Chapter 1
Introduction
&
Review of Literature
1
1.1. What are Drug Delivery Systems (DDS)?
1.2. Routes of drug delivery systems
1.3. Controlled drug Release
1.4. Bionanocomposites (BNCs)
The key components of the bionanocomposites
(A) The clay and clay minerals
(B) Biopolymers
1.5. The Clay and Clay minerals
1.5.1. Montmorillonite a nano Clay
1.5.2. Structure of layered materials (Montmorillonite)
1.5.3. Pharmaceutical uses & biologically active effects of MMT
1.5.4. Mechanisms of clay–drug interactions
1.6. Biopolymers
1.6.1. Alginate (Anionic polysaccharide)
1.6.2. Chitosan (CS)
1.6.3. Polylactide (PLA)
1.7. Examples of bionanocomposites (BNCs)
1.7.1. Chitosan (CS)-MMT bionanocomposites (CS-MMT)
1.7.2. Polyacrylamide (PAA) and alginate (AL) BNCs hydrogels
1.8. Controlling the drug release kinetics from BNCs
1.9. Colon specific drug delivery by using BNCs
1.10. Physicochemical characterization of BNCs
1.11. Objectives of the work
References
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
1
1.1. What are Drug Delivery Systems (DDS)?
“DDS are systems used for the delivery of drugs to target sites of
pharmacological actions. Technologies employed include those concerning drug
preparation, route of administration, site specific, metabolism, and toxicity”. In easy way
to say, Drug delivery systems are methods which are used to ensure that drugs get into
the body and reach the area where they are needed. These systems must take a number of
needs into account, ranging from ease of delivery to effectiveness of the drugs. Several
companies specialize in developing methods of drug delivery, marketing these products
to pharmaceutical companies, and other pharmaceutical companies develop their own
systems. Many of these methods are patented and proprietorized. The earliest drug
delivery systems, first introduced in the 1970s, were based on polymers derived from
lactic acid. While the conventional drug delivery forms are simple oral, topical, inhaled,
or injections, new sophisticated delivery systems need to take into account
pharmacokinetic principles, precise drug characteristics, and changeability of response
from one person to another and inside the same person under different conditions. DDS
are intended to alter the pharmacokinetics (PK) and biodistribution (BD) of their
associated drugs, or to function as drug reservoirs [1] and it plays an important role in the
development of pharmaceutical dosage forms for the healthcare industry because often
the duration of the drug release needs to be extended over a period of time [2]. To evade
troubles associated with conventional drug therapies such as limited drug solubility, poor
biodistribution, lack of selectivity, and uncontrolled pharmacokinetics, in recent decade
considerable research has been directed towards the development of new and more
competent drug delivery systems [3]. The improvement of DDS intends to use more
efficient chemical or physical barriers to control the rapidity of release and to assure the
preferred dose maintenance. In this sense, the development of delivery systems is strictly
dependent on the choice of a suitable carrier agent able to control drug release. For more
than two decades, the researchers have focused on finding better ways for delivering
drugs to the body at a sustained rate, directly to the site of action, with lower toxicity and
in a disease-specific manner [4]. The development of drug delivery systems requires a
wide range of tasks, such as route of administration, drug properties, biocompatibility of
materials and the development of materials suitable to the specific application
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
2
(biodegradable, pH-sensitive, flexible, etc.), the ability of drug loading and type of
release kinetics (slow, fast, pulsatile), duration of therapy and proof of efficacy (Fig.1.1).
In addition, it is important to demonstrate the systems safety, which includes two major
entities: (1) the safety of the systemically distributed drug, and (2) the biocompatibility of
the drug delivery system [4].To obtain a given therapeutic response, the suitable amount
of the active drug must be absorbed and transported to the site of action at the right time
and the rate of input can then be adjusted to produce the concentrations required to
maintain the level of the effect for as long as necessary. The distribution of the drug-to-
tissues other than the sites of action and organs of elimination is unnecessary, wasteful,
and a potential cause of toxicity. The modification of the means of delivering the drug by
projecting and preparing new advanced drug delivery devices can improve therapy. The
current methods of drug delivery exhibit specific problems that scientists are attempting
to address. For example, many drugs’ potencies and therapeutic effects are limited or
otherwise reduced because of the partial degradation that occurs before they reach a
desired target in the body. The goal of all sophisticated drug delivery systems, therefore,
is to deploy medications intact to specifically targeted parts of the body through a
medium that can control the therapy’s administration by means of either a physiological
or chemical trigger. To achieve this goal, researchers are turning to advances in the
worlds of micro-and nanotechnology. Fig.1.2. illustrates the strategic tools for controlled
drug delivery systems.
1.2. Routes of drug delivery systems
Pharmaceutical dosage forms for drug delivery includes tablets, pills, capsules,
aerosols, suppositories, ointments, creams, liquids, and injections [5].On this basis, there
are four key routes of drug delivery involves oral, inhalation, transdermal/implantable,
and injectables (Fig.1.3). The choice of a delivery route is driven by patient acceptability,
the properties of the drug (such as its solubility), access to a disease location, or
effectiveness in dealing with the specific disease [6]. Typically, oral route of drug
delivery is most favored one and the most user-friendly means of drug administration
having the highest degree of patient compliance. Therefore, foremost requirement of the
drug delivery system is to identify orally active candidates that would provide
reproducible and effective plasma concentrations in vivo [7-9].
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
3
Fig.1.1.Overview of drug delivery systems
Fig.1.2.The strategic tools for controlled drug delivery systems
1.3. Controlled drug Release
The drug concentration at the site of action in the human body is of central
importance for the success of a pharmacotherapy. Too high drug concentrations can lead
to serious side effects, whereas too low drug levels lead to the failure of the medical
treatment [10]. For conventional formulations, the plasma concentration of a drug is
directly proportional to the administrated dose. These formulations have difficuly in
maintaing the therapeutic dose for extended periods of time, which usually require
multiple administrations to obtain therapeutic effect. In addition, systemic circulation of
high drug concentration often induces the adverse effect, because in this case, drug
delivery solely depends on simple diffusion or partition from blood stream to target site.
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
4
The only advantage of conventional formulations is that the cost of development is low.
Controlled drug delivery technology represents one of the most rapidly advancing areas
of science in which chemists and chemical engineers are contributing to human health
care and represent an ever-evolving field for biomedical and materials science [11].
Fig.1.3.Routes of drug delivery systems
Fig.1.4.Concept of controlled drug delivery systems
0 8 16 24 32 40 48
Systemic window
Drug at therapeutic site Systemic drug concentration
Time ( h )
Dru
g C
once
ntra
tion
at si
te o
f act
ion
Therapeutic window
Systemic concentration at which side-effects occur
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
5
It has received increasing attention in many applied scientific fields including
medicine, pharmaceutics, agriculture, chemistry, and materials science, as it offers
numerous advantages over the conventional routes of delivering drugs, agrochemicals,
and other biologically active agents. Primary concern of a controlled release system is to
deliver a drug at a predetermined rate (programmability) and for an extended period of
time at which the drug appears at the target site can be adjusted (optimized
pharmacotherapy) (Fig.1.4) [12]. These systems offer the following advantages compared
to other methods of administration:(i) the possibility to maintain plasma drug levels at
therapeutically desirable range (improved efficacy), (ii) the possibility to eliminate or
reduce harmful side effects from systemic administration by local administration from a
controlled release system, (ii) drug administration may be improved and facilitated in
under privileged areas where good medical supervision is not available, (iv) the
administration of drugs with a short in vivo half-life may be greatly facilitated, (v)
continuous small amounts of drug may be less painful than several large doses, (vi)
improvement of patient compliance, and (vii) the use of drug delivery systems may result
in a relatively less expensive product and less waste of the drug. This improvement can
take the form of increasing therapeutic activity compared to the intensity of side effects,
drug release can be controlled over prolonged periods of time, reducing the number of
drug administrations required during treatment, or eliminating the need for specialized
drug administration (e.g., repeated injections). In brief, all controlled release systems aim
to improve the effectiveness of drug therapy [13-17]. A controlled drug delivery system
requires simultaneous consideration of several factors, such as the drug property, route of
administration, nature of delivery vehicle, mechanism of drug release, ability of targeting,
and biocompatibility. This concept prompted active and intensive investigations for the
design of degradable materials, intelligent delivery systems, and approaches for delivery
through different portals in the body. The chemists, biochemists, and chemical engineers
are all looking beyond traditional polymer networks to find other innovative drug carrier
systems. Two of the more interesting cutting-edge technologies involve the use of
bionanocomposites (a combination of layered inorganic materials and biopolymers) and
modified layered inorganic materials to deploy medications capable of providing site-
specific drug delivery [18-21]. Such systems are capable of adjusting drug release rates in
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
6
response to a physiological need. The release rate of these systems can be modulated by
external stimuli or self regulation process.
1.4.“Bionanocomposites (BNC) ” has become a common term to designate
nanocomposites involving a biopolymer in combination with an inorganic moiety e.g
layered silicate that show at least one dimension on the nanometer scale”[21].
Bionanocomposites are an emerging group of hybrid materials derived from natural
polymers and inorganic solids interacting at the nanometric scale. These nanostructured
organic–inorganic materials could be designed and prepared using a wide type of
biopolymers and also layered silicates with different compositions and topologies. Up to
now only the layered inorganic solids like layered silicate (clay) have attracted the
attention of the biomedical industry. This is due to their ready availability and low cost,
and also their significant enhancement of product properties and relative simple
processing [22]. This progress was enabled by the utilization of specially designed
organophilic clays as nanofillers in polymer composites [23-24]. Conceptually, clay
modifications intend the intercalation of organophilic substances into the interlayer space
of the layered silicates to weaken the interlayer interactions, increase the interlayer
spacing, and improve clay–polymer compatibility. This allows macromolecules like
drugs, proteins, DNA etc to penetrate into the interlayer space during processing, leading
to the separation of the individual layers and uniform dispersion of the separated clay
layers in a polymer matrix. Bionanocomposites offer surplus returns like mechanical
properties, dimensional stability, solvent or gas resistance, low density, transparency,
good flow, better surface properties, and recyclability with respect to the pristine polymer
[22, 25-27]. In addition to these characteristics, bionanocomposites show the remarkable
advantage of exhibiting biocompatibility, biodegradability and, in some cases, functional
properties provided by either the biological or inorganic moieties. The great interest
towards DDS in BNC area is supported by the strong increase in the number of scientific
publications according to the Institute for Scientific Information (ISI) database (Fig.1.5).
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
7
20012002
20032004
20052006
20072008
20092010
20110
2000
4000
6000
8000
10000
Drug delivery (2001-2011)
Publ
ishe
d It
ems
Years
[A]
20012002
20032004
20052006
20072008
20092010
20110
25
50
75
100
125
150
175[B]
Nanocompositesin DDS (2001-2011)
Publ
ishe
d It
ems
Years
Fig.1.5.Increase in the number of scientific publications according to the Institute for
Scientific Information (ISI) database
The key components of the bionanocomposites
(A) The clay and clay minerals
(B) Biopolymers
1.5. The clay and clay minerals
“Clay minerals are the basic constituents of clay raw materials (Argillaceous
rocks). Their crystal structure, with a few exceptions, consists of sheets (hence the terms
sheet silicates or phyllosilicates) firmly arranged in structural layers” [28]. Clays are
inexpensive materials, which can be modified by ion exchange, metal/metal complex
impregnation; pillaring and acid treatment to simply desired functionality for wide range
of applications and Nanoclay can be obtained by the ion exchange reaction of hydrophilic
clay. The clays having a platy structure and a thickness of less than one nanometer are the
clays of choice. The length and width of the choice clays are in the micron range. Aspect
ratios of the choice clays are in the 300:1 to 1,500:1 range. The surface area of the
exfoliated platelets is usually in the range of 700 meters squared per gram. Nanoclay
minerals possess exceptional properties such as low or null toxicity, superior
biocompatibility, and guarantee for controlled drug release, thus giving rise to the
incessant curiosity to their progress for biological applications, for example,
pharmaceutical, cosmetic, and even medical purposes [29-30]. The nano clays that
researchers have concentrated on are listed below;
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
8
(1). Hydrotalcite, (2). Montmorillonite, (3). Mica fluoride, (4). Octasilicate
Hydrotalcite and Octasilicate have limits of use both from a physical and cost standpoint.
The mica fluoride is synthetic clay while the monrmorillonite (MMT) is a natural one.
The montmorillonite clays have had the widest acceptability for use in polymers [31].It
was concluded that MMT alone could be considered to be safe for a myriad of
applications.
1.5.1. Montmorillonite a nano Clay
Montmorillonite (MMT), a natural nanoclay mineral and platy structure, is a
bioinspired layered material with high internal surface area, high cation exchange
capacity (CEC), high adsorption ability, and low toxicity [32-33]. MMT with net
negatively charged layers has good swelling property in the presence of water, and
therefore, the positively charged bioactive compounds can be intercalated into the
interlayer spaces by electrostatic interaction under this condition [34]. Many attempts
have been made to develop MMT as a delivery carrier, for example, to improve water
solubility of insoluble drugs and release control of bioactive molecules [34-42].
1.5.2. Structures of layered materials (Montmorillonite)
Cationic clay minerals composed of octahedral and tetrahedral sheets have been
known for the excellent layer components in preparing organic-inorganic or bio-inorganic
nanohybrids. MMT belongs to the smectite (or clays) group of phyllosilicates subclass of
silicates class. Its crystalline lattice consists of an aluminum-oxygen and aluminum-
hydroxyl octahedral sheet sandwiched by two silicon-oxygen tetrahedral sheets, which
are frequently called medical clay. The triple sheets structure is stacked in layers bound
together by van der Waals forces [37, 42-50]. This kind of clay is referred to as 2:1 layer
structure. The layer thickness is around 1 nm and the lateral dimensions of these layers
may vary from 100 nm-1000 nm [51]. The elementary structure of clay is based on the
mica skeleton, as shown in Fig.1.6. Furthermore, being lamellar clay, MMT has swelling
capability by the stepwise hydration of the interlayer cations and intercalation with
positively charged biomolecules [52-53].The cations in the tetrahedral sheet are typically
Si 4+ and Al3+, while those in the octahedral sheet are Al3+, Fe3+, Mg2+. Because of the
isomorphic substitution of cations in both tetrahedral (Si 4+) and/or octahedral (Al3+, Fe3+,
Mg2+) sheets by lower valent cations, the layer framework acquires a permanent negative
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
9
charge [54-56]. The Na+ can be exchanged with organic cations, such as those from
biomolecules [57], drug and dye [37, 42-45, 58-62]. The extent of the negative charge of
the clay is characterized by the cation exchange capacity, i.e., CEC. The typical cation
exchange capacity (CEC) of montmorillonite is in the 70-100 meq/100 g range. The X-
ray d-spacing of completely dry Na+-Montmorillonite is 0.96 nm while the platelet itself
is about 0.94 nm thick [63]. When the Na+ is replaced with cationic polymers, drugs and
biomolecules, the interlayer gallery increases and the X-ray d-spacing may enlarge by as
much as 2 to 3-fold [19, 64-65], while the thickness of Montmorillonite sheets remains a
well-defined crystallographic dimension.
Fig.1.6.Structures of MMT (Montmorillonite)
1.5.3. Pharmaceutical uses and biologically active effects of MMT
The biochemical characteristic which makes clay valuable in pharmaceutical
applications are the high adsorption capacity, elevated internal surface area, immense
cation exchange ability, interlayer space reactions with drug molecules, chemically
inactive and little or null toxicity [15, 19, 37, 41, 66-69]. Smectites have been extensively
used as both active principle and excipient in pharmaceutical formulations [70-72]. A
class of cationic clays, Montmorillonite (MMT) is a bio-inspired layered silicate
possessing high internal surface area, exceptionl swelling properties and high adsorption
ability [73].In pharmaceutical engineering, MMT has found extensive applications as a
suspending and stabilizing agent, as well as an adsorbent or clarifying agent. Also, MMT
has been employed in the drug formulations to act as drug carriers or excipients [41-44,
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
10
69, 74-79]. MMT has attracted much consideration as an oral delivery carrier, since it
acts as a controlled delivery vehicle streamlined in terms of the potential for drug
molecules to become adsorbed onto the hydrated alumino-silicate layers, which in
aqueous media exist as dispersions of individual platelet and release of intercalated drug.
The ion exchange capacity of MMT enables replacement of Na+ with other organic and
inorganic cations to add functionality, spurring research into the use of MMT and other
clay species as drug delivery and tissue regeneration agent for molecules such as
Docetaxel, 5-fluorouracil, Paclitaxel, Ibuprofen, Timolol maleate, Temoxifen citrate,
Procainamide, Buspiron, and Epidermal Growth Factor [15-16, 19-20, 41-44, 63-64, 69,
79, 80-81] (Table 1.1). For example, organic modified silicate nanoparticles (Cloisite
clay) were added to poly (ethylene-co-vinyl acetate) to study the release kinetics of
dexamethasone. The authors discovered that increase of silicate nanoparticle
concentration resulted in higher mechanical strength of the polymer nanocomposite and a
sustained release of dexamethasone. The drug release kinetics was suggested to be
dependent on the aspect ratio and degree of dispersion of the silicate nanoparticle [82].
Lin et al. [37] intercalated 5-fluorouracil into the interlayer of MMT through ion
exchange. The total amount of loaded drug was 87.5 mg for each gram MMT. Such a
modified formulation was expected to be effective in colorectal cancer therapy. Lin et al
[83] MMT with cationic hexadecyltrimethylammonium (HDTMA) and preparations of
various DNA–HDTMA–MMT complexes. DNA also was successfully transfected into
the nucleus of human dermal fibroblast which expressed enhanced green fluorescent
protein (EGFP) gene with green fluorescence emission. MMT was also investigated as a
novel vector for oral gene delivery by Kawase et al. [84]. The complex of MMT and
plasmid DNA encoding the EGFP gene was prepared at various ratios. Gene expression
was detected in cultured cells and in the small intestine of mice with oral administration
of plasmid DNA complex with MMT, while no gene expression was detected for naked
plasmid DNA. Wang et al [77]. Prepared quaternized chitosan-montmorillonite
(HTCC/MMT) complex nanocomposites and applied as protein drug carrier. Shameli et
al [85], applied green physical synthetic route for Montmorillonite (MMT)/chitosan (CS)
nanoparticle fabrication and its antibacterial application. Katti et al [55] studied
intercalation mechanisms of amino acids arginine and lysine in interlayer space of
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
11
montmorillonite and its mechanical behavior in interlayer spacing by using molecular
dynamics simulations. Lee & Fu [86] also found that release properties of drug could be
controlled by their loading into nanocomposites of N-isopropylacryamide and
montmorillonite. Release property of loaded drug could be controlled by handling
electrostatic interaction between the drug molecules and clay layers. Electrostatic
attraction decreases the release ratio, while electrostatic repulsion increases the release
ratio. Overall, the ion exchange nature, intercalation capability and biocompatibility of
MMT make them ideal candidates for drug delivery. Besides pharmaceutical uses, MMT
and its nanocomposites are also biologically active agents for a wide range of
applications. MMT plays a role as a potent detoxifier in the intestine, since it can adsorb
dietary, bacterial, and metabolic toxins as well as abnormally increased hydrogen ions
observed in acidosis. Also, MMT can be orally administered for detoxification of the
digestive system, constipation reduction, elimination of internal parasites, immune
system support, fixing free oxygen in the blood stream, trace mineral supplement action,
liver detoxification, reduction of stomach aches and bacterial food poisoning, soothing
ulcers etc. the regenerative medicine and tissue engineering applications include bone
regeneration, use as growth factor reservoirs and in wound dressing. MMT has also been
used extensively in the treatment of pain, bone and muscle damage, chronic headaches,
open wounds, skin conditions (acne, eczema, rashes etc.), colitis, diarrhea, hemorrhoids,
stomach ulcers, intestinal problems, anemia, rapid healing of injuries (bruises, sprains,
burns etc.), severe bacterial infections, skin rejuvenation and deep cleaning and a variety
of other health issues. MMT has been regarded as bioinert clay as it has no chemical
effects on the body. Its actions are purely physical. Following ingestion, there’s no or
very little MMT absorbed from the gastrointestinal tract, and it is excreted in the feces.
1.5.4. Mechanisms of clay–drug interactions
According to the prevailing paradigm, the principle of controlled drug delivery
using layered materials lies mostly in the intercalation via ion exchange mechanisms of
drugs in inorganic layered silicate materials. The supramolecular assembly between drug
and these layered silicates is characterized by a lamellar organization in which drugs are
sandwiched between layers of silicates. It may be carried out by mixing solid substrates
(namely ion exchangers) with ionic drugs in solution. In biological fluids, “counter-ions”
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
12
can displace the drug from the substrate and deliver it into the body. The exchanger may
be then eliminated or biodegraded (Fig.1.7). Clay minerals are naturally occurring
inorganic cationic exchangers and may undergo ion exchange with basic drugs in
solution. Smectites, especially montmorillonite and saponite, have been more commonly
studied because of their higher cation exchange capacity compared to other
pharmaceutical silicates (such as talc, kaolin and fibrous clay minerals). The relevance of
specific mechanism depends on the clay mineral involved as well as on the functional
groups and the physical-chemical properties of the organic compounds [87-89]. Several
mechanisms may be involved in the interaction between clay minerals and organic
molecules such as: (1) Hydrophobic interactions (van der Waals) (2) Hydrogen bonding
(3) Protonation (4) Ligand exchange (5) Cation exchange (6) pH-dependent charge sites
(7) Cation bridging (8) Water bridging.The clay–drug complexes prepared by clay
particles are dispersed in aqueous drug solutions, dispersions are allowed to equilibrate
for a suitable time, and finally solid phases are recovered and dried. To “entrap” bioactive
molecules by inducing coagulation in nanoclay dispersions or by using dry method
(specifically helpful for poorly soluble molecules) was also reported, consisting of
grinding clay and drug together or putting them in contact at the melting temperature of
the drug [90].
Fig.1.7.Mechanism of controlled release of drug from MMT and absorption in body
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
13
Table 1.1. List of drugs/biomolecules formulated in clay.
Drug Reference
5- Fluorouracil (anti-cancer) Lin et al., 2002 [37]
Amino acids Kollar et al., 2003 [36]
Plasmid DNA (Gene Delivery) Kawase et al., 2004 [84]
Paclitaxel (anticancer drug) Dong et al., 2005 [43]
Ibuprofen (non-steroidal anti-inflammatory ) Zheng et al., 2007 [35]
BSA ( Model protein) Lin et al., 2007 [207]
BSA ( Model protein) Wang et al., 2008 [77]
Donepezil (alzheimer) Park et al., 2008 [38]
Docetaxel (anticancer drug) Feng et al., 2009 [44]
Ibuprofen (anti-inflammatory) Depan et al., 2009 [79]
Captopril (hypertension) Madurai et.al., 2011 [209]
Vitamin B1
Buspirone hydrochloride (anti-anxiety)
Timolol maleate (β-adrenergic blocking agent)
Ranitidine hydrochloride (antacid)
Quinine (antimalarial drug)
Joshi et al., 2009,
2010,2011,2012
[16, 20, 63-64, 80, 206]
Procainamide hydrochloride (antiarrythmia drug)
Lidocaine (local anesthetic drug)
5-fluorouracil (anticancer drug)
Tamoxifen (anticancer drug)
Kevadiya et al.,
2010, 2011, 2012
[15, 19, 41-42]
Epidermal Growth Factor (Tussie Engineering) Vaiana et al., 2011 [81]
Glutathione (Anti oxidant) Baek et.al., 2012 [40]
Doxorubicin (anticancer drug) Anirudhan et.al., 2012 [208]
Chapter 1 Introduction & Review of Literature
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1.6. Biopolymers
1.6.1. Alginate (Anionic polysaccharide)
Alginate is a linear copolymer composed of 1-4-linked β-D-mannuronic acid (M)
and its C-5-epimer, α-L-guluronic acid (G), extracted from brown algae and is also an
exopolysaccharide of bacteria including Pseudomonas aeruginosa [91-95]. The amounts
of (M) and (G) and their sequential distribution vary depending on the alginate source
[96-97]. It is most frequently employed for cell immobilization/encapsulation [98-99] for
drug delivery [100–102] and tissue engineering [103] due to its abundance, superior
gelling properties, biocompatibility, low toxicity, and biodegradability [104-106]. At
neutral pH, carboxyl groups of alginate are deprotonated so that the polymer is highly
negatively charged. Soluble sodium alginate can be transformed into a hydrogel through
crosslinking with divalent cations (Ca2+) [107-108].The advantage of this gelling process
is that it maintains the biological activity of incorporated molecules in the calcium-
crosslinked hydrogel or bead under mild aqueous conditions without the need for toxic
reagents [109-110].
COOH + Ca2+ + COOH → COO─Ca─COO + 2 H+
The pKa value of carboxyl group ranges between 3.4 and 4.4. In acidic conditions
(pH=3 ~ 4), the crosslinking is retained. In neutral or basic condition (epH 7), however,
the crosslinking is broken due to the pKa characteristics of carboxyl group [111]. The
broken cross linking leads to the burst of hydrogel, releasing the drug.
1.6.2. Chitosan
Chitosan, which is an amino (2-amino-2-deoxy-β-D-glucan) polysaccharide
obtained via the alkaline deacetylation of chitin [112-115], is soluble in acidic aqueous
solutions and because of the protonation of its amino groups at pH < 6.2 [116-117]. In
addition to its solubility, chitosan is in vivo biodegradable, biocompatible, avirulant and
compassionate. The degradation products of chitosan are metabolized by the action of
human enzymes, especially lysozyme, which enables chitosan to be incorporated into
glycoproteins, found in connective tissue [118-124].These properties have lead to
significant study of chitosan for use in biomedical applications, such as drug delivery
[125-128], wound-dressing materials [129-130], artificial skin [131-134], and blood
anticoagulants [135-136] along with orthopaedic, periodontal, cosmetics, tissue
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
15
engineering and more recently, gene therapy [137-139].Compared with other biological
polymers, chitosan is more cationic, which allows it to approach cell membranes more
easily and promote ionic crosslinkage with multivalent anions. In addition, it has
mucoadhesive properties that prolong its retention to targeted substrates [140-143].
Additionally, chitosan does not induce allergic reactions or immune rejection, and its
bacteriostatic properties discourage bacterial uptake [144].
1.6.3. Polylactide (PLA)
PLA produced from renewable resources is linear aliphatic thermoplastic
polyester and is readily biodegradable through hydrolytic and enzymatic pathways [145-
148]. PLA can be synthesized by condensation polymerization of the lactic acid
monomers or also by ring-opening polymerization of lactide monomers which are
obtained from the fermentation of corn, potato, sugar beat and sugar cane [149]. PLA has
high mechanical properties, thermal plasticity, fabric ability and biocompatibility [150-
152]. These features together make PLA attractive alternative for preparation of
composites for controlled drug delivery systems [153], surgical implants [154], tissue
culture [155], resorbable sutures [156], wound closure, and controlled release systems
[157-160]. Many investigations have been performed to enhance the impact resistance of
PLA and make it competitive with low cost commodity polymers. Considerable progress
has been made to enhance the mechanical properties by blending PLA with other
biodegradable and nonbiodegradable polymers [161]. From biomedical point of view, the
mechanical properties of neat PLA might not be adequate for high-load-bearing
application [162] which makes it necessary to additionaly incorporate reinforced filler,
such as clay [153, 163-166].
Poly (ε-caprolactone) (PCL) is biodegradable aliphatic polyester that is currently
being investigated for use in medical devices, pharmaceutical controlled release systems
and in degradable packaging [167].
1.7. Examples of bionanocomposites (BNCs)
1.7.1. Chitosan (CS)-MMT bionanocomposites (CS-MMT)
Research on hybrid CS-MMT materials is one of the most attractive topics
currently being investigated for the development of tunable systems in which the synergy
between its components may allow properties that are unattainable by either organic or
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
16
inorganic components. CS-MMT composed of chitosan and MMT (clay) have been
widely investigated in order to produce new advanced materials. It has been suggested
that both the physical and functional properties of chitosan can be improved when it is
adsorbed onto clay minerals [168-171].Thus, Darder et al. [168] showed that chitosan
(CS) can be intercalated into Na+-saturated montmorillonite providing compact and
robust three-dimensional nanocomposites with interesting functional properties. Chitosan
chains form mono- or bilayer structures within the clay mineral interlayer depending on
the relative amount of chitosan with respect to the cationic exchange capacity (CEC) of
the clay. Subsequent studies have shown that a number of factors, such as pH and
temperature can affect the extent and mode of chitosan adsorption on montmorillonite
[170]. CS can be intercalated in MMT by cationic exchange and hydrogen bonding
processes, whereby the resulting bionanocomposites (BNCs) show interesting structural
and functional properties [171]. For example, given that the pKa of the primary amine
groups in the chitosan structure is 6.3, an increase in pH leads to a decrease in the degree
of protonation of the biopolymer, which increases the amount of adsorption on
montmorillonite [170]. Adsorption of chitosan on montmorillonite, particularly when in
excess of the CEC of the clay mineral results in structures with good adsorption
properties for anions because the –NH3+ groups not directly involved in the interaction
with the clay surfaces can act as anionic exchange sites [168]. Conversely, BNCs are
made of a natural polymeric matrix and inorganic/organic filler with at least one
dimension on the nanometer scale. The CS-MMT BNCs exhibited excellent
biomechanical behavior and better pulsatile release and prolonged delivery of drugs as
compared with neat chitosan [41,172]. The benefits that can be envisaged for a chitosan–
clay nanocomposite carriers include: (a) The intercalation of cationic chitosan in the
expandable aluminosilicate structure of clay is expected to neutralize the strong binding
of cationic drug by anionic clay; (b) The solubility of chitosan at the low pH of gastric
fluid will decrease and premature release of the drug in the gastric environment can be
minimized (c) Cationic chitosan provides the possibility of efficiently loading negatively
charged drugs compared with clay and (d) The presence of reactive amine groups on
chitosan provides ligand attachment sites for targeted delivery. The limited solubility of a
chitosan–clay nanocomposite drug carrier at gastric pH offers significant advantages for
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
17
colon-specific delivery because some drugs are destroyed in the stomach at acidic pH and
in the presence of digestive enzymes. Furthermore, the mucoadhesive property of
chitosan can enhance the bioavailability of drugs in the gastrointestional tract [173].
1.7.2. Polyacrylamide (PAA) and alginate (AL) Bionanocomposite hydrogels
The design and preparation of hydrogels have attracted a great deal of interest in
biomedical engineering, pharmaceutical applications and biomaterial sciences because of
their tunable chemical and three-dimensional (3D) hydrophilic polymeric networks that
swell but do not dissolve when brought into contact with water, good mechanical
properties and biocompatibility. There are some hydrogels that sometimes undergo a
volume change in response to a change in surrounding conditions such as temperature,
pH, solvent composition and salt concentration [174-175].These unique properties offer
great potential for the utilization of hydrogels in tissue engineering, biomedical implants,
drug delivery and bionanotechnology [176–180]. In the design of oral delivery of drugs
with short half-life, pH sensitive hydrogels have attracted increasing attention. Swelling
of such hydrogels in the stomach is minimal and thus the drug release is also minimal.
Because of the increase in pH, the swelling degree increases as the hydrogels pass down
the intestinal tract [181]. During the past two decades, research into preparation of clay-
polymer hydrogel has focused primarily on systems containing polyacrylamide (PAA)
and alginate (AL) backbones. PAA/AL-MMT hydrogels are known for their super-
absorbency and ability to form extended polymer networks through hydrogen bonding. In
addition, they are excellent bioadhesives, which means that they can adhere to mucosal
linings within the gastrointestinal tract for extended periods, releasing their encapsulated
medications slowly over time [15, 182-191].
1.8. Controlling the drug release kinetics from BNCs
By controlling the drug release kinetics from BNCs, one can not only optimize the
therapeutic effects of the drug, but also influence its biological activity. The
drug/biopolymer intercalated clay should be more organophilic and compatible with
organic materials. In addition, the surface charge of MMT is negative [192] which is
dissimilar to that of drug molecules. Drug molecule is easy to intercalate into the
interlayer space or attach to the surface of MMT due to electrostatic attraction. However,
in the development of MMT-based sustained release formulations, modulation of its
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
18
properties may be needed to improve its affinity for bioactive molecules. Both thermal
and chemical treatments have been reported to be useful for this purpose [74]. Silicate
based biopolymer BNCs demonstrate good barrier properties due to the tortuous diffusion
pathways that small molecules must travel in order to clear the material (Fig.1.8) [193].
This property can be used towards the development of sustained drug release
applications. For example, organic modified silicate nanoparticles were added to poly
(ethylene-co-vinyl acetate) to study the release kinetics of dexamethasone. The authors
discovered that the increase of silicate nanoparticle concentration resulted in higher
mechanical strength of the polymer nanocomposite and a sustained release of
dexamethasone. The drug release kinetics suggested to be dependent on the aspect ratio
and degree of dispersion of the silicate nanoparticle [194]. Kevadiya et al. demonstrated
that the drug release kinetics using BNCs and interpreted the drug release follow de-
intercalation mechanism with swelling of biopolymer/clay matrixes [15, 19-20, 41-42].
1.9. Colon specific drug delivery by using BNCs
A number of approaches have been developed to achieve site-specific and time-
controlled delivery of therapeutics to improve therapeutic efficacy while minimizing
undesired side effects [195]. In the past two decades, oral drug delivery systems for colon
have been extensively investigated for the local treatment of a variety of bowel diseases
[196–197] and for improving systemic absorption of drugs susceptible to enzymatic
digestion in the upper gastrointestinal tract [198]. Targeting of drugs to the colon can be
achieved in several ways [199–204]. Prodrugs can provide site-specific drug delivery, but
they are new chemical entities and detailed toxicological studies need to be performed
before their use. The pH-sensitive delivery systems, such as enteric-coating, can be a
simple and practical means for colon-specific drug delivery. However, such methods do
not have sufficient site specificity because the large variations in the pH of the
gastrointestinal tract. Although, the time-controlled release systems seem promising, the
disadvantage of such systems is that the colon arrival time cannot be accurately predicted
because of significant variations of gastric emptying time and small intestinal transit time
between different patients [205], which result in poor colonic availability. BNC matrix
systems are very promising, because they are only the biopolymers from clay matrix
which are degraded by colonic bacterial enzymes and not degraded in the stomach and
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
19
small intestine [15, 19-20, 42-43]. Finally, recent research has shown that BNC hydrogel-
type materials can be used to shepherd various medications through the stomach and into
the more alkaline intestine [15]. BNC Hydrogels are cross-linked, hydrophilic, three-
dimensional BNC networks that are highly permeable to various drug compounds, can
withstand acidic environments and can be tailored to “swell” there by releasing entrapped
molecules through their weblike surfaces. Depending on the BNC chemical composition,
different internal and external stimuli (e.g., changes in pH, application of magnetic or
electric field, variations in temperature and ultrasound) may be used to trigger the
swelling effect. Once triggered, however, the rate of entrapped drug release is determined
solely by the cross-linking ratio of the biopolymer network with clay and drugs.
Fig.1.8.Drug release mechanism from BNCs by de-intercalation of MMT plates and
biopolymer swelling
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
20
1.10. Physicochemical characterization of BNCs
Different characterization techniques e.g. X-ray diffraction, UV-visible, HPLC,
NMR, FT-IR spectroscopy and thermal (TGA & DSC) analyses are widely used to
confirm the intercalation of drugs with clay minerals. In order to understand the spatial
arrangement of organic host molecules with clay minerals, molecular modeling has
recently been introduced. The arrangement and orientation of the intercalated molecules
depends on the type of bonding, the polarization power of the cations, properties of the
guest molecules, association tendencies of the guest molecules and their van der Waals
interaction with the silicate layer. The structure of the intercalation compounds are often
derived by considering the size and shape of the guest molecules and the basal spacing
obtained from XRD and molecular dynamics simulation studies [74, 192]. The particles
were analyzed on the basis on the dynamic light scattering technique (DLS) and Zeta
potential was estimated on the basis of electrophoretic mobility under an electric field by
zeta sizer. The morphology of drug-clay hybrid and bionanocomposite particles were
observed by scanning/ Transmission electron microscope (SEM/TEM).
1.11. Objectives of the work
The thesis divulges important applications of MMT (Clay) and biopolymer based
bionanocomposite materials for drug delivery and biomedical applications. The inherent
properties of these materials like high surface area, enormous functionality, ability to
accommodate homogeneously different drug molecules and biopolymers in inter layered
gallery. The superior cation exchange ability of these materials is explored for the
controlled release of vital drugs.
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
21
The objectives of the present thesis are:
Objective1: Preparation and characterization of bionanocomposites
Purification of MMT (Indian origin bentonite)
Preparation of alginate/chitosan/ poly (ε-caprolactone)/Poly(L-lactide)/MMT
nanocomposites
Preparation of Acrylamide/MMT nanocomposite hydrogels
Systematic characterization of nanocomposites/hydrogels by modern
instrumentation techniques (XRD, HPLC, FTIR,NMR,TEM/SEM/AFM, GC-
MS, LC-MS, Zeta sizer etc)
Objective 2: Loading of drugs in bionanocomposites, drug-clay interaction & In vitro
release kinetics
Loading of drugs into interlayer space of MMT/ nanocomposites / hydrogels
Evaluation of drug-clay interaction by computational and Langmuir-Freundlich
(MLF) isotherm model
To design site specific (e.g. Colon) release of drugs by using specific polymeric
coatings/modifications with biopolymers
Evaluation of drug efficacy by in vitro release study
Investigation of drug release kinetics by different mathematical models
Objective 3: Evaluation of drug loaded bionanocomposites in biological systems
The antibacterial activities of nanocomposite/drug carriers
In vitro testing in animal cell culture
In vitro genotoxicity (% DNA damage) assessments
In vivo drug efficacy in animal model (a) pharmacokinetics and (b) biodistribution
Estimation of drug toxicity biomarkers in rat plasma/serum (a) SGPT/SGOT (b)
Troponin (c) Alkaline phosphatase (d) Serum creatinine etc
Assessment of organ specific drug toxicity by histopathological analysis of rat
organs
Chapter 1 Introduction & Review of Literature
Ph.D Thesis B.D. Kevadiya
22
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