chapter ii literature on controlled release drug delivery
TRANSCRIPT
6
CHAPTER II
LITERATURE ON CONTROLLED RELEASE
DRUG DELIVERY SYSTEMS
(MICROCAPSULES AND MATRIX TABLETS)
Controlled release drug delivery systems 1 are those dosage formulations
designed to release an active ingredient at rates, which differ significantly from
their corresponding conventional dosage forms. The controlled release drug
delivery systems are aimed at controlling the rate of drug delivery, sustaining the
duration of therapeutic activity and/or targeting the delivery of the drug to a tissue.
Drug release from these systems should be at a desired rate, predictable and
reproducible.
Controlled drug delivery occurs when a polymer, whether natural or
synthetic, is judiciously combined with a drug or active agent in such a way that
the active agent is released from the material in a predesigned manner. The release
of the active agent may be constant over a long period, it may be cyclic over a
long period, or it may be triggered by the environment or other external events.
Controlled release drug delivery systems provided one or more of the following
advantages.
1. Maintenance of optimum therapeutic drug concentration in the blood with
minimum fluctuations.
2. Predictable and reproducible release rates for extended duration.
7
3. Enhancement of therapeutic activity duration for drugs having short
biological half - life.
4. Elimination of side effects, frequent dosing and wastage of drugs.
5. Optimized therapy and better patient compliance.
6. To mask the unpleasant taste and odour of drugs.
7. Prevention of vaporization of volatile drugs.
8. Alteration of site of absorption.
9. Elimination of incompatibilities among the drugs.
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.
In recent years, controlled drug delivery formulations and the polymers
used in these systems have become much more sophisticated, with the ability to
do more than simply extend the effective release period for a particular drug. For
example, current controlled-release systems can respond to changes in the
biological environment and deliver-or cease to deliver – drugs based on these
changes. In addition, materials have been developed that should lead to targeted
delivery systems, in which a particular formulation can be directed to the specific
cell, tissue or site where the drug it contains is to be delivered. While much of this
work is still in its early stages, emerging technologies offer possibilities that
scientists have only begun to explore.
8
2.1 ORAL CONTROLLED RELEASE SYSTEMS
The oral route is the most convenient and common mode for
administration of controlled release systems.
Oral route has been the most popular and successfully used for controlled
delivery of drugs because of convenience and ease of administration, greater
flexibility in dosage form design (possible because of versatility of g.i. anatomy
and physiology ) and ease of production and low cost of such a system. These
systems have gained importance because of the technological advances made in
fabrication, which help to achieve zero order release rates of therapeutic moiety.
The majority of oral controlled release systems rely on dissolution, diffusion or a
combination of both mechanisms to generate slow release of drug to the gastro-
intestinal milieu. Starting with limited data on a drug candidate for sustained
release, such as dose, rate constants for absorption and elimination, some elements
of metabolism and some physico-chemical properties of the drug, one can
estimate a desired release rate for the dosage form, the quantity of the drug
needed, and a preliminary strategy for the dosage form to be utilized. The
advantages of oral drug delivery systems are i) Reduced dosing frequency, ii)
Better patient convenience and compliance, iii) Reduced gastro-intestinal side
effects and toxic effects, iv) Less fluctuating plasma drug level, v) Most uniform
drug therapeutic effect, vi) Better stability of the drug.
The following are the major types of controlled release systems intended for
oral use.
9
1. Matrix tablets
Matrix tablets are monolithic systems in which drug is homogeneously
dispersed throughout a rate controlling medium. To control the release of the
drugs, hydrophobic and hydrophilic matrices have been used. For water soluble
drugs; the hydrophobic and hydrophilic matrices are mixed. For moderately or
poorly soluble drugs hydrophilic matrices are used. The drug dissolution is
controlled by controlling the rate of penetration of dissolution fluid in to the
matrix by altering the porosity of tablet, decreasing its wettability or by itself
getting dissolved at slower rate. The widely used hydrophobic and hydrophilic
materials for the preparation of matrix tablets are bees wax, hydrogenated castor
oil, hydroxy propyl methyl cellulose, xanthum gum and ethyl cellulose.
2. Mucoadhesive tablets
Mucoadhesive tablets are the controlled release drug delivery systems,
bind to the gastric epithelial cell surface or mucin and serve as a potential means
of extending the gastric retention time of drug delivery system in the stomach.
These systems prolong the intimacy and duration of contact of drug with the
biological membrane. Mucoadhesive polymers used in the preparation of tablets
utilize the property of adhesive interaction with a biological or gastrointestinal
mucosal surface. The characteristics of a mucoadhesive polymer are molecular
flexibility, hydrophilic functional groups, specific molecular weight, chain length
and conformation. These dosage forms are readily localized in the region applied
to enhance the bioavailability of drugs. These dosage forms facilitate intimate
contact of the formulation with the underlying absorption surface. This allows
modification of tissue permeability for absorption of drugs. Mucoadhesive
polymers are water insoluble and water soluble polymers, which form swellable
10
networks jointed by the cross linking agents. The commonly used polymers are
sodium carboxy methyl cellulose, carbopol, polycarbophil, sodium alginate,
hydroxy propyl methyl cellulose and gelatin.
The mucoadhesive drug delivery systems in the form of tablets, patches,
films and solutions have been developed for oral, buccal, vaginal, rectal and
ocular routes for enhancing bioavailability and for controlled release.
3. Microcapsules and microspheres
Microcapsules and microspheres are polymeric particles ranging in size
from 1-1000 µm. Microencapsulation is the process used to encase liquids, solids
and gases enclose within the polymeric embryonic membrane. The mechanism of
release is either by dissolution or diffusion of drug and the formulations are either
as encapsulated (microcapsules) or matrix (microspheres) form. Various methods
such as interfacial polymerization, coacervation-phase separation are used to
prepare microcapsules/microspheres. The thickness of the microcapsule coat can
be adjusted from 1 µm to 200 µm by changing the amount of coating material
applied from 3-30% of total weight. The coating material can be selected from a
wide variety of natural and synthetic polymers depending on the material to be
coated and the release characteristics desired. Microcapsules posses additional
advantage that sustained release of drug can be achieved with taste masking and
better g.i. tolerability.
11
4. Ion-exchange resins
The use of ion exchange resins is an attractive method for sustained drug
delivery. These types of systems are developed by embedding the drug molecules
in the ion-exchange resin matrix. In these systems drug release characteristics
largely depend only on the ionic environment of the resins containing drug. Ion
exchange based drug delivery systems are better suitable for drugs that are highly
susceptible to degradation by enzymatic processes. Ion exchange resins can be
divided into cation exchange resins and anion exchange resins. The most widely
used and safe ion-exchange resin is divinyl benzene sulphonate.
5. Film coated tablets
Coating of the tablets by using film forming polymers can control the
dissolution rate of drug from the tablets. Various polymers such as hydroxy propyl
methyl cellulose (HPMC), ethyl cellulose and eudragit have been used for the
polymeric film coating of the tablets. The polymer coatings act as diffusion
controlling mechanisms. By using both hydrophilic and hydrophobic polymers
one can accelerate the drug release. Thickness of the polymer coat is the important
parameter for the desired dissolution rate.
6. Floating tablets
Increased gastro intestinal transit time is the consequent property of
floating tablets. Floating tablets are used for local action in the proximal g.i. tract.
These systems are designed to have lesser specific gravity than the gastric
contents, thereby float on the gastro intestinal fluid for extended period. Poorly
soluble and unstable as well as poorly absorbable (in intestine) drugs are suitable
12
for floating dosage units. Hydrodynamically balanced systems are the typical
examples of floating tablets.
7. Swellable tablets
Swellable tablets are developed in a size, which can be swallowed and
when they reach stomach fluid, swell quickly and attain considerably larger size.
The dosage form is larger than the pylorus opening; it cannot pass through
pylorus, thereby, the residence time in stomach increases. The gastric emptying of
the swellable tablets is affected by their physical properties such as size, shape and
flexibility. In addition to the swelling, the gel forming property of the polymer can
retain the drug molecules within dosage form, there by sustaining the release of
drug from the formulations. Swellable tablets are prepared in various shapes such
as disk, string, pellet and tetrahedron. The tetrahedron shaped tablets showed an
increased residence time in stomach than tablets of other shapes. The commonly
used materials are gum karaya, guar gum, hydroxyl ethyl methacrylate and
polyethylene glycol.
8. Osmotic tablets
The osmotic tablets are comprised of a drug contained in a rigid, semi
permeable membrane in which an aperture (300 µm approx.) is created by a
mechanical drill or a laser beam. These systems are suitable for the controlled
release of water soluble drugs. The dispersion of drug molecules in the hydrogel
with in the tablet leads to controlled release. When water penetrates through the
semi-permeable membrane into the tablet mass by osmosis, osmotic pressure is
developed with in the tablet and as a result saturated solution of drug is forced out
of the tablet through the aperture. The two major factors, which control the
13
release, are the membrane permeability and the quality and quantity of hydrogel
polymer. Semi-permeable polymers such as cellulose acetate, ethyl carbamate,
polyamide and polyurethane are widely used.
9. Micro and multiple emulsions
Micro or sub-micron emulsions are having the dispersed phase diameter less
than 0.1µm and appear translucent or transparent and they are thermodynamically
stable compared to conventional emulsions. Multiple emulsions are containing
three phases either o/w/o or w/o/w type. The selection of type of emulsion
depends on the hydrophilic or lipophilic nature of the drugs. Lipid soluble drugs
are more suitable to these systems for improved absorption.
10. Electrically stimulated release devices2
These are monolithic devices prepared by using polyelectrolyte gels
which swell when an external electrical stimulus is applied, causing a change in
pH. The release could be modulated, by the current, giving a pulsatile release
profile.
11. Bioadhesive systems
Bioadhesive can be defined as any substance that can adhere to a
biological membrane and remain there for an extended period of time. If the
membrane substrate is then the polymer is referred to as mucoadhesive3. The
bioadhesives increase the residence time and contact time at the area of absorption
and provide a high concentration gradient across the membrane.
14
Among the various techniques, microencapsulation and matrix tablets have
been widely accepted for controlled release. In the present work
microencapsulation and matrix tablet by starch acetate and EVA was tried for
obtaining controlled release of glipizide. An overview of literature on
microencapsulation and matrix devices is given here.
2.2 MICROENCAPSULATION AND MICROCAPSULES
Microencapsulation may be defined as the process of surrounding or
enveloping one substance within another substance on a very small scale, yielding
capsules ranging from less than one micron to several hundred microns in size.
Microcapsules may be spherically shaped, with a continuous wall surrounding the
core, while others are asymmetrically and variably shaped, with a quantity of
smaller droplets of core material embedded throughout the microcapsule. Types of
microcapsules are shown in Fig. 2.1. All three states of matter (solids, liquids, and
gases) may be microencapsulated. This allows liquid and gas phase materials to be
handled more easily as solids, and can afford some measure of protection to those
handling hazardous materials.
Microencapsulation may be achieved by a myriad of techniques, with
several purposes in mind. Substances may be microencapsulated with the
intention that the core material be confined within capsule walls for a specific
period of time. Alternatively, core materials may be encapsulated so that the core
material will be released either gradually through the capsule walls, known as
controlled release or diffusion, or when external conditions trigger the capsule
walls to rupture, melt, or dissolve. The substance that is encapsulated may be
called the core material, the active ingredient or agent, fill, payload, nucleus, or
15
internal phase. The material encapsulating the core is referred to as the coating,
membrane, shell, or wall material. Microcapsules may have one wall or multiple
shells arranged in strata of varying thicknesses around the core.
Fig. 2.1: Various Types of Microcapsules
16
Applications:
There are almost limitless applications for microencapsulated material.
Microencapsulated materials are utilized in agriculture, pharmaceuticals, foods,
cosmetics and fragrances, textiles, paper, paints, coatings and adhesives, printing
applications, and many other industries.
Historically, carbonless copy paper was the first marketable product to
employ microcapsules. A coating of microencapsulated colorless ink is applied to
the top sheet of paper, and a developer is applied to the subsequent sheet. When
pressure is applied by writing, the capsules break and the ink reacts with the
developer to produce the dark color of the copy.
Today‟s textile industry makes use of microencapsulated materials to
enhance the properties of finished goods. One application increasingly utilized is
the incorporation of microencapsulated phase change materials (PCMs). Phase
change materials absorb and release heat in response to changes in environmental
temperatures. When temperatures rise, the phase change material melts, absorbing
excess heat, and feels cool. Conversely, as temperatures fall, the PCM releases
heat as it solidifies, and feels warm. This property of microencapsulated phase
change materials can be harnessed to increase the comfort level for users of sports
equipment, military gear, bedding, clothing, building materials, and many other
consumer products. Microencapsulated PCMs have even been used in NASA-
patented thermal protection systems for spacecraft.
Pesticides are encapsulated to be released over time, allowing farmers to
apply the pesticides less often rather than requiring very highly concentrated and
17
perhaps toxic initial applications followed by repeated applications to combat the
loss of efficacy due to leaching, evaporation and degradation. Protecting the
pesticides from full exposure to the elements lessens the risk to the environment
and those that might be exposed to the chemicals and provides a more efficient
strategy to pest control.
Ingredients in foods are encapsulated for several reasons. Most flavorings
are volatile; therefore encapsulation of these components extends the shelf-life of
products by retaining within the food flavors that would otherwise evaporate out
and be lost. Some ingredients are encapsulated to mask taste, such as nutrients
added to fortify a product without compromising the product‟s intended taste.
Alternatively, flavors are sometimes encapsulated to last longer, as in chewing
gum. The amount of encapsulated flavoring required is substantially less than
liquid flavoring, as liquid flavoring is lost and not recovered during chewing.
Flavorings that are comprised of two reactive components that, when encapsulated
individually, may be added to the finished product separately so that they do not
react and lose flavor potential prematurely. Some flavorings must also be
protected from oxidation or other reactions caused by exposure to light. Many
varieties of both oral and injected pharmaceutical formulations are
microencapsulated to release over longer periods of time or at certain locations in
the body. Aspirin, for example, can cause peptic ulcers and bleeding if doses are
introduced all at once. Therefore aspirin tablets are often produced by
compressing quantities of microcapsules that will gradually release the aspirin
through their shells, decreasing risk of stomach damage.
18
Microencapsulation Processes:
Microencapsulation processes can be classified as follows4
I. Chemical processes
i) Interfacial polymerization
ii) In situ polymerization
iii) Orifice method
II. Physico-chemical processes
i) Coacervation - phase separation from aqueous solution
ii) Coacervation - phase separation in organic solution
iii) Complex coacervation
iv) Complex emulsion
v) Meltable dispersion
vi) Powder bed
III. Mechanical processes
i) Air suspension or fluidized bed coating
ii) Pan coating
iii) Spray - drying
iv) Spray - congealing
v) Electrostatic bonding
Microencapsulation processes are usually categorized into two groupings:
chemical processes and mechanical or physical processes. These labels can,
however, be somewhat misleading, as some processes classified as mechanical
might involve or even rely upon a chemical reaction, and some chemical
19
techniques rely solely on physical events. A clearer indication as to which
category an encapsulation method belongs is whether or not the capsules are
produced in a tank or reactor containing liquid, as in chemical processes, as
opposed to mechanical or physical processes, which employ a gas phase as part of
the encapsulation and rely chiefly on commercially available devices and
equipment to generate microcapsules.
Chemical Methods:
Capsules for carbonless paper and for many other applications are
produced by a chemical technique called complex coacervation. This method of
encapsulation takes advantages of the reaction of aqueous solutions of cationic
and anionic polymers such as gelatin and gum arabic. The polymers form a
concentrated phase called the complex coacervate. The coacervate exists in
equilibrium with a dilute supernatant phase. As water-immiscible core material is
introduced into the system, thin films of the polymer coacervate coat the dispersed
droplets of core material. The thin films are then solidified to make the capsules
harvestable.
Interfacial polymerization (IFP) is another chemical method of
microencapsulation. This technique is characterized by wall formation via the
rapid polymerization of monomers at the surface of the droplets or particles of
dispersed core material. A multifunctional monomer is dissolved in the core
material, and this solution is dispersed in an aqueous phase. A reactant to the
monomer is added to the aqueous phase, and polymerization quickly occurs at the
surfaces of the core droplets, forming the capsule walls. IFP can be used to
prepare bigger microcapsules, but most commercial IFP processes produce
20
smaller capsules in the 20-30 micron diameter range for herbicides and pesticide
uses, or even smaller 3-6 micron diameter range for carbonless paper ink.
Polymer-polymer incompatibility, also called phase separation, is
generally grouped with other chemical encapsulation techniques, despite the fact
that usually no actual chemical reaction is involved in the process. This method
utilizes two polymers that are soluble in a common solvent; yet do not mix with
one another in the solution. The polymers form two separate phases, one rich in
the polymer intended to form the capsule walls, the other rich in the incompatible
polymer meant to induce the separation of the two phases. The second polymer is
not intended to be part of the finished microcapsule wall, although some may be
caught inside the capsule shell and remain as an impurity.
In situ polymerization is a chemical encapsulation technique very similar
to interfacial polymerization. The distinguishing characteristic of in situ
polymerization is that no reactants are included in the core material. All
polymerization occurs in the continuous phase, rather than on both sides of the
interface between the continuous phase and the core material, as in IFP. Examples
of this method include urea-formaldehyde (UF) and melanine formaldehyde (MF)
encapsulation systems.
Centrifugal force processes were developed in the 1940s to encapsulate
fish oils and vitamins, protecting them from oxidation. In this method an oil and
water emulsion is extruded through small holes in a cup rotating within an oil
bath. The aqueous portion of the emulsion is rich in a water-soluble polymer, such
21
as gelatin, that gels when cooled. The resulting droplets are cooled to form gelled
polymer-matrix beads containing dispersed droplets of oil that are dried to isolate.
Similar in concept to centrifugal force processes, submerged nozzle
processes produce microcapsules when the oil core material is extruded with
gelatin through a two-fluid nozzle. The oil droplets are enveloped in gelatin as
they are extruded through the nozzle. Then the capsules are cooled to gel the
walls, before being collected and dried.
Physical Methods:
Spray drying is a mechanical microencapsulation method developed in the
1930‟s. An emulsion is prepared by dispersing the core material, usually an oil or
active ingredient immiscible with water; into a concentrated solution of wall
material until the desired size of oil droplets are attained. The resultant emulsion is
atomized into a spray of droplets by pumping the slurry through a rotating disc
into the heated compartment of a spray drier. There the water portion of the
emulsion is evaporated, yielding dried capsules of variable shape containing
scattered drops of core material. The capsules are collected through continuous
discharge from the spray drying chamber. This method can also be used to dry
small microencapsulated materials from aqueous slurry that are produced by
chemical methods.
Fluid bed coating, another mechanical encapsulation method, is restricted
to encapsulation of solid core materials, including liquids absorbed into porous
solids. This technique is used extensively to encapsulate pharmaceuticals. Solid
particles to be encapsulated are suspended on a jet of air and then covered by a
22
spray of liquid coating material. The capsules are then moved to an area where
their shells are solidified by cooling or solvent vaporization. The process of
suspending, spraying, and cooling is repeated until the capsules‟ walls are of the
desired thickness. This process is known as the Wurster process when the spray
nozzle is located at the bottom of the fluidized bed of particles. Both fluidized bed
coating and the Wurster process are variations of the pan coating method. In pan
coating, solid particles are mixed with a dry coating material and the temperature
is raised so that the coating material melts and encloses the core particles, and
then is solidified by cooling; or, the coating material can be gradually applied to
core particles tumbling in a vessel rather than being wholly mixed with the core
particles from the start of encapsulation.
Centrifugal extrusion processes generally produce capsules of a larger size,
from 250 microns up to a few millimeters in diameter. The core and the shell
materials, which should be immiscible with one another, are pushed through a
spinning two-fluid nozzle. This movement forms an unbroken rope which
naturally splits into round droplets directly after clearing the nozzle. The
continuous walls of these droplets are solidified either by cooling or by a gelling
bath, depending on the composition and properties of the coating material.
Another mechanical encapsulation process is rotational suspension
separation, or the spinning disk method. The internal phase is dispersed into the
liquid wall material and the mixture is advanced into a turning disk. Droplets of
pure shell material are thrown off the rim of the disk along with discrete particles
of core material enclosed in a skin of shell material. After having been solidified
23
by cooling, the microcapsules are collected separately from the particles of shell
material.
2.3 CONTROLLED RELEASE THROUGH MICROENCAPSULATION
Microencapsulation has been widely employed in the design of controlled
release dosage forms. The capsule shells can be designed to release their
ingredients at specific rate and/or under specific set of conditions.
Microencapsulation is perhaps the most widely accepted technique for oral and
parenteral controlled release. The use of microencapsulation for the production of
oral SR dosage forms has been widely employed in the last 50 years since the
successful introduction by Smith, Kline and French (SKF) in the early 1950s of
their „spansule‟ products. These products usually consist of large number of
microencapsules, having variable release rates because of the composition or
amount of the coating applied, filled into hard gelatin capsule shells. Upon
ingestion the outer shell quickly disintegrates in the stomach to liberate up to
1000-3000 microcapsules, which spread over the g.i. tract, thus ensuring more
reproducible drug absorption with less local irritation that occurs with many non-
disintegrating tablets designed for sustained release. Less frequently,
microcapsules are tabletted because of the risk of capsule rupture during
compression. Microcapsules have been formulated into suspensions having
controlled drug release properties.
Microencapsulation is the most promising technique for the design of
controlled release products for parenteral administration. The structure of the
microcapsules varies according to the process of preparation, but generally, there
24
are two distinctive types. The reservoir type possesses a central core of drug
coated with thin membrane of the polymer, whereas in the monolithic type (or
microspheres) the drug is dispersed homogeneously through out a polymeric
matrix. Polymers utilized for parenteral products must meet certain qualities
regarding their tissue compatibility, mechanical characteristics, drug permeability
and the specific property of being biodegradable (or bio-erodible).
The mechanism by which the active ingredient is released from the
microcapsules includes diffusion of the drug through the polymeric matrix, its
direct release through the pores of the polymer or as the polymeric material
erodes. In the case of reservoir microcapsules, the release rate is constant (i.e.
zero order rate), where as in monolithic microcapsules, the release rate generally
decreases with time.
A wide variety of medicaments were investigated for microencapsulation
majorly for obtaining sustained and controlled release. The medicaments studied
in the recent past (1995-2011) for oral controlled release include anti-infective
drugs (pyrimethamine5, isoniazid
6, norfloxacin
7,8, cephalexine
9, tetracycline
10),
analgesic and anti-inflammatory drugs (aspirin11
, indomethacin12,13
, ibuprofen14-18
,
diclofenac19-24
, naproxen25
, pentazocin26
, ketoprofen27-29
, apomorphine30
,
acetaminophen31
), anti-asthmatic and anti-allergic drugs (salbutamol32,33
,
theophylline34-39
, aminophylline40
), cardio-vascular drugs (nifedipine41-43
,
nicardipine44-45
, isosorbide dinitrate46
, captopril47
, diltiazem48
, propranolol49
) and
miscellaneous drugs such as lactobacilli50,51
(anti-diarrhoeal), chlorpromazine52
(anti-emetic), and cimetidine53
(anti-ulcer), chloroquine phosphate54
(anti-
malarial), isoxsuprene55
(uterine sedative), cephadrine56,57
(anti-microbial) and
25
sulphadiazine58
(anti-bacterial), doxifluridine59
, protein (bovine serum albumin60
),
gliclazide61
, tebuconazole62
, metronidazole63
, amifostine64
, vancomycin65,86
,
nifedipine66
, doxorubicin67
, insulin68
, clozapid69
, vitamin D270
, amoxicillin71,72
,
felodipine73
, alkannin74
, bupivacaine75
, lycopene76
, dexamethasone77
, verapamil78
,
atenolol79
, zidovudine80
, haloperidol81
, ethopropazine82
, thymopentin83
, isosorbide
dinitrate84
, tetracycline85
, zidovudine87
, celecoxib88
, melatonin89
, paclitaxel90
,
metformin91
, capreomycin sulfate92
, salbutamol93
, diltiazem hydrochloride94
,
lamivudine95
, clarithromycin96
and famotidine.97
Among the drugs that have been incorporated in microcapsules for
parenteral administration are steroids, especially contraceptives such as nor-
ethisterone and high molecular weight compounds such as peptides and proteins.
Water-soluble antibiotics with short half-lives such as ampicillin have also been
microencapsulated to achieve long acting therapeutic effect in an effort to prevent
infection and improve methods of treating wounds.
Research in microencapsulation has been receiving increasing attention for
controlled release and drug targeting. Many studies with biodegradable polymers
as coat materials were aimed at targeting. Polymers such as polylactide (PLA),
polyglycolide (PGA) and polyglactin 370 (PLGA) have been extensively studied
as microencapsulating materials.
Among the medicaments, biotechnology based protein drugs were
extensively investigated for controlled release and targeting through
microencapsulation. Biotechnology based drugs such as proteins as vaccine
adjuvants98
, β-glucuronidase recombinant hepatitis B antigen99
, hepatocytes100
,
26
recombinant human erythropoietin101
, nerve growth factor102
(NGF),
soneatropin103
, recombinant human interferon-gamma104
, immunoglobulin Y105
,
interleukin-2106
, transforming growth factor-beta (TGF-beta)107
, recombinant
human growth hormone (rhGH)108
and hormones109
like α-ovine leutinizing
hormone, β-human chorionic gonnadotropin, recombinant aminopeptidase
(PepN)110
interferon alpha-2B111
, DNA vaccine112
, ciliary Neurotrophic factor
(CNTF)113
and tetanus toxoid114,115
were microencapsulated and were
investigated.
Much research work on microencapsulation was carried out with known
coat materials such as gelatin, gelatin-acacia, ethyl cellulose, cellulose acetate
phthalate, shellac, eudragits (RS100, RL100), albumin, calcium alginate and poly
(DL-lactide). In a few studies new substances such as propylene glycol rosin
ester116
, abietic acid-sorbitol derivatives117
, cellulose acetate118-122
, poly(epsilon-
caprolactone)123
, hGH dextran124
, Alginate-cellulose sulphate-oligocation125
, ethyl
cellulose126
, poly (lactide-co-glycolide) (PLG)127
, poly(D,L-lactide-co-
glycolide)128
, gellan gum129
, olibanum resin130
, colophony131
, chitosan132
,
bharagum97
and polystyrene133
were evaluated as microencapsulating materials.
In the present study starch acetate, a new modified starch and EVA have
been evaluated as microencapsulating agents and to prepare starch acetate and
EVA coated microcapsules of glipizide for controlled release.
27
2.4 CONTROLLED RELEASE THROUGH MATRIX (MONOLITHIC)
DEVICES
Matrix (monolithic) devices are possibly the most common of the devices
for controlling the release of drugs. This is possibly because they are relatively
easy to fabricate, compared to reservoir devices, and there is not the danger of an
accidental high dosage that could result from the rupture of the membrane of a
reservoir device. In such a device the active agent is present as a dispersion within
the polymer matrix, and they are typically formed by the compression of a
polymer/drug mixture or by dissolution or melting. The dosage release properties
of monolithic devices may be dependent upon the solubility of the drug in the
polymer matrix or, in the case of porous matrices, the solubility in the sink
solution within the particle's pore network, and also the tortuosity of the
network134
(to a greater extent than the permeability of the film), dependent on
whether the drug is dispersed in the polymer or dissolved in the polymer. For low
loadings of drug, (0 to 5% w/v) the drug will be released by a solution-diffusion
mechanism (in the absence of pores). At higher loadings (5 to 10% w/v), the
release mechanism will be complicated by the presence of cavities formed near
the surface of the device as the drug is lost; such cavities fill with fluid from the
environment increasing the rate of release of the drug.
It is common to add a plasticizer (e.g. a poly ethylene glycol), or
surfactant, or adjuvant (i.e., an ingredient which increases effectiveness), to matrix
devices (and reservoir devices) as a means to enhance the permeability (although,
in contrast, plasticizer may be fugitive, and simply serve to aid film formation135
and, hence, decrease permeability - a property normally more desirable in polymer
28
paint coatings). It was noted that the leaching of PEG acted to increase the
permeability of (ethyl cellulose) films linearly as a function of PEG loading by
increasing the porosity, however, the films retained their barrier properties, not
permitting the transport of electrolyte136
. It was deduced that the enhancement of
their permeability was as a result of the effective decrease in thickness caused by
the PEG leaching. This was evidenced from plots of the cumulative permeant flux
per unit area as a function of time and film reciprocal thickness at a PEG loading
of 50% w/w plots showing a linear relationship between the rate of permeation
and reciprocal film thickness, as expected for a (Fickian) solution-diffusion type
transport mechanism in a homogeneous membrane. Extrapolation of the linear
regions of the graphs to the time axis gave positive intercepts on the time axis; the
magnitude of which decreased towards zero with decreasing film thickness. These
changing lag times were attributed to the occurrence of two diffusional flows
during the early stages of the experiment (the flow of the 'drug' and also the flow
of the PEG), and also to the more usual lag time during which the concentration of
permeant in the film is building-up.
Efentakis et al137
investigated the effects of added surfactants on
(hydrophobic) matrix devices. It was thought that surfactant may increase the drug
release rate by three possible mechanisms namely (i) Increased solubilization, (ii)
Improved „wettability‟ to the dissolution media and (iii) Pore formation as a result
of surfactant leaching.
For the system studied (Eudragit® RL 100 and RS 100 plasticized by
sorbitol, flurbiprofen as the drug, and a range of surfactants) it was concluded that
improved wetting of the tablet led to only a partial improvement in drug release
29
(implying that the release was diffusion, rather than dissolution, controlled),
although the effect was greater for Eudragit® RS than Eudragit
® RL, whilst the
greatest influence on release was by those surfactants that were more soluble due
to the formation of 'disruptions' in the matrix allowing the dissolution medium
access to within the matrix. This is of obvious relevance to a study of latex films
which might be suitable for pharmaceutical coatings, due to the ease with which a
polymer latex may be prepared with surfactant as opposed to surfactant-free.
Differences were found between the two polymers - with only the Eudragit®
RS
showing interactions between the anionic/cationic surfactant and drug. This was
ascribed to the differing levels of quaternary ammonium ions on the polymer.
Matrix properties of a new plant gum in controlled drug delivery were
investigated by V. D. Kalu et al.138
A new plant gum, Okra (extracted from the
pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in
modified release matrices, in comparison with sodium carboxy methyl cellulose
(NaCMC) and hydroxy propyl methyl cellulose (HPMC), using paracetamol as a
model drug. Okra gum matrices provided a controlled-release of paracetamol for
more than 6h and the release rates followed time-independent kinetics. The release
rates were dependent on the concentration of the drug present in the matrix. The
addition of tablet excipients, lactose and Avicel, altered the dissolution profile and
the release kinetics. Okra gum compared favourably with Na CMC, and a
combination of Okra gum and Na CMC or on further addition of HPMC resulted
in near zero-order release of paracetamol from the matrix tablet.
Formulation of sustain release matrix systems of highly water soluble
drugs was investigated by S. Siddique et al.139
Matrix systems are of favour
30
because of their simplicity, patient compliance etc., than traditional drug delivery
which have many drawbacks like repeated administration, fluctuation in blood
concentration level etc. Developing oral sustained release matrix tablets for
highly water soluble drugs, if not formulated properly, may readily release the
drug at a faster rate, and are likely to produce toxic concentration of the drug on
oral administration. Hydrophilic polymer has become material of choice as an
important ingredient for formulating sustained release formulations of highly
water soluble drugs. Drug release to matrix system is determined by water
penetration, polymer swelling, drug dissolution, drug diffusion and matrix
erosion. Highly water soluble drugs like metoprolol tartrate, diltiazem, primodol,
ranitidine has been formulated as sustained release matrix tablets.
Drug release from matrix device:
Drug in the outside layer exposed to the bathing solution is dissolved first
and then diffuses out of the matrix. This process continues with the interface
between the bathing solution and solid drug moving toward the interior.
Obviously, for this system to be diffusion-controlled, the rate of dissolution of
drug particles within the matrix must be much faster than the diffusion rate of
dissolved drug leaving the matrix.
Fig. 2.2: Drug Delivery from a Typical Matrix Drug Delivery System
31
The equations, which describe the rate of release of drugs dispersed in an
inert matrix system have been derived by Higuchi140
. The following equation
can be written
dm/dh =d C0dh- Cs/2 ------ (1)
Where: dm = change in the amount of drug released per unit area.
dh = change in the thickness of the zone of matrix that has been depleted of drug.
Co = total amount of drug in a unit volume of the matrix.
Cs = saturated concentration of the drug within the matrix.
From the diffusion theory:
dm = Dm Cs/h dt ---------- (2)
where: Dm is the diffusion coefficient in the matrix.
Equating equations (1) and (2), integrating and solving for h gives
M = [Cs Dm (2Co-Cs)t]1/2
------(3)
when the amount of drug is in excess of the saturation concentration, that is
Co>>Cs
M = (2CsDmCot)1/2
-----------(4)
which indicates that the amount of drug released is a function of the square root of
time. In a similar manner, the drug release from a porous or granular matrix can
be described by
M= [DsC2 p/t (2co- pc
2]
1/2 ------(5)
where
p = porosity of the matrix
t = tortuosity
32
C2 = solubility of the drug in the release medium
Cs = diffusion coefficient in the release medium
This system is slightly different from the previous matrix system. In that
the drug is able to pass out of the matrix through fluid-filled channels and does not
pass through the polymer directly.
For purposes of data treatment, equation (4) or (5) can be reduced to
M = Kt1/2
where K is a constant.
So that a plot of amount of drug release versus the square root of time will
be linear, if the release of drug from the matrix is diffusion controlled. If this is
the case, then, by the Higuchi model, one may control the release of drug from a
homogeneous matrix system by varying141-145
initial concentration of drug in the
matrix, porosity, tortuosity, polymer system forming the matrix and solubility of
the drug.
In the present study starch acetate and EVA have been evaluated as release
retarding and rate – controlling polymer in matrix tablets for controlled release of
glipizide.
33
REFERENCES
1. Ballard, B.E. and Robinson, J.R., Eds., In; An overview of prolonged action
drug dosage form, In sustained and controlled release drug delivery
systems, Marcel Dekker, New York, 795, 1978.
2. Yuk, S.H., Cho, S.H. and Lee, H.B., Pharm. Res., 9 (7), 955, 1992.
3. Vyas, S. P. and Roop, K. Khar., Controlled Drug Delivery: Concepts and
Advances, 1st Ed., 258, 2004.
4. Kondo, A., Valkenburg, J.W.V., Eds., In; Microcapsules Processing and
Technology, Marcel Dekker, New York, 32, 1979.
5. Bhalla, H.L. and Menon, M.D., Indian Drugs, 35, 705, 1998.
6. Barik, B.B., Gupta, B.K. and Pal, M., Indian J. Pharm. Sci., 59, 110, 1997.
7. Chen, X.M., Ao, B.C. and Xin, J.F., J. China Pharmacy, 6, 7, 1995.
8. Pitchai Mani, R. and Shirwaikar, A.A., Indian J. Pharm. Sci., 57, 105, 1995.
9. Nimmannit, U. and Sumanpatra, N., J. Microencapsul., 13, 643, 1996.
10. Tsankov, S., Lansbov, N. and Minkov, E., Pharm. Ind., 57, 1044, 1995.
11. Vachon, M.G. and Nairn, J.G., J. Microencapsul., 14, 281, 1997.
12. Tirkkonen, S., Urtti, A. and Paronen, P., Int. J. Pharm., 124, 219, 1995.
13. Mohsen, A. and Bayomi, B., Drug Dev. Ind. Pharm., 30, 329, 2004.
14. Kakkar, A.P., Eastern Pharmacist, 39, 129, 1996.
15. Chowdhury, S.R., Mukherjee, P.K., Singha, D., Ghosh, L.K. and Pal, M.,
Eastern Pharmacist, 38, 137, 1995.
16. Sarry, E.M. and Abdel Zaher, A.O., Bull. Pharm. Sci., 19, 1, 1996.
17. Rafiee,T. M. and Sadegh, S. N., Drug Ind. Pharm., 21, 1193, 1995.
18. An, Z., Lu, G., Mohwald, H. and Li, J., J. Chemistry, 11, 121, 2004.
34
19. Ichikawa, H., Fukumori, Y. and Moji Adeye, C., Int. J. Pharm., 156,
39,1997.
20. Palomo, M.E., Ballesteros, M.P. and Frutos, P., Drug Dev. Ind. Pharm., 23,
273, 1997.
21. Chowdary, K.P.R. and Sastry, V.H., Eastern Pharmacist, 40, 119, 1997.
22. Rani, S.H.R., Nargund, L.V. and Prakasam, K., Indian Drugs, 33, 615,
1996.
23. Khopade, A.J. and Jain, N.K., Pharmazie, 50, 812, 1995.
24. Biju, S.S., Saisivam, S., Rajan, N.S. and Mishra, P.R., Eur. J. Pharm.
Biopharm., 58(1), 61, 2004.
25. Akbuga, J. and Bergisadi, N., Drug Dev. Ind. Pharm., 23, 407, 1997.
26. Mandal, M. and Gupta, B.K., Indian J. Pharm. Sci., 59, 181, 1997.
27. Palmieri, G.F., Martell, S., Lauri, D. and Wehrle, P., Drug Dev. Ind.
Pharm., 22, 951, 1996.
28. Ricci, M., Blasi, P., Giovagnoli, S., Rossi, S., Macchiarulo, G., Luca, G.,
Basta, G. and Calafiore, R., J. Controlled Release, 107(3), 395, 2005.
29. Habib, M.J. and Mesue, R., Drug Dev. Ind. Pharm., 21, 1463, 1995.
30. Ugwoke, M.I., Verbeke, N. and Kinget, R., Int. J. Pharm., 148, 23, 1997.
31. Pollock, D.K., Pharm. Tech., 22, 6, 1998.
32. Amperiadou, A. and Georgarakis, M., Int. J. Pharm., 115, 1, 1995.
33. Nagarajan, M., Ganesan, M. and Nalluri, B.N., Eastern Pharmacist, 39, 123,
1996.
34. Narisawa, S., Nagata, M., Hirakawa, Y., Kobayashi, M. and Yoshino, H., J.
Pharm. Sci., 85, 184, 1996.
35. Donbrow, M., Hoffman, A. and Benita, S., J. Microencapsul., 12, 273, 1995.
35
36. Phuapradit, W., Shah, N.H., Railkar., Williams, L. and Infield, M.H., Drug
Dev. Ind. Pharm., 21, 955, 1995.
37. Badawi, A.A., El-Samaligy, M., Badawi, S.S. and Aziz, R.L., Pharmazie,
53, 556, 1998.
38. Yao, T., Yamada, M., Yamahara, H. and Yoshida, M., Chem. Pharm. Bull.,
46, 826, 1998.
39. Amperiadou, A. and Georgarakis, M., Drug Dev. Ind. Pharm., 21, 1339,
1995.
40. Valleri, M and Mura, P., Drug Dev. Ind. Pharm., 21, 2139, 1995.
41. Chowdary, K.P.R. and Girijasankar, G., Drug Dev. Ind. Pharm., 23, 331,
1997.
42. Antal. I., Zelko, R., Roczey, N., Plachy, J. and Racz, I., Int. J. Pharm., 55,
83, 1997.
43. Chowdary, K.P.R., Nagarajan, M. and Nalluri, B.N., Indian J. Pharm. Sci.,
58, 152, 1996.
44. Yuksel, N. and Baykara, T., Int. J. Pharm. Adv., 1, 398, 1996.
45. Yuksel, N., Tincer, T. and Baykara, T., Int. J. Pharm., 140, 145, 1996.
46. Gohel, M.C. and Patel, M.M., Eastern Pharmacist, 39, 133, 1996.
47. Jayaswal, S.B. and Reddy, T.S.R., Indian Drugs, 32, 454, 1995.
48. Kristmundsdottir, T., Gudmundsson, O.S. and Ingvarsdottir, K., Int. J.
Pharm., 137, 159, 1996.
49. Jones, D.S. and Pearce, K.J., Int. J. Pharm., 118, 199, 1995.
50. Kala, V., Dabre, R. and Bhusari, K.P., Indian Drugs, 35, 281, 1998.
51. Chen, H., Ouvang. W., Jones, M., Haque, T., Lawuvi, B. and Prakash, S., J.
Microencapsul., 22(5), 539, 2005.
36
52. Samanta, M.K., Tamilvanan, S., Babu, K. and Suresh, B., Indian J. Pharm.
Sci., 59. 68, 1997.
53. Dutta, U.K. and Ghosal, S.K., Indian Drugs, 32, 484, 1995.
54. Ndesendo, V.M.K. and Meixner, W., J. Microencapsul., 13, 1, 1996.
55. Shettiger, R. and Damle, A.V., Indian J. Pharm. Sci., 57, 210, 1995.
56. Tang, H. Q., Jiang, W. L., Zhao, G.H. and Zou, L. J., Chinese J. Pharm., 27,
11, 1996.
57. Tuncel, T., Bergisadi, N., Akin, L., Otuk, G. and Kuscu, I., Pharmazie, 51,
168, 1996.
58. Kondo, T., Hafez, E., Abdel-Monem, H., EI-Harras, S. and EI-Gibaly, I. et
al., Pharmazeutische Industrie, 58, 552, 1996.
59. Tomoaki, Y., Machida, Y., Hiraku, O. and Nagai, T., Drug Dev. Ind.
Pharm., 29, 417, 2003.
60. Anil, K., Bhopatkar, A.D., Seiiclu, T., Hiroshi, T. and Stevens, W.F., Drug
Dev. Ind. Pharm., 29. 713, 2003.
61. Zhao, Y., Chen, W., Cai, Q., Wang, S., Bo. J. and Wu, C., Macromol.
Biosci., 4(3), 308, 2004.
62. Asrar, J., Ding, Y., La Monica, R.E. and Ness, L.C., J. Agric. Food Chem.,
52(15), 4814, 2004.
63. Portero, A., Remunan-Lopez, C., Criado, M.T. and Alonso, M. J., J.
Microencapsul., 19(6), 797, 2002.
64. Mandal, T.K., Bostanian, L.A., Graves, R.A., Chapman, S.R. and Womack,
I., Drug Dev. Ind. Pharm., 28(3), 339, 2002.
65. Ozalp, Y., Ozdemir, N., Kocagoz, S. and Hasirci, V., J. Microencapsul.,
18(1), 89, 2001.
37
66. Hombreio-Perez, M., Siepmonn, J., Zinuti, C., Lamprecht, A., Ubrich, N.,
Hoftman, M., Bodmeier, and Maincent, P., J. Controlled Release, 88, 413,
2003.
67. Kevin A., Jones, M.P., Fresneau, A.M., Angels, F. and Maria, J.A., J.
Controlled Release, 73, 255, 2001.
68. Dinesh, B., Shenoy, R.J., Sandip, B. and Udupa, N., Drug Dev. Ind. Pharm.,
29, 555, 2003.
69. Agnihotri, S.A. and Aminabhavi, T.M., J. Controlled Release, 28, 245,
2004.
70. Shi, X.Y. and Ton, T.W., Biomaterials, 23 (23), 4469, 2002.
71. Obeidat, W.M. and Price, J.C., J. Microencapsul., 21, 47, 2004.
72. Song, M., Li, N., Sun, S., Tiedt, L.R., Liebenberg, W. and de Villiers, M.M.,
Farmaco., 60(3), 261, 2005.
73. Savolainen, M., Herder, J., Khoo, C., Lorgvist, K., Dahigvist, C., Glad, H.
and Juppo, A.M., Int. J. Pharm., 27, 47, 2003.
74. Assimopoulou, A.N. and Papageorgiou, V.P., J. Microencapsul., 21(2), 161,
2004.
75. Pedersen, J.L., Lilleso, J., Hammer, N.A., Werner, M.U., Holte, K.,
Lacouture, P.G. and Kehlet, H., J. Anesth. Analg., 99, 912, 2004.
76. Wang, H. J., Li, X.R., Huang, Y.Q., Zhang, Y.L., Hu, X. and Liu, Y., Yao
Xue Xue Bao., 40(9), 787, 2005.
77. Pargaonkar, N., Lvov, Y.M., Li, N., Steenekamp, J.H. and de Villiers, M.M.,
Pharm. Res., 22(5), 826, 2005.
78. Mukherjee, B., Mahanti, B., Panda, P. and Mahapatra, S., American J.
Therapeutics, 12(5), 417, 2005.
38
79. Yasmeen, R., Shoaib, M.H. and Khalid, H., Pak. J. Pharm. Sci., 18, 47,
2005.
80. Rao, K.R., Senapati, P.and Das, M.K., J. Microencapsul., 22, 863, 2005.
81. Budhian, A., Siegel, S.J. and Winey, K.I., J. Microencapsul., 22, 773, 2005.
82. Persyn, J.T., McDonough, J. A., Nino, J. A., Dixon, H. and Boland, E.J., J.
Microencapsul., 22, 737, 2005.
83. Yuan, X.J., Zhang, Z.R., Song, Q.G. and He, Q., Arch. Pharm. Res., 29,
795, 2006.
84. Yang, G.M., Kuo, J.F. and Woo, E.M., J. Microencapsul., 23, 622, 2006.
85. Govender, S., Lutchman, D., Pillay, V., Chetty, D.J. and Govender, T., J.
Microencapsul., 23, 750, 2006.
86. Nettey, H., Haswani, D., Oettinger, C.W.and D‟Souza, M.J., J.
Microencapsul., 23, 632, 2006.
87. Das, M.K. and Rao, K.R., Acta. Pol. Pharm., 63, 141, 2006.
88. Homar, M., Ubrich, N. E., Ghazouani, F., Kristl, J., Kerc, J. and Maincent, P.,
J. Microencapsul., 24, 621, 2007.
89. Schaffazick, S.R., Pohlmann, A.R.and Guterres, S.S., Pharmazie, 62, 354,
2007.
90. Jackson, J.K., Hung, T., Letchford, K. and Burt, H.M., Int. J. Pharm., 342,
6, 2007.
91. Kar, M. and Choudhury, P.K., Pharmazie, 62, 122, 2007.
92. Giovagnoli, S., Blasi, P., Schoubben, A., Rossi, C. and Ricci, M., Int. J.
Pharm., 333, 103, 2007.
93. Jaspart, S., Bertholet, P., Piel, G., Dogne, J.M., Delattre, L. and Evrard, B.,
Eur. J. Pharm. Biopharm., 65, 47, 2007.
39
94. Gal, A. and Nussinovitch. A., J. Pharm. Sci., 96, 168, 2007.
95. Amitava, G., Uday Kumar, N., Prasant, R., Tanusree, N. and Partha, R.,
Research J. Pharm. and Tech., 1(4), 353, 2008.
96. Rajinikanth, P. S., Karunagaran, L. N., Balasubramaniam, J. and Mishra, B.,
Chem. Pharm. Bull., 56(12), 1658, 2008.
97. Bhabani Shankar, N., Uday kumar, N., Balakrishna, K. P. and Prasant kumar,
R., Research J. Pharm. and Tech., 1(4), 433 , 2008.
98. Sah, H., Toddywala, R. and Chien, Y.W., J. Controlled Release, 35, 137,
1995.
99. Uchida, T., Shiosaki, K., Nukada, Y., Fukada, K. and Matsuyama, K. et al.,
Pharma. Res., 15,1708, 1998.
100. Haque, T., Chen, H., Ouyang, W., Martoni, C., Lawuyi, B., Urbanska, A.M.
and Prakash, S., Biotechnol. Lett., 27(5), 317, 2005.
101. Bittner, B., Morlock, M., Koll, H., Winter, G. and Kissel, T., Eur. J. Pharm.
Biopharm., 45, 295, 1998.
102. Pean, J.M., Venier-Julienne, M.C., Boury, F., Menei, P. and Benoit, J.P. et.
al., J. Controlled Release, 56, 175, 1998.
103. Cleland, J.L. and Jones A.J., Pharm. Res., 13, 1464, 1996.
104. Hermann, J. and Bodmeier, R., Int. J. Pharm., 126, 129, 1998.
105. Kovacs-Nolan, J. and Mine, Y., J. Immunol. Methods, 296(1-2), 199, 2005.
106. Thomas, T.T., Kohane, D.S., Wang, A. and Langer, R., J. Pharm. Sci., 93
(5), 1100, 2004.
107. Holland, T.A., Tabata, Y. and Mikos, A.G., J. Controlled Release, 91(3),
299, 2003.
40
108. Takada, S., Yamagata, Y., Misaki, M., Taira, K. and Kurokawa, T., J.
Controlled Release, 88(2), 229, 2003.
109. Singh, M., Singh, O. and Talwar, G.P., Pharm. Res., 12, 1796, 1995.
110. Azarnia, S., Lee, B.H., Robert, N. and Champagne, C.P., J. Microencapsul.,
25, 46, 2008.
111. Badkar, A.V., Smith, A.M., Eppstein, J.A.and Banga, A.K., Pharm. Res.,
24, 1389, 2007.
112. Ho, J., Wang, H. and Forde, G. M., Biotechnol. Bioengg., 101(1), 172, 2008.
113. Nkansah, M. K., Tzeng, S. Y., Holdt, D. T. and Lavik, E. B., Biotechnol.
Bioeng., 100(5), 1010 , 2008.
114. Saravanakumar, A., Sunita, M., Madulika, P., Pavani, S., Chandu, A. N.,
Umesh, M., Kamalakannan, K. and Sivakumar, T., Research J. Pharm. and
Tech., 1(4), 453, 2008.
115. Jiang, W. and Schwendeman, S. P., Mol. Pharm., 5(5), 808, 2008.
116. Dorle, A.K. and Pathak, Y.V., Drug Dev. Ind. Pharm., 14, 2557, 1998.
117. Dorle, A.K. et al., Indian J. Pharm. Sci., 54, 10, 1992.
118. Chowdary, K.P.R. and Vijaya Ratna, J., Indian J. Pharm. Sci., 52, 279,
1990.
119. Chowdary, K.P.R. and Vijaya Ratna, J., Indian Drugs, 28, 361, 1991.
120. Chowdary, K.P.R. and Vijaya Ratna, J., Indian Drugs, 29, 494, 1992.
121. Chowdary K.P.R. and Ramesh, K.V.R.N.S., Drug Dev. Ind. Pharm., 21,
1183, 1995.
122. El-Fahan, T.H. and Massoud, A.A., J. Controlled Release, 32, 279, 1994.
123. Gutierrez-Pauls, L., Gonzalez-Alvarez, I., Lareo, Barone, M., Gil-Alegre, M.
E. and Torres-Suarez, A.I., Pharmazie, 62, 864, 2007.
41
124. Vlugt-Wensink, K.D., de Vrueh, R., Gresnigt, M.G., Hoogerbrugge, C.M.,
van Buul-Offers, S.C., de Leede, L.G., Sterkman, L.G., Crommelin, D.J.,
Hennink, W.E. and Verrijk, R., Pharm. Res., 24, 2239, 2007.
125. Schuidt, U. and Hunkeler, D., J. Microencapsul., 24, 1, 2007.
126. Kar, M. and Choudhury, P.K., Pharmazie, 62, 122, 2007.
127. Berchane, N.S., Jebrail, F.F., Carson, K.H., Rice- Ficht, A.C. and Andrews,
M.J., J. Microencapsul., 23, 539, 2006.
128. McCarron, P.A., Donnelly, R.F. and Marouf, W., J. Microencapsul., 23,
480, 2006.
129. Singh, B.N.and Kim, K.H., J. Microencapsul., 22, 761, 2005.
130. Chowdary, K.P.R., Mohapatra, P. and Murali Krishna, M.N., Indian J.
Pharm. Sci., 68, 497, 2006.
131. Chowdary, K.P.R. and Mohapatra, P., International J. Chemical
Sciences.,4, 747, 2006.
132. Panos, I., Acosta, N. and Heras, A., Curr. Drug Discov. Technol., 5(4),
333, 2008.
133. Tamilvanan, S. and Sa, B., PDA J. Pharm. Sci. Technol., 62(3), 177,2008.
134. Singh, P., Desai, S. J., Simonelli, A. P. and Higuchi, W. I., J. Pharm. Sci.,
57 (2), 217, 1968.
135. Nakagami, H., Keshikawa, T., Matsumura, M. and Tsukamoto, H., Chem.
Pharm. Bull., 39 (7), 1837, 1991.
136. Donbrow, M. and Friedman, M., J. Pharm. Pharmac., 27, 633, 1975.
137. Efentakis, M., Al-Hmoud, H., Buckton, G. and Rajan, Z., Int. J. Pharm.,
70, 153, 1991.
42
138. Kalu, V.D., Oeniyi, M.A. and Jaiyeoba, K.T., Arch. Pharm. Res., 30(7), 884
- 889, 2007.
139. Siddique, S., Yaseenkhan, Md., Verma, C.J., Pal, T.K., and Khanam, J., The
Pharma Review., 144, feb – march 2008.
140. Higuchi, T., J. Pharm. Sci., 50, 874, 1961.
141. Desai, S. J., Singh, P., Simonelli, A. P. and Higuchi., W. I., J. Pharm. Sci.,
55, 1224, 1966.
142. Desai, S. J., Simonelli, A.P. and Higuchi, W. I., J. Pharm. Sci., 54, 1459,
1965.
143. Desai, S. J., Singh, P., Simonelli, A. P. and Higuchi, W. I., J. Pharm. Sci.,
55, 1230, 1966.
144. Desai, S. J., Singh, P., Simonelli, A. P. and Higuchi, W. I., J. Pharm. Sci.,
55, 1235, 1966.
145. Lapidus, H. and Lordi, N.G.., J. Pharm. Sci., 55, 840, 1966.