CHAPTER I

INTRODUCTION

his chapter deals with the recent developments in the field of controlled

T drug delivery systems using polymers as carriers. Various novel drug

delivery systems including micro/nanoparticles, electrically modulated drug
delivery systems (EMDDS) and in-situ gel forming solutions (GFS) are
covered with respect to their production, characterization and applications.
Different types of polymers have been used to design such delivery systems
that can effectively deliver various classes of drugs to a target site and thus
increase the therapeutic benefit, while minimizing the side effects.

A part of discussion presented in this chapter has appeared as a review article in: J.
Controlled Release, 100 (2004) 5-28.

CHAPTER I 1
1.1. Introduction

Drugs are administered through many routes by a variety of dosage

forms. However, maintaining the constant in-vivo therapeutic drug
concentrations for an extended period of time has been problematic. Peaks and
troughs in drug concentration are often observed when the drug is administered
either intermittently via the intravenous route or upon oral administration.
High drug concentrations may cause toxicity, whereas low drug concentrations
may be sub-therapeutic. The best approach to eliminate the peaks and troughs
during drug therapy is by continuous intravenous infusion. However, this
requires constant monitoring, which can only be performed by health-care
professionals. Recently [1,2], the importance of delivery was addressed and it
was stated that the delivery of therapeutics could be considered as the next
frontier of molecular medicine. The extraordinary advances made in the past
decade in molecular biology and biotechnology have helped identifying novel
targets and developing a vast array of therapeutic agents. However, the
understanding of the delivery of therapeutic agents has lagged behind.

In the past decades, extensive investigation on polymeric materials for

biomedical applications has promoted the development of new concepts in the
treatment of human diseases. The new approaches to drug delivery are based
on the realization that optimum biological response occurs when the temporal
(time-dependent) and the spatial (site-specific) delivery of bioactive agents are
optimized. Controlled drug delivery technology represents one of the most
rapidly advancing areas of science where polymer and pharmaceutical
scientists are contributing to biomedical research. These delivery systems offer
many advantages over the conventional dosage forms, which include improved
efficacy, reduced toxicity, improved patient compliance and cost effective
therapeutic treatment.

Targeted delivery results in a tremendous enhancement of the

therapeutic efficacy and lowering of the toxic effects. Controlled and targeted
drug delivery systems can have an incredible impact on nearly every branch of

CHAPTER I 2
medicine. Fundamental characteristics of drug delivery systems are the ability
to incorporate drugs without altering their original properties, prolonged in-vivo
stability, tunable release kinetics and targeting to specific organs/tissues. These
fundamental characteristics can be successfully achieved by using polymer as a
.1
carrier for the bioactive molecules.

The basic components in most of the drug delivery systems are

therapeutic agents and polymers. The therapeutic agents are either physically or
chemically combined in the delivery systems. If the combination is physical,
drugs are dispersed or dissolved in the polymer matrix (matrix system), or are
constrained inside a compartment by polymer membrane (reservoir system). If
the combination is chemical, drug molecules are covalently attached to the
polymer chains [3].

The final design or choice of an appropriate delivery system will first

require a proper consideration of three related issues; the properties of the drug;
the disease and the destination in the body. To alleviate this kind of problem, a
number of drug delivery systems such as oral controlled release dosage forms,
transdermal, injectable and implantable drug delivery systems have been
investigated and commercialized. However, this chapter addresses the
technological and research developments occurred over the past few decades in
the area of hydrogel-based micro/nanoparticles, EMDDS and in-situ GFS for
the controlled release (CR) of drugs. Even though there are many other
delivery devices, but present thesis covers only those aspects mentioned above.

1.2. Hydrogels

Hydrogels are the three-dimensional, water-swollen structures composed

of mainly hydrophilic homopolymers or copolymers [4]. They are rendered
insoluble due to the presence of chemical or physical crosslinks. The physical
crosslinks can be entanglements, crystallites or weak associations such as van
der Waals forces or hydrogen bonds. The crosslinks provide the network

structure and physical integrity.

CHAPTER I 3
 Two of the most important characteristics in evaluating the ability of a
hydrogel to function in a particular CR application are the network
permeability and the swelling behavior. The permeability and swelling
behavior of hydrogels are strongly dependent on the chemical nature of the
polymer(s) composing the gel as well as the structure and morphology of the
network. As a result, there are different mechanisms that control the release of
drugs from the hydrogel-based delivery devices. Such systems are classified by
their drug release mechanism as diffusional-controlled release systems,
swelling-controlled release systems, chemically controlled release systems and
environmentally responsive systems [5].

There are many different macromolecular structures that are possible for
physical and chemical hydrogels. These include: crosslinked or entangled
networks of linear homopolymers, linear copolymers, and block or graft
copolymers; polyion-multivalent ion, polyion-polyion or H-bonded
complexes; hydrophilic networks stabilized by hydrophobic domains; and IPNs
or physical blends.

Hydrogels have emerged as the promising materials for CR technology

as well as site-specific delivery of bioactive molecules. Hydrogels possess
several specific advantages such as: (i) have high drug holding capacity, (ii)
protection of drug from the hostile environment e.g., the presence of enzymes
and low pH in the stomach, (iii) control the release of drugs by chaining the gel
structure in response to environmental stimuli and (iv) hydrogels are non-toxic
and biocompatible. As compared to other synthetic biomaterials, hydrogels
resemble the living tissues closely in their physical properties because of their
relatively high water content in addition to soft and rubbery nature. Hydrogels
show a minimum tendency to adsorb proteins from the body fluids because of
their low interfacial tension. Further, the ability of molecules of different sizes
to diffuse into (drug loading) and out of (drug release) the hydrogels allow the
possible use of dry or swollen polymeric networks as drug delivery systems for

CHAPTER I 4
oral, nasal, buccal, rectal, vaginal, ocular and parenteral routes of
administration.

In the current niche of drug delivery technologies, hydrogels have made

an irreplaceable space because of their unique characteristics. However, this
chapter presents a brief introduction to stimuli-responsive hydrogels as well as
interpenetrating polymer network hydrogels.

1.2.1. Stimuli-Responsive Hydrogels

Several terms used for hydrogels are “intelligent” or “smart” polymers

[6]. The smartness of any material is the key to its ability to receive, transmit or
process a stimulus, and respond by producing a useful effect [7]. Once
triggered by stimuli, the hydrogel can result in changes in phases, shapes,
optics, mechanics, electric fields, surface energies, recognition, reaction rates
and permeation rates. Hydrogels are “smart” or “intelligent” in the sense that
they can perceive the prevailing stimuli and respond by exhibiting changes in
their physical or chemical behavior, resulting in the release of the entrapped
drug in a controlled manner [8], Various stimuli that have been explored for
modulating drug delivery are presented in Table 1.1.

Hydrogels can exhibit dramatic changes in their swelling behavior,

network structure, permeability or mechanical strength in response to different
stimuli, both internal and external to the body [9]. The mechanisms of action of
these stimuli on structural changes in the polymer network and corresponding
modulation in drug release have been well documented in the literature
[7,8,10,11], External stimuli have been produced with the help of different
stimuli-generating devices, whereas internal stimuli are produced within the
body to control the structural changes in the polymer network and to exhibit the
desired drug release.

Ionic hydrogels are swollen polymer networks containing pendent

groups, such as carboxylic or sulfonic acid, which show a sudden or gradual
change in their dynamic and equilibrium swelling behavior as a result of a

CHAPTER I 5
 Table 1.1
External Stimuli-Responsive Hydrogels: Factors Affecting Their Swelling
and Mechanism of Bioactive Agent Release
Stimulus Hydrogel Mechanism
pH Acidic or Basic Change in pH- swelling - release of
drug
Ionic Ionic Change in ionic strength - change in
strength concentration of ions inside gel -
change in swelling - release of drug
Enzyme- Hydrogel containing Substrate present - enzymatic
substrate immobilized enzymes conversion - product changes
swelling of hydrogel - release of
drug
Chemical Hydrogel containing Electron - donating compounds -
species electron - accepting groups formation of charge/transfer
complex - change in swelling -
release of drug
Electrical Polyelectrolyte hydrogel Applied electric field- membrane
charging - electrophoresis of
charged active ingredient - change
in swelling - release of drug
Thermal Thermoresponsive hydrogel Change in temperature - change in
poly(JV- polymer- polymer and water -
isopropylacrylamide) polymer interactions - change in
swelling - release of drug
Magnetic Magnetic particles Applied magnetic field - change in
dispersed in alginate pores in hydrogel - change in
microspheres swelling - release of drug
Ultrasound Ethylene -vinyl alcohol Ultrasound irradiation - temperature
irradiation hydrogel increase - increase in hydrogel
swelling - release of drug

change in the external pH. Ionization occurs when the pH of the environment is
above the pKa of the ionizable group [12-24]. As ionization increases
(increased system pH), the number of fixed charge will increase, resulting in
increased electrostatic repulsions between the chains. This would result (i) in
an increased hydrophilicity of the network and (ii) in electrostatic repulsion,
thus resulting in greater swelling ratio.

The cationic materials contain pendent groups such as amines [12-20,

25-27], These groups ionize in media, which are at a pH below the pKb of the
ionizable species. Thus, in a low-pH environment, ionization increases, thereby

CHAPTER I

v
causing increased electrostatic repulsions. The hydrogels become increasingly
hydrophilic and swell to give a high swelling ratio. More importantly, the
associated drug-diffusion coefficient could increase up to three orders of
magnitude.

The pH-sensitivity of these hydrogels can be exploited in a wide variety

of biomedical applications such as mucoadhesive CR devices, prodrugs and
adjuvants, and biocompatible materials [28]. The swelling of polyelectrolyte
gels is significantly affected by the ionic strength of the swelling agent [12-
27]. As the ionic strength of the swelling agent increases, the concentration of
ions within the hydrogel must also increase in order to satisfy the Donnan
equilibrium condition. The swelling force is reduced due to increased gel-
counterion interaction and a decrease in osmotic swelling forces.

Numerous researchers have studied the dynamic swelling of pH-

sensitive networks. Katchalsky and Michaeli [12] established that the collapse
and expansion of poly(methacrylic acid) (PMA) hydrogels occurred reversibly
by simply adjusting the pH of the fluid. Ohmine and Tanaka [23] observed the
sudden collapse of ionic networks in response to sudden changes in the ionic
strength of the swelling medium. Studies by Khare and Peppas [24] examined
the swelling kinetics of PMA or poly(acrylic acid) (PAA) with
poly(hydroxyethyl methacrylate). They observed pH- and ionic strength-
dependent swelling kinetics in these hydrogels.

1.2.2. Interpenetrating Polymer Networks (IPNs)

IPNs have been extensively investigated over the past three decades due
to the their ability to produce versatile materials with the required combination
of properties. IPN is a combination of two crosslinked polymers that (ideally)
are both in network form and are not bonded to each other. Usually these are
the intimate mixture of two polymers, which are in network form; at least one
is synthesized and /or crosslinked in the immediate presence of the other.
Formation of full and semi-IPN structure is schematically represented in Figure
1 . 1.

CHAPTER I 7
 Semi-IPN hydrogel Full-IPN hydrogel
(Only polymer A crosslinked) (Both polymer A & B crosslinked)

Figure 1.1. Schematic representation of the formation of foil and semi-IPN

structures.

CHAPTER I 8
 IPNs represent the structurally complex polymer systems, since their
structures can be changed not only by using a variety of chemical building
blocks, but also by following various sequences of preparation to manipulate
the relative rates of network formation. Due to the chemical crosslinking, IPNs
can be thermosets and these do not dissolve in ordinary solvents, but only
swell.

In a polymer network, hydrophilic groups or domains are present, which

are hydrated in an aqueous environment, thereby creating the hydrogel
structure. As the term, ‘network’ implies, crosslinks are to be present to avoid
dissolution of the hydrophilic polymer chains/segments into the aqueous phase.
Hydrogels can also be described in a rheological way. Aqueous solutions of
hydrophilic polymers at low or moderate concentrations, where no substantial
entanglement of chains occurs, but normally exhibit the Newtonian behavior.
On the other hand, once crosslinks between different polymer chains are
introduced, the networks obtained will show viscoelastic or sometimes, pure
elastic behavior. Because of their water absorbing capacity, hydrogels are not
only subject of investigation by researchers interested in aspects of swollen
polymeric networks, but such systems have found a widespread applications in
different areas like developing materials for contact lenses and protein
separation, matrices for cell-encapsulation and devices for the CR of drugs and
proteins [29-33],

Yao and Sun [34] have developed the pH-sensitive poly [(ethylene
glycol-co-propylene glycol )-g-acrylamide] IPN polymer crosslinked with PAA.
The pH-dependent swelling mechanism was proposed on the basis of the
formation of intramolecular complexation by hydrogen-bonding between the -
COOH group of acrylic acid and the -CONH2 /ether functional groups at lower
pH. Yuk et al. [35] reported the anionic pH-sensitive drug delivery systems of
semi-IPN beads of PAA and sodium alginate-loaded with hydrocortisone. It
was observed that at pH = 1, swelling was minimum, but at pH = 4 and above,
a remarkable swelling was observed. Kurisawa and Yui [36] have proposed a

CHAPTER I 9
dual-stimuli-responsive drug release device from the IPN-structured hydrogels
of gelatin and dextran, wherein lipid microspheres have been incorporated as
drug micro-reservoirs.

1.3. Polymeric Micro/Nanoparticles as Drug Delivery System

In recent years, polymeric micro/nanoparticles have attracted a

considerable attention as potential drug delivery devices in view of their
applications in the CR of drugs, drug targeting to particular organs/tissues, as
carriers of DNA in gene therapy, in the delivery of proteins and peptides
through the peroral route of administration [37-48]. Chitosan-based drug
delivery systems prepared by different methods for various kinds of drugs are
summarized in Table 1.2.

1.3.1. Methods ofPreparation ofHydrogel Micro/Nanoparticles

Different methods have been used to prepare the hydrogel particulate

systems. Selection of any of the methods depends upon factors such as particle
size requirement, thermal and chemical stability of the active agent,
reproducibility of the release kinetics profiles, stability of the final product and
residual toxicity associated with the final product. Different methods used in
the preparation of hydrogel micro/nanoparticles are discussed in this section.
However, the selection of any of these methods depends upon the nature of the
active molecule as well as the type of the delivery device.

CHAPTER I 10
 Table 1.2
Chitosan-Based Drug Delivery Systems Prepared by Different Methods for Various Kinds
of Drugs
Type of
Method of Preparation Drug
System
Tablets Matrix Diclofenac sodium, Pentoxyphylline, Salicylic
acid, Theophylline
Coating Propranolol HC1
Capsules Capsule shell Insulin, 5-Amino salicylic acid
Microspheres/ Emulsion cross-linking Theophylline, Cisplatin, Pentazocine, Insulin,
Microparticles Phenobarbitone, Theophylline, 5-Fluorouracil,
Diclofenac sodium, Griseofulvin, Aspirin,
Diphtheria toxoid, Pamidronate, Progesterone,
Suberoylbisphosphonate, Mitoxantrone
Coacervation/Precipitation Prednisolone, Interleukin-2, Propranolol-HCl
Spray-drying Cimetidine, Famotidine, Nizatidine, Vitamin D-2,
Diclofenac sodium, Ketoprofen, Metoclopramide,
Bovine serum albumin, Ampidllin, Cetyl
pyridinium chloride, Oxytetracycline,
Betamethasone
Ionic gelation Felodipine
Sieving method Clozapine
Nanoparticles Emulsion-droplet Gadopentetic acid
coalescence
Coacervation/ Precipitation DNA, Doxorubicin
Ionic gelation Insulin, Ricin, Bovine serum albumin
Reverse micellar method Doxorubicin
Beads Coacervation/ Precipitation Adriamycin, Nifedipine, Bovine serum albumin,
Salbutamol sulfate, Lidocaine-HCl, Riboflavin
Films Solution casting Isosorbide dinitrate, Chlorhexidine gluconate,
Trypsin, Granulocyte-macrophage colony-
stimulating factor, Acyclovir, Riboflavine,
Testosterone, Progesterone, Beta-oestradiol
Gel Crosslinking Chlorpheniramine maleate, Aspirin,
Theophylline, Caffeine, Lidocaine-HCl,
Hydrocortisone acetate, 5-Fluorouracil

CHAPTER I 11
1.3.1.1. Emulsion Crosslinking

In this method, a water-in-oil (w/o) emulsion is prepared by emulsifying

the polymer aqueous solution in the oil phase. Aqueous droplets are stabilized
using a suitable surfactant. The stable emulsion is crossliiked by using an
appropriate crosslinking agent such as glutaraldehyde to harden the droplets.
Microspheres were filtered and washed repeatedly with n-hexane followed by
alcohol and then dried [49]. By this method, size of the particles can be
controlled by controlling the size of aqueous droplets. However, the particle
size of the final product depends upon the extent of crosslinking agent used,
while hardening in addition to speed of stirring during the formation of
emulsion. The emulsion crosslinking method has few drawbacks, since it
involves the tedious procedures as well as use of harsh crosslinking agents,
which might possibly induce chemical reactions with the active agent.
However, complete removal of the unreacted crosslinking agent may be
difficult in this process.

1.3.1.2. Coacervation/Precipitation

This method utilizes the physicochemical properties of the polymers.

For instance, chitosan is insoluble in alkaline pH medium, but
precipitates/eoacervates upon contact with the alkaline solution. Particles are
produced by blowing chitosan solution into an alkali solution like sodium
hydroxide, NaOH-methanol or ethanediamine using a compressed air nozzle to
form coacervate droplets [50]. Separation and purification of particles was
done by filtration/centrifugation followed by successive washing with hot and
cold water. Varying compressed air pressure or spray-nozzle diameter
controlled the size of the particles and then by using the cross-linking agent to
harden the particles could control the drug release. In another technique [51],
sodium sulfate solution was added drop-wise to an aqueous acidic solution of
chitosan containing the surfactant under constant stirring and ultrasonication
for 30 min. Microspheres were purified by centrifugation and re-suspended in
demineralized water. Particles were crosslinked with glutaraldehyde. The

CHAPTER I 12
particles produced by this method have better acid stability than those observed
by the other methods.

1.3.1.3. Spray-Drying

Spray-drying is a well-known technique used to produce powders;

granules or agglomerates from the mixture of drug and excipient solutions as
well as suspensions. The method is based on drying of atomized droplets in a
stream of hot air. In this method, polymer is first dissolved in a suitable
solvent, drug can then be dissolved or dispersed in the solution and afterwards,
a suitable crosslinking agent is added. This solution or dispersion is then
atomized in a stream of hot air. Atomization leads to the formation of small
droplets from which solvent evaporates instantaneously leading to the
formation of free-flowing particles [52]. Various process parameters are to be
controlled to get the desired size of particles. Particle size depends upon the
size of the nozzle, spray flow-rate, atomization pressure, inlet air temperature
and extent of crosslinking.

1.3.1.4. Emulsion-Droplet Coalescence Method

The novel emulsion-droplet coalescence method was developed by

Tokumitsu et al. [53], which utilizes the principles of both emulsion
crosslinking and precipitation. However, in this method, instead of cross-
linking the stable droplets, precipitation is induced by allowing the coalescence
of chitosan droplets with NaOH droplets. First, a stable emulsion containing
aqueous solution of chitosan along with drug is produced in liquid paraffin oil
and then, another stable emulsion containing chitosan aqueous solution of
NaOH is produced in the same manner. When both emulsions are mixed under
high-speed stirring, droplets of each emulsion would collide at random and
coalesce, thereby precipitating the chitosan droplets to give small size particles.

1.3.1.5. Ionic Gelation

The use of complexation between oppositely charged macromolecules to

prepare microspheres has attracted much attention, because the process is very

CHAPTER I 13
simple and mild [54,55]. In addition, reversible physical crosslinking by
electrostatic interaction, instead of chemical crosslinking, has been applied to
avoid the possible toxicity of reagents and other undesirable effects. Recently,
many researchers have explored the ionic gelation technique for potential
pharmaceutical usage [56-61]. Cationic polymers such as chitosan can undergo
ionic gelation when reacted with polyanion such as tripolyphosphate (TPP),
whereas the anionic polymers like sodium alginate and gellan gum undergo
ionic gelation with bivalent cations such as calcium or zinc. In this method, the
polymer is dissolved in aqueous solution to get the charged species of the
polymer. This aqueous solution of the polymer is then added dropwise under
constant stirring condition to a solution containing the oppositely charged
species. Due to the complexation between oppositely charged species, polymer
undergoes ionic gelation and precipitates to form spherical particles.

1.3.1.6. Reverse Micellar Method

Reverse micelles are thermodynamically stable liquid mixtures of water,

oil and surfactant. Macroscopically, they are homogenous and isotropic,
structured on a microscopic scale into aqueous and oil microdomains separated
by surfactant rich films. One of the most important aspects of reverse micelle
hosted systems is their dynamic behavior. Nanoparticles prepared by the
conventional emulsion polymerization methods are not only large (> 200 nm),
but also have a broad size range. Preparation of ultrafine polymeric
nanoparticles with narrow size distribution could be achieved by using a
reverse micellar medium [62]. Aqueous core of the reverse micellar droplets
can be used as a nanoreactor to prepare such particles. Since the size of the
reverse micellar droplets usually lies between 1 and 10 nm [63], and these
droplets are highly monodispersed, the preparation of drug-loaded
nanoparticles in reverse micelles would produce extremely fine particles with a
narrow size distribution. Since micellar droplets are in the Brownian motion,
they undergo continuous coalescence followed by re-separation on a time-scale
that varies between millisecond and microsecond [64], The size, polydispersity

CHAPTER I 14
and thermodynamic stability of these droplets are maintained in the system by a
rapid dynamic equilibrium.

In this method, the surfactant is dissolved in an organic solvent to

prepare* the reverse micelles. To this, the aqueous solution of mixture of
polymer and drug is added with constant vortexing to avoid any turbidity. The
aqueous phase is regulated in such a way as to keep the entire mixture in an
optically transparent microemulsion phase. To this transparent solution, a
crosslinking agent is added with constant stirring, and crosslinking is achieved
by stirring overnight. The maximum amount of drug that can be dissolved in
reverse micelles varies from drug to drug and this has to be determined by
gradually increasing the amount of drug until the clear microemulsion is
transformed into a translucent solution. The organic solvent is then evaporated
to obtain the transparent dry mass. The material is dispersed in water and then
adding a suitable salt precipitates the surfactant out. The mixture is then
subjected to centrifugation. The supernatant solution is decanted, which
contains the drug-loaded nanoparticles. The aqueous dispersion is immediately
dialyzed through the dialysis membrane for about 1 h and the liquid is
lyophilized to dry powder.

1.3.1.7. Sieving Method

Recently, Agnihotri and Aminabhavi [65] have developed a simple, yet

novel method to produce chitosan microparticles. In this method,
microparticles were prepared by crosslinking chitosan to obtain a non-sticky
glassy hydrogel followed by passing through a sieve. A suitable quantity of
chitosan was dissolved in 4 % acetic acid solution to form a thick jelly mass
that was crosslinked by adding glutaraldehyde. The non-sticky crosslinked
mass was passed through a sieve with a suitable mesh size to get the
microparticles. The microparticles were washed with 0.1 N NaOH solution to
remove the un-reacted excess glutaraldehyde and dried overnight in an oven at
40°C. This method is devoid of the tedious procedures, and can be scaled up
easily.

CHAPTER I 15
1.3.2. Drug Loading into Hydrogel Micro/Nanoparticles

Drug loading in hydrogel micro/nanoparticulate systems can be done by

two methods i.e., during the preparation of particles (incorporation) and after
the formation of particles (incubation). In these systems, drug is physically
embedded into the matrix or adsorbed onto the surface. Various methods of
loading have been developed to improve the efficiency of loading, which
largely depends upon the method of preparation as well as physicochemical
properties of the drug. Maximum drug loading can be achieved by
incorporating the drug during the formation of particles, but it may get affected
by the process parameters such as method of preparation, presence of additives,
etc.

Both water-soluble and water-insoluble drugs can be loaded into

hydrogel-based particulate systems. Water-soluble drugs are mixed with
polymer solution to form a homogeneous mixture, and then, particles can be
produced by any of the methods discussed earlier. Water-insoluble drugs can
be loaded by the soaking method [66] or by using the multiple emulsion
technique.

1.3.3. Drug Release and Release Kinetics

Methods to study the in-vitro release are by: (i) side-by-side diffusion
cells with the artificial or biological membranes, (ii) dialysis bag diffusion, (iii)
reverse dialysis sac, (iv) ultracentrifugation or (v) ultrafiltration. Despite the
continuous efforts in this direction, there are still some technical difficulties to
study the in-vitro drug release from the micron and submicron size particles
[67,68]. In order to separate the particles and to avoid the tedious and time-
consuming separation techniques, dialysis has been used; here, the suspension
of micro/nanoparticles is added to the dialysis bags/tubes of different molecular
mass cut-off. These bags are then incubated in the dissolution medium for the
release study [69-71].

CHAPTER I 16
 Drag release from the hydrogel-based particulate systems depends upon
the extent of cross-linking, morphology, size and density of the particulate
system, physicochemical properties of the drug as well as the presence of
adjuvants. In-vitro release also depends upon pH, polarity and the presence of
enzymes in the dissolution media. The release of drug from the particulate
systems involves three different mechanisms: (a) release from the surface of
particles, (b) diffusion through the swollen rubbery matrix and (c) release due
to polymer erosion.

In majority of cases, the drug release follows more than one type of
mechanism. In case of release from the surface, adsorbed drag instantaneously
dissolves when it comes in contact with the release medium. Drag entrapped in
the surface layer of particles also follows this mechanism. This type of drug
release leads to the burst effect [52]. Increasing the crosslinking density can
prevent the burst release. This effect can also be avoided by washing the
microparticles with a proper solvent, but it may lead to low encapsulation
efficiency.

Drag release by diffusion involves three steps. First, water penetrates

into the particulate system, which causes swelling of the matrix; secondly, the
conversion of glassy polymer into rubbery matrix takes place, while the third
step is the diffusion of drag from the swollen rubbery matrix. Hence, the
release is slow initially and later, it becomes fast. This type of release is more
prominent in case of hydrogels.

The most commonly used equation for diffusion-controlled matrix

system is an empirical equation used by Ritger and Peppas [72], in which early
time release data can be fitted to obtain the diffusion parameters using,

M±_
= ktn (1.1)
Moo

Here, M/M„ is the fractional drag release at time t, k is a constant characteristic

of the drug-polymer interaction and n is an empirical parameter characterizing

CHAPTER I 17
the release mechanism. Based on the diffusional exponent [73], drug transport
is classified as Fickian (n = 0.5), Case II transport (n = 1), non-Fickian or
anomalous (0.5 < n <1) and super Case II (n > 1).

In swelling controlled release systems, drug is dispersed within a glassy

polymer. Upon contact with the biological fluid, the polymer swells, but no
drug diffusion occurs through the polymer phase. As the penetrant enters the
glassy polymer, glass transition temperature of the polymer is lowered due to
relaxation of the polymer chains. Drug could diffuse out of the swollen rubbery
polymer. This type of system is characterized by the two moving boundaries:
the front separating the swollen rubbery portion and the glassy region, which
moves with a front velocity and the polymer fluid interface. The rate of drug
release is controlled by the velocity and position of the front dividing the glassy
and rubbery portions of the polymer.

1.4. Electrically Modulated Drug Delivery Systems

Drug delivery systems composed of electrically responsive polymeric

materials that are actuated by electric stimulus are particularly interesting due
to the fact that mechanical energy is triggered by an electric signal [74,75).
Electrically responsive hydrogels are usually made of polyelectrolytes and
insoluble, but swellable polymer networks having cations or anions. Such a
system can transform the chemical free energy directly into mechanical work to
give isothermal energy conversion and can be used as actuators,
electromechanical engines, artificial muscle, chemical valve and drug delivery
systems. Electrically controlled drug delivery may particularly offer the unique
advantages for providing ‘on-demand’ release of drug molecules from implants
or transdermal systems.

Electro-sensitive hydrogels undergo shrinking or swelling in the

presence of an applied electric field [76]. Sometimes, hydrogels show swelling
on one side and deswelling on the other side, resulting in bending of the
hydrogels. However, the change in the hydrogel shape (including swelling,

CHAPTER I 18
shrinking and bending) depends on a number of conditions. If the surface of
hydrogel is in contact with the electrode, the result of applying electric field to
the hydrogel may be different from systems where the hydrogel is placed in
water (or acetone-water mixture) without touching the electrode. The result
will be different yet if the aqueous phase contains electrolytes.

Polymers used to develop stimulus responsive systems are hydrogels

with ionizable groups. However, the magnitude of their response depends on
the type of functional group and the basic polymer repeat unit Kim and Lee
[77] investigated the electrically modulated properties of interpenetrating
polymer network (IPN) containing poly(vinyl alcohol) (PVA) and PAA. They
synthesized the IPNs by UV irradiation method and studied loading and release
behavior of the two model drugs viz., cefazoline (ionic) and theophylline (non­
ionic). The amount of loaded drug significantly increased with an increase in
the PAA content, which contains the ionizable groups. The loading of ionic
drug cefazoline, was greater than the non-ionic theophylline and the release
rate of cefazoline was higher than that of theophylline. Diffusion of drug
molecules from the IPN hydrogels “switched-on and -off” in a pulsatile
manner and applied electric voltage played important role. As the voltage was
increased from 5 to 10 volts, the drug release was also increased. An applied
voltage, ionic group content of the polymer and ionic properties of the drug,
influenced the rate of drug release.

Electro-sensitive hydrogels have been applied in controlled drug

delivery [78-89]. Hydrogels made of poly(2-acrylamido-2-methylpropane
sulfonic acid-co-n-butylmethacrylate) could release edrophonium chloride and
hydrocortisone in a pulsatile manner under the influence of electric current
[90], Control of ‘on-off drug release was achieved by varying the intensity of
electric stimulation in distilled-deionized water. For edrophonium, a positively
charged drug, the release pattern was explained in terms of an ion exchange
mechanism between the positively charged solute and the hydrogen ion
produced by electrolysis of water.

CHAPTER I 19
 Chemomechanical shrinking and swelling of PMA hydrogels under an
electric field was used to study the pulsatile delivery of pilocarpine and
raffinose. Microparticles of PAA hydrogels, which showed a rapid and sharp
shrinkage after the application of electric current, recovered their original size
when the electric field was turned off. The electric field-induced changes in the
size of the microparticles resulted in ‘on-off release profiles. The electric
field-induced volume changes of poly(dimethylaminopropyl acryl amide)
hydrogels were used for the pulsatile release of insulin [79]. The monolithic
device composed of sodium alginate and PAA was also used to release
hydrocortisone in a pulsatile manner using electric stimulus [91].

In addition to hydrogel swelling and contraction, electric fields have also

been used to control the erosion of hydrogels made of poly(ethyloxazoline)-
PMA complex in a saline solution [89]. The two polymers form the hydrogel
via intermolecular hydrogen-bonding between carboxylic and oxazoline
groups. When the hydrogel matrix was attached to a cathode surface,
application of electric current caused disintegration of the complex into water-
soluble polymers at the hydrogel surface facing the cathode. The surface
erosion of this system was controlled either in a stepwise or continuous fashion
by controlling the applied electrical stimulus. However, the pulsatile insulin
release was achieved by applying a step function of electric current.

1.5. In-situ Gel Forming Solutions as Drug Delivery Systems

The in-situ gel forming solutions are viscous liquids that shift to a gel
phase upon exposure to physiological conditions. The term “in-situ gelling”
also describes a stimulus-induced response, but is generally used more
narrowly to denote formulations that gel upon contact with the mucosa. The
most prominent advantage of such formulations is that they are fluid like prior
to contact with the mucosa, and can thus be easily administered as a drop or by
a spray device.

CHAPTER I 20
 In-situ gelling formulations have been evaluated for several
administration routes such as ophthalmic [92-110], nasal [111-114], parenteral
[115-118], oral [119-124], rectal [125,126] and vaginal [127], These kinds of
formulations have shown to increase the residence time and improve the drug
* 1
absorption. Various mechanisms are involved in the phase transition of these
polymers. The viscosities of cellulose acetate phathalate (CAP) latex [128] and
carbopol solution increase when the pH is raised from its native value to the
body pH (pH = 7.4). Gellan gum [129] and alginates [130] gel in the presence
of mono or divalent cations. The pluronics [131], a class of block copolymers
of poly(oxyethylene) and poly(oxypropylene), and tetronics [132] as well as
ethyl(hydroxyethyl) cellulose [133], exhibit thermoreversible gelation. That is,
their solutions show increase in viscosity upon increasing the temperature.

Bioadhesion can be used as a means to improve the intimacy of contact,

as well as a way to increase the dosage form residence time to various
administration routes [134-136]. Furthermore, in order to fortify the adhesion
of the administered drugs onto the mucosal surfaces, mucoadhesive polymers
such as polycarbophil, . carbopol, hydroxypropyl cellulose,

polyvinylpyrrolidone have been added to the in situ-gelling liquids

[134,137,138]. There are several ways to sustain the release of drug from the
gels, which would allow us to take the lull advantage of the contact time. The
drug can be dispersed in the gel, giving a concentration that is higher than that
corresponding to the solubility of the drug [139], formulated as particles
[140,141], distributed in liposomes [142,143], interacting with an oil phase that
has been included in the gel [144].

The evaluation of rheological properties for the gel-type dosage forms

would be important for predicting their in-vivo behavior. The rheological
properties of eye gels were reported to affect the ocular residence time of the
gels [141,145,146]. The flow properties of semi-solid vaginal dosage forms
might be of use to predict the spreading and coating of the formulations over
the vaginal epithelia. Especially, in the thermosensitive gels containing a

CHAPTER I 21
mucoadhesive polymer, the rheological characteristics need to be controlled
and understood, since the multi-component gels do exhibit complex flow
behaviors due to the feasible interaction among the components.

However, most of the systems require the use of high concentrations of

polymers. For instance, it needs 25% (w/v) pluronics and 30% (w/v) CAP,
respectively, to form the stiff gel upon instillation in the eye. As the
concentration of carbopol increases in the vehicle, its acidic nature would cause
stimulation to the eye tissue. In order to reduce the total polymer content and
improve the gelling properties, Joshi et al. [147], first used the combination of
polymers in the delivery system. The main idea here is that the aqueous
compositions reversibly gel in response to simultaneous variations in at least
two physical parameters viz., pH, temperature, and ionic strength.

Kumar and co workers [109] following the invention of Joshi et al., have
developed an ocular drug delivery system based on a combination of carbopol
and methylcellulose. Carbopol is a PAA polymer, which shows a “sol-to-gel”
transition in aqueous solution as the pH is raised above its pKa of about 5.5
[148]. Methylcelluclose, a viscosity-enhancing polymer [149] exhibits a “sol-
to-gel” transition in aqueous solution in the range of 50-55°C. Kumar and
Himmelstein [150] also developed a similar delivery system by a combination
of carbopol and hydroxypropyl methylcellulose (HPMC). For both the systems,
it was found that a reduction in carbopol concentration without compromising
the in-situ gelling properties as well as overall rheological behaviors was
achieved by adding a suitable viscosity-enhancing polymer [109,150].

Srividya et al. [102] developed the in-situ gel forming ophthalmic

delivery system based on carbopol and HPMC for the delivery of ofloxacin,
based on the concept of pH-triggered in-situ gelation. Thus produced gel
forming solution was pH-sensitive and released drug up to 8 h. Better
rheological properties were obtained by blending these polymers to give
improved antibacterial activity without producing the adverse effect on the eye.
Gel forming solution also reduces the systemic absorption of the drug, which is

CHAPTER I 22
intended for local application in the eye. Jarvinen et al. [151] reported that
systemic absorption of timolol could decrease in rabbit when PAA was
incorporated in the formulation. Bioavailability of timolol containing PVA and
PAA formulations were compared. The PAA-based formulation has shown a
slow release and retained in the eye for a longer period.

1.6. The Thesis Research Problem

In view the applications of polymeric matrices for the development of

CR products; the present thesis covers several newer approaches or
modifications on the existing protocols to develop CR devices by
encapsulation. The release study of the active agents in a controlled manner
was achieved using a variety of polymers fabricated as various delivery
systems. The necessary pre-formulation studies and variations in formulation
parameters have been studied for the development of novel CR formulations
for the active agents. Several novel methods of encapsulation procedures to
encapsulate some of the typical bioactive molecules have been developed
because of the difficulties involved in encapsulation of such molecules by
using the conventional methods. These aspects will be covered in subsequent
chapters of this thesis. It is anticipated that results of this research will be
useful in the area of pharmaceutics.

CHAPTER I 23
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