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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



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(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].



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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.



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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



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



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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).



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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;



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(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



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,



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



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”



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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



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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]



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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



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



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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



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



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



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



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.



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



22

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