Chapter-1 Introduction I....

Chapter-1 Introduction

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I. INTRODUCTION

This chapter deals with the recent developments in the field of novel

controlled release devices, such as polymeric hydrogels, films, micro and

nano-particulates etc. Various synthetic strategies for the production of

films, micro and nanoparticles as controlled drug delivery systems and

hydrogels used for the production of silver nanoparticles and their study

in biological applications have been included in this chapter. It also covers

the brief discussion about the factors affecting the drug release profiles

and controlled release mechanisms etc. A brief account about the historical

development of the drug delivery systems along with the literature survey

related to the present study is also included in this chapter. The aim of the

present research work is also discussed briefly in this chapter.

Men and medicine are inseparable from times immemorial.

Although the physical forms of medication have not changed dramatically,

the attitude of the public toward accepting medicines have changed with

the passage of time. This fact is also reflected in the strategies adopted by

the pharmaceutical companies in the field of research. The cost involved,

both in terms of time and money, has made it mandatory for the

companies to reconsider their research focus. In an attempt to reduce the

cost of drug development process and advantageously reap the benefits of

the patent regime, drug delivery systems have become an integral part of

the said process.

Drug delivery system is a dosage form, containing an element that

exhibits temporal and/or spatial control over the drug release. The

ultimate aim of such system is tailoring of the drug formulation to

individual requirements under the control of pathophysiological or in-vivo

conditions rather than in-vitro characteristics. This field of pharmaceutical

technology has grown and diversified rapidly in recent years. The field of

drug delivery system is dynamic and extensive. Probably it would need an


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encyclopedia to cover all the types of drug delivery systems. The aim of

this work is to compile major drug delivery systems and offer a source of

information for all those working in pharmaceutical academia as well as

industry.

1.1. General introduction on biodegradable polymers

Polymers are applied for a large number of medical applications: as

medical supplies, as support or replacement of malfunctioning body parts

or as a drug reservoir providing a local therapeutic effect. The

specifications for the selected material strongly depend on the application.

For temporary applications, biodegradable polymers may be the preferred

candidate. In the past 3 decades, a large range of biodegradable polymers

have been developed, tested and applied for a wide variety of medical

applications.

A polymer based on the C-C backbone is non-biodegradable.

Biodegradable polymers commonly contain chemical linkages such as

anhydride, ester, or amide bonds. These polymers degrade in vivo either

enzymatically or non-enzymatically to biocompatible and non-toxic

byproducts. These can be further metabolized or excreted via normal

physiological pathways. Biodegradable polymers not only have been

extensively used in controlled delivery systems, but also extended to

medical devices [1], wound dressing [2], and for fabricating scaffolds in

tissue engineering [3]. In addition to biocompatibility, biodegradable

polymers also offer other advantages including thermoplasticity, high

mechanical strength, and controlled degradation rate.

Biodegradable polymers are available in nature or in synthetic way.

The investigation of natural biodegradable polymer as drug carrier has

been concentrated on proteins and polysaccharides. Natural

biodegradable polymers are attractive because they are natural products


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of living organisms, readily available, relatively inexpensive and capable of

multitude of chemical modifications [4].

Natural biodegradable polymers

Protiens Globulin Gelatin, Collagen, Casein, Bovine serum

albumin, Human serum albumin

polysaccharides Starch, Cellulose, Chitosan, Dextran, Alginic acid

Synthetic biodegradable polymers have gained more popularity

than natural biodegradable polymers. The major advantages of synthetic

polymers include high purity of the product, more predictable lot-to-lot

uniformity, and free of concerns of immunogenicity. In the past 30 years,

there are numerous biodegradable polymers synthesized. Most of these

polymers contain labile linkages in their backbone such as esters,

orthoesters, anhydrides, carbonates, amides, urethanes, etc. The synthesis,

biodegradability, and application of these polymers have been well

reviewed.

Synthetic biodegradable polymers

Poly orthoesters

Poly anhydrides

Poly alkyl cyanoacxrylates

Poly esters (PLA and PLGA)

Poly caprolactones

Poly phosphazenes

Pseudo-poly aminoacids

I.1.1. Need for Biodegradable polymers

It was recognized that the surgical removal of a drug depleted from

the delivery system was difficult yet leaving non-biodegradable

foreign materials in the body for an indefinite time period caused

toxicity problem.


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While diffusion controlled release is an excellent means of achieving

controlled drug delivery, it is limited by the polymer permeability

and the characteristics of a drug increase, its diffusion coefficient

decrease.

There is no need for a second surgery for removal of Polymers.

Avoid stress shielding

Offer tremendous potential as the basis for controlled drug delivery

I.1.2 Advantage of biodegradable polymers

It provides a drug at a constant controlled rate over a prescribed

period of time.

The polymer carrier would degrade into nontoxic, absorbable

subunits which would be subsequently metabolized.

The system would be biocompatible would not exhibit dose

dumping at any time and polymer would retain its characteristics

untill after depletion of the drug.

Degradable system eliminates the necessity for surgical removal of

implanted device following depletion of a drug.

They are broken down into biologically acceptable molecules that

are metabolized and removed from the body via normal metabolic

pathways.

I.1.3. Disadvantages

Sometimes the degradable polymers exhibit substantial dose

dumping at some point following implantations.

A “burst effect” or high initial drug release soon after administration

is typical of most system.

Degradable systems which are administered by injection of a

particulate form are non-retrievable


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I.1.4. Factor affecting biodegradation of polymers

Chemical structure.

Chemical composition.

Distribution of repeat units in multimers.

Presence of ionic groups.

Presence of unexpected units or chain defects.

Configuration structure.

Molecular weight.

Molecular-weight distribution.

Morphology (amorphous/semicrystalline, microstructures, residual

stresses).

Presence of low-molecular-weight compounds.

Processing conditions.

Annealing.

Sterilization process.

Storage history.

Shape.

Site of implantation.

Adsorbed and absorbed compounds (water, lipids, ions, etc.).

Physicochemical factors (ion exchange, ionic strength, pH).

Physical factors (shape and size changes, variations of diffusion

coefficients, mechanical stresses, stress- and solvent-induced

cracking, etc.).

Mechanism of hydrolysis (enzymes versus water).

I.2. Controlled drug delivery systems

Controlled drug delivery systems have an enormous impact on

pharmaceutical technology. They greatly improve the performance of

many existing drugs and enable the use of entirely new therapies. Such


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systems are designed to have following functions. Firstly, they attempt to

maintain the drug in the desired therapeutic range by a single

administration. Secondly, they attempt to preserve drugs from being

rapidly destroyed by the body, which is very important for biologically

sensitive molecules such as proteins and peptides. Thirdly, they allow

localized delivery of the drug to a particular body compartment. Other

advantages include the reduced need for follow-up care, increased comfort

and improved compliance [5].

Among various drug delivery systems, polymer-based drug delivery

system (PDDS) is one of the most effective and efficient approaches [6-8].

The concept of PDDS is that it consists of a drug and a polymeric carrier

capable of delivering the drug to a specific site where the drug is to be

released from the carrier. Although other controlled delivery systems have

some similar advantages as mentioned above, potential disadvantages do

exist. For instance, the materials may be toxic or non-biocompatible,

resulting in undesirable side effects. Also, surgery may also be required to

implant or remove the system in some cases. Moreover, the higher cost of

other controlled release systems may limit their application. In PDDS, a

polymer is combined with drugs in a pre-designed manner so that drug

delivery can be tailored and controlled [9].

In addition to the advantages as stated above, PDDS are easy to

process. In particular, their chemical and physical properties can be easily

controlled via molecular synthesis. Furthermore, it allows targeted

delivery of the drug to specific tissues or organs.

The type of polymer used for controlled release can be natural or

synthetic, biodegradable or non-biodegradable [10]. As drug carriers,

these polymers exist in the form of matrices, reservoirs, polymer-drug

conjugate, hydrogels, micropsheres, nanoparticles, micelles and so on.


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They can be administered via parenteral, implantation, oral, insert and

transdermal routes [5].

An appropriate selection of polymers is necessary in order to

develop a successful drug delivery system since the polymer is used as a

protector for drug during drug transfer in the body until the drug is

released. An ideal polymer for drug delivery should meet the following

requirements. Firstly, the polymer must be biocompatible and

biodegradable. In other words, the polymer should be able to degrade in

vivo into smaller fragments that can be excreted from the body. The term

degradation refers to the process of polymer chain cleavage, which leads

to a loss in molecular weight. Degradation induces the subsequent erosion

(mass loss) of the materials.

Two different erosion mechanisms have been proposed:

homogeneous or bulk erosion and heterogeneous or surface erosion [11].

Bulk eroding polymers degrade all over their cross section because the

penetration of water into the polymer bulk is faster than the degradation

of polymer. In contrast, degradation is faster than the penetration of water

into bulk for surface eroding polymers. Therefore, these polymers erode

mainly from their surface. However, erosion of most polymers exhibits

both mechanisms [12]. If the polymer is non-biodegradable, the molecular

weight of the polymer should be small enough to be excreted through the

kidneys. Otherwise, it must be surgically removed after drugs are released.

Secondly, the degradation products must be non-toxic and not triggering

any inflammatory response. Also, they must also have an appropriate

physical structure, with minimal undesired aging, and be readily

processable. Finally, the degradation of the polymer should occur within a

reasonable period of time. A schematic representation of controlled drug

delivery is shown in Fig. I.1.


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Figure I.1. Schematic representation of controlled Drug Delivery (CDD)

I.3. Conventional drug therapy versus controlled release

Providing control over the drug delivery can be the most important

factor at times when traditional oral or injectable drug formulations

cannot be used. These include situations requiring the slow release of

water-soluble drugs, the fast release of low-solubility drugs, drug delivery

to specific sites, etc. The ideal drug delivery system should be inert,

biocompatible, mechanically strong, comfortable for the patient, capable of

achieving high drug loading, safe from accidental release, simple to

administer and remove, and easy to fabricate and sterilize.

Controlled Release systems aim to achieve a delivery profile that

would yield a high blood level of the drug over a long period of time. With

traditional formulations, the drug level in the blood follows the profile

shown in Fig. I.2a, in which the drug level rises after each administration

of the drug and then decreases until the next administration. With

traditional drug administration the blood level of the drug exceeds toxic

level immediately after drug administration, and falls down below

effective level after some time. Controlled drug delivery systems are

designed for long-term administration where the drug level in the blood


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follows the profile shown in Fig. I.2b, remaining constant, between the

desired maximum and minimum, for an extended period of time [9].

Figure I.2. Drug levels in the blood plasma (a) traditional drug dosing and (b) controlled-delivery dosing

I.4. Controlled release mechanisms

Polymeric release systems can be classified into reservoir and

matrix systems (Fig. I.3). In reservoir systems the drug forms a core

surrounded by polymer that forms a diffusion barrier. The drug release is

by dissolution into the polymer and then diffusion through the polymer

wall. In polymeric matrix systems the drug is dispersed or dissolved in a

polymer. The drug release can be diffusion, swelling, and/or erosion

controlled. Compared to reservoir systems, matrix systems are easier to be

manufactured because they are homogeneous in nature and they are also

safer since a mechanical defect of the reservoir device rather than matrix

device may cause dose dumping. However, if polymer matrix is non-


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degradable, the constant release profile is difficult to be achieved with

matrix system [13].

The polymer used in controlled release systems could be

biodegradable or nonbiodegradable. The first polymeric controlled release

devices is a reservoir system based on nonbiodegradable polymer silicone

rubber [14]. The major disadvantages of such system lay in that the

surgery is required to take these polymers out of the body once they are

depleted of the drug. Biodegradable polymers alleviate this problem.

These polymers used for the fabrication of delivery systems are eventually

absorbed or excreted by the body. This avoids the need for surgical

removal and thus improves the patient acceptance [15].

Figure I.3. Polymeric drug delivery systems; (A) Reservoir systems; (B)

Matrix systems

I.4.1. Polymer erosion

The choice of a particular erosion mechanism is dictated by the specific

application. The various polymer erosion mechanisms are of 3 basic types.

Type I erosion involves hydrolysis of hydrogels and these are useful

in the controlled release of macromolecules entangled within their

network structure (Fig. I.4)

Type II erosion involves solubilization of water-insoluble polymers by

reactions involving groups pendant from the polymer backbone. Of

particular interest are polymers that solubilize by ionization of


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carboxylic acid groups, and the utilization of those systems is

described.

Type III erosion involves cleavage of hydrolytically labile bonds

within the polymer backbone and four distinct polymer systems

within this category are under development. One system involves the

diffusion of drugs from a reservoir through a bioerodible membrane,

another system utilizes microcapsules, a third system utilizes

monolithic devices, and the fourth system utilizes drugs chemically

bound to a bioerodible polymer.

In addition, there are 2 mechanisms of polymer release from

bioerodible polymers: one approach involves surrounding the drug core

with a rate controlling bioerodible membrane, while the other involves

dispersing the drug within a polymer to form a bioerodible monolithic

device [16]. The use of biodegradable systems for the sustained release of

fertility-regulating agents is based on type III erosion. Polymer erosion

tends to lead drug release, and there is some indication that drug release

from the implant is controlled by rate of solubilization of the highly water-

insoluble steroid [17].

I.4.2. Diffusion

Diffusion occurs when a drug or other active agent passes through

the polymer that forms the controlled-release device [18]. The diffusion

can occur on a macroscopic scale as through pores in the polymer matrix

or on a molecular level, by passing between polymer chains. For the

diffusion-controlled systems, the drug delivery device is fundamentally

stable in the biological environment and does not change its size either

through swelling or degradation. In these systems, the combinations of

polymer matrices and bioactive agents chosen must allow for the drug to

diffuse through the pores or macromolecular structure of the polymer


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upon introduction of the delivery system into the biological environment

without inducing any change in the polymer itself [19]. In Fig. I.4A, a

polymer and active agent have been mixed to form a homogeneous system,

also referred to as a matrix system. Diffusion occurs when the drug passes

from the polymer matrix into the external environment. As the release

continues, its rate normally decreases with this type of system, since the

active agent has a progressively longer distance to travel and therefore

requires a longer diffusion time to release.

Figure I.4. Drug delivery from typical matrix drug delivery systems (A) and typical reservoir systems (B): (a) implantable or oral systems, and (b)

transdermal systems

For the reservoir systems shown in Fig. I.4B, the drug delivery rate

can remain fairly constant. In this design, a reservoir—whether solid drug,

dilute solution, or highly concentrated drug solution within a polymer

matrix is surrounded by a film or membrane of a rate-controlling material.

The only structure effectively limiting the release of the drug is the

polymer layer surrounding the reservoir. Since this polymer coating is

essentially uniform and of a nonchanging thickness, the diffusion rate of

the active agent can be kept fairly stable throughout the lifetime of the

A B


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delivery system. The system shown in Fig. I.4B(a), is representative of an

implantable or oral reservoir delivery system, whereas the system shown

in Fig. I.4.B(b), illustrates a transdermal drug delivery system in which

only one side of the device will actually be delivering the drug.

I.4.3. Swelling

They are initially dry and, when placed in the body will absorb

water or other body fluids and swell. The swelling increases the aqueous

solvent content within the formulation as well as the polymer mesh size,

enabling the drug to diffuse through the swollen network into the external

environment. Examples of these types of devices are shown in Fig. I.5(a)

and Fig. I.5(b), for reservoir and matrix systems, respectively.

Figure I.5. Drug delivery from (a) reservoir and (b) matrix swelling controlled release systems

Most of the materials used in swelling-controlled release systems

are based on hydrogels, which are polymers that will swell without

dissolving when placed in water or other biological fluids. These hydrogels

can absorb a great deal of fluid and, at equilibrium, typically comprise 60–


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90% fluid and only 10–30% polymer. One of the most remarkable, and

useful, features of a polymer's swelling ability manifests itself when that

swelling can be triggered by a change in the environment surrounding the

delivery system. Depending upon the polymer, the environmental change

can involve pH, temperature, or ionic strength, and the system can either

shrink or swell upon a change in any of these environmental factors.

I.4.4. Degradation

Biodegradable polymer degrades within the body as a result of

natural biological processes, eliminating the need to remove a drug

delivery system after release of the active agent has been completed. Most

biodegradable polymers are designed to degrade as a result of hydrolysis

of the polymer chains into biologically acceptable, and progressively

smaller, compounds [20]. Degradation may take place through bulk

hydrolysis, in which the polymer degrades in a fairly uniform manner

throughout the matrix as shown schematically in Fig. I.6(a).

Figure I.6. Drug delivery from (a) bulk-eroding and (b) surface-eroding

biodegradable systems.


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For some degradable polymers, most notably the polyanhydrides

and polyorthoesters, the degradation occurs only at the surface of the

polymer, resulting in a release rate that is proportional to the surface area

of the drug delivery system Fig. I.6(b). Once the active agent has been

released into the external environment, one might assume that any

structural control over drug delivery has been relinquished. However, this

is not always the case. For transdermal drug delivery, the penetration of

the drug through the skin constitutes an additional series of diffusional

and active transport steps.

I.5. Hydrogels

The hydrogel can be defined as a crosslinked polymeric network

which has the capacity to hold water within its porous structure. The

water holding capacity of the hydrogels arise mainly due to the presence of

hydrophilic groups such as amino, carboxyl, hydroxyl, sulphonic and

others that can be found within the polymer chains. It is also possible to

produce hydrogels containing a significant portion of hydrophobic

polymers, by blending or copolymerizing hydrophilic and hydrophobic

polymers, or by producing interpenetrating polymeric networks (IPN) or

semi-interpenetrating polymer networks (semi IPN) of hydrophobic and

hydrophilic polymers.

An interpenetrating polymer network, IPN, is defined as a blend of

two or more polymers in a network form, at least one of which is

synthesized and/or crosslinked in the immediate presence of the other(s)

(see Fig. I.7). An IPN can be distinguished from polymer blends, blocks, or

grafts in two ways (1) an IPN swells, but does not dissolve in solvents, and

(2) creep and flow are suppressed.


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Semi interpenetrating polymer networks are compositions in which

one or more polymers are crosslinked and one or more polymers are

linear or branched.

Figure I.7. Formation and structure of full and semi-interpenetrating

polymer networks (IPN).

I.5.1. Silver nanocomposite hydrogels

Nanocomposite polymer hydrogels may be defined as crosslinked

three dimensional polymer networks swollen with water or biological

fluids in the presence of nanoparticles. The design and development of

such materials containing metallic nanoparticles have scientific and

technological research interest in recent years due to their unique and

versatile properties [21-25]. These properties lead to potential

applications in the field of numerous physical, biological, biomedical and

pharmaceutical sectors [26-33] as well as optical, electrical, chemical and

data storage [34-38]. These properties are known for silver in the form of

ions, colloidal particles, nanoparticles, metallic silver as well as silver

compounds and many workers study their use to inhibit the proliferation

of microorganisms for medical [39-41], food packaging [42,43] and water

treatment [44,45] applications.


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I.5.2. Silver as antimicrobial agent

For centuries silver is being in use for the treatment of burns and

chronic wounds. As early as 1000 B.C. silver was used to make water

potable [46,47]. Silver nitrate was used in its solid form and was known by

different terms like, “Lunar caustic” in English, “Lapis infernale” in Latin

and “Pierre infernale” in French [48]. In 1700, silver nitrate was used for

the treatment of venereal diseases, fistulae of salivary glands, and bone

and perianal abscesses [48,49]. In the 19th century granulation tissues

were removed using silver nitrate to allow epithelization and promote

crust formation on the surface of wounds. Varying concentrations of silver

nitrate was used to treat fresh burns [47,48]. In 1881, Carl S.F. Crede cured

opthalmia neonatorum using silver nitrate eye drops. Crede's son, B. Crede

designed silver impregnated dressings for skin grafting [46,50]. In the

1940s, after the introduction of penicillin, the use of silver for the

treatment of bacterial infections was minimized [50-52]. Silver again came

in picture in the 1960s when Moyer introduced the use of 0.5% silver

nitrate for the treatment of burns. He proposed that this solution does not

interfere with epidermal proliferation and possess antibacterial property

against Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia

coli [53,54]. In 1968, silver nitrate was combined with sulfonamide to form

silver sulfadazine cream, which served as a broad-spectrum antibacterial

agent and was used for the treatment of burns. Silver sulfadazine is

effective against bacteria like E. coli, S. aureus, Klebsiella sp., Pseudomonas

sp. It also possesses some antifungal and antiviral activities [55]. Recently,

due to emergence of antibiotic-resistant bacteria and limitations of the use

of antibiotics the clinicians have returned to silver wound dressings

containing varying level of silver [49,52].


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I.5.3. Metallic silver

The antimicrobial property of silver is related to the amount of

silver and the rate of its release. Silver in its metallic state is inert but it

reacts with the moisture present in the skin and the fluid of the wound and

gets ionized. The ionized silver is highly reactive, as it binds to tissue

proteins and brings structural changes in the bacterial cell wall and

nuclear membrane leading to cell distortion and death. Silver also binds to

bacterial DNA and RNA and by denaturing inhibits bacterial replication

[47,52].

I.5.4. Mechanism of action of silver

The exact mechanism of action of silver on the microbes is still not

known but the possible mechanism of action of metallic silver, silver ions

and silver nanoparticles have been suggested according to the

morphological and structural changes found in the bacterial cells.

The mechanism of action of silver is linked with its interaction with

thiol group compounds found in the respiratory enzymes of bacterial cells.

Silver bounds to the bacterial cell wall and cell membrane and inhibits the

respiration process [49]. In the case of E. coli, silver acts by inhibiting the

uptake of phosphate and releasing phosphate, mannitol, succinate, proline

and glutamine from E. coli cells [57-61].

I.5.5. Mechanism of action of silver ions/AgNO3

The mechanism of antimicrobial action of silver ions is not properly

understood. However, the effect of silver ions on bacteria can be observed

by the structural and morphological changes. It is suggested that when

DNA molecules are in relaxed state the replication of DNA can be

effectively conducted. But when the DNA is in condensed form it loses its

replication ability. When the silver ions penetrate inside the bacterial cell,


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the DNA molecule turns into condensed form and loses its replication

ability leading to cell death. Also, it has been reported that heavy metals

react with proteins by getting attached with the thiol group and the

proteins get inactivated [62,63].

I.5.6. Mechanism of action of silver nanoparticles

The silver nanoparticles shows efficient antimicrobial property

compared to other salts due to their extremely large surface area, which

provides better contact with microorganisms. The nanoparticles get

attached to the cell membrane and also penetrate inside the bacteria. The

bacterial membrane contains sulfur-containing proteins and the silver

nanoparticles interact with these proteins in the cell as well as with the

phosphorus containing compounds like DNA. When silver nanoparticles

enter the bacterial cell it forms a low molecular weight region in the center

of the bacteria to which the bacteria conglomerates thus, protecting the

DNA from the silver ions. The nanoparticles preferably attack the

respiratory chain, cell and division finally leading to cell death. The

nanoparticles release silver ions in the bacterial cells, which enhance their

bactericidal activity [63-66].

I.5.7. Effect of size and shape on the antimicrobial activity of silver

nanoparticles

The surface plasmon resonance absorption peak plays a major role

in the determination of optical absorption spectra of metal nanoparticles

that shifts to a longer wavelength with increase in particle size. The size of

the nanoparticle implies that it has a large surface area to come in to

contact with the bacterial cells therefore, it will have higher percentage of

interaction when compared to bigger particles [65,67-69]. The

nanoparticles smaller than 10 nm interact with bacteria and produce

electronic effects, which enhances the reactivity of nanoparticles. Thus, it


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is corroborated that the bactericidal effect of silver nanoparticles is size

dependent [70,71]. The antimicrobial efficacy of the nanoparticles also

depends on the shapes of the nanoparticles. This can be confirmed by

studying the inhibition of bacterial growth by using different shaped

nanoparticles [71]. According to Pal et al. [69] the truncated triangular

nanoparticles shows bacterial inhibition with silver content of 1 μg. But, in

the case of spherical nanoparticles a total silver content of 12.5 μg is

needed. The rod shaped particles need a total of 50 to 100 μg of silver

content. This indicates that, the silver nanoparticles with different shapes

have different effects on bacterial cells.

I.6. Biodegradable Films

Drug delivery systems have been developed for the past two

decades using engineered polymers that have a variety of unique

properties. These polymers have various specific functions that allow for

formulations such as time-controlled release (delayed release, immediate

release, and pulsed release), pH sensitivity, temperature sensitivity,

receptor specificity, and biocompatibility [72]. Biocompatibility, an

important factor for polymers, has been utilized for developing

implantable controlled release systems for applications such as ocular

disease treatment, contraception treatment, dental treatment,

immunotherapy, anti-coagulation treatment, cancer therapy, narcotic

antagonism, and insulin delivery [73].

Among the most promising materials for implantable controlled

release systems are poly-α-hydroxyacids such as poly (lactic acid) (PLA)

and poly (lactic-co-glycolic acid) (PLGA), owing to their excellent

biocompatibility and controllable biodegradability through natural

pathways. In addition, poly-α-hydroxyacids can easily be processed to

obtain several types of devices, namely, micro- and nano-spheres,

scaffolds, and microfibers [74]. Therefore, these implantable functional


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polymers play a key role in formulations for regenerative medicine, which

aims to regenerate, replace, repair, or enhance the biological function of

damaged cells or tissues.

In general, to enhance the efficacy of regenerative medicine,

invariable shapes serving as templates are required. To date, the three-

dimensional (3D) scaffold has attracted attention because it serves as both

a temporary substrate for defect sites and a delivery carrier for controlled

release of regenerative medicine. Macro porosity, pore size, and open

structures of an artificially designed 3D scaffold are crucial factors to

control the release of regenerative medicine. However, the difficulty of

obtaining the desired macro/micro porosity and structures of the 3D

scaffolds is matter of concern [75,76]. Therefore, we focused on the

formulation of a biodegradable film [77], which is placed around the defect

site without affecting tissue regeneration. An advantage of film

formulations over 3D scaffolds is that the effects of film porosity and

structure do not require consideration. In addition, biodegradable film has

flexibility of design because it can be freely adjusted to various shapes and

sizes simply by cutting it to fit. This property enables films to control the

release of medicine. Accordingly, film formulations can potentially be

applied extensively in regenerative medicine, including bone regeneration.

I.6.1. Fabrication methods for biodegradable films

Depending upon the polymer and the desired thickness, thin films

can be fabricated by various methods including co‐extrusion, spin coating

and solventcasting among others. The former uses high heat and pressure

to extrude raw polymer though a specially designed mold, to create single

or multi‐layered films of nanoscale thickness. The later takes advantage of

centrifugal force to uniformly coat a polymer solution onto a spinning

substrate, which is then subsequently cured or annealed to yield thin films,


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usually in the micron range. However, after a review of existing

methodologies for the fabrication of biodegradable films, solvent‐casting

emerges as a preferred method. The solvent‐casting method essentially

consists of dissolving the polymer or copolymer into a suitable organic

solvent. The choice of solvents is dictated not just by their ability to

dissolve the polymer and any subsequent additions, but also their toxicity,

given that trace amounts of solvent are likely to remain in the final

product. Chloroform, dichloromethane, and acetone are commonly used as

solvents [78-82]. Excipients, such as peptides [83], calcium compounds

[84], and various drugs [78,79,85,86,] may be added to the polymer

solution. The solution is then cast onto a leveled substrate such as a metal

[84,85] or polymeric mold [87,88], glass slide, cover slip or Petri dish

[78,86,82]. The solvent is then allowed to evaporate in air, as well as under

vacuum. Alternatively, films may also be annealed in an oven, or freeze‐

dried, to remove remaining traces of solvent. Films may be briefly (10‐30

minutes) soaked in deionized distilled water or PBS, to facilitate removal

from the substrate. They are then dehydrated and sterilized, either in

ethanol or under U.V. light, prior to use.

I.6.2. Recent Applications of Biodegradable Films

While they are commonly used for characterizing controlled drug

release [85,78,79,89], biodegradable films have also seen independent use

in recent years as therapeutically useful platforms [90,91,87,86,92,80,93].

Because of their structural flexibility, thin films naturally lend themselves

to drug‐delivery for ophthalmic applications [86]. Wound‐healing patches

for external injuries and burns seem to be another intuitive application

[90,91]. Films with nanoscale surface features are being pursued for tissue

engineering applications, as substrates for improving cellular adhesion


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[87]. Finally, of particular interest from the perspective of this dissertation,

PLGA films loaded with paclitaxel have been recently investigated for

cardiovascular applications, both as coatings for drug‐eluting stents

[78,79], as well as in perivascular wraps for arresting restenosis [93].

I.7. Micro/Nano-particle systems

Drug-delivery systems (DDS) offer several advantages compared

with conventional dosage forms. The systems usually act as a reservoir of

therapeutic agents, with specific time-release profiles of the drug, thus

leading to a partial control of the pharmacokinetics. This control becomes

complete if the system is also designed for the active targeting release of

the drug with specific influences on its biodistribution. In addition, the

delivery system safeguards the drug from spoilage caused by enzyme

attack; it can enhance the penetration of the active agent in the diseased

tissues, improving its bioavailability with an increase in efficacy and

toxicity reduction. A better compliance and convenience for the patient are

also achieved [94]. The possibility of optimizing the pharmaceutical

dosage forms of bioactive agents by means of drug-delivery technology

opens the door to new biotechnological drugs, such as peptides, proteins

and oligonucleotides, which have high activity and are often also

characterized by a narrow therapeutic window. The dimensions of the

carrier have a critical role in the achievement of optimized therapeutic

regimes. In recent years, it has been shown that nanocarriers can

penetrate through small capillaries, across numerous physiological

barriers and can be taken up by cells, thus inducing efficient drug

accumulation at the target sites. Nanocarriers can be designed for different

administration routes: intravenous, intramuscular, subcutaneous, oral,

nasal, and ocular or transdermal, either fluidized with a liquid carrier or as

a solid powder [95].


24

In the development of a DDS, the rationale behind it should be

modified according to the specific biological substance and/or the

particular therapeutic protocol. Among the general characteristics that

DDS should present, the ability to incorporate the drug without damaging

it, tunable release kinetics, long in vivo stability, biocompatibility, in terms

of lack of toxicity and immunogenicity, and the potential to target specific

organs and tissues are particularly important. All of these features are

strictly related to the nature of the materials that constitute the

continuous matrix of the delivery system. In particular, the pursuit of an

adequate compromise of both bulk and surface property represents an

important issue that must be addressed. Systems based on nanoparticles

obtained by low-molar-mass nanostructure molecular assemblies, such as

solid lipids and lipid-drug conjugates, have already been described as

peptides and protein carriers in pharmaceutical and cosmetic applications

[96-98]. Organic macromolecules have highly tunable physico-chemical

characteristics and, in some cases, polymeric materials can be further

processed or functionalized to more coherent systems. Accordingly, they

probably represent the best-suited class of materials for modern drug-

delivery technology [99].

I.7.1. Polymeric materials as matrices for drug-delivery nanosystems

Currently, polymers are used as physical carriers for drugs,

components of prodrugs, conjugates or in complexes with proteins or

nucleic acids, as well as being direct therapeutics in their own right [100].

The role of polymers in DDS covers multiple aspects, from the

enhancement of the physico-chemical stability of the drug to the

regulation of the drug-release profile and targeting [101].

Generally, polymeric biomaterials are based on polymers of

synthetic as well as natural origin or on suited combinations of the two

polymer categories. All the polymers applied in the biomedical field must


25

respect minimal requirements, such as being biocompatible, nontoxic,

nonpyrogenic, noncarcinogenic, nonhemolytic and sterilizable [102].

I.7.2. Techniques for micro & nano -particle preparation

There are several techniques available for the preparation of drug-

loaded nano-structured systems and each method has its own pros and

cons. The choice of a particular technique depends on polymer and drug

features, site of action and therapy regimes [103-106]. The optimized

preparation process should guarantee the chemical stability and biological

activity of the incorporated drug. In particular, when the active-loaded

agent is a protein, their denaturation on contact with hydrophobic organic

solvents or acidic/basic aqueous solutions should be avoided by using

appropriate preparation conditions. The encapsulation efficiency and the

yield of the process should be high enough for mass production and the

obtained nanoparticles should display a homogeneous size distribution, in

agreement with their end-use requirements. Nevertheless, the preparation

and purification processes must lead to reproducible results and the

release-profile of the drug should meet the specific final application

requisites. Finally, in case of final pharmaceutical dosage forms that

involve the recovery of a suspension of nanoparticles in appropriate

media, free-flowing nanoparticles should be prepared and appropriate

storage conditions should be investigated.

The detailed procedures relevant to the preparation of polymeric

nanoparticles by direct polymerization of the low-molar-mass building

blocks are reported in literature [107-109].

I.7.2.1. Emulsion-solvent evaporation/extraction methods

I.7.2.1a. Single emulsion method


26

This method has been used primarily to encapsulate hydrophobic

drugs through the oil-in-water (o/w) emulsification process [110]. The

hydrophobic drug is dissolved or dispersed in an organic solvent into the

polymer solution, emulsified by high-speed homogenization or sonication

and is then added into an aqueous solution to make an o/w emulsion, with

the aid of amphiphilic macromolecules, termed the

emulsifier/stabilizer/additive [111,112]. Afterwards, the solvent in the

emulsion is removed by either evaporation at elevated temperatures or

extraction in a large amount of water, resulting in the formation of

compact particles.

The solvent-evaporation method has been used extensively to

prepare polylactide nano- and microparticles [113,114]. Many types of

drugs with different physical and chemical properties have been

formulated into polymeric systems, including anticancer drugs, narcotic

agents, local anesthetics, steroids and fertility-control agents [115].

I.7.2.1b. Double-emulsion method

Water-soluble drugs can be encapsulated by the double-emulsion

water-in-oil-in-water (w/o/w) method [110,116]. The aqueous solution of

the water-soluble drug is emulsified with polymer-dissolved organic

solution to form the water-in-oil emulsion. This primary emulsion is then

transferred into an excess amount of water containing an emulsifier under

vigorous stirring, thus forming a w/o/w emulsion. The solvent is then

removed by either evaporation or an extraction process.

I.7.2.2. Phase separation

This method involves phase separation of a polymer solution by

adding an organic nonsolvent. Drugs are first dispersed or dissolved in a

polymer solution. An organic nonsolvent is then added under continuous

stirring, the polymer solvent is gradually extracted and soft coacervate


27

droplets containing the drug are generated. The commonly used

nonsolvents include silicone oil, vegetable oil, light liquid paraffin and low-

molecular-weight polybutadiene. The coacervate phase is then hardened

by exposing it to an excess amount of another nonsolvent, such as hexane,

heptane or diethyl ether. The main disadvantage of this method is a high

possibility of forming large aggregates. Extremely sticky coacervate

droplets frequently adhere to each other before complete phase

separation occurs [117,118].

I.7.2.3. Solvent displacement

I.7.2.3a. Nanoprecipitation method

The nanoprecipitation technique was first developed and patented

in 1989 [119]. It is a straightforward technique, rapid and easy to perform.

The nanoparticle formation is instantaneous and the entire procedure is

carried out in only one step. The polymer and drug are dissolved together

and are precipitated in a non-solvent, miscible with that used to dissolve

the nanoparticle components. Nanoprecipitation occurs by a rapid

desolvation of the polymer and enables the production of small

nanoparticles (100-300 nm) with narrow size distribution. A wide range of

preformed polymers can be used, such as polylactides, poly caprolactones

or cellulose derivatives. The nanoprecipitation method has been used

extensively to load many different drugs into nanoparticles [114,120]. The

technique is most suitable for compounds that are hydrophobic in nature,

although formulation and process modifications were investigated

recently to encapsulate hydrophilic drugs (e.g., proteins) [121] and for

relevant process scale-up [122].

I.7.2.3b. Coprecipitation method

The coprecipitation method is an original and straightforward

procedure developed recently, which appears advantageous for the


28

loading of protein drugs into a polymer matrix [123,124]. The polymer is

dissolved in a water-miscible organic solvent and added dropwise to an

aqueous solution containing the selected drug and appropriate stabilizers.

During the coprecipitation process, the polymeric material gives rise to

microphase separation because of its low water solubility and the

concurrent interaction with drug and stabilizer leads to nanoparticle

formation. This methodology does not entail the use of chlorinated

solvents and vigorous shear mixing, therefore, the biological activity of the

loaded drugs, typically proteins, is preserved [125-127]. Albumin, [alpha]-

interferon, trypsin, urokinase and hemoglobin have been loaded into

bioerodible polymeric nanoparticles by applying the described technique

[128-132].

I.7.2.3c. Dialysis method

It is a simple and effective method applied mostly to block-graft

copolymers and other amphiphilic materials for the preparation of small

and narrow size-distributed nanoparticles [133]. Polymer, drug and

surfactants are dissolved in the same organic solvent and placed inside a

dialysis tube with proper molecular-weight cutoff. The dialysis is

performed against a non-solvent, miscible with that used to dissolve the

nanoparticle components. The displacement of the solvent inside the

membrane is followed by the progressive aggregation of polymer, drug

and surfactants owing to a loss of solubility and by the formation of

homogeneous suspensions of micro/nanoparticles. Nanoparticles loaded

with an anticancer drug were obtained by using the dialysis method and

without the use of additional surfactants/emulsifiers [134].

I.7.2.4. Self-assembling

It has recently been demonstrated that nanoparticles can be

obtained by an interaction between charged polymers and oppositely


29

charged molecules. Such an association depends on many factors,

including coulombic interactions, hydrophobicity of the polymer-molecule

pair and the conformational features of the polymer. Typically, self-

assembled complexes are formed by polyions with opposite charges. The

solution behavior of these complexes depends strongly on their

composition. Electroneutral complexes that contain equivalent amounts of

polyion units and monomers are water insoluble. Nonstoichiometric

complexes containing an excess of one of the components are generally

soluble in water. Because these complexes are capable of forming

aggregates of nanometer size, they have been termed as polyion complex

micelles or block ionomer complexes [135,136].

This approach can be used for the sustained release of numerous

charged therapeutic agents, such as proteins, polysaccharides and

oligo/polynucleotides. The release of the active agent is the consequence

of the weakening of the electrostatic interactions between drug and

carrier, owing to environmental changes, such as ionic strength or pH;

alternatively, it could be related to the degradation of the polymer-carrier

itself. This is probably the mechanism of the in vivo release and justifies

the correlation between cross-linking density and drug-release

kinetics [137]. Thermo-sensitive [138,139], pH-sensitive [140,141] and

temperature-sensitive [142] micelles have been engineered recently.

Another class of micro/nano-colloids, namely polymerosomes, can

be formulated by self-assembly of amphiphilic block copolymers in water.

The symmetry and stability of the lamellar structure depend intimately on

chain size and chemistry [143]. Hydrophilic active compounds can be

incorporated readily in the polymerosomes by adding the compound to

the aqueous phase during the polymerosome preparation and the release

profile can be tuned by changing copolymer composition and molecular

weight of the blocks [144]. Typically, amphiphilic PEG-b -


30

polyester [144] and PEO-b -polybutadiene [145] are applied. Di-block

copolymer micelles have been investigated extensively as drug-delivery

vehicles for lipophilic drugs [146,147]. In all cases, the hydrophobic drug

partitions into the hydrophobic micelle core, whereas the hydrophilic shell

maintains contact with the bulk aqueous environment. In these cases, the

lipophilic drug is generally mixed with the polymer matrix by the solution-

casting method and, afterwards, is dispersed into aqueous solutions to

form polymeric micelles. Among polymeric self-assembled micelles, a

special group is formed by lipid-core micelles based on conjugates of

soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl

ethanolamine conjugate) [148]. Furthermore, amphiphilic-block

copolymers that contain a segment with physical or chemical properties

that respond to small changes under environmental conditions can form

'stimuli-responsive' micelles, in which drug-release kinetics,

biodistribution and interactions with tissues and cells are affected by

specific pH, temperature or osmotic changes [149]. One of the most

investigated blocks for smart thermoresponsive copolymers is poly(N -

isopropylacrylamide), which is associated with polyesters [150] and

polyethers [151].

With the perspective of therapeutic applications, new

supramolecular nanoassemblies based on a [beta]-cyclodextrin polymer

(p[beta]-CD) and hydrophobically modified dextran grafted with alkyl

moieties are under investigations. The cohesion of these stable structures

of approximately 200 nm in size is based on a key-lock mechanism

between the hydrophobic alkyl chains and the molecular cavities of the

p[beta]-CD, which ensures the stability of the nanoassemblies [152-154].

I.7.2.5. Rapid expansion of supercritical fluid solution

Supercritical fluid technology has had a significant role in particle-

formation applications. A supercritical fluid is defined loosely as a solvent


31

at a temperature above the critical temperature, at which the fluid remains

in a single phase regardless of pressure. However, for practical purposes,

such as high density for solubility considerations, fluids of interest to

materials processing are typically kept at near-critical temperatures.

The production of polymeric nanoparticles through 'rapid

expansion of a supercritical solution' into either air (RESS) or liquid

solvent (RESOLV) may be divided conceptually into two related processes.

One is the initial formation of nanoparticles in the rapid expansion and the

other is the stabilization of the suspended nanoparticles. Evidently, the

protection of initially formed polymeric nanoparticles represents a

different set of technical challenges, which are largely independent of the

rapid-expansion process itself, especially if the protection agent is added

immediately after the expansion. However, many methods for stabilizing

nanoparticle suspensions are already available in the literature, some of

which have shown promise in use with RESOLV [155,156]. A new method,

called supercritical fluid extraction of emulsions (SFEE), has also been

investigated. The method combines the advantages of traditional

emulsion-based techniques, namely control of particle size and surface

properties, with the advantages of a continuous supercritical fluid-

extraction process, such as efficient scale-up, higher product purity and

shorter processing times [157].

I.7.2.6. Spray drying

Compared with other conventional methods, spray drying offers

several advantages. It shows good reproducibility, involves relatively mild

conditions, enables control of the particle size and is less dependent on the

solubility of the drug and the polymer. Generally, the polymer is dissolved

in volatile solvents and the drug is dispersed or dissolved in the polymer

solution.


32

Solutions or dispersions are sprayed against a stream of cold air (-

60°C; top-spraying) using a two-fluid pneumatic nozzle with heating

facilities. The frozen droplets formed by this spray-freezing step are dried

during the following atmospheric freeze-drying in the cold desiccated air

stream by sublimation. A filter holds the fine product back in the drying

chamber, while the water vapor is removed by the circulating air in the

cooling systems, where the humidity condenses on the refrigerated

surfaces [158]. Recently, this method has been used to prepare dry-

powder aerosol particles [159], powder formulations for controlled

delivery of paciltaxel [160] and powders for aerosol delivery to the lung

[161].

I.7.3. Biomedical and pharmaceutical applications of micro and nano-

particle systems

Today, the combination of chemistry, biology, pharmaceutical

techniques and nanotechnology has opened new avenues and perspectives

into the treatment of many different diseases by means of targeted and

controlled delivery of bioactive agents [162]. Examples of polymeric nano-

carriers and their applications are reported [162], according to their

treatment of specific diseases.

I.8. In-vitro drug release studies

Methods to study in-vitro release are by: (i) side-by-side diffusion

cells with artificial or biological membranes, (ii) dialysis bag diffusion, (iii)

reverse dialysis sac, (iv) ultracentrifugation or (v) ultra filtration. Despite

continuous efforts in this direction, there are still some technical

difficulties to study the in-vitro drug release from micron and submicron

size particles [163,164]. In order to separate the particles and to avoid the

tedious and time-consuming separation techniques, dialysis has been

used; here, the suspensions of micro/nanoparticles are added to the


33

dialysis bags/tubes of different molecular mass cut-off. These bags are

then incubated in the dissolution medium for the release study [165-167].

Release profiles of the drugs from spherical particles depend upon

the nature of the delivery system. In case of a matrix device, drug is

uniformly distributed/dissolved in the matrix and the release occurs by

diffusion or erosion of the matrix. A biphasic release is observed for the

micro/nanoparticles i.e., an initial rapid release followed by a delayed

release phase; the rapid initial release is due to the release of the drug

migrated to the surface of the particles. However, the later phase is due to

the diffusion of the drug from the matrix.

Recently, Polakovic, et al. [168] theoretically studied the release

from PLA particles loaded with varying amounts (7-32 % w/w) of

lidocaine. Two models were used to study the drug release: (i) by crystal

dissolution and (ii) by diffusion through the polymer matrix. When the

drug loading is < 10 % (w/w) (the drug is molecularly dispersed), the

release kinetics shows a better fit to the diffusion model. The existence of

lidocaine crystals at higher concentration (>10 %) is observed. Since the

drug should dissolve first from the crystals and then diffuse from the

matrix, the overall release mechanism was described by a dissolution

model.

The most commonly used equation for diffusion- controlled matrix

system is an empirical equation proposed by Ritger and Peppas [169], in

which early time release data can be fitted to obtain the diffusion

parameters using,

(Mt/M∞) = ktn

Here, Mt/M∞ represents the fractional drug release at time t; k is a

constant characteristic of drug- polymer system and n is an empirical

parameter characterizing the release mechanism. If n=0.5, the drug


34

diffuses and release out of the polymer matrix following a Fickian

diffusion. For n > 0.5, anomalous or non-Fickian type drug diffusion occurs.

If n = 1, a completely non- Fickian or case II release kinetics is operative.

The intermediary values ranging between 0.5 and 1.0 are attributed to

anomalous type diffusive transport [169,170].

I.9. Survey of literature relevant to present study

Biodegradable polymers used as biomaterials have been recently

reviewed [171-173]. To be used as biomaterials, biodegradable polymers

should have three important properties: biocompatibility, bioabsorbability

and mechanical resistance. The use of enzymatically degradable natural

polymers, as proteins or polysaccharides, in biomedical applications began

thousands of years ago whereas the application of synthetic biodegradable

polymers dates back some fifty years. The application of the natural

polymers is limited due to their physicochemical limitations; there is

significant exploration of synthetic materials which can be readily tailored

to offer properties for specific applications [174]. The ability to design

biomaterials with specific release, mechanical and processing properties

has opened opportunities for synthetic polymers in the area of controlled

release.

Murthy et al. [175] confirmed for the first time that for semi-IPN

hydrogel silver nano-composites, the silver nanoparticles are highly

distributed throughout the gel networks. For this, a number of different

IPN hydrogels were prepared by varying the concentration of

interpenetrate polymer, i.e., poly (vinyl pyrrolidone), cross-linker,

initiator, and activators. It was found that highly cross-linked semi-IPN gel

networks allow the silver nanoparticles to grow and alignment of particles

inside the gel networks. The developed semi-IPN hydrogel silver nano-

composite exhibited excellent antibacterial characteristics.


35

Ramesh Babu et al. [176] have developed a Semi-interpenetrating

carbohydrate polymer network [semi-IPN] hydrogels are composed with

combination of carbohydrate polymers, chitosan and sodium alginate with

2-hydroxyethyl methacrylate. The silver nanoparticles were formed inside

hydrogel networks with size range of 10–20 nm. The silver nanoparticles

in semi-IPN hydrogel showed very good antibacterial activity on

Escherichia coli.

Kim et al. [177] developed co-polymeric silver nano-composite

hydrogels via free radical polymerization and thereby reduction of silver

ions in to silver nanoparticles. The developed silver nanoparticles are well

characterized using different techniques, to conform the formation of

silver nanoparticles and its anti bacterial activity on gram-positive and

gram-negative bacteriocides. Percentage of swelling varied with varying

amounts of monomer and crosslinking agent. Thermal analysis, X-RD data

and UV-visible spectra revealed the formation of silver nanoparticles in the

hydrogel matrix. SEM, particle size distribution curve and TEM images

showed the narrow distribution and spherical shape of silver

nanoparticles with size range of 5 - 10 nm. The newly synthesized co-

polymeric hydrogel silver nano-composites showed an excellent

antibacterial activity and it can be used as drug.

Wang et al. [178] reported the preparation of multi structural film

with CM-chitosan and PVA. An In-vitro release study of ornidazole release

from the carrier was studied. The drug released from the multi structure

carries little faster than that from the pure CMCS. Ornidazole release from

the carriers performed a burst release in the initial 2 h then followed a

gradual release.

Jinmei Pang et al. [179] developed poly (lactic-co-glycolic acid) films

by controlling the weight ratios of drug and polymer for controlled release

of Ibuprofen. The thickness of the all the films with different weight ratios


36

is in the range of 2 to 5 µm. The X-Ray diffraction studies indicated the

amorphous dispersion of drug in the films. The drug release rate could be

controlled by the drug loading content and the release medium.

Freiberg S et al. [180] reviewed that the polymer microspheres can

be employed to deliver medication in a rate-controlled and sometimes

targeted manner. Medication is released from a microsphere by drug

leaching from the polymer or by degradation of the polymer matrix. Since

the rate of drug release is controlled by these two factors, it is important to

understand the physical and chemical properties of the releasing medium.

Author reviewed the methods used in the preparation of microspheres

from monomers or from linear polymers and discusses the physio-

chemical properties that affect the formation, structure, and morphology

of the spheres. Topics including the effects of molecular weight, blended

spheres, crystallinity, drug distribution, porosity, and sphere size are

discussed in relation to the characteristics of the release process.

Bodmeier R et al. [181] reported that Poly (DL-lactide) (PLA)

microspheres containing quinidine or quinidine sulfate were prepared by

the solvent evaporation technique. The successful entrapment of drug

within the microspheres was associated with: (a) a fast rate of

precipitation of the polymer from the organic solvent phase; (b) a low

water solubility of the drug in the aqueous phase; and (c) a high

concentration of the polymer in the organic phase. The author postulated

that the rate of polymer precipitation was strongly affected by the rate of

diffusion of the organic solvent into the aqueous phase. Organic solvents of

low water solubility resulted in a slow polymer precipitation, causing the

drug to partition completely into the aqueous phase. Water-miscible

organic solvents when added to the organic phase further enhanced the

drug content in the microspheres.


37

Shadab Md et al. [182] reported that a new approach investigated to

over ride normal gastric emptying is the use of mucoadhesive

microspheres for gastroretention. Based on this approach mucoadhesive

microspheres in gastroretentive delivery system present the promising

area for continued research. This delivery system offers the advantages of

controlled release with an enhanced bioavailability. The degree of success

of this approach lies on the thorough understanding of mucoadhesive

polymers, methodologies for preparation and evaluation techniques for

mucoadhesive microspheres.

Haznedar S et al. [183] investigated the influence of formulation

factors (stirring speed, polymer: drug ratio, type of polymer, ratio of the

combination of polymers) on particle size, encapsulation efficiency and in

vitro release characteristics of the microspheres were investigated. The

yields of preparation and the encapsulation efficiencies were high for all

formulations the microspheres were obtained. Mean particle size changed

by changing the polymer: drug ratio or the stirring speed of the system.

Mishra et al. [184] have reported increased entrapment efficiency of

doxycycline (DXY)-loaded PLGA: PCL NPs by up to 70% by varying the

different formulation parameters such as polymer ratio, amount of drug

loading (w/w), solvent selection, electrolyte addition and pH in the

formulation. Biodegradable polymers PLGA and PCL are used in various

ratios for NP preparation using the water-in-oil-in-water double emulsion

technique for water soluble DXY. The results indicated that DXY-loaded

NPs are more effective than native DXY due to the sustained release of DXY

from NPs in the E. coli strain.

Owen et al. [185] investigated the mechanism of release of active

pharmaceutical ingredients (APIs) both small molecules (ketoprofen,

indomethacin, and coumarin-6) and macromolecules (human serum

albumin, and ovalbumin), from PLGA (50:50) nanoparticulates (NPs). The


38

NPs were prepared by emulsification/solvent evaporation methods and

the release was determined in phosphate buffer pH 7.4 at 37 °C. The

release profiles exhibited an initial burst release phase, a slower lag phase

and a second increased release rate phase.

Hirenkumar et al. [186] reported that PLGA polymers have been

shown to be excellent delivery carriers for controlled administration of

drugs, peptides and proteins due to their biocompatibility and

biodegradability. In general, the PLGA degradation and the drug release

rate can be accelerated by greater hydrophilicity, increase in chemical

interactions among the hydrolytic groups, less crystallinity and larger

volume to surface ratio of the device. All of these factors should be taken

into consideration in order to tune the degradation and drug release

mechanism for desired application.

I. 10. Aim of the present study

From the literature it is noticed that no attempts were made to use

the naturally occurring polymer like NaCMC and synthetic polymers like

polylactides and their co-polymers to develop the polymeric controlled

drug delivery systems as well as polymeric silver nanocomposites and

their applications.

The aim of this thesis is to synthesize and develop novel

biodegradable polymer based films/micro/nanoparticle systems for

controlled release of drugs as well as silver nanocomposite hydrogels for

antibacterial applications, by using the more efficient naturally occurring

polysaccharides (sodium carboxymethyl cellulose), synthetic polymers

(PLA, PLGA) and monomers like acrylamide, acrylamidomethyl propane

suphonicacid. Such studies are important in developing successful

formulations for their large-scale commercialization, once-a-day

formulation and controlled release/sustained release tablets. The fields of


39

controlled release using biodegradable polymeric systems are therefore

versatile areas of research used in medicine and pharma companies. Thus,

the 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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