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TABLE OF CONTENTS
CHAPTER 1.............................................................................................. 3
CHAPTER 2.............................................................................................. 3
2.1.
Coatings Based on Ethylcellulose......................................................................3
2.2.
Polyvinylacetate.................................................................................................4
2.3.
Poly (-caprolactone)..........................................................................................5
CHAPTER 3.............................................................................................. 6
3.1.
Introduction........................................................................................................6
3.2.
Hydrosol and Hydrogel......................................................................................6
3.3.
Physical and Chemical Gels...............................................................................6
3.4.
Responsive Hydrogels........................................................................................7
3.5.
Hydrogel Properties............................................................................................7
3.6.
Hydrogels in Pharmaceutical Applications.........................................................7
A. Inverse Thermoresponsive Hydrogels...................................................7
B. pH Responsive............................................................................... 8
C. Natural Polymer Based Hydrogels.......................................................8
D. Nonionic Synthetic Hydrogels............................................................9
E. Superdiintegrants............................................................................ 9
F. Ion Exchanging Hydrogels..............................................................10
G.
Macroporous Hydrogels..............................................................10
CHAPTER 4............................................................................................ 10
4.1.
Brief Introduction to Biodegradable Polymers.................................................10
4.2.
Mechanism of drug release from Biodegradable polymer................................10
4.3.
Natural biodegradable polymers.......................................................................11
A. Collagen..................................................................................... 11
B. Gelatin....................................................................................... 12
C. Alginate..................................................................................... 12
D. Pectin........................................................................................ 13
CHAPTER 5............................................................................................ 13
5.1.
Brief Overview of Preparation and Properties..................................................13
5.2.
Liposomes in Vivo : Achievements and Problems............................................15
5.3.
Administration Routes for Liposomes-Based Preparations..............................16
5.4.
Liposomes as Immunological Adjuvants..........................................................16
5.5.
Liposomes in Medical Imaging........................................................................17
CHAPTER 6............................................................................................ 17
6.1.
Brief Introduction.............................................................................................17
6.2.
Formation of Complexes and Coacervates.......................................................18
5.3.
Covalent-Bond Conjugates...............................................................................20
5.4.
Complexes of Protein with Polysaccharide-Protein Conjugates.......................21
CHAPTER 1
INTRODUCTION
Health is one of the essential thing that we need to maintain. Everyone
would wish a healthy body and mind. When we are sick, we would consumed
drugs. In order to make an effective drugs, one of the things we need to consider
is its delivery mechanism. We need to measured the drugs release and its effect
on the body. This activities can be determined not only by drug substances but
also from its carrier material. Thats why In drug, we need to combine a suitable
carrier with its drug substance.
In this report, we would talk about many kinds of drug carrier. We could
differentiate each material by its properties, for example from its hydrophobicity,
natural/synthetic ingredients, its molecular structure, etc. With its specialized
properties, we could determine a suitable carries for a drug with its properties. By
pairing a drug and its suitable carrier, we would achieve a better result especially
in its drug delivery system.
CHAPTER 2
HYDROPHOBIC POLYMERS OF PHARMACEUTICAL SIGNIFICANCE
2.1.
release from Kollidon SR formulations depends on the drug loading, type and
amount of hydrophilic additives added to the formulations. Attention must be
taken upon storage of PVAc based matrices at temperatures above its glass
transition temperature. The effect of extrusion temperature on the drug release
profiles from Kollidon SR matrices depends on the type of drug used and its
miscibility and interactions with Kollidon SR, which as well may affect the
solid state properties of the drug within the matrix tablets.
Polyvinylacetate (PVAc)
PVA is a thermoplastic synthetic amorphous homopolymer. It has
relatively low glass transition temperature MW = 12,000 Tg = 32.70C MW
=45,000 Tg = 35.90C. Predominantly, it is water insoluble polymer Coatings
Based on Polyvinylacetate. The Coatings Based on Polyvinylacetate depends on
several aspects, such as The coating levels (increasing the coating levels resulted
in a decrease in the release rate due to increased diffusion ) and composition of the
cores and the films.
Polyethylenevinylacetate (EVA)
EVA composed of long chain of ethylene and vinyl acetate groups. It is
inexpensive, non-biodegradable, and a biocompatible polymer. Also, it is
thermoplastic. heat processable, and flexible.
Hydrophobic Matrices Based on Polyethylenevinylacetate
It is widely used to produce controlled-release polymeric implant devices
of high (macromolecules) or small molecular weight compounds. It can be
manufactured using HME (hot melt extrusion). Some advantages from using it is
the ability to produce long term drug release profiles and applicable in wide range
of drug delivery systems
2.3. Poly (-caprolactone)
Poly (-caprolactone) (PCL) is an aliphatic, biodegradable, semicrystalline
polyester that has found several applications as a biodegradable drug delivery
system. PCL is highly permeable to small drug molecules of molecular weight
less than 400 Da. This high permeability of PCL coupled with the long
controllable induction period prior to polymer weight loss enables the
development of delivery devices that offer diffusion-controlled drug delivery.
Increasing PCL crystallinity reduces the permeability of the polymer,
thereby lowering the drug release rate. In particular, the slow rate of degradation
of PCL renders it suitable for long-term delivery of therapeutic agents, for periods
greater than 1 year. Conversely, for many drug delivery applications, the
degradation rate of PCL is too slow to directly influence drug release. Therefore,
to increase the rate of degradation, PCL has been copolymerized with other more
hydrophilic cyclic esters, including L-LA and g-butyrolactone. Additionally, it has
been demonstrated that copolymerization of -caprolactone with hydrophilic
segments such as poly (ethylene glycol) (PEG), methoxy poly (ethylene glycol)
CHAPTER 3
HYDROGEL BIODEGRADABLE POLYMERS
3.1.
Introduction
Hydrogels are crosslinked polymers with the ability to swell in an aqueous
medium. Crosslinking in hydrogels occurs by chemical or physical means
depending on the polymer properties and experimental conditions. Due to a large
variety in chemical structure and crosslinking methods, various hydrogels have
been prepared for various applications in pharmaceutical and biomedical fields. In
this summary will discuss about with hydrogel classification, properties, and their
methods of preparation, intelligent hydrogels, and known hydrogel applications in
the pharmaceutical area.
3.2. Hydrosol and Hydrogel
Hydrosol is a sol which formed when polymer is hydrophilic and the
liquid is water. The extent of this reaction is generally dependent on the polymer
structure, functional groups, type, and amounts of ions in the polymer structure as
well as in the solution, pH, and temperature. Dissolution of a hydrophilic polimer
in water can be prevented by adding crosslinks and crosslinkes hyrdosol is called
hydrogel.
3.3.
3.4.
Responsive Hydrogels
3.5.
Hydrogel Properties
Hydrogels are generally characterized by their ultimate capacity to absorb
liquids (swelling thermodynamics), the rate at which the liquid is absorbed into
their structure (swelling kinetics), as well as their mechanical property in wet or
hydrated state (wet strength).
Figure 3. Hydrogel swelling and hydrosol solubility dependence on (a) temperature, (b) pH, and(c)
nonsolvent concentration
where a faster drug release is attributed to a faster swelling and disappearing the
glassy core of the hydrogel
PEG-Based Hydrogels
An aqueous solution of PEGPLGAPEG triblock copolymers at low
molecular weight and specific composition has been shown to become gel at the
body temperature. A thermoreversible gel with gelling temperature close to the
body temperature has been designed based on hyaluronic acid and poloxamer
polymers.
B. pH Responsive
Polymers which containing carboxyl groups or amino groups will respond
to the pH changes by changing their size in the swollen state. At low pH values,
the carboxyl containing anionic polymers display minimum ionization and hence
reduced hydration.
Chitosan-Based Hydrogels
Enteric coated multiparticulate chitosan hydrogel beads with pH-sensitive
property have been reported as potential orally administrable drug carriers for site
specific colon delivery. The hydrogel swelling was decreased with an increase in
glutaraldehyde concentration, and was higher in basic medium than in acidic
environment.The hydrogel showed a significantly higher swelling capacity in
alkaline than in acidic media, showed a good mechanical strength in its hydrated
wet state, claimed to be nontoxic and offered a prolonged release with 5flurouracil as a model drug. The protein was released up to 20 and 80%
respectively at simulated gastric and intestine conditions, which suggests its
application as a potential drug carrier for site-specific intestinal delivery.
C. Natural Polymer Based Hydrogels
Depending on their source and structure, hydrocolloids offer a vast range
of solubility and gelling properties in aqueous media. Moreover, rheological
properties of the drug solutions, dispersions, or emulsions can also be modified
using hydrocolloids or hydrocolloid hybrids. They are also well established as
food ingredients in nutraceutical industries.
Natural
Polymer
Based
Hydrogels
Cellulose
Derivatives
Based on
Alginic Acid
Based on
Guar Gum
Based on
Chitosan
Hydrocolloid
s
Based on
Carrageenan
Scleroglucan
-Based
Hydrogels
Based on
Hyaluronic
Acid
Pectin Based
Hydrogels
Miscellaneou
s
HydrocolloidBased
Hydrogels
Hydrogels of this class do not carry functional groups, and hence they are
not sensitive to the pH of the swelling medium. Their swelling only governed by
polymer-liquid interaction.
Nonionic
Synthetic
Hydrogels
Based on
Hydroxyethy
l
Methacrylate
Poly
(Ethylene
Glycol)
Hydrogels
Hydrogels
Based on
Poly (Vinyl
Alcohol)
Acrylamide
Based
Hydrogels
Polyvinylpyrr
olidoneBased
Hydrogels
Polyvinylpyrr
olidoneBased
Hydrogels
Based on
Cellulose
Based on
Polyvinylp
yrrolidone
StarchBased
Hydrogels
CHAPTER 4
NATURAL POLYMER
4.1.
profile from delivery systems prepared using natural polymers. Natural polymers
typically lack a reproducible degradation rate and typically have a short drug
release half life. Collagen and gelatin are the most common natural polymers used
in marketed products.
A Collagen
Collagen is a fibrous protein found in connective tissue. Collagen consists
of three polypeptide chains intertwined to form a right handed triple helix. There
are more than 22 different types of collagen currently identified in the human
body. Type I collagen is the most abundant protein present in mammals and is the
most thoroughly studied protein. The three polypeptide subunits of Type I
collagen have similar amino-acid compositions. Each polypeptide is composed of
about 1,050 amino acids, containing approximately 33% glycine, 25% proline,
and 25% hydroxyproline with a relative abundance of lysine.Native collagen is
water insoluble, and for many pharmaceutical applications collagen is modified to
improve its water solubility. Collagen undergoes enzymatic degradation in the
body via enzymes, such as collagenases and metalloproteinases.Drug release from
collagen matrices is controlled by varying the degree of crosslinking and other
physical properties such as porosity, density, and degree of degradation by
enzymes in vivo.Collagen is a major component of the extracellular matrix and
natural collagen is therefore an ideal matrix material for tissue engineering and
wound dressing applications. Furthermore, collagen gels are one of the first
natural polymers to be used as a promising matrix for drug delivery and tissue
engineering.
B Gelatin
Gelatin (denatured collagen) is a modified natural polymer formed by
hydrolysis of fibrous insoluble collagen. Gelatin is typically isolated from bovine
or porcine skin or bone by partial acid hydrolysis (Type A) or partial alkaline
hydrolysis (Type B). It has been used in pharmaceutical and medical applications
due to its outstanding properties such as biodegradability, biocompatibility, and
low antigenicity. In addition, gelatin can be easy to manipulate due to its
with pectin formulations is that they can swell under physiological conditions
which may result in premature drug release the effect can be minimised by the use
of pectin in combination with other polymers: cellulosic or acrylic polymers ,
chitosan ,and hydroxypropylmethyl cellulose.
CHAPTER 5
LIPOSOMES IN DRUG DELIVERY
5.1.
enter cell via micropinocytosis (4). Liposome can undergo the direct or transfer
protein-mediated exchange of lipid components with the cell membrane (5). It can
also be subjected to a specific or nonspecific endocytosis (6). In this case, a
liposome can be delivered by the endosome into the lysosome (6a) or, enroute to
lysosome, liposome can provoke endosome destabilization, which results in drug
liberation into the cell cytoplasm (6b). Drug-loaded liposome modified with
certain viral components can specifically interact with cells, provoke endocytosis,
and, via the interaction of viral components with the inner membrane of the
endosome, allow for the drug efflux into the cell cytoplasm (7)
Liposomes are in general biocompatible, cause no or very little antigenic,
pyrogenic, allergic, and toxic reactions (unless contain impurities or
contaminations), easily undergo biodegradation, protect the host from any
undesirable effects of the encapsulated drug, and protect an entrapped drug from
premature inactivation by the physiological medium.Liposomes loaded with drugs
can incorporate these drugs in a variety of fashions: water-soluble drugs are
entrapped in the liposomal inner aqueous space (and, in case of multilammellar
liposomes, into the aqueous space between bilayers), while less soluble drugs may
be incorporated in the phospholipid membrane (see Fig. 2).
Fig. 6 Attachment of various modifiers to the liposome surface. Notes: 1 liposome; 2 soluble
drug in inner aqueous space; 3 insoluble drug in the membrane; 4 targeting ligand attached to a
distal end of protective polymer chain; 5 stimuli-sensitive or cell-penetrating function on the
surface of liposomes; 6 contrast moiety attached to the liposome surface for liposome
visualization in the body.
5.2.
retention (EPR) effect. Different methods have been suggested to achieve long
circulation of liposomes in vivo, including coating the liposome surface with
inert, biocompatible polymers, such as PEG. Long circulating liposomes are now
investigated in detail and widely used in biomedical in vitro and in vivo studies
and have also found their way into clinical practice. Long circulating liposomes
demonstrate dose independent, non-saturable, log linear kinetics, and increased
bioavailability.
Targeting of long-circulating liposomes. Further development of liposomal
carriers has involved attempts to combine the properties of long-circulating
liposomes and targeted liposomes in one preparation, since longevity should also
allow for the better interaction of targeted liposomes with the target. Currently,
various advanced technologies for the preparation of targeted long-circulating
liposomes are used, and the targeting moiety is usually attached above the
protecting polymer layer, to minimize the steric hindrances for the interaction with
the target, by coupling it with the distal water-exposed terminus of a liposomegrafted polymer molecule.
Bringing liposomes inside cells. In many cases, drug loaded liposomes
should bring the drug inside cells and allow for its release from the endosomes
into cell cytoplasm to escape the lysosomal degradation. To achieve this, the
liposome could be made pH-sensitive, i.e. made of pH-sensitive components and,
after being endocytosed, it interacts with the endovacuolar membrane under the
action of lowered pH inside the endosome, releasing its content into the
cytoplasm.
5.3. Administration Routes for Liposomes-Based Preparations
Liposomes as a dosage form allow for a broad variety of administration
routes, each having its own limitations. Some aspects of parenteral (intravenous)
administration have been already discussed. Oral administration requires high
liposome stability and drug loaded liposome delivery from the gut to the blood
with subsequent drug release. After liposome drying methods were developed,
aerosolized liposomal preparations were suggested for lung delivery. Liposomes
loaded with various drugs and decorated with various targeting moieties, such as
sugar residues, have also been utilized for nasal and ocular drug delivery.
According to that, the following quality control assays should be applied to
liposomal formulations for use in humans:
Basic characterization assays, such as pH; osmolarity; trapped volume;
phospholipid concentration; phospholipid composition; phospholipid acyl
chain composition; cholesterol concentration; active compound
concentration; residual organic solvents and heavy metals; active
compound/phospholipid ratio; and proton or ion gradient before and after
remote loading.
Physical characterization assays, such as appearance; vesicle size distribution;
submicron range; micron range; electrical surface potential and surface pH;
5.4.
CHAPTER 6
COMPLEXES AND CONJUGATES OF BIOPOLYMERS AS DELIVERY
MATERIALS
6.1.
Brief Introduction
Recently, Biopolymers have been developed as a carrier for drug and
nutriceuthical ingredients. They are researched thoroughly because they show new
ability which is not appeared on their parent compounds. With this ability, new
methods could furtherly be studied and applied on various ingredient. For
example, they could form a surfactant which stabilizes in a two-phase liquid
solution or they could self-assemble to form nanoparticle coating.
In associative interaction between biopolymer such as proteins and
polysaccharides, complex formation could occur mainly between opposite
charged biopolymers in food. This formation could greatly affect the formation,
stability, appearance and other sensory properties of the product also the
development in applications connected to the special functionalities such as
delivery, analysis, quality preservation and packaging.
However, in using these complexes and conjugates, we need to consider
several advantages and disadvantages :
Advantages
1. Recognized as GRAS
2. Relatively inexpensive
3. Widely available
4. Varied in structures, properties and
functionalities
5. Able to form emulsion in oil-water surface
6. Long Shelf-life
7. Form stabil formation
8. Has a controllable release profile
6.2.
Disadvantages
1. Expensive
2. Sensitive to pH, ionic strength and
temperature
3. Difficult to create a transparent surface.
This type of complex can be used to encapsulate protein, cell or enzyme. For
example complex of alginate and chitosan. Other studies about drug-loaded
fibers, complexes that are formed at the interface between alginate and
chitosan solution and contained the drug).
5.3. Covalent-Bond Conjugates
Another type of complexes is the conjugates which are covalently bonded
polymers. This type of conjugates could combined the properties of its parent
biopolymers but also able to show superior properties. A conjugate of protein has
hydrophobic domain and a polysaccharide that could form a block copolymer, can
act as surfactant (adsorb to oil-water interface) and also form as a stabilizing
layer with the block. The layer stabilizes the colloidal emulsion system by steric
exclusion, electrostatic repulsion between droplets and increasing viscosity of the
continuous phase around the droplet. This conjugates is more effective as
surfactant and self-assemblers than non-covalent conjugates of polysaccharide and
protein.
There are some naturally occurring conjugates of proteins and
polysaccharide such as :
a. Gum Arabic (GA)
Gum Arabic has branched and anionic heteropolmer with complex structure.
It also contain small protein fraction which is significant in adsorption at oilwater interface. GA can act as an excellent emulsifier for aroma oils in acid
drinks and natural nano-encapsulator for water insoluble compounds (flavor,
nutraceuticals and conjugated linoleic acid). However, it is expensive.
b. Soybean Water Soluble Polysaccharide/SSPS
SSPS is used in flavor emulsion because it has high water solubility, pH
stability, low bulk viscosity, emulsifying properties and able to form strong
interfacial films. It could be separated to high MW fraction (HMF) and low
MW fraction (LMF) by SEC (size exclusion chromatography). Both HMF
and LMF could be used for microencapsulation of linoleic acid by
emulsification and spray drying. Increase in weight fraction in LMF means
increase in stability to oxidation of encapsulant too. This could be explained
by high free radical scavenging effect.
There are also man-made conjugates, such as combination of egg-protein
with polysaccharide or WPI-dextran conjugates which emulsion is more stable
than GA. It happens because it has enhances steric stabilization provided by the
bulk hydrophilic polysaccharide moiety. Sodium caseinate-dextran conjugates
also analyzed in controlling the release of vit B12. It has smaller yield and more
narrowly distributed water-containing oil droplet emulsions. Even under acidic
condition, the emulsions were more stable to coalescence than SC only emulsion
and had slow drug release.
5.4. Complexes of Protein with Polysaccharide-Protein Conjugates
Lasly, we would talk about the complexes of a protein with
polysaccharide-protein conjugates. In this complex, we study about the