and was
grieved thereat.
Ishmael often boasted, “I am the eldest son, and I shall have a
double portion of my father’s inheritance.” These words were
reported to Sarah, and she hated Ishmael for them in her heart.
One day when Isaac was five years old, but others say fifteen,
Ishmael said to him, “Come forth into the field and let us shoot.”
Isaac was well pleased. And when they were in the field, Ishmael
turned his bow against his brother, but he did it in jest. Sarah saw
him from the tent door, and she ran out, and caught away her son
Isaac, and she went to Abraham and told him all the evil she knew of
Ishmael; how he had gone after idols and had learnt the ways of the
Canaanites that were in the land, how he had boasted of his
majority, and how he had sought Isaac’s life. And she said, “Give the
maid-servant a writing of divorcement, and send her away. Cast out
this bond-woman and her son; for the son of this bond-woman shall
not be heir with my son, even with Isaac. Then she will no more vex
Isaac. Do thou leave to Isaac all thy possessions. Never shall
Ishmael inherit anything from thee, for he is not my son.”
Abraham was grieved at heart, for he loved Ishmael his son, but
nothing that he said could alter Sarah’s determination. She insisted
on the expulsion of Hagar and her son, and she stirred up the wrath
of Abraham against Ishmael, because he had fallen into idolatry.
Sarah, say the Mussulmans, was so fierce in her jealousy, that she
would not be satisfied till she had washed her hands in the blood of
Hagar. Then Abraham quickly pierced Hagar’s ears, and drew a ring
through them, so that Sarah could fulfil her oath, without
endangering the life of Hagar.[320]
It was long before Abraham could be brought to consent to Sarah’s
desire, but God appeared to him in a dream and said, “Fear not to
obey the voice of Sarah, for she is the wife of thy youth, and was
chosen for thee from her mother’s womb. But Hagar is not thy wife;
she is but a bond-woman. Sarah also is a prophetess, and sees into
things that shall be in the latter days, further than thou. Unto Isaac
and those of his seed who believe in the Two Worlds are the
promises made; and they alone shall be accounted as thy seed.”[321]
Abraham now did what he was commanded. Next morning he gave
Hagar a writing of dismissal, and took twelve loaves of bread and a
pitcher of water, and laid them upon Hagar, for Sarah had cast an
evil eye upon Ishmael, so that he was ill, and unable to carry any
burden. And Abraham attached the pitcher by a cord to the hips of
Hagar, that all might know she was a slave, and the pitcher hung
down and trailed on the sand. Ishmael was sent away without
garments; he went forth naked as he came into the world: thus it
may be seen how implacable was the anger of Sarah, because he
had boasted of his birthright, and the wrath of Abraham, because he
had fallen into idolatry.
But when they went along their way, Abraham looked after them for
long, standing in the door of his tent, for his bowels yearned after his
son, and he saw the trail in the sand of the water pitcher which
Hagar had dragged sadly along, and thereby Abraham knew the
direction which they had taken.
Now God forsook not the outcast in her affliction, but filled the pitcher
with water as fast as she and her son drank out of it, and the water
was always sweet and cold. Thus they penetrated the wilderness,
and there they lost their way, and Hagar forgot the God of Abraham,
and in her distress turned to the false gods of her father Pharaoh,
and besought their protection, for she said, “Where are the promises
of the God of Abraham, that of Ishmael would He make a great
nation?”
Now Ishmael was sick of a burning fever, and the water in the pitcher
failed when Hagar forsook the God of Abraham. So she cast him
under a thorn bush, and went from him the space of two thousand
ells, that she might not hear his cries. But Ishmael prayed to the Lord
God of Heaven and Earth, and said, “O Lord God of my father
Abraham! thou canst send death in so many forms; take my life
speedily or give me a drop of water, that I suffer this agony no
longer.”
And the Lord in His compassion heard the prayer of the weeping
child, and He sent His angel and showed Hagar that fountain which
He had created on the sixth day at dusk, and of which the children of
Israel were destined to drink when they came forth out of Egypt.
But the accusing angel murmured against this judgment of God, and
said, “O Lord of the whole earth! shall this one, of whom a nation of
robbers shall arise, who will war upon thine elect people, and be a
scourge upon the face of the earth, shall he be delivered now, and
given to drink of a fountain destined for thine elect?”
The Lord answered, “Is the youth guilty, or is he not guilty?”
The angel answered, “He is not himself guilty, but his posterity will
sin.”
Then God said, “I punish men for what they have done, and not for
what their children will do. Ishmael hath not merited a death of
suffering, therefore shall he not die.” And God opened the eyes of
Hagar, and she saw the spring of water, and filled her pitcher, and
took it to Ishmael to drink. She filled the pitcher before she gave her
son a draught of water, for she had little faith, and thought that the
fountain would be withdrawn before she could return to it again.
Then Ishmael was strengthened and could go, and he and his
mother went further, and were fed by the shepherds; and they
reached Paran, and there they found springs of water, and they
settled there. Ishmael took a wife, a daughter of Moab, named
Aischa, or Aifa, or Asiah; but others say she was an Egyptian
woman, and was named Meriba (the quarrelsome), and by her he
had four sons and one daughter.
Ishmael lived a wandering life in tents with his wife and cattle; and
the Lord blessed his flocks, and he had great possessions. But his
heart remained the same; and he was a master of archery, and
instructed his neighbours in making bows.
After three years, Abraham, whose heart longed after his son, said to
Sarah, “I must see how my son Ishmael fares.” And she answered,
“Thou shalt go if thou wilt swear to me not to alight from off thy
camel,” for she hated Hagar, and feared to suffer her husband to
meet her once more. So Abraham swore. Then he went to Paran,
over the desert, seeking Ishmael’s tent; and he reached it at noon,
but neither Hagar nor her son were at home. Only Ishmael’s wife
was within, and she was scolding and beating the children.
So Abraham halted on his camel before the tent door, and the sun
was hot in the blue sky above, and the sand was white and glaring
beneath. And he called to her, “Is thy husband within?”
She answered, without rising from her seat, “He is hunting.” Or, say
others, she said without looking at him or rising, “He is gathering
dates.”
Then Abraham said, “I am faint and hungry; bring me a little bread
and a drop of water.”
But the woman answered, “I have none for such as thee.”
So Abraham said to her, “Say to thy husband, even to Ishmael, these
words: ‘An old man hath come to see thee out of the land of the
Philistines, and he says, The nail that fastens thy tent is bad; cast it
away or thy tent will fall, and get thee a better nail.’” Then he
departed, and went home.
Now when Ishmael returned, his wife told him all these words, and
he knew that his father had been there, and he understood the tenor
of his words, so he sent away his wife, and he took another, with his
mother’s advice, out of Egypt, and her name was Fatima.
And after three years, Abraham’s bowels yearned once more after
his son, and he said to Sarah, “I must see how Ishmael fares.” And
she answered, “Thou shalt go, if thou wilt swear to me not to alight
from off thy camel.” So Abraham swore.
Then he went to Paran, over the desert, seeking Ishmael’s tent, and
he reached it at noon; but neither Hagar nor her son was at home.
Only Ishmael’s wife, Fatima, was within, and she was singing to the
children.
So Abraham halted on his camel before the tent door, and the sun
was hot in the blue sky above, and the sand was white and glaring
beneath. And when Fatima saw a stranger at the door, she rose from
her seat, and veiled her face, and came out and greeted him.
Then said Abraham, “Is thy husband within?”
She answered, “My lord, he is pasturing the camels in the desert;”
and she added, “Enter, my lord, into the cool of the tent and rest, and
suffer me to bring thee a little meat.”
But Abraham said, “I may not alight from off my camel, for my
journey is hasty; but bring me, I pray thee, a morsel of bread and a
drop of water, for I am hungry and faint.”
Then she ran and brought him of the best of all that she had in the
tent, and he ate and drank, and was glad.
So he said to her, “Say to thy husband, even to Ishmael, that an old
man out of the land of the Philistines hath been here, and he says,
The nail that fastens thy tent is very good; let it not be stirred out of
its place, and thy tent will stand.”
And he returned. And when Ishmael came home, Fatima related to
him all the words that the old man had spoken, and he understood
the tenor of the words.
Ishmael was glad that his father had visited him, for he knew thereby
that his love to him was not extinguished.[322]
Shortly after, he left his wife and children, and went across the desert
to see his father in the land of the Philistines. And Abraham related
to him all that had taken place with the first wife, and why he had
exhorted him to put her away.
 8. THE STRIFE BETWEEN THE SHEPHERDS.

Abraham lived twenty-six years in the land of the Philistines; then he

went to Hebron, and there his servants dug wells, and there they
encamped.
When Abimelech’s servants heard of these wells that they had dug,
they came with their flocks, and desired to use them also, and the
largest of the wells they claimed as their own. But Abraham’s
shepherds said, “Let the well belong to those to whom it gives water.
The Lord shall decide between us!”
To this the servants of Abimelech agreed. And when the flocks of
Abraham came to drink, the well sprang up and overflowed; but
when the flocks of Abimelech drew near, the water sank and
disappeared.
Now when Abimelech heard of the strife, he came with Phicol, his
chief captain, to seek Abraham, and to be reconciled with him. “God
is with all that thou doest,” said Abimelech; “He protected thee when
Sodom was destroyed. He has given thee a son in thine old age. He
rescued thy first-born when perishing in the desert. Swear to me, as I
have offered thee my whole land, my own palace not excepted, in
which to dwell, that thou wilt show equal love and liberality to my
descendants to the third generation.”
Abraham swore to him, and they made a covenant together.[323]
And Abraham set apart seven lambs as a witness and token, that
just as the well had sprung up when his flocks had come to water at
it, so, in after days should it spring up to water the descendants of
Abraham; as it is said, “From thence they went to Beer, that is, the
well whereof the Lord spake unto Moses, Gather the people
together, and I will give them water. Then Israel sang this song,
Spring up, O well; sing ye unto it.”[324]
But such condescension and courtesy ill became Abraham in his
dealings with a rude and savage people, and therefore there came to
him a voice from heaven which said: “Because thou hast given these
seven innocent lambs into the hands of a barbarous nation, therefore
seven of thy descendants shall be slain by their hands (Samson,
Hophni and Phinehas, Saul and his three sons); also seven
dwellings that thy people shall raise to my Name shall they destroy
(the Tabernacle, Gilgal, Nob, Gibeon, Shiloh, and twice the Temple
at Jerusalem), and seven months shall the ark of my covenant
remain in the land of the Philistines.”
 9. THE GROVE IN BEER-SHEBA.

“And Abraham planted a grove in Beer-sheba, and called there on

the name of the Lord.”[325] The reason was as follows:—
Once Abraham asked Shem the son of Noah, otherwise called
Melchizedek, king of Salem, what service he and his father and
brethren rendered to the Lord in the ark, which was so acceptable to
God that He preserved them alive and brought them in safety to
Ararat; and Shem answered, “The service we rendered to God, all
the time of our sojourn in the ark, was charity.”
And when Abraham wondered and asked how that could possibly
be, as there were none in the ark save themselves and the beasts,
Shem answered,—
“Even so; we showed charity and forethought and hospitality to the
animals. We fed them regularly, and we slept not at night; so busy
were we with them in making them comfortable. Once, when we had
delayed somewhat, the lion was hungry and bit Noah, my father.”
Then said Abraham to himself, “In very truth, if it was reckoned to
Noah and his sons as so great righteousness, that they fed and
tended the dumb and senseless beasts, how much more pleasing
must it be to the Most High, to be kind and generous to men who are
made in His image, after His likeness!”
Filled with this thought, Abraham settled at Beer-sheba, where was
an abundant spring of fresh water, and there he resolved to do
service acceptable to the living God, and to honour His name, as
Noah and his sons had done Him service and honoured Him in the
ark.
So Abraham planted a grove in Beer-sheba, one hundred ells long
and one hundred ells broad, and he planted it with vines and figs,
pomegranates and other fruit trees; and he built a guest-house
adjoining this garden, and he made in it four doors, one towards
each quarter of the heavens; and when a hungry man came by,
Abraham gave him food; if there came a man who was thirsty, he
gave him drink; if one who was naked, he clothed him; if one who
was sick, he took him in and nursed him; and he gave to every man
who passed by what he most needed for his journey.
He would receive neither thanks nor payment; and when any one
thanked him, he said hastily, “Give thanks, not to me the servant, but
to the Master of this house, who openeth His hand, and filleth all
things living with plenteousness.”
Then when the traveller asked, “Who, and where is this Master?”
Abraham answered, “He is the God who rules over heaven and
earth; He is Lord of all; He kills and makes alive; He wounds and
heals; He forms the fruit in the mother’s womb, and gives it life; He
makes the plants and trees to grow; He brings man to destruction,
and raises him from his grave again.”
Thus Abraham instructed those whom he relieved. And if a traveller
asked further, how he was to worship the great God, Abraham
answered, “Say only these words, Praised be the Eternal One who
reigns over heaven and earth! Praised be the Lord of the whole
world, who filleth all things living with plenteousness.” And no
traveller went on his way without thanking God.
Thus that guest-house was a great school, in which men were taught
the true religion, and gratitude to the Almighty God.
 10. THE OFFERING OF ISAAC.[326]

Abraham loved the son of his old age, and Isaac grew up in the fear
of God, and his good conduct heightened the love Abraham bore
him; but the Patriarch thought in his heart, “I prepare gifts to give of
my abundance to every man that asks of me, and to every passer-
by; but to my Lord and God, the Giver of all good things, have I given
nothing!”
There was a day when the sons of God (the angels) stood before the
Eternal One, and amongst them was the accusing angel, Satan or
Sammael. The Lord asked him, “Whence comest thou?”
“From walking to and fro upon the face of the earth,” he replied.
“And what hast thou beheld there of the doings of the sons of men?”
The Accuser answered, “I saw that the sons of earth no longer
praise Thee, and adore Thee; when they have obtained their
petition, then they forget to give Thee thanks. I saw that Abraham,
the son of Terah, as long as he was childless, built altars and
proclaimed Thy name to all the world: now he has been given a son
at the age of a hundred, and he forgets Thee. I went to his door as a
beggar, on the day that Isaac was weaned, and I was turned away
without an alms. I have seen him strike alliance with the King of the
Philistines, a nation that knows Thee not, and to him has he given
seven lambs. He has built a large house and he gives to strangers,
but to Thee he gives no sacrifice of value. Ask of him any sacrifice
that is costly, and he will refuse it.”
“What shall I ask?” inquired the Almighty.
“Ask of him now his son, and he will refuse him to Thy face.”
“I will do so, and thou shalt be confounded,” answered the Holy One.
The self-same night God appeared to Abraham, and addressed him
gently so as not to alarm him, and He said to him, “Abraham!”
The patriarch in deep humility answered, “Here am I, Lord; what
willest Thou of Thy servant?”
The Lord answered, “I have come to ask of thee something. I have
saved thee in all dangers; I delivered thee out of the furnace of
Babylon; I rescued thee from the army of Nimrod; I brought thee into
this land, and gave thee men-servants and maid-servants and cattle
and sheep and horses, and I have given thee a son in thine old age,
and victory over all thine enemies, and new temptations await thee,
for I must prove thee, and see if thou art grateful in thy heart, and
that thy righteousness may be manifest unto all, and that thy
obedience may be perfected. Take therefore thy son——”
Abraham answered trembling, “Which son? I have two.”
The voice of God.—“That son which alone counteth with thee.”
Abraham.—“Each is the only son of his mother.”
The voice of God.—“The one you love.”
Abraham.—“I love both.”
The voice of God.—“The one you love best.”
Abraham.—“I love both alike.”
The voice of God.—“Then I demand Isaac.”
Abraham.—“And what shall I do with him, O Lord?”
The voice of God.—“Go to the place that I shall tell thee, where,
unexpectedly, hills shall arise in sight out of the valley bottom. Go to
that place whence once My Light, My Teaching issued, which My eye
watches over untiringly, and where the smoke of incense shall arise
to Me, to the place where prayer is heard and sacrifice shall be
offered, where at the end of time I shall judge the nations, and cast
the ungodly into the pit of Gehinom;—to the land of Moriah that I
shall show thee, there shalt thou take thy son Isaac as a whole burnt
offering.”
Abraham.—“Shall I bring Thee such an offering as this, O Lord?
Where is the priest to prepare the sacrifice?”
The voice of God.—“I have taken from Shem his priesthood, and
thou art clothed therewith.”
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