1

CHAPTER I

Introduction

Abstract

This chapter covers historical background, fundamentals, classifications and

advantages of drug delivery systems. It introduces hydrogels and various stimuli

responsive hydrogels as controlled release (CR) systems. The most common methods

of preparations of micro/nanoparticles of polymeric blends, graft copolymers and

interpenetrating polymer networks are discussed along with drug loading, drug release

kinetics and release mechanisms.

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I.1. Historical Background of Drug Delivery System

Perspective drug delivery systems can be defined as mechanisms to introduce

therapeutic agents into the body. Chewing leaves and roots of medical plants and

inhalation of soot from the burning of medical substances are examples of drug

delivery from the earliest times. However, these primitive approaches of delivering

drugs lacked a very basic need in drug delivery; that is, consistency and uniformity (a

required drug dose). This has led to the development of different drug delivery

systems during the later part of the eighteenth and early nineteenth century. Those

methods include pills, syrups, capsules, tablets, solutions, extracts, emulsions and

suspensions [1,2].

The classical era of medicine development started with the discovery of

vaccines in 1885 and techniques for purification of drugs from plant sources in the

late nineteenth century, followed by macromolecular drug delivery. Along with drug

development, the mode of systemic administration and drug delivery systems were

also developed to improve therapeutic efficacy of drugs to reduce toxic effects by

augmenting the amount and persistence of drugs in the vicinity of the target cells,

while reducing drug exposure to non-target cells. This basic rationale gave birth to

controlled drug delivery science. The controlled drug delivery system requires

simultaneous consideration of factors such as drug property, route of administration,

nature of delivery vehicle, mechanism of drug release, ability of targeting and

biocompatibility [3,4].

I.2. Fundamentals of Drug Delivery System

The main purpose of using a drug delivery system (DDS) is not only to deliver

a biologically active compound in a controlled manner (time period and releasing

rate) without altering their original properties, but also to maintain the drug

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concentration in the body within therapeutic window (Figure I.1.). To obtain a given

therapeutic response, a suitable amount of the active drug must be absorbed and

transported to the site of action at the right time and the rate of input can then be

adjusted to produce the concentrations required to maintain the level of the effect for

as long as necessary. Besides, one can tune the release kinetics and direct drug

targeting towards a specific organ or diseased tissue (targeted drug delivery). The first

two features were addressed by using drug carriers, usually biopolymers or synthetic

polymers, whose properties can be manipulated to improve the DDS efficiency.

Owing to rapid advances in recent years, the application of polymers to drug delivery

has grown rapidly [5,6].

Figure I.1. Scheme of the effect of drug concentration in the body when using

different administration methods

I.3. Classification of Drug delivery Systems

Drug delivery systems can be broadly classified into temporal and targeted

drug delivery systems. Temporal drug delivery systems are designed to release

therapeutic levels of drugs from a matrix for the desired period of time. There are two

Pretended therapeutic time

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strategies to achieve controlled release using temporal DDS. First approach is to

prepare the matrix that release drugs over extended duration. Numerous works have

been done based on biodegradable polymers in which the rate of drug release matches

the rate of drug elimination. Therefore, drug concentration is within the therapeutic

range for a longer time. This release pattern is highly beneficial for drugs that are

rapidly metabolized and eliminated from the body after administration [7-10]. The

second approach is to prepare a feedback controlled devices that release the

appropriate amount of drug in response to a therapeutic marker.

In recent years, several research groups have been developing responsive

systems [11-15]. These systems can be classified as external regulated and self-

regulated systems. The external controlled devices apply external triggers for pulsed

delivery such as: magnetic, ultrasonic, thermal and electric triggers. In the self-

regulated system, the release rate is controlled by feedback information. The self-

regulated systems utilize several approaches such as pH-sensitive polymers, enzyme

substrate reactions and competitive binding as rate-control mechanisms. The

advantage of temporal delivery system is that therapeutic concentration of a drug can

be maintained in the body for longer times without repeated administration, thereby

eliminating the problems of drug under or over dosage. Furthermore, it is more

economical due to lower drug wastage, reproducible and it increases patient

compliance. Attempts are still being made to develop novel delivery systems that can

further control the drug release pattern by synthesizing novel polymers as matrix

systems as well as by developing smart systems that can deliver multiple drugs in a

controlled manner or under the effect of an external stimulus.

Targeted drug delivery systems are designed to deliver drugs at the proper

dosage for the required amount of time to a specific site of the body where it is

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needed, thereby preventing any adverse effects of drugs on other organs or tissues.

There are two basic types of targeting systems: passive and active. Passive targeting

systems rely on non-specific interactions such as hydrophobic or electrostatic

interactions and the body physical characteristics. The size of drug carriers has been

extensively studied for passive targeting. It was found that particles larger than 5-7

μm in diameter usually become trapped in the lung [16] and particles smaller than 1

μm in diameter rapidly phagocytosed by the Kupffer cells of the liver [17]. When the

particle size is reduced below 100 nm, the particles can appear in the bone marrow

[18].

It was also demonstrated that drug carriers smaller than 200 nm can be

accumulated efficiently in tumor through enhanced permeability and retention (EPR)

effect due to the abnormality of tumor tissue, resulting in the enhanced vascular

permeability compared to healthy tissues [19-21]. On the other hand, active targeting

systems utilize specific interactions, such as antigen-antibody and ligand receptor

binding, to achieve specific targeting goals. In this approach, the therapeutic index of

drugs could be enhanced by keeping drugs away from healthy cells. The types of

receptors that have been utilized for this purpose include transferrin receptors (tumor

cells) [22], folate receptors (tumor cells) [23], albumin receptors (cardiac and lung)

[24] and growth factors receptors [25]. Targeted delivery assumes great importance

particularly in the case of highly toxic drugs such as chemotherapeutic drugs and

highly active and fragile biotechnological molecules such as peptides and proteins.

Furthermore, targeted drug delivery systems can be employed to deliver drugs to sites

that are inaccessible under normal conditions such as the brain.

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I.4. Advantages of Controlled Drug Delivery

In the past 30 years, controlled drug delivery technology has represented one

of the most rapidly advancing research areas. The field is driven by the belief that

controlled drug delivery will contribute significantly to human health [26-30]. These

drug delivery systems offer numerous advantages compared to conventional dosage

forms:

♦ increasing the efficacy of currently used drugs

♦ providing opportunities for the use of new agents currently precluded from

clinical use due to challenges including low drug solubility and systemic toxicity

♦ reducing harmful side effects

♦ precise control of dose

♦ decreasing number of dosages

♦ improving patient compliance and convenience

I.5. Hydrogels as Drug Delivery Systems

Hydrogels are hydrophilic polymer networks which absorb water or biological

fluids from 10-20 % (an arbitrary lower limit) up to thousands of times their dry

weight. Hydrogels may be chemically stable or they may degrade and eventually

disintegrate and dissolve. They are called reversible or physical gels when the

networks are held together by molecular entanglements, and/or secondary forces

including ionic, H-bonding or hydrophobic forces. Physical hydrogels are not

homogeneous, since clusters of molecular entanglements, or hydrophobically- or

ionically-associated domains, can create inhomogeneities. Free chain ends or chain

loops also represent transient network defects in physical gels. Hydrogels are called

permanent or chemical gels when they are covalently-crosslinked networks [31-35].

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I.5.1 Classification of Hydrogels

Based on their nature hydrogels are classified as:

I.5.1.1. pH Sensitive Hydrogels as CR Systems

The pH sensitive hydrogels can be neutral or ionic in nature. In neutral

hydrogels, the driving force for swelling arises from the water-polymer

thermodynamic mixing contributions and elastic polymer contributions. In ionic

hydrogels, swelling is due to the previous two contributions as well as ionic

interactions between charged polymer and free ions [35]. The presence of ionizable

functional groups like carboxylic acid, sulfonic acid or amine groups renders the

polymer more hydrophilic and results in high water uptake. In the case of anionic

polymeric network containing carboxylic or sulfonic acid groups, ionization takes

place, as the pH of the external swelling medium rises above the pKa of that ionizable

moiety [36-38].

The dynamic swelling change of the anionic hydrogels can be used in the

design of intelligent controlled release (CR) devices for site-specific drug delivery of

therapeutic proteins to large intestine, where the biological activity of the proteins is

prolonged. The change in the pH of the external environment will act as a stimulus

and the response to the stimulus leads to the change in swelling properties of the

hydrogels, causing the release of the encapsulated bioactive species. The cationic

hydrogels show swelling at pH values below pKa of the cationic group. The amine

groups are protonated at pH lower than pKa and become hydrophilic and absorb

water. At pH greater than pKa, the polymer is hydrophobic and excludes water [39-

40].

Numerous researchers have studied dynamic swelling of pH-Sensitive

networks. Katchalsky and Michaeli [41] established that the collapse and expansion of

poly(methylacrylic acid) (PMA) hydrogels occurred reversibly by adjusting the pH of

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the fluid. Ohmine and Tanaka [42] observed the sudden collapse of ionic network in

response to sudden changes in the ionic strength of the swelling medium. Studies by

Khare and Peppas [43] examined pH and ionic strength dependent swelling kinetics in

case of hydrogels of PMA or poly(acrylic acid) (PAA) with poly(hydroxyethyl

methacrylate). Kim et al. [44] prepared the pH-sensitive anionic hydrogels based on

poly(methacrylic acid-co-methacryloxyethyl glucoside) and poly(methacrylic acid-g-

ethylene glycol). The hydrogels showed limited swelling in a pH 2.2 buffer but rapid

swelling was observed in the pH 7.0 buffer solution.

I.5.1.2. Temperature Sensitive Hydrogels as CR systems

Thermosensitive hydrogels are one of the widely studied responsive polymer

systems. Thermosensitive polymers are characterized by the presence of hydrophobic

groups, such as methyl, ethyl and propyl groups. The most widely studied temperature

sensitive polymer is poly(N-isopropylacrylamide) (PNIPAAm). PNIPAAm is a non-

biodegradable polymer with a LCST ~32° in water and cross-linked gels of this

material collapse around this temperature [45].

Temperature sensitive hydrogels are classified into negatively

thermosensitive, positively thermosensitive and thermally reversible gels [46].

Certain hydrogels formed by IPNs show swelling at high temperature and shrinking

at low temperature. IPNs of poly(acrylic acid) and polyacrylamide or

poly(acrylamide-co-butyl methacrylate), have positive temperature dependence of

swelling. Such types of hydrogels are called positively thermosensitive hydrogels.

The negatively thermosensitive hydrogels swell when the temperature is decreased

and deswell when the temperature is increased.

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Figure I.2. Response of polymeric hydrogels to various environmental stimuli.

I.5.1.3. Enzyme Sensitive Hydrogels as CR Systems

Since many biodegradable polymers can be digested by specific enzymes,

enzyme sensitive hydrogels can be prepared from such biodegradable polymers. Some

enzymes are used as important signals for diagnosis to monitor several physiological

changes and specific enzymes in specific organs have become useful signals for site

specific drug delivery [47]. Therefore, the enzyme sensitive hydrogels are promising

candidates as enzyme sensitive drug delivery systems.

Hovgaard et al. [48] focused on the fact that microbial enzymes in the colon,

such as dextranases, can degrade the polysaccharide dextran. They prepared dextran

hydrogels cross linked with diisocynate for colon specific drug delivery. The dextran

hydrogels were degraded in vitro by a model dextranase, as well as in vivo in rats and

in human colonic fermentation model. Release of a drug from the dextran hydrogels

can be controlled by the presence of dextranase. Drug release from the dextran

hydrogels in the absence of dextranase was observed to be based on simple diffusion

process, however in the presence of dextranase it was mainly governed by the

degradation of the dextran. Thus, it follows that dextran hydrogels are dextranase

sensitive and may hold promise as intelligent systems for colon specific drug delivery.

change in

pH

Temperature

Electric Field Light

Ultrasound

Magnetic Field

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I.5.1.4. Glucose Sensitive Hydrogels as CR Systems

Glucose sensitive hydrogels are very useful for the development of self

regulated insulin delivery systems and enable us to construct an artificial pancreas that

can administer the necessary amount of insulin in response to the blood glucose

concentration. Combining glucose oxidase with pH sensitive hydrogels to sense

glucose and regulate insulin release is the method that many researchers have used to

develop glucose sensitive insulin delivery systems. Within the pH sensitive hydrogels

containing glucose oxidase, glucose is converted to gluconic acid by glucose oxidase,

thus lowering the pH in the hydrogels. Insulin can be released by the pH sensitive

swelling of the hydrogels. Thus, the pH sensitive hydrogels containing glucose

oxidase can control insulin release in response to the glucose concentration [49].

I.5.1.5. Electrical Sensitive Hydrogels as CR Systems

Electric current can also be used as an environmental signal to induce

responses of hydrogels. Hydrogels, sensitive to electric current, are usually made of

polyelectrolytes. An electric field as an external stimulus has advantages, such as the

availability of equipment, which allows precise control with regards to the magnitude

of current, duration of electric pulses, intervals between pulses, etc.

The electrical behavior of hydrogels composed of sodium alginate (SA) and

oly(diallyldimethylammonium chloride) (PDADMAC) was studied by Kim et al.

[50]. The SA/ PDADMAC IPN hydrogel exhibited pH and electrolyte concentration

sensitive behavior. When an electric field is applied to a strip of the SA/PDADMAC

hydrogel in an aqueous HCl solution, the gel showed significant and quick bending

towards the cathode. It was concluded that the deformation of a polymer hydrogel

under an electric field was due to voltage-induced motion of ions and concomitant

expansion of one side of the polymer and the contraction of other side of the polymer.

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I.5.1.6. Light Sensitive Hydrogels as CR Systems

Light (ultraviolet or visible) is a desirable external stimulus for drug delivery

systems because it is inexpensive and easily controlled. Light-sensitive drug carriers

are fabricated from polymers that contain photo-sensitizers such as azobenzene,

stilbene and triphenylmethane [51,52]. Suzuki and Tanaka [53] have investigated

visible light-responsive hydrogels using the trisodium salt of copper chlorophyllin in

PNIPAAm hydrogels. When light is applied to the hydrogels, the chromophore

absorbs the light, increasing the local temperature of the hydrogel. The resulting

temperature change alters the swelling behavior.

Vivero-Escoto et al. [54] prepared gold capped mesoporous silica nanospheres

for photo-induced intracellular release of drugs in human cells. The 100 nm silica

nanospheres were capped with 5 nm gold nanospheres and functionalized with a

cationic photo-reactive linker. Photoirradiation using ultraviolet light for 10 min at

0.49 mW/cm2 cleaved the photolabile linker, causing uncapping of the silica due to

charge repulsion between the gold and silica nanospheres, allowing drug to be

released [55]. Fomina et al. [56] developed a novel light-sensitive polymer containing

a quinone-methide moiety. Nile Red, a hydrophobic dye, was released from the

nanoparticles after only one minute of 350 nm light exposure. Light can be effective

in modulating drug release because it can be used to increase the local temperature

and to cleave bonds.

I.5.1.7. Ultrasound Sensitive Hydrogels as CR Systems

Ultrasound has been shown to trigger the drug release by raising the local

temperature or causing cavitation [57]. Both processes can increase the permeability

of cell membranes and accelerate polymer degradation [58]. Ultrasound sensitive

vehicles have the potential to treat tumorigenic cancers due to their invasive character,

ability to penetrate deeply into the human body and ease of control.

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In 2002, Pruitt and Pitt [59] investigated ultrasound mediated doxorubicin

release using stabilized Pluronic P105 micelles. Doxorubicin was encapsulated within

polymeric micelles composed of 10% Pluronic P105 and N,N-diethylacrylamide and

delivered systemically to rats. Application of low-frequency ultrasound at the tumor

site resulted in doxorubicin release; this resulted in a significant reduction in tumor

volume. Lin et al. [60] have investigated the physical and chemical properties of lipid

membranes subjected to ultrasound treatment. They showed that high permeability

resulting from ultrasound treatment is correlated with lipid packing and can be useful

for efficient drug release and ultrasound-mediated DNA transfection. In 2007, Ferrara

et al. [61] reviewed that small gas bubbles, used to enhance ultrasound contrast, can

be used for drug delivery applications and monitoring. When driven by an ultrasonic

pulse, small gas bubbles oscillate with a wall velocity on the order of tens to hundreds

of meters per second and can be deflected to a vessel wall or fragmented into particles

on the order of nanometers. Also, a focused ultrasound beam can be used for

disruption of delivery vesicles and blood vessel walls, which offer the opportunity to

locally deliver a drug or gene. Ultrasound does not damage the surrounding tissue,

making it attractive for triggering the drug release.

I.5.1.8. Magnetically Sensitive Hydrogels as CR Systems

Magnetically modulated particulate systems have recently attracted much

attention for in vivo imaging and targeted drug delivery [62]. In this approach,

imaging agents or drugs can be localized to specific sites through the application of an

external magnetic field. Superparamagnetism in many biomedical applications such as

drug delivery is useful because the superparamagnetic iron oxide devices (SPIOD)

can be transported by electrical field effects to the desired site and once the external

magnetic field is removed, magnetization disappears and the SPIOD can remains at

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the target site for a certain period [63]. Two types of iron oxide have mainly been

investigated for their use in magnetic formulation: maghemite (γ-Fe2O3) and

magnetite (Fe3O4) due to their high saturation magnetization and high magnetic

susceptibility; the magnetite (Fe3O4) particles are preferred because of their greater

saturation magnetization and biocompatibility that make them more promising

candidates for various biomedical applications [64].

I.6. Interpenetrating Polymer Networks (IPNs)

The term “Interpenetrating Polymer Networks” (IPNs) was coined by Miller

[65] in 1960. IPNs have been extensively investigated over the past four decades due

to their ability to produce versatile materials with the required combination of

properties. Usually they are intimate mixture of two polymers which are in network

form; at least one is synthesized and /or cross-linked in the immediate presence of the

other. As the IPNs are cross-linked networks that are insoluble in water, but absorb

large quantity of water or biological fluid and they are soft and rubbery in nature

resembling those of living tissues in their physical properties and hence they are

highly biocompatible and non-toxic. In IPNs, two or more different polymers are

individually cross-linked in the immediate presence of other. So, the cross-linked

chains are intermingled resulting in considerable phase mixing through the restriction

of domain size. This result in an appreciable improvement in strength and dynamic

mechanical properties of IPNs compared to single polymeric hydrogels.

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Figure I.1. Representation of IPN structure

The IPNs are classified mostly by the method of their synthesis as:

(i) Sequential IPNs- a cross-linked polymer-A is swollen in monomer-B along with

active agents such as cross-linking agents and initiators. Then the monomer-B is

polymerized in situ to get polymer-B.

(ii) Simultaneous IPNs- the synthesis of this type of IPNs involves two independent

non-interfering reactions that can simultaneously be run under the same conditions

and in the same reaction vessel.

(iii) Semi IPNs- these networks are formed essentially by grafting of polymers to

another linear counterpart. Then the cross-linking of the grafted part yields a semi

IPN. Semi IPNs are of two types: In first type semi IPN, polymer A is cross-

linked in presence of linear chain of polymer B and in second type semi IPN,

polymer B is cross-linked in presence of linear polymer B. Figure 1.2 illustrates

the formation of IPN between two polymers.

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I.7. Polymeric Micro/Nanoparticles as Drug Delivery Systems

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 organ/tissues, as carriers of DNA in gene therapy,

in the delivery of proteins and peptides through the peroral route of administration

[66-69].

I.7.1. Most Commonly Used Methods for Preparation of Polymeric

Micro/Nanoparticles

I.7.1.1. Emulsion Crosslinking Method

In this method, 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 crosslinked by using an appropriate

crosslinking agent such as gluteraldehyde to harden the droplets. Microspheres were

filtered and washed repeatedly with n-hexane followed by alcohol and then dried [70].

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. In addition microparticles were prepared by

crosslinking the polymer to obtain a non-sticky glassy hydrogel followed by passing

through a sieve [71]. Schematic representation of the preparation of microspheres by

emulsion crosslinking method is in.

I.7.1.2. Solvent Evaporation Method

In this method, polymer is dissolved in an organic solvent like

dichloromethane, chloroform or ethyl acetate. Drug is dissolved or dispersed in the

performed polymer solution and the drug containing polymer solution is emulsified

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into an aqueous solution to make an oil-in-water (o/w) emulsion by using a surfactant

or emulsifying agent like gelatin, poly(vinyl alcohol) (PVA), polysorbate-80 etc.

After the formation of stable emulsion, organic solvent is evaporated either by

increasing the temperature, under vacuum or by continuous stirring [72-74].

I.7.1.3. Spontaneous Emulsification/Solvent Diffusion Method

This is a modified version of solvent evaporation method [75], wherein water-

soluble solvents like acetone or methanol along with the water insoluble organic

solvents like dichloromethane or chloroform are used as an oil phase. Due to the

spontaneous diffusion of water-soluble solvent, an interfacial turbulence is created

between the two phases, leading to the formation of smaller particles. In this method,

the particle size can be varied by varying the concentration of water-soluble solvent.

I.7.1.4. Double Emulsion method

In this method, drug dissolved in an aqueous solvent is emulsified with the

non-miscible organic solution of polymer to form w/o emulsion. The organic solvent,

dichloromethane is mainly used and the homogenization step is carried out using

either high-speed homogenizer or sonicator. This primary emulsion is then rapidly

transferred to an excess of aqueous medium containing a stabilizer, usually PVA.

Again, homogenization or intensive stirring is necessary to initially form the double

emulsion of w/o/w. Subsequent removal of organic solvent by heat, vacuum or both

would result in the phase separation of polymer and the core to produce microspheres

[76].

I.7.1.5. Spray Drying Method

In this method, the polymer is dissolved in a volatile organic solvent such as

dichloromethane or acetone; the drug in solid form is then dispersed in polymer

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solution by high speed homogenization or it can be dissolved in a solvent; then this

solution is atomized in a stream of heated air. From the droplets formed, the solvent

evaporates instantaneously yielding free flowing microparticles [77-79]. Size of

microparticles depends upon atomizing conditions, size of the nozzle, spray flow rate

and inlet air temperature. The microspheres are collected from air streams by cyclone

separator. Residual solvents are removed by vacuum drying.

I.7.1.6. Coacervation/Precipitation Method

This method utilizes the physiochemical properties of the polymers. For

instance, chitosan is insoluble in alkaline pH medium, but precipitates/coacervates

upon contact with the alkaline solution. Particles are produced by blowing chitosan

solution into an alkali solution like sodium hydroxide using a compressed air nozzle

to form coacervates droplets [80]. 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.

I.7.1.7. Emulsion-Droplet Coalescence Method

The novel emulsion-droplet coalescence method was developed by Tokumitsu

et al. [81], which utilizes the principles of both emulsion crosslinking and

precipitation. However, in this method, instead of cross-linking the stable droplets,

allowing the coalescence of chitosan droplets with NaOH droplets induces

precipitation. 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

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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.

I.7.1.8. Ionic Gelation Method

The use of complexation between the oppositely charged polymers to prepare

microspheres has attracted much attention, because the process is very simple and

mild. 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 [82,83] have explored the

ionic gelation technique for potential pharmaceutical usage. Cationic polymers such

as chitosan can undergo ionic gelation when reacted with polyanion such as

tripolyphosphate (TPP), whereas the anionic polymers such like sodium alginate and

gellan gum undergo ionic gelation with bivalent cations such as calcium, barium or

zinc [84].

I.7.1.9. Dispersion Polymerization Method

Couvreur et al. [85] reported the production of nanoparticles (≈200 nm) by

polymerizing mechanically the dispersed methyl or ethyl cyanoacrylate in an aqueous

acidic medium in the presence of polysorbate-20. The cyanoacrylic monomer is added

to an aqueous solution of a surface-active agent (polymerization medium) under

vigorous mechanical stirring to polymerize alkylcyanoacrylates at the ambient

temperature. Drug is dissolved in the polymerization medium either before the

addition of the monomer or at the end of the polymerization reaction. The suspension

is then purified by ultracentrifugation or by resuspending the particles in an isotonic

surfactant free medium.

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I.7.2. Drug Loading in to Polymer Micro/Nanoparticles

Drug loading in 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

polymeric 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 [86]. Water-insoluble drugs can be loaded by the soaking

method [87] or by using the multiple emulsion technique.

I.8. Graft Copolymers as Drug Delivery Systems

Recently, much attention has been paid to the graft copolymerization of

natural polysaccharides [88-90] in order to obtain novel tailored hybrid materials with

minimum loss of the initial properties of the substrate. Due to their structural diversity

and water solubility, natural polysaccharides could be interesting starting materials for

the synthesis of graft copolymers. A graft copolymer is a macromolecular chain with

one or more species of block connected to the main chain as side chain(s). Thus, it can

be described as having the general structure, where the main polymer backbone

(commonly referred to as the trunk polymer), has branches of another polymeric chain

emanating from different points along its length. This fascinating technique may be

considered as an approach to achieve novel polysaccharide-based materials with

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improved properties including all the expected usefulness of these biomaterials. After

a thorough literature survey, it was found that polysaccharide-based graft copolymers

are mainly synthesized by free radical polymerization under the influence of different

chemical initiating systems [91,92]. These graft copolymers could be applied in the

design of various stimuli-responsive CR systems.

I.9. Drug Release and Release Kinetics

Drug release from micro/nanoparticles and subsequent biodegradation are

important in developing successful formulations. Drug release from the hydrogel-

based particulate systems depends upon the extent of crosslinking, morphology, size

and density of the particulate system, physiochemical properties of the drug as well as

the presence of adjuvants. In case of biodegradable polymer, the release depends on

matrix erosion and a combined erosion/diffusion process. 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 of drug from the surface of particles, (b) diffusion through

the swollen rubbery matrix and (c) release due to polymer erosion. Drug release by

diffusion involves three steps. First, water penetrates into the particulate system,

which causes swelling of the matrix; secondly, the glassy polymer converts into

rubbery matrix, while the third step is the diffusion of drug from the swollen rubbery

matrix. Hence, the release is slow initially and later, it becomes fast.

To ascertain the kinetics of release parameters, following empirical equations

[94,95] were used to estimate the release kinetics parameters. According to zero order

release, we have:

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where Q is the amount of drug at time, t; Q0 is the amount of drug at t = 0 and K0 is

zero order release constant. The first order equation is:

where K1 is the first order release constant. Higuchi square root equation is given as:

where Mt is the amount of drug released at time, t and KH is Higuchi rate constant.

Hixson-Crowell cube root equation is:

where Kc is cube root law release constant. Cumulative release data were also

analyzed using [96, 97]:

here, Mt/M represents the fractional drug release at time t, k is a kinetic parameter,

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

characterizing the release mechanism. For spheres, n values below 0.43 indicates that

the drug release is diffusion controlled, while the values of n between 0.43 and 0.85

are indicative of both diffusion controlled as well as swelling-controlled release

(anomalous), but the values >0.85 indicate swelling-controlled release that is related

to polymer relaxation phenomenon during swelling. If n value is >1, then drug release

follows Super Case II transport mechanism [98].

I.10. Present Thesis Research Problem

Careful literature analysis revealed that plethora of work is being done on

development of polymeric matrices as drug delivery systems in order to address

l n Q = ln Q 0 – K 1 t (7 ) (I.2)

M t = K H t

1/ 2 ( 8 ) (I.3)

Q

1 / 3 = Q 0

1 / 3 - K c t ( 9 ) (I.4)

M t / M = kt

n (10) (I.5)

Q = Q 0 - K 0 t ( 6 ) (I.1)

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pharmaceutical hurdles to improve the human life. In the same view, the present

thesis covers newer approaches to develop CR drug delivery systems by

encapsulating different drugs. Different polymeric microspherical delivery systems

were developed and their release characteristics were tuned by modifying the

polymeric system by blending two different natured polymers. Such studies are

important in developing successful formulations for their large-scale

commercialization, once-a-day formulation, CR/sustained release tablets. Thus, theme

of the thesis is timely and presents the comprehensive approach to the above

mentioned problem. Details of each of these problems will be covered in subsequent

chapters.

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I.11. Literature Cited

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