chapter-1 introduction i....
TRANSCRIPT
Chapter-1 Introduction
1
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
Chapter-1 Introduction
2
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
Chapter-1 Introduction
3
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.
Chapter-1 Introduction
4
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
Chapter-1 Introduction
5
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
Chapter-1 Introduction
6
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.
Chapter-1 Introduction
7
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.
Chapter-1 Introduction
8
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
Chapter-1 Introduction
9
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-
Chapter-1 Introduction
10
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
Chapter-1 Introduction
11
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
Chapter-1 Introduction
12
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
Chapter-1 Introduction
13
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–
Chapter-1 Introduction
14
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.
Chapter-1 Introduction
15
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.
Chapter-1 Introduction
16
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.
Chapter-1 Introduction
17
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].
Chapter-1 Introduction
18
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,
Chapter-1 Introduction
19
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
Chapter-1 Introduction
20
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
Chapter-1 Introduction
21
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,
Chapter-1 Introduction
22
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
Chapter-1 Introduction
23
[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].
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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 -
Chapter-1 Introduction
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
Chapter-1 Introduction
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.
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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.
Chapter-1 Introduction
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
Chapter-1 Introduction
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.
Chapter-1 Introduction
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
Chapter-1 Introduction
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
Chapter-1 Introduction
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.
References
[1] J. W. Leenslag, A. J. Pennings, Polymer 28 (1987) 1695.
[2] J. A. Hubbell, Journal of Controlled Release 39 (1996) 305.
[3] X. Shi, Y. Wang, L. Rena, N. Zhao, Y. Gong, D. Wang, Acta Biomater. 5 (2009) 1697.
[4] V. R. Sinha, A. Trehan, J. Control. Release 90 (2003) 261.
[5] J.R. Robinson, H.L. Lee, Controlled drug delivery: fundaments and applications, second edition, Marcel Dekker Inc., New York (1990) 3.
[6] W.R. Gombotz, D.K. Pettit, Bioconjug Chem. 6 (1995) 332.
[7] V.R. Sinha, L. Khosla, Drug Dev Ind Pharm. 24 (1998) 1129.
[8] R. Langer, Science 392 (1998) 5.
[9] L. Brannon-Peppas, “Polymers in Controlled Drug Delivery”, Medical Plastics and Biomaterials Magazine, November (1997).
[10] K.W. Leong, R. Langer, Advanced drug delivery reviews 1 (1987) 199.
[11] S.M. Li, M. Vert, Biodegradable polymers: polyesters, Encyclopedia of controlled drug delivery (1999) 71.
[12] G. Winzenburg, C. Schmidt, S. Fuchs, T. Kissel, Advanced drug delivery reviews 56 (2004) 1453.
[13] L. K. Fung, W.M. Saltzman, Advanced Drug Delivery Reviews 26 (1997) 209.
[14] J. Folkman, P. Cole, S. Zimmerman, Ann. Surg. 164 (1966) 491.
[15] M. Danckwerts, A. Fassihi, Drug Development and Industrial Pharmacy 17 (1991) 1465.
Chapter-1 Introduction
40
[16] K.I. Shingel, R.H. Marchessault, H. Robert. Marchessault, Francois Ravenelle, A.C.S. Symposium Series 934, American Chemical Society, Xiao Xia Zhu (Eds.) 2006, 271.
[17] S.P. Vyas, R.K. Khar. Isted. Vallabhprakashan, New Delhi. 2002, 156.
[18] P. Khullar, R.K. Khar, S. P. Agarwal. Ind. J. Pharm. Sci. 61 (1999) 342.
[19] M. Nokano ,A. Ogata. Ind. J. Pharm. Sci. 68 (2006) 824.
[20] R.K. Poddar, P. Rakha, S.K. Singh, D. N. Mishra. Research. J. Phama. Dosage form and Tech. 21 (2010) 40.
[21] M.M. Demir, M.A. Gulgun, Y.Z. Menceloglu, B. Erman, S.S. Abramchuk, E.E. Makhaeva, A.R. Khokhlov, V.G. Matveeva, M.G. Sulman, Macromolecules 37 (2004) 1787.
[22] S. Porel, S. Singh, S.S. Harsha, D.N. Rao, T.P. Radhakrishnan, Chem. Mater. 17 (2005) 9.
[23] E. Delamarche, M. Geissler, J. Vichiconti, W.S. Graham, P.A. Andry, J.C. Flake, P.M. Fryer, R.W. Nunes, B. Michel, E.J. O’Sullivan, H. Schmid, H. Wolf, R.L. Wisnieff, Langmuir 19 (2003) 5923.
[24] S.G. Boyes, B. Akgun, W.J. Brittain, M.D. Foster, Macromolecules 36 (2003) 9539.
[25] S. Yoda, A. Hasegawa, H. Suda, Y. Uchimaru, K. Haraya, T. Tsuji, K. Otake, Chem. Mater. 16 (2004) 2363.
[26] W.C.W. Chan, S. Nie, Science 281 (1998) 2016.
[27] A.P. Alivisatos, Science 271 (1996) 933.
[28] W.C.W. Chan, D.J. Maxwell, X. Gao, R.E. Bailey, M. Han, S. Nie, Curr. Opin. Biotechnol. 13 (2002) 40.
[29] M. X. Wu, H. Liu, J. Liu, K.N. Haley, J.A. Treadway, J.P. Larson, E. Ge, F. Peale, M.P. Bruchez, Nat. Biotechnol. 21 (2003) 41.
[30] I. Brigger, C. Dubernet, P. Couvreur, Adv. Drug Deliver. Rev. 54 (2002) 631.
[31] F. Forestier, P. Gerrier, C. Chaumard, A.M. Quero, P. Couvreur, C.J. Labarre, Antimicrob. Chemother. 30 (1992) 173.
[32] I. Sondi, O. Siiman, E. Matijevi´c, Langmuir 16 (2000) 3107.
Chapter-1 Introduction
41
[33] O. Siiman, E. Matijevi´c, I. Sondi, U.S. Patent 6 235, 540 B1.
[34] A.; Biswas, O. Aktas, C. Schurmann, U. Saeed, V. Zaporojtchenko, F. Faupel, T. Strunskus, Appl. Phys. Lett. 84 (2004) 2655.
[35] P.M. Ajayan, L.S. Schadler, P.V. Braun, (2003) ‘‘Nanocomposite Science and Technology’’, Wiley VCH, Weinheim, Germany.
[36] Y.M. Mohan, K. Lee, T. Premkumar, K. E. Geckeler, Polymer 48 (2007) 158.
[37] Y. Lu, P. Spyra, Y. Mei, M. Ballauff, A. Pich, Macromol. Chem. Phys. 208 (2007) 254.
[38] J.Y. Ouyang, C.W. Chu, C.R. Szmanda, L.P. Ma, Y. Yang, Nat. Mater. 3 (2004) 918.
[39] K. Yoshida, M. Tanagava, S. Matsumoto, T. Yamada, M. Atsuta, European Journal of Oral Science 107 (1999) 290.
[40] F. Furno, K.S. Morley, B. Wong, B.L. Sharp, P.L. Arnold, S.M. Howdle, R. Bayston, P.D. Brown, P.D. Winship, H.J. Reid, Journal of Antimicrobial Chemotherapy 54 (2004) 1019.
[41] W.F. Lee, K.T. Rao, Journal of Applied Polymer Science 100 (2006) 3653.
[42] S. Quintavalla, L. Vicini, Meat. Science 62 (2002) 373.
[43] R. Tankhiwale, S.K. Bajpai, Colloids and Surfaces B : Bioinformatics 69 (2009) 164.
[44] R. Bandyopadhyaya, M. Sivaiah, S.P. Venkata, Journal of Chemical Technology and Biotechnology 83 (2008) 1177.
[45] C. Maioli, A. Bestetti, A. Mauri, C. Pozzato, R. Paroni, Environmental Toxicology and Pharmacology 27 (2009) 49.
[46] J.W. Richard, B.A. Spencer, L.F. McCoy E. Carina, J. Washington, P. Edgar, J Burns Surg Wound Care 1 (2002) 11.
[47] J.J. Castellano, S.M. Shafii, F. Ko, G. Donate, T.E. Wright, R.J. Mannari, Int Wound J 2 (2007) 114.
[48] H.J. Klasen, Burns 1 (2000) 30.
[49] A.B.G. Landsdown, J Wound Care 11 (2002) 125.
[50] W.B. Hugo, A.D. Russell, Oxford UK 106 (1982) 8.
Chapter-1 Introduction
42
[51] R.H. Demling, L. DeSanti, Wounds 13 (2001) 4.
[52] I. Chopra, J Antimicrob Chemother 59 (2007) 587.
[53] C.A. Moyer, L. Brentano, D.L. Gravens, H.W. Margraf, W.W. Monafo, Arch Surg 90 (1965) 812.
[54] C.G. Bellinger, H. Conway, Plast Reconstr Surg 45 (1970) 582.
[55] C.L. Fox, S.M. Modak, Antimicrob Agents Chemother 5 (1974) 582.
[56] C.G. Gemmell, D.I. Edwards, A.P. Frainse, J Antimicrob Chemother 57 (2006) 589.
[57] H.S.Rosenkranz, H.S. Carr, Antimicrob Agents Chemother 5 (1972) 199.
[58] P.D. Bragg, D.J. Rainnie, Can J Microbiol 20 (1974) 883.
[59] W.J.A. Schreurs, H. Rosenberg, J Bacteriol 152 (1982) 7.
[60] C. Haefili, C. Franklin, K. Hardy, J Bacteriol 158 (1984) 389.
[61] M. Yamanaka, K. Hara, J Appld Env Microbiol 71 (2005) 7589.
[62] S.Y. Liau, D.C. Read, W.J. Pugh, J.R. Furr, Lett Appl Microbio 25 (1997) 279.
[63] Q.L. Feng, J. Wu, G.Q. Chen, F.Z. Cui, T.N. Kim, J.O. Kim, J Biomed Mater 52 (2000) 662.
[64] I. Sondi, B. Salopek-Sondi, J Colloid Interface 275 (2007) 177.
[65] J.R. Morones, J.L. Elechiguerra, A. Camacho, J.T. Ramirez, Nanotechnology 16 (2005) 2346.
[66] H.Y. Song, K.K. Ko, L.H. Oh, B.T. Lee, Eur Cells Mater 11 (2006) 58.
[67] U. Kreibig, M. Vollmer, Optical properties of metal clusters. Berlin,Germany, Springer 24 (1995) 55.
[68] P. Mulvaney, Langmuir 12 (1996) 788.
[69] S. Pal, Y.K. Tak, J.M. Song, Appl Environ Microbiol 27 (2007) 1712.
[70] K.T. Dhermendra, J. Behari, S. Prasenjit, World Appli Sci J Biomedical Applications 3 (2008) 417.
[71] T. Thimma Reddy, K. Arihiro, Biomacromolecules 9 (2008) 4.
Chapter-1 Introduction
43
[72] S. Kim, J.H. Kim, O. Jeon, I.C. Kwon, K. Park, Eur. J. Pharm. Biopharm. 71 (2009) 420.
[73] R. Langer, Pharmacol. Ther. 21 (1983) 35.
[74] M. Sokolsky-Papkov, K. Agashi, A. Olaye, K. Shakesheff, A.J. Domb, Adv. Drug Deliv. Rev. 59 (2007) 187.
[75] B.C. Kang, K.S.Kang, Y.S. Lee, Exp. Anim. 54 (2005) 37.
[76] G. Wei, P.X. Ma, Adv. Funct. Mater. 18 (2008) 3566.
[77] T. Hadlock, J. Elisseeff, R. Langer, J. Vacanti, M. Cheney, Arch. Otolaryngol. 124 (1998) 1081.
[78] C.J. Pan, Z.Y. Shao J.J. Tang J. Wang, N. Huang, Journal of Biomedical Materials ResearchPart- A 82 (2007) 740.
[79] U. Westedt M. Wittmar, M. Hellwig, P. Hanefeld, A. Greiner, A.K. Schaper, T. Kissel, Journal of Controlled Release 111 (2006) 235.
[80] Z.G. Tang, J.T. Callaghan, J.A. Hunt, Biomaterials 26 (2005) 6618.
[81] J.H. Jeong, D.W. Lim, D.K. Han, T.G. Park, Colloids and Surfaces B, Biointerfaces 18 (2000) 371.
[82] T. Paragkumar, D. Edith, S. Jean‐luc, Applied Surface Science 253
(2006) 2758.
[83] M.L. Houchin, K. Heppert, E.M. Topp, Journal of Controlled Release 112 (2006) 111.
[84] M. Ara, M. Watanabe, Y. Imai, Biomaterials 23 (2002) 2479.
[85] M.J. Dorta, A. Santovena, M. Llabres, J.B. Farina. International journal of pharmaceutics 248 (2002) 149.
[86] Y. Wang, P. Challa, D.L. Epstein, F. Yuan, Biomaterials 25 (2004) 4279.
[87] D.C. Miller, K.M. Haberstroh, T.J. Webster, Journal of Biomedical Materials Research Part A 73 (2005) 476.
[88] H. Kranz, N. Ubrich, P. Maincent, R. Bodmeier, Journal of pharmaceutical sciences 89 (2000) 1558.
[89] L. Lu, C.A. Garcia, A.G. Mikos, Journal of biomedical materials research 46 (1999) 236.
Chapter-1 Introduction
44
[90] Y.H. Bae, K.M. Huh, Y. Kim, K. Park, Journal of Controlled Release 64 (2000) 3.
[91] B.S. Harrison, D. Eberli, S.J. Lee, A. Atala, J.J .Yoo, Biomaterials 28 (2007) 4628.
[92] L. Lu, C.A. Garcia, A.G. Mikos, Journal of Biomaterials Science: Polymer Edition 9 (1998) 1187.
[93] J.K. Jackson, J. Smith, K. Letchford, K.A. Babiuk, L. Machan, P. Signore, W.L. Hunter, K. Wang, H.M. Burt, International journal of pharmaceutics 283 (2004) 97.
[94] F.M. Veronese, P. Caliceti, Drug delivery systems. In: Integrated Biomaterials Science. Barbucci, R, Kluwer (Eds). Academic/Plenum Publishers, New York, NY, USA (2002) 833.
[95] P.H.M. Hoet, I. Brüske-Hohlfeld, O.V. Salata, J. Nanobiotechnol. 2 (2004) 12.
[96] W. Mehnert, K. Mader, Adv. Drug Deliv. Rev. 47 (2001) 165.
[97] A.J. Almeida, E. Souto, Adv. Drug Deliv. Rev. 59 (2007) 478.
[98] R.H. Muller, R.D. Petersen, A. Hommoss, J. Pardeike, Adv. Drug Deliv. Rev. 59 (2007) 522.
[99] N. Kashyap, S. Modi, J.P. Jain, Polymers for advanced drug delivery. CRIPS 5 (2004) 7.
[100] B. Twaites, C. de las Heras Alarcón, C. Alexander, J. Mater. Chem. 15 (2005) 441.
[101] J.K. Vasir, M.K. Reddy, V.D. Labhasetwar, Curr. Nanosci. 1 (2005) 47.
[102] F. Chiellini, J. Bioact. Compat. Polym. 21 (2006) 257.
[103] K. Avgoustakis, Curr. Drug Deliv. 1 (2004) 321.
[104] S. General, A.F. Thünemann, Int. J. Pharm. 230 (2001) 11.
[105] Y.N. Konan, R. Gurny, E. Allemann, Int. J. Pharm. 233 (2002) 239.
[106] C. Vauthier, E. Fattal, D. Labarre, In: Biomaterial Handbook- Advanced Applications of Basic Sciences and Bioengineering, Yaszemski MJ, Trantolo DJ, Lewamdrowski KU, Hasirci V, Altobelli DE, Wise DL (Eds). Marcel Dekker, Inc., NY, USA (2004) 563.
Chapter-1 Introduction
45
[107] C.P. Reis, R.J. Neufeld, A.J. Ribeiro, F. Veiga, Nanomedicine 2 (2006) 8.
[108] K. Bouchemal, S. Briançon, E. Perrier, H. Fessi, I. Bonnet, N. Zydowicz, Int. J. Pharm. 269 (2004) 89.
[109] C. Vauthier, D. Labarre, G. Ponchel, J. Drug Target. 15 (2007) 641.
[110] J.H. Park, M. Ye, K. Park, Molecules 10 (2005) 146.
[111] F. Si-Feng, Expert Rev. Med. Devices 1 (2004) 115.
[112] S. Desgouilles, C. Vauthier, D. Bazile, J. Vacus, J.L. Grossiord, M. Veillard, Langmuir 19 (2003) 9504.
[113] D.H. Kim, D.C. Martin, Biomaterials 27 (2006) 3031.
[114] C. Fonseca, S. Simoes, R. Gaspar, J. Control Release 83 (2002) 273.
[115] P. O'Donnell J. McGinity Adv. Drug Deliv. Rev. 28 (1997) 25.
[116] H. Gao, Y. Wang, Y. Fan, J. Ma, J. Appl. Polym. Sci. 107 (2008) 571.
[117] C. Zhao, K. Yang, X. Zhou, Colloid J. 67 (2005) 140.
[118] H. Yoshizawa, E. Kamio, E. Kobayashi, J. Jacobson, Y. Kitamura, J. Microencapsul. 24 (2007) 349.
[119] H. Fessi, F. Puisieux, J.P. Devissaguet, N. Ammoury, S. Benita, Int. J. Pharm. 55 (1989) 1.
[120] Y. Dong, S.S. Feng, Biomaterials 25 (2004) 2843.
[121] U. Bilati, E. Allemann, E. Doelker, Eur. J. Pharm. Sci. 24 (2005) 67.
[122] P. Legrand, S. Lesieur, A. Bochot, Int. J. Pharm. 344 (2007) 33.
[123] J. Cowdall, J. Davies, M. Roberts et al., Microparticles based on hybrid polymeric materials for controlled release of biologically active molecules. A process for preparing the same and their uses for in vivo and in vitro therapy, prophylaxis and diagnostics. PCT Int. Appl. WO9902131 (1999).
[124] J. Cowdall, J. Davies, M. Roberts et al., Microparticles for controlled delivery of biologically active molecules, Int. Appl. WO9902135 (1999).
[125] R. Pawar, A. Ben-Ari, A.J. Domb, Expert Opin. Biol. Ther. 4 (2004) 1203.
Chapter-1 Introduction
46
[126] M.F. Zambaux, F. Bonneaux, R. Gref, E. Dellacherie, C. Vigneron, J. Control. Release 60 (1999) 179.
[127] T.G. Park, W. Lu, G. Crotts, J. Control. Release 33 (1995) 211.
[128] E.E. Chiellini, F. Chiellini, R. Solaro, J. Nanosci. Nanotechnol. 6 (2006) 3040.
[129] A.M. Piras, F. Chiellini, C. Fiumi, C. Bartoli, E. Chiellini, Int. J. Pharm. 357 (2008) 260.
[130] F. Chiellini, C. Bartoli, D. Dinucci, A.M. Piras, R. Anderson, T. Croucher, Int. J. Pharm. 343 (2007) 90.
[131] F. Chiellini, D. Dinucci, C. Bartoli, A.M. Piras, E. Chiellini, J. Bioact. Compat. Polym. 22 (2007) 667.
[132] F. Chiellini, A.M. Piras, C. Fiumi et al.: Bioerodible/bioeliminable nanoparticles as versatile Vectors for the targeted and controlled release of protein drugs, bioactive principles and as oxygen carriers. Presented at: 20th European Conference on Biomaterials. Nantes, France, 27 September - 1 October 2006.
[133] Y.I. Jeong, C.S. Cho, S.H. Kim, J. Appl. Polym. Sci. 80 (2001) 2228.
[134] Z. Zhang, S.S. Feng, Biomacromolecules 7 (2006) 1139.
[135] K. Gupta, M. Ganguli, S. Pasha, S. Maiti, Biophys. Chem. 119 (2006) 303.
[136] A. Drogoz, L. David, C. Rochas, A. Domard, T. Delair, Langmuir 23 (2007) 10950.
[137] X.M. Liu, Y.Y. Yang, K.W. Leong, J. Colloid. Interface Sci. 266 (2003) 295.
[138] S. Young, M. Wong, Y. Tabata, A.G. Mikos, J. Control. Release 109 (2005) 256.
[139] H. Wei, X.Z. Zhang, Y. Zhou, S.X. Cheng, R.X. Zhuo, Biomaterials 27 (2006) 2028.
[140] G.H. Hsiue, C.H. Wang, C.L. Lo, C.H. Wang, J.P. Li, J.L. Yang, Int. J. Pharm. 317 (2006) 69.
[141] M. Hruby, C. Konàk, K. Ulbrich, J. Control. Release 103 (2005) 137.
[142] M.D. Determan, J.P. Cox, S. Seifert, P. Thiyagarajan, S.K. Mallapragada, Polymer 46 (2005) 6933.
Chapter-1 Introduction
47
[143] B.M. Discher, Y.Y. Won, D.S. Ege Science 284 (1999) 1143.
[144] F. Meng, G.H.M. Engbers, J. Feijen, J. Control. Release 101 (2005) 187.
[145] S. Li, B. Byrne, J.E. Welsh, A.F. Palmer, Biotechnol. Prog. 23 (2007) 278.
[146] C. Allen, J. Han, Y. Yu, D. Maysinger, A. Eisenberg, J. Control. Release 63 (2000) 275.
[147] R.T. Liggins, H.M. Burt, Adv. Drug Delivery Rev. 54 (2002) 191.
[148] V.P. Torchilin, Pharm. Res. 24 (2007) 1.
[149] K. Na, V.T. Sethuraman, Y.H. Bae, Anticancer Agents Med. Chem. 6 (2006) 525.
[150] H. Wei, X.Z. Zhang, W.Q. Chen, S.X. Cheng, R.X. Zhuo, J. Biomed. Mater. Res. A. 83 (2007) 980.
[151] D. Neradovic, O. Soga, C.F. Van Nostrum, W.E. Hennink, Biomaterials 25 (2004) 2409.
[152] R. Gref, C. Amiel, K. Molinard, J. Control. Release 111 (2006) 316.
[153] S. Daoud-Mahammed, C. Ringard-Lefebvre, N. Razzouq, J. Colloid Interface Sci. 307 (2007) 83.
[154] S. Daoud-Mahammed, P. Couvreur, R. Gref, Int. J. Pharm. 332 (2007) 185.
[155] M.J. Meziani, P. Pathak, T. Desai, Y.P. Sun, Ind. Eng. Chem. Res. 45 (2006) 3420.
[156] Y.P. Sun, M.J. Meziani, P. Pathak, L. Qu, Chem. Eur. J. 11 (2005) 1366.
[157] P. Chattopadhyay, R. Huff, B.Y. Shekunov, J. Pharm. Sci. 95 (2006) 667.
[158] H. Leuenberger, J. Nanopart. Res. 4 (2002) 111.
[159] S. Azarmi, X. Tao, H. Chen, Int. J. Pharm. 319 (2006) 155.
[160] L. Mu, M.M. Teo, H.Z. Ning, C.S. Tan, S.S. Feng, J. Control. Release 103 (2005) 565.
Chapter-1 Introduction
48
[161] J.O.H. Sham, Y. Zhang, W.H. Finlay, W.H. Roa, R. Lobenberg, Int. J. Pharm. 269 (2004) 457.
[162] P. Couvreur, C. Vauthier, Pharm. Res. 23 (2006) 1417.
[163] W. E. Rudzinski, A. M. Dave, U. H. Vaishnav, S. G. Kumbar, A. R. Kulkarni and T. M. Aminabhavi, Des. Monomers Polym. 5 (2002) 39.
[164] A. S. Hoffman, A. Afrassiabi and L. C. Dong, J. Control. Rel. 4 (1986) 213.
[165] E. L. Cussler, M. R. Stokar and J. E. Vaarberg, Am. Ind. Chem. Eng. J. 30 (1984) 578.
[166] J. Kost and R. Langer, Adv. Drug. Deliv. Rev. 46 (2001) 125.
[167] K. Ishihara, M. Kobayashi, N. Ishimaru, I. Shono-Hara, Polym. J. 16 (1984) 625.
[168] M. Shahinpoor, J. Intell. Mater. Syst. Struct. 6 (1995) 307.
[169] P.L. Ritger, N.A. Peppas, J. Control. Rel. 5 (1987) 37.
[170] T.M. Aminabhavi, H.G. Naik, J. Hazard. Mater. 60 (198) 175.
[171] G. Pathiraja, R. Mayadunne, R. Adhikari, Biotech. Ann. Rev. 12 (2006) 301.
[172] L.S. Nair, C.T. Laurencin, Progr. In Polym. Sci. 32 (2007) 762.
[173] B. Saad, U.W. Suter, Biodegradable polymeric materials. Encyclopedia Mater. Sci. Technol. (2008) 551.
[174] K.E. Uhrich, S.M. Cannizzaro, R.S. Langer, K.M. Shakesheff, Chem. Rev. 99 (1999) 3181.
[175] P.S.K. Murthy, Y.M. Mohan, K. Varaprasad, B. Sreedhar, K.M. Raju, J. Colloid Interface Sci., 318 (2008) 217.
[176] V. Ramesh Babu, C. Kim, S. Kim, C. Ahn, Yong-Ill Lee, Carbohydr. Polym. 81 (2010) 196.
[177] Y. Kim, V. Ramesh Babu, D.T. Thangadurai, K.S.V. Krishna Rao, H. Cha, C. Kim, W. Joo, Y. Lee, Bull. Korean Chem. Soc. 32 (2011) 553.
[178] L.C. Wang, X.G. Chen, C.S. Liu, L.D. Li, Q.X. Ji, L.J. Yu, J. Appl. Polym. Sci. 110 (2008) 1136.
Chapter-1 Introduction
49
[179] J. Pang, Y. Luan, F. Li, X. Cai, J. Du, Z. Li, International Journal of Nanomedicine 6 (2011) 659.
[180] S. Freiberg, X.X. Zhu, International Journal of Pharmaceutics 282 (2004) 1.
[181] R. Bodmeier, J.W. McGinity, International Journal of Pharmaceutics 43 (1988) 179.
[182] S. Md, G.K. Singh, A. Ahuja, R.K. Khar, S.Baboota, J.K. Sahni, J. Ali, Syst. Rev. Pharm. 3 (2012) 4.
[183] S. Haznedar, B. Dortunc, International Journal of Pharmaceutics 269 (2004) 131.
[184] R. Mishra, S. Acharya, F. Dilnawaz, S.K. Sahoo, Nanomedicine 4 (2009) 519.
[185] O.I. Corrigan, X. Li, European journal of Pharmaceutical Sciences 37 (2009) 477.
[186] H.K. Makadia, S.J. Siegel, Polymers 3 (2011) 1377.