1.1. controlled drug delivery systems -...

Chapter 1 Introduction

Ph. D. Thesis 1 Ghanshyam V. Joshi

1.1. Controlled drug delivery systems

1.1.1. Why controlled drug delivery systems?

In spite of rapid progress in our understanding of the fundamental biological

processes underlying many diseases, we have yet to achieve comparable advances in

the detection, diagnosis, and treatment of these diseases. Such a discrepancy mainly

arises from the fact that most therapeutic agents do not efficiently accumulate in the

desired sites due to their nonspecific distribution throughout the body. As a result,

conventional therapeutic agents require high doses [1]. Moreover, drug discovery and

development involves highly challenging, laborious, and expensive processes. The

development process of each new drug takes an average of 15 years with an estimated

cost of about US $ 0.802 billion. However, most of the drugs fail to achieve favorable

clinical outcomes in the clinical phase, because they do not have the ability to reach

the target site of action. Thus, the optimization of the drug molecules for achieving a

plasma drug concentration associated with a safe clinical effect is the major challenge

in drug development [2, 3]. An effective approach to overcome this critical issue is

the development of controlled drug delivery systems. This could increase patient

compliance and therapeutic efficacy of pharmaceutical agents through improved

pharmacokinetics and biodistribution [2].Therefore, delivering drug at controlled rate,

slow delivery, targeted delivery are very attractive ways and being pursued very

vigorously [4]. Although conventional drug delivery formulations have contributed

greatly to the treatment of disease, the development of controlled delivery systems has

escalated [5].Figure 1.1 illustrates the strategic tools for controlled drug delivery

systems.

Figure 1.1 Strategic tools for drug delivery systems

Scientific

Meet clinical

need

Improved

compliance

Reduce side

effects

Delivery by usual

route

Optimize

PK profile

Controlled

Drug

Delivery Business

Patent/

Exclusivity

New patient

population

Market

image

Competitive

Advantage

Market

penetration



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 [3]. The development of drug

delivery systems requires a wide range of tasks, such as the development of materials

suitable to the specific application (biodegradable, pH-sensitive, flexible, etc.), the

ability of drug loading and type of release kinetics (slow, fast, pulsatile), and proof of

efficacy. In addition, it is important to demonstrate the system‟s safety, which

includes two major entities: (1) the safety of the systemically distributed drug, and (2)

the biocompatibility of the drug delivery system [6].

1.1.2. What is controlled drug delivery systems?

The system that delivers a pharmacologically active substance at a relevant in

vivo location with minimal side effects known as controlled delivery systems. It is a

valuable management tool of drug lifecycle. 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 [7]. Moreover, this

technology is an interdisciplinary approach that combines polymer science,

pharmaceutics, bioconjugate chemistry, and molecular biology [8].

Figure 1.2 Current drug delivery markets

In the past few years, there has been an exceptional growth in research focused

on controlled drug delivery systems (Figure 1.2). The drug delivery research is driven

by the need to develop systems that can deliver precise quantities of a therapeutic

$50 billion in 2003

$75 billion by the end of 2007

It is expected to reach ～ $145 billion by the

end of 2011



agent at a specific target site or tissue at a tailored release rate and/or after a specific

trigger. The Figure 1.3 demonstrates the desired targets that motivated to develop

drug delivery systems. The conventional techniques are not suitable for administering

several drug molecules, as they exhibit poor water solubility or suffer from limited

stability in a complex environment such as the human body [9]. The explosion of drug

delivery system has induced due to the features and possibilities that these systems

offer to biomedicine [10].

Figure 1.3 Desired targets of drug delivery systems

In order to achieve most effective drug therapy, it is required to have desired

pharmacological response at the target without harmful side effect at other sites. This

requires the correct dose of drug to be absorbed into the body and transported to the

target [1115]. The way in which a drug delivered to the target can have a significant

effect on its efficacy. Some drug molecules have an optimum concentration range

within which maximum benefit is derived, and concentrations above or below

optimum range can be toxic or yield no therapeutic benefit at all (Figure 1.4) [8].

More recently, there has been increasing interest in developing methods where drug

release can be controlled either by an interaction between a “smart” material and

Controlled delivery at predetermined rate

Less fluctuating plasma drug levels

Patient‟s convenience and compliance

Reduction in adverse side effects and dosing

frequency

Economical drug delivery systems



changes in its environment. Ideally, such systems could determine the timing,

duration, dosage, and even location of drug release [16].

Figure 1.4 Drug level in the blood with controlled release delivery

Controlled drug delivery systems offer numerous advantages compared to

conventional dosage forms [2, 7, 8, 16–20]. The benefit characteristics of controlled

drug delivery systems are as follows:

Controlled delivery of active agent at predetermined rate

Reduced dosing frequency

Better patient convenience and compliance

Reduced GI side effects

Improved efficacy/safety ratio

Less fluctuating plasma drug levels

More uniform drug effect

Reduction in adverse side effects

Lesser total dose

Moreover, mathematical modeling of drug delivery and predictability of drug

release is a field of steadily increasing academic and industrial importance with an

enormous potential. Depending on the type of drug(s), incorporated drug dose(s),

types and amounts of excipients, preparation technique, environmental conditions

during drug release, geometry and dimensions of the drug delivery system, numerous

Time (h)

Dru

g c

on

cen

tra

tio

n i

n b

lood Toxic

level

Controlled release

Minimum

Effective level



mass transport phenomena, and chemical reaction phenomena affect the resulting

drug release kinetics [21, 22].

1.1.3. Carrier modulated drug delivery systems

Carrier modulated drug delivery has emerged as a powerful methodology for

the treatment of various pathologies. There is an enhancement in the therapeutic index

of traditional and novel drugs via the increase of specificity due to targeting of drugs

to a particular tissue [23]. Thus, the design and construction of a drug carrier

represents a pivotal task in drug delivery system [24]. Varieties of materials have been

studied as drug delivery carrier and these “smart” materials have attracted the interest

of a broad range of researchers in recent years [25]. Both natural and synthetic

materials have been tested and proposed as carriers of controlled drug delivery

systems [26]. Generally, natural or synthetic polymers, lipids, surfactants, dendrimers,

hydrogels, micelles, vesicles, liquid crystals, liposomes, nanocapsules, nanospheres,

and inorganic solids have been employed as drug carriers (Figure 1.5) [2, 8, 23, 25,

27, 28]. The carriers take up or release drug molecules in response to external stimuli

such as temperature, pH, light irradiation, ionic strength, redox reagents, and enzymes

[25]. While using these carriers, the goal is to obtain systems with optimized drug

loading and release properties, long shelf life and low toxicity [8].

Figure 1.5 Different drug delivery carriers

Micelles

Vesicle Dendritic polymers

Liquid crystal

Nanocapsules

Nanospheres

Clay minerals

Liposomes

Pharmaceutical carriers



However, biodegradable nano-particulate drug carriers have created

tremendous impact on research and applications in the pharmaceutical and biomedical

fields in the 21st century [27, 28]. Nano-particulate drug carriers consist of solid

biodegradable particles in sizes ranging from 1 to 1000 nm. They are used as carriers

due to their size, simple preparation methods, and easy surface-modification

characteristics [29]. This nano-particulate also improves the therapeutic value of

various water soluble/insoluble medicinal drugs and bioactive molecules by

improving bioavailability, solubility and retention time [30]. As drug delivery system,

nanoparticles can entrap drugs or biomolecules into their interior structures and/or

absorb drugs or biomolecules onto their exterior surfaces, and can release it in a

controlled way [31, 32]. Nano-particulate drug carriers exhibit several advantages;

including tunable size, high drug loading capacity, tailorable surface properties,

controllable or stimuli-responsive drug release kinetics, improved pharmacokinetics,

and biocompatibility [1, 27, 28].

1.1.4. Routes of drug delivery systems

Pharmaceutical dosage forms for drug delivery includes tablets, pills, capsules,

aerosols, suppositories, ointments, creams, liquids, and injections [33].On this basis,

there are four key routes of drug delivery involves oral, inhalation, transdermal, and

injection (Figure 1.6).

Figure 1.6 Routes of drug delivery

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 [8]. 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

Oral Inhalation Transdermal Injection



delivery system is to identify orally active candidates that would provide reproducible

and effective plasma concentrations in vivo [18]. The oral drug delivery is the largest

and the oldest segment of the total drug delivery market (Figure 1.7) [34, 35].

Figure 1.7 Current global business scenarios

1.2. Clay & Clay minerals

In order to define clay and clay minerals, the societies like JNC (Joint

Nomenclature Committees), AIPEA (Association Internationale Pour l‟Étude des

Argiles), and CMS (Clay Minerals Society) have made great efforts [36, 37].

According to them, clay can be defined both as a rock term and as a particle size term.

As a rock term, clay is naturally occurring material composed of fine-grained

minerals become plastic at suitable water content and hardens when dried or fired. As

a particle size term, clay is used for the category that includes the smallest particles.

Soil investigators and mineralogists generally use 2 µm as the maximum size,

although the Wentworth scale defines clay as material finer than 4 µm [37, 38].

While, clay minerals are fine-grained fraction of rocks, sediments or soils, and, more

precisely, are defined as components of clays which acquire plasticity in water and

dry when heated [36, 39]. As opposed to clays, which are only natural, some synthetic

inorganic materials considered as clay minerals if they follow the previously cited

properties [39]. The properties that distinguish clay and clay minerals are summarize

in Table 1.1 [36]. Clay minerals are characterized by certain properties [36], including

A layered structure with one dimension in the nanometer range

The anisotropy of the layers or particles

The existence of several types of surfaces: external basal (planar) and edge

surfaces as well as internal (interlayer) surfaces

Pulmonary

18%

Transdermal

10%

Transmucosal

8%Others

2%

Polymer

12%

Oral CR

50%



The ease with which the external and internal surface can be modified (by

adsorption, ion exchange, or grafting)

Plasticity

Hardening on drying or firing

Table 1.1: Distinction between clay and clay mineral

Clay Clay mineral

Natural Natural and synthetic

Fine-grained (<2 µm or <4 µm) No size criterion

Phyllosilicates as principal constituents May include non-phyllosilicates

Plastic Plastic

Hardens on drying or firing Hardens on drying or firing

It is believed that clays and clay minerals, either as such or after modification,

will be recognized as the materials of the 21st century, because they are abundant,

inexpensive, and environment friendly [36]. The following properties differentiate

clay minerals from other colloidal materials [40]:

Highly anisometric and often irregular particle shape

Broad particle size distribution

Flexibility of the layers

Different types of charges (permanent charges on the faces, pH-dependent

charges at the edges)

Heterogeneity of the layer charges

Cation exchange capacity

The basic building units of clays are tetrahedral sheets in which silicon is

surrounded by four oxygen atoms, and octahedral sheets in which a metal like

aluminum is surrounded by eight oxygen atoms (Figure 1.8). Therefore, in 1:1 layered

structures a tetrahedral sheet fused with an octahedral sheet. On the other hand, the

crystal lattice of 2:1 layered silicates consists of two-dimensional layers where a

central octahedral sheet of alumina is fused to two external silica tetrahedral (Figure

1.9). Structures with all the six octahedral sites occupied known as trioctahedral. On

the other hand, if four of the six octahedral are occupied, the structure is referred to as

dioctahedral [36].



Figure 1.8 Models of Si-tetrahedral and Al-octahedral

Figure 1.9 Models of 1:1 and 2:1 layer structure

Figure 1.10 Clay mineral layer; a particle, made up of stacked layers; and an aggregate

An assembly of layers known as „particle‟, while an assembly of particles

known as an „aggregate‟. Accordingly, interlayer, and interparticle pores can be

distinguished (Figure 1.10). In general, all the phyllosilicates are porous, containing

pores of varied size and shape [36]. The layer thickness is around one nm and the

lateral dimensions may vary from 300 Å to several microns, and even larger,

depending on the particulate silicate, the source of the clay and the method of

preparation [36, 41, 42]. The layers or sheets may be negatively charged, positively

1:1 layer

2:1 layer



charged, or uncharged [39]. Due to the sheet like structure, clay minerals offer a huge

specific surface area and hence optimal properties for modification through adsorption

[43].

Since the ancient time, clay minerals have shown great potential for the

applications in drilling mud, foundry, polymer nanocomposites, agriculture, civil

engineering, and catalysis. This is due to their wide-ranging properties such as, high

resistance to atmospheric conditions, geochemical purity, easy access to their deposits

near the earth‟s surface, and low price [44]. Nowadays, clay minerals are the versatile

source for the preparation of nanostructured advanced materials including

organoclays, pillared clays, intercalation compounds, polymer-clay nanocomposites,

etc. [45].

The increased application of clay minerals in the various industries raises the

need for purification, as clay minerals collected from the mines or rocks may contains

several impurities like quartz, silt, sand, iron-stained impurities, calcite etc. The

technique mainly used for the purification of clays includes hydro cyclone,

centrifugation, sedimentation method and chemical treatment [42]. Among them,

sedimentation considered as the best technique. Sedimentation aims at separation of

clay from other minerals based on size. Typically, clay lumps or powdered clay

dispersed in water under vigorous agitation at ambient temperature and after

calculated time slurry allowed for settling. Clay platelets delamination occurs with the

formation of colloidal structure.

1.2.1. Smectite

Smectite is the name for a group of sodium, calcium, magnesium, iron, and

lithium containing aluminum silicates [46]. It is 2:1 phyllosilicates with a total

(negative) layer charge between 0.2 and 0.6 per half unit cell [36, 47]. The octahedral

sheets are dominantly occupied by either trivalent cations (dioctahedral smectites) or

divalent cations (trioctahedral smectites) (Table 1.2) [36].

The rock, in which the smectite minerals are usually dominant, is bentonite.

The name, bentonite was suggested in 1898 by Knight, and is the term commonly

used to describe the industrial mineral. Bentonites of different origin differ in

exchangeable cations, montmorillonite content, number and abundance of associate

minerals [37, 48].



Table 1.2: The members of dioctahedral and trioctahedral smectites

Dioctahedral Trioctahedral

Montmorillonite Hectorite

Beidellite Saponite

Nontronite Sauconite

Volkonskoite

During the 20th century, the processing of smectites resources has evolved

from low technology operations to highly sophisticated chemical and engineering

processes. Smectites are strongly involved in material science studies and are parent

materials of organic-inorganic composites due to its amazing properties like [36, 49]:

2:1 expandable layers

Particles of colloidal size

Variable interlayer separation

Rich intercalation chemistry

Moderate layer charge

High cation exchange capacity

Very thin flakes

High surface area

High absorption capacity

High swelling capacity

High viscosity

Thixotropic

Abundance in nature

Availability at low cost

They are widely used for industrial purposes, either in their natural form or

after appropriate modifications. There are different ways to modify 2:1 clay minerals

such as [50, 51]:

Adsorption

Ion exchange with inorganic cations, organic cations and cationic complexes

Binding of inorganic and organic anions, mainly at the edges

Grafting of organic compounds

Reaction with acids



Pillaring by different types of poly (hydroxo metal) atom

Interlamellar or intraparticle and interparticle polymerization

Dehydroxylation and calcination

Delamination and reaggregation

Physical treatments such as lyophilisation, ultrasound and plasma

The common uses of smectite includes [44],

Adsorbents and adhesive

Bleaching earth

Foundry sand

Iron ore palletizing

Oil and gas-well drilling mud

Water proofing and sealing

Organoclay and nanoclay

Insecticide and pesticides carrier

Paper and paint industries

Pharmaceuticals

Figure 1.11 Total sales for US bentonite

In civil engineering, bentonite used in the construction of landfills, in the

encapsulation of contaminated soils, as drilling fluids, and as slurry shields for

tunneling processes. Their technical applications are wide-ranging in industry and

extend from cat litter, odor adsorbents, paint, paper industry, foundry industry, and

wastewater treatment to bleaching agents in the food industry, as an additive in

detergents, and in many more applications [36, 52]. The total sales for US bentonite is



illustrated in Figure 1.11, according to which, its highest consumption as adsorbents

(26 %) was recorded. The estimated deposits of bentonite clay in India are about 0.2

billion tonnes. Bentonite production in India estimated to be around 400,000 tonnes

per annum. Major producers of bentonite in India are states of Gujarat (0.1 billion

tonnes) and Rajasthan (0.09 billion tonnes).

1.2.1.1. Montmorillonite

Montmorillonite (MMT), the name derived from Montmorillon, a town in the

Poitou area, France (Figure 1.12) are the most abundant minerals within the smectite

group of 2:1 clay minerals. They are the determinative components in bentonite (˃

50%) [36, 40, 46, 53].

Figure 1.12 Montmorillon, named for its location in Montmorillon, France

MMT is a hydrophilic mineral that consists of nanometer-thick layers formed

by sandwiching an aluminum octahedron sheet between two silicon tetrahedron sheets

[54–57]. Al atoms are present in octahedral sites, forming the central layer (O) of each

clay sheet. Si atoms are present in tetrahedral sites, forming two layers (T) on either

side of the octahedral layer. Thus, the overall configuration of a single clay sheet is

T–O–T (Figure 1.13). Substitutions in the octahedral and tetrahedral leads to a

negative charge at the basal surface, balanced by a cationic charge (e.g. Na+, K

+, Ca

2+,

and Mg2+

) which is mostly located in the space created between two almost parallel

layers. Stacking of the layers leads to a van der Waals gap between the layers [36, 39,

58]. As the binding forces between layers are much weaker than those within sheets,

the cations are loosely held and easily exchangeable [48, 53]. Therefore, the interlayer

inorganic cations can be exchanged by other inorganic or organic cations that are

present within a surrounding liquid [59].



Figure 1.13 Structure of MMT

Commonly, Si4+

, Al3+

, and Fe3+

are observed in tetrahedral sites. While, the

octahedral sites are occupied by Al3+

, Fe3+

, Fe2+

, and Mg2+

[36]. A layer is composed

of basal and lateral surfaces, having different properties. The basal siloxane surfaces

are chemically neutral. Whereas, hydroxyl groups (silanol and aluminol), located at

the broken edges of the lateral surfaces are charged; depends on the ambient pH [39].

Due to unique structure of MMT, the layer thickness is only one nanometer, although

its dimensions in length and width measured in hundreds of nanometers [42].

Therefore, the aspect ratio is very high, close to 1000 (1 nm/l m) [39]. The interlayer

space is about 1.2 nm when the interlayer spaces occupied by cation with low-field

strength and water molecules [36]. The MMT particles are of irregular shape, and

look like paper sheets. The particles are never true crystals, but are more like

assemblages of silicate layers [40].

1.2.1.2. Hectorite

Hectorite is a clay mineral similar in structure to MMT, but having more

charges that are negative on its surface. It is hydrophilic swelling clay composed of

silicate sheets, which delaminate in water to provide an open three-dimensional

structure [42]. They are composed of two tetrahedral silicate layers sandwiching a

central magnesium octahedral layer in a so-called 2:1 arrangement. Isomorphous

substitutions in the lattice of Li+ for Mg

2+ in the octahedral layers cause an overall

negative charge compensated by the presence of interlayer cations. A significant

amount of interlayer water is also present and the cations are easily exchangeable

[60–64].



From the last two decades, the synthetic hectorites have gained much

attention. The main limitations that led to the preference for synthetic clay minerals

are inhomogenity of natural clay minerals in composition and particle size [65]. In a

typical synthesis of hectorites, the sol–gel heated to crystallize an organic–clay

composite. The organic moiety removed by calcinations, which generates an

inorganic network with a narrow distribution of pores in the mesoporous range.

Generally, pore size depends on the organic engaged in the synthesis [61, 64].

However, synthetic MMT typically requires high temperatures, in the 300–400 °C,

and autogenous pressure conditions to afford the best purity and crystallinity. On the

other hand, hectorite requires much less rigorous conditions, as it forms at low

temperatures and pressures in nature. Generally, the surface area of natural and

synthetic hectorites found to be different. The surface area of natural hectorite is ~71

m2/g, while it is ~200 m

2/g for synthetic hectorite [64]. Because of their potential

applications in the field of catalysts, catalyst supports, and clay-polymer

nanocomposites, many efforts are directed to tailor both pore size and structure of this

clay [66].

1.3. Scope of clay minerals in drug delivery systems

1.3.1. Adsorption of organic molecules on clay minerals

Adsorption and desorption of organic molecules on different solids were

studied extensively because of their great importance in many industrial fields.

Natural or synthetic clays have been used for such purpose [67]. After the

introduction of X-ray diffraction in 1913, the interactions of organic molecules with

swelling clay minerals have begun [51]. Moreover, intercalation of organic species

into layered inorganic solids provides a useful and convenient route to prepare

organic-inorganic hybrids that contain properties of both the inorganic host and

organic guest in a single material [68]. Among the several approaches, ion exchange

is the best way for the interaction of organic molecules to the clay layers [69].

Gieseking et al. placed an example of ion exchange process between clay mineral and

methylene blue dye in 1939 [70]. They successfully intercalated the dye into layers of

clay via ion exchange process. The results indicated that the ammonium ions of the

NH3R+, NH2R2

+, NHR3

+, and NR4

+ type easily replaced by cations presents in the

clay. The hydrochlorides of a variety of amines were interacted with clay minerals.



The replacement of the inorganic exchangeable cations with organic cations in the

interlayer spacing of the layered silicates will increase the basal spacing of the clay

minerals [51].

1.3.2. Clay minerals in drug delivery system

In the 1960's, it was observed that co-administration of clay-based intestinal

adsorbents or by the presence of clay stabilizers in liquid formulations reduces the

absorption of several drugs. The absorption of promazine (an antidepressant agent)

decreased when the drug was administered in association with antidiarrhea mixtures

containing attapulgite [71, 72]. Many studies have reported a decrease in

bioavailability of several drugs by co-administration with antacid (Mg trisilicate),

antidiarrheal (attapulgite, kaolin) and suspending agents (talc, bentonite). It was soon

realized that the effects of such interactions in the concomitant administration of clay

minerals with active substances might not be purely negative, but could also be used

to achieve technological and biopharmaceutical benefits. This was the starting point

for the use of clays in drug delivery systems [69].

Nowadays, the importance of controlled delivery of various drugs and

bioactive molecules in medicine leads to advanced development in novel area of

chemistry–biology–material sciences [73]. In recent years, clay minerals have been

investigated for their superior ability regarding to storage and delivery of intercalated

substances, such as biologically active drugs, vitamins, amino acids, and mono-

oligonucleotides [74–78]. Hybridization of drugs with the clay minerals offers some

fascinating features such as protected delivery, controlled release, enhanced water

solubility, increased dispersion ability, and the feasibility of target delivery [73].

The use of clay minerals for medicinal purposes is almost as old as humanity

itself. Among the clay minerals, smectites, palygorskite, kaolinite and talc are used in

pharmaceutical formulations [36, 79]. Their specific function in any particular

formulation depends on both their physical properties (particle size and shape,

specific surface area, texture, color and brightness) and chemical features (surface

chemistry and charge) [80]. These minerals can act as active principles or excipients

[36, 79]. Modification of the properties of the clay mineral (specific surface area,

porosity, hydrophilic character, kind of exchangeable cations) could be helpful to

improve its affinity with the bioactive molecules. Both the thermal and chemical



(mineral acid dissolutions, intercalation with inorganic or organic compounds)

treatments have been reported for this purpose [15, 69].

1.3.3. Favorable properties

The fundamental properties for which clay minerals are used in

pharmaceutical formulations are [36, 73, 79, 81, 82]:

High specific surface area

High adsorption ability

High swelling capacity

High cation exchange capacity

Favorable rheological characteristics

Interlayer reactions

Chemical inertness

Low or null toxicity for the patient

Low price

Among all the mentioned positive properties of clay minerals, cation exchange

capacity (CEC) has proven to be very important for the interaction of cationic drug

molecules into the interlayer space of smectites. CEC is highly dependent on the

nature of the isomorphous substitutions in the tetrahedral and octahedral layers and

therefore on the nature of the soil where the clay was formed [41].

Moreover, clay minerals can remove bacteria, fungi, parasites, chemicals,

toxins and even help resolve viral infections from the body. The extensive use of clay

for the treatment of pain, open wounds, colitis, diarrhea, hemorrhoids, stomach ulcers,

constipation and intestinal problems, acne, anemia, and a variety of other health issues

is well known. As clays do not decomposes and get absorb into the body, it offers

wonderful, safe, inexpensive and effective medicine for the 21st century. Since clay is

not digested and absorbed as it passes through the alimentary canal, the clay and the

absorbed positively charged ions are both eliminated together [83]. Therefore, clay

minerals are not pathogenic in humans. Lee et al. have studied the toxicity of MMT

on yeast and rats models, and concluded that MMT can be considered non-toxic to S.

cerevisiae. In addition, the result of biostatistics analysis (hematological analysis,

blood-biochemical analysis) and histopathological supported the non-toxicity of

MMT [84, 85].



1.3.4. Drug loading and interaction mechanism

There are many reports for obtaining clay–drug interaction products.

Intercalation reactions occur by the insertion of mobile guest species into the

accessible vacant sites located between the layers in the layered host structure [86].

The clay lumps were purified using Stoke‟s law of sedimentation. The clay lumps

were dispersed in water, and were allowed to sediment for pre-calculated time, and

height. Finally, the slurry was decanted, dried at 90100 °C, and ground to pass

through sieve to obtain powder. In order to get claydrug composite, the clay particles

were dispersed in aqueous drug solutions, the resulting dispersions were allowed to

equilibrate for a appropriate time, and finally solid phases were recovered and dried

(Figure 1.14) [69, 87, 88]. Therefore, the process is mainly based on the adsorptive

properties of clay minerals.

Figure 1.14 Schematic for preparation of clay-drug hybrid

In particular, clay minerals mainly undergo ion exchange with basic drugs in

solution, as they are naturally occurring inorganic cationic exchangers (Figure 1.15)

[15, 69]. Smectites, especially montmorillonite have been the more commonly studied

because of its higher cation exchange capacity compared to other pharmaceutical

silicates (such as talc, kaolin and fibrous clay minerals) [87].

Purified clay Clay lumps

Addition of

Water Sedimentation

Filtered, washed,

dried

Clay-drug hybrid



Figure 1.15 Clay particle (composed of exchangeable cations and water molecules) and exchange of

cationic drug molecules into interlayer

Solution intercalation is the most widely used method to prepare clay–drug

interaction products. Apart from the solution intercalation method, dry procedures

were also reported. It consists; melt intercalation, and grinding intercalation. In melt

intercalation method, the clay and drug are mixed at the melting temperature of the

drug. The grinding intercalation method consist of simple mechanical grinding of clay

and drug together [55, 69, 8890].

Several mechanisms may be involved in the interaction between clay minerals

and organic molecules such as:

Hydrophobic interactions (van der Waals)

Hydrogen bonding

Protonation

Ligand exchange

Cation exchange

pH-dependent charge sites

Cation bridging

Water bridging

The relevance of a specific mechanism depends on the clay mineral involved

as well as on the functional groups and the physical–chemical properties of the

organic compounds [69].



1.3.5. Characterization techniques

Different characterization techniques e.g. X-ray diffraction, UV-visible, IR

spectroscopy, and thermal (TGA) 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 [36, 69].

1.3.6. Drug release methodology

The method used for drug release should simulate the environment to which

the dosage form of drug will be exposed in the gastrointestinal tract [91]. Dissolution

testing is the most widely used methodology for evaluating oral modified release

delivery systems. The dissolution method should be reproducible, scientifically

justifiable, and more importantly biorelevant. Currently, USP dissolution apparatus I

(basket), and II (paddle method) are routinely employed to evaluate orally modified

release delivery systems (Figure 1.16) [92]. Moreover, the release property of loaded

drug could be controlled by handling electrostatic interaction between the drug

molecules and the clay layers. Electrostatic attraction decreases the release ratio,

while electrostatic repulsion increases the release ratio [73].

Figure 1.16 USP dissolution apparatus

Basket Paddle



1.4. Currently engaged inorganic materials in drug delivery systems

Many inorganic nanomaterials such as calcium phosphate, gold, carbon

materials, silicon oxide, iron oxide and layered double hydroxide (LDH) have been

studied as drug delivery carriers. The different types of carriers are briefly compared

in Table 1.3 [93]. To the date, viral and cationic carriers (lipids and polymers) are

widely used as drug carrier. However, their use is limited due to its toxicity. In

contrast, inorganic nanoparticles show low toxicity and promise for controlled

delivery properties, thus presenting a new alternative to viral carriers and cationic

carriers. Inorganic nanoparticles generally possess versatile properties suitable for

cellular delivery, including wide availability, rich functionality, good

biocompatibility, potential capability of targeted delivery and controlled release of

carried drugs [93, 94]. The most important advantage of inorganic nanostructured

materials is their structures. They are able to resist degradation and hence facilitate

release of drugs at requisite times [95]. This is why increasing efforts in research and

development worldwide have been devoted to various inorganic nanomaterials as

novel non-viral carriers in the last decade [93, 94].

Table 1.3: Comparison in properties of various inorganic nanoparticles

Type Size (nm) Shape Functional group

Gold 1–100 Spherical/rod Au

Carbon nanotubes 1–10 Tubular C-COOH

LDH 30–200 Sheet M-OH & AECa

SiO2 5–100 Spherical Si-OH

Fe3O4 1–50 Spherical Fe-OH

MMT 1 (Sheet)

< 1000 nm (Particle)

Sheet Si-OH & CECb

aAnion exchange capacity; bCation exchange capacity

1.4.1. Mesoporous silica

Owing to nontoxic nature and good biocompatibility of mesoporous silica,

intensive research has been carried out in using this material for hosting and further

delivering of a variety of drug molecules [3, 12]. Mesoporous silica seems to be ideal

for encapsulation of pharmaceutical drug, proteins and other biogenic molecules due

to its following properties [10, 13, 9698]:



An ordered pore network

High pore volume

High surface area

A silanol-containing surface

Due to the presence of a high concentration of silanol groups on the surface

(Figure 1.17), silica can be functionalized to control pore size and surface properties,

which makes them suitable for controlled drug delivery [99].

Figure 1.17 Nanostructured mesoporous silica matrices

1.4.2. Layered double hydroxides

The Layered double hydroxides (LDHs) are host solids whose structure is

built by positively charged brucite-like layers, balanced by exchangeable anions

(Figure 1.18). The ion-exchange intercalation chemistry of the LDHs are extensive, as

a variety of inorganic and organic anions may be incorporated between the LDH

layers [68, 100102].

Due to their high flexibility in composition, the easy synthesis, versatility,

biodegradability, and good biocompatibility, numerous LDH materials with

intercalated drugs and biomolecules have been prepared via anion exchange and co-

precipitation methods [103]. LDHs have some great ability such as, to release the

encapsulated drugs in a controlled manner, to facilitate cellular interaction, and

enhance cellular uptake and eventually lead to a high efficacy of drugs [104].

Figure 1.18 Structure of LDH



1.4.3. Montmorillonite

Table 1.4: List of drugs adsorbed on clay

Drug Reference

5- Fluorouracil (anti-cancer) Lin et al., 2002 [107]

Promethazine hydrochloride

(anti-histaminic)

Buformin hydrochloride (anti-diabetic)

Benzalkonium chloride (anti-septic)

Fejer et al., 2002 [75]

Amino acids Kollar et al., 2003 [76]

Trimethoprim (anti-bacterial) Qtaitat et al., 2004 [108]

Promethazine hydrochloride Seki et al., 2006 [109]

Acyclovir (anti-viral) Zheng et al., 2006 [110]

Salicylic acid (anti-inflammatory ) Bonina et al., 2006 [111]

Ibuprofen (non-steroidal anti-

inflammatory )

Zheng et al., 2007 [112]

Sertraline hydrochloride (anti-depressive) Nunes et al., 2007 [74]

BSA protein Lin et al., 2007 [113]

Trimethoprim (TMP) (anti-biotics) Bekci et al., 2007 [114]

5-Fluorouracil Akalin et al., 2007 [115]

Donepezil (alzheimer‟s disease) Park et al., 2008 [116]

Tetracyclines (anti-biotics) Chang et al., 2009 [117]

Chlorhexidine acetate (anti-bacterial) Meng et al., 2009 [118]

Timolol maleate (-adrenergic blocking agent) Joshi et al., 2009 [119]

Nicotine (alkaline liquid) Pongjanyakul et al., 2009 [120]

Vitamin B1 and Vitamin B6 Joshi et al., 2009 [121, 122]

Promethazine hydrochloride Seki et al., 2009 [123]

Ciprofloxacin (anti-biotic) Wu et a., 2010 [124]

Ranitidine hydrochloride (antacid) Joshi et al., 2010 [125]

Ciprofloxacin Wang et al., 2010 [126]

Carvedilol (-adrenergic blocking agent) Lakshmi et al., 2010 [88]

Buspirone hydrochloride (anti-anxiety) Joshi et al., 2010 [127]

Tramadol hydrochloride (analgesic) Chen et al., 2010 [128]



MMT can react with different types of organic compounds to form clay-

organic composites. In general, organic molecules can intercalate into the interlayer

space or can adsorb on the MMT surface. The intercalation of an organic drug

(oxprenolol hydrochloride) with MMT was for the first time studied by Sanchez et al.

in 1983 [105]. Afterward, up to the end of 20th century, a very few drug molecules

e.g. sotalol hydrochloride [106], N-methyl 8-hydroxy quinoline methyl sulfate [89],

phenyl salicylate, methyl cinnamate, ethyl cinnamate, and p-aminobenzoic acid [90]

were adsorbed on the MMT layers. However, in the 21st century, review articles on

clay minerals for drug delivery application appeared [69, 79]. Consequently, the

research on clay-drug composites and its release behavior were provoked. The list of

drugs adsorbed on MMT is summarized in Table 1.4.

1.5. Biodegradable polymers in drug delivery systems

Generally, polymers may be classified in to two categories, (I) biodegradable

or (II) non-biodegradable. Among them, biodegradable polymers have increasing

interest over the past two decades in the fundamental research as well as in the

chemical industry. Biodegradable means, hydrolysable at temperatures up to 50 °C

over a period of several months to one year. Non-toxic degradation products are other

important requirements for any potential application [129]. A biodegradable product

has the ability to break down, safely, reliably, and relatively quickly, by biological

means, into raw materials of nature and disappear into nature. Degradation may be

take place by (I) chemical means or (II) Physical means. In chemical degradation,

chemical changes occur in polymers, which include cleavage of covalent bonds,

hydrolysis, ionization or protonation. Whereas, in physical erosion, degradation takes

place through dissolution, and diffusion processes [7].

For drug delivery applications, biodegradable systems seem to be better,

because the non-biodegradable systems need retrieval or further manipulation after

administration into the human body [7]. Various natural and synthetic biodegradable

polymers have been intensively studied as a delivery carrier due to their well-known

therapeutic benefits, such as biocompatibility, biodegradability, low cost, high

performance, and long-term safety of drugs [116].



1.5.1. Natural biodegradable polymers

As natural biodegradable polymers, polysaccharides are the most widely used,

because they are highly stable, safe, non-toxic, hydrophilic and biodegradable. In

addition, polysaccharides have abundant resources in nature and low cost in their

processing [31, 130, 131]. In nature, polysaccharides have various resources from

algal origin (e.g. alginate), plant origin (e.g. pectin, guar gum), microbial origin (e.g.

dextran, xanthan gum), and animal origin (chitosan, chondroitin). Due to the presence

of various functional groups on molecular chains, polysaccharides can be easily

modified chemically and biochemically. Particularly, most of natural polysaccharides

have hydrophilic groups such as hydroxyl, carboxyl and amino. For the application of

these naturally occurring polysaccharides for drug carriers, issues of safety, toxicity

and availability are greatly simplified. Therefore, a large number of studies have been

conducted on polysaccharides and their derivatives for their potential application as

nanoparticle drug delivery systems [31, 130132].

1.5.1.1. Sodium alginate

Sodium alginate (SA) is a sodium salt of alginic acid, a naturally occurring

non-toxic polysaccharide found in brown algae [133]. Alginate is an anionic

copolymer of 1, 4-linked-β-D-mannuronic acid and α-L-guluronic acid residues

(Figure 1.19) [134]. Due to its ability to form firm gels on addition of di and trivalent

metal ions (e.g. Ca2+

or Al3+

) in aqueous solution, it has been widely exploited for

fabrication of vehicles for sustained delivery of bioactive molecules. The formation of

gel is a result of ionic interaction and intramolecular bonding between the carboxylic

acid groups and the cations that are present. The preparation of alginate gel is a

simple, mild and eco-friendly process [135]. The following properties of alginate have

enabled it to be used as a matrix for controlled drug delivery [136].

Easily available

Inexpensive

Non-toxic when taken orally

Biodegradable

Biocompatible

Forms hydrogels under mild conditions



Figure 1.19 Chemical structure of sodium alginate

The release of drugs can be significantly reduced in low pH solutions from

alginate beads. This could be advantageous in the development of an oral delivery

system. As, the hydrated sodium alginate is converted into a porous, insoluble alginic

acid skin in gastric fluid, the alginate beads and microparticles are stable in low pH

conditions (gastric environment). Therefore, the encapsulated drugs are not released.

Once passed through the higher pH of the intestinal tract, it swells in weak basic

solutions, followed by disintegration and erosion. This pH dependent behavior of

alginate can be utilized in the development of colon specific delivery [136, 137]. In

pharmaceutical aspects, the alginate has been used as tablet binder, disintegrate, and

gelling agent because of its protection effect on gastrointestinal mucus and

nontoxicity [138140].

1.5.1.2. Chitosan

Chitosan [CS, (1→4) 2-amino-2-deoxy-b-D-glucan] obtained by the alkaline

deacetylation of chitin, is a copolymer of N-acetyl-D- glucosamine and D-

glucosamine (Figure 1.20) [137, 141]. Most of the naturally occurring

polysaccharides are neutral or acidic in nature, whereas CS is highly basic

polysaccharide [142]. CS is a natural amino polysaccharide having unique structures,

multidimensional properties, highly sophisticated functions and wide-ranging

applications in biomedical and other industrial areas. The presence of amino

functionality makes it an interesting polysaccharide, as it could be suitably modified

to impart desired properties and distinctive biological functions. Apart from the amino

groups, they have two hydroxyl functionalities for effecting appropriate chemical

modifications to enhance solubility [143].



Figure 1.20 Chemical structure of chitosan

Chitosan has been widely used as a scaffolding material in tissue engineering,

orthopedic implants and drug delivery vehicles for many years because of its low

price and outstanding characters, such as osteoconductivity, biodegradability, and

biocompatibility. The positive attributes of excellent biocompatibility and

biodegradability with ecological safety and low toxicity have provided many

opportunities in the development of drug delivery systems [143]. Most commonly in

drug delivery, CS is the carrier or functional excipient (e.g. permeation enhancer) of

the active compound [144].

1.5.2. Synthetic biodegradable polymers

Synthetic biodegradable polymers have been intensively studied as a delivery

carrier due to their well-known therapeutic benefits, such as biocompatibility,

biodegradability, and long-term safety of drugs. Among various synthetic polymers,

poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly (e-caprolactone) (PCL),

poly (lactide-co-glycolides) (PLGA), and methacrylic acid copolymer (Eudragits) are

the most popular [30, 116, 145]. Compared to natural materials, synthetic polymers

are normally more expensive. However, they are available at high purity and the

efficiency of drug encapsulation is higher [146].

The use of different types of Eudragits for controlled drug delivery is also well

known. In general, there are two types of Eudragits, polycations and polyanions.

Polycations e.g. Eudragit type E, RL, RS, and NE have positively charged groups

such as dimethylamino or quaternary amino groups. Whereas, polyanions e.g.

Eudragit types L and S have negatively charged group such as carboxylate [147].

Eudragits are pH-dependent methacrylic acid polymers containing carboxyl groups,

which are stable at acid pH but dissolved at near neutral pH. Thus, it protects the drug

in the stomach and subsequently releases it in the GI tract [91]. However, Eudragit E

is gastro soluble up to pH 5. Eudragits have been used as not only an enteric coating



material but also as a sustained release coating one in the pharmaceutical field due to

their biological safety [148]. Moreover, Eudragits have a unique advantage that after

performing their function they degrade into non-toxic monomers. Table 1.5 specifies

the types of Eudragits used in the study.

Table 1.5: List of different Eudargits used in the study

Polymer Chemical structure Dissolution pH

EUDRAGIT L 100

Soluble from pH 6

EUDRAGIT L 100 55

Soluble from pH 5.5

EUDRAGIT E 100

Gastro Soluble up to pH 5.0

1.6. Bio-nanocomposites (combination of biopolymer and clay) in drug delivery

systems

Biopolymers and clays are common ingredients in fluid and solid

pharmaceutical products due to their distinct advantages such as; they are versatile

(they possess a wide range of mechanical, chemical, and physical properties), usually

considered inert, and available at reasonable costs. In the last decades, clays and

biopolymers have been proposed as interesting materials for drug delivery systems.

The delivery of a drug by a simple conventional dosage form will normally result in



the drug being released rapidly in an uncontrolled way and distributed to the various

body organs and compartments in an unselective manner. To avoid these

inconveniences, colloidal clay particles and biopolymers have the potential to provide

predictable, precise and reproducible patterns of controlled release and site-specific

delivery [15].

Bio-nanocomposites are young members of the material family with

increasing applications in pharmaceutical, medical and biomedical engineering [149].

They are an emerging group of hybrid materials derived from natural polymers and

inorganic solids interacting at the nano scale. These nanostructured organic–inorganic

materials could be designed and prepared using a wide type of biopolymers and

inorganic solids. Among the inorganic solids, special attention is devoted to layered

materials (e.g. smectite) that show the ability to intercalate biopolymers giving

hybrids with functional properties [150]. The nanocomposites of clay and a polymeric

matrix give the properties that could not be achieved by either phase alone. That is

why they have gained much interest in pharmaceutical technology, in particular in the

development of new drug delivery materials with improved polymer and/or clay

properties [15, 151153].

There are some reports suggesting clay-polymer bio-nanocomposites e.g.

CS/MMT [151, 154157], Poly (AA-co-PEGMEA)/bentonite [158], PEG/MMT [149,

152], PLGA/MMT [159, 160], EVAc/MMT [161], PLA/MMT [162], PEG/laponite

(synthetic hectorite) [163] in drug delivery systems.



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