MICROENCAPSULATION; A NOVEL DRUG DELIVERY SYSTEM FOR

NSAIDs IN ARTHRITIS-A REVIEW

*.Manjanna K.M. 1Shivakumar.B.
*Department of Pharmaceutics, T.V.M.College of Pharmacy, Bellary Karnataka, Indi
a
1Department of Pharmaceutical Chemistry, S.C.S.College of Pharmacy, Harapanahall
i,
Karnataka, India.
Author for Corresponds- * K.M.Manjanna. Assistant professor.
T.V.M.College of pharmacy, Dept, of pharmaceutics.
Gandhinagar, Bellary-583103. Karnataka.
Email-kmhuruli@rediffmail.com
Phone-08392-257919. Fax-257945. mobile-09449409683.
1
ABSTACT
Arthritis refers to different medical conditions associated with disorder of the
primary
structures that determine joint functions such as bones, cartilage and synovial
membranes.
Drug discovery and delivery to retard the degeneration of joint tissues are chal
lenging.
Current treatment of different arthritis involves administration of ideal non-st
eroidal antiinflammatory
drugs (NSAIDs) mainly by oral and parenteral route. Most of them have short
biological half-lives, required for frequent dosing often leads to patient non c
ompliance.
Accounting this problem, drug delivery technologies should be developed which ar
e reduces
frequency of dosing along with sustained release of medicament. Among several no
vel drug
delivery systems microencapsulation is one of the novel plot form technology emp
loyed to
sustain the drug release and reduce or/ eliminate gastrointestinal irritation, d
ose intake and
ultimately improve the patient compliance in the pharmacotherapy of arthritis, T
his review
reports a comprehensive overview of newly developed microencapsulation technolog
ies as
therapeutic targets in arthritis which are may be potentially to reduce adverse
side effects
induced by NSAIDs.
Key-words- Microencapsulation, NSAIDs, Arthritis, Sustained release, Dose-relate
d adverse
effects, Inflammation and pain, micropaticulate.
2
INTRODUCTION; The major target of pharmaceutical sciences is to design a success
ful
and suitable dosage forms for effective therapy, considering individual patient
needs and
better compliance for the entire period of treatment. Development of new dosage
forms from
using the existing technology is growing in importance and attracting increased
interest, as
they are significantly effective at a comparably low dose
The human skeleton and muscle help to make possible the peaceful gyration as wel
l as more
safe routine movements of everyday life. Our body naturally produces Glucosamine
, which is
used to produce proteoglycans, the principal lubricating proteins in our cartila
ge, tendons,
ligaments, synovial fluid and mucous membranes. Imbalance in the regeneration pr
ocess of
these functional elements of the joint leads to friction, pain and inflammation,
due to cartilage
repair decreases/ceases, cartilage become thinner and bones grind against one an
other.
Arthritis and many other rheumatic diseases are mainly disorders of the supporti
ve or
connective tissues of the bones, tendons, heart valves and joints ranging from m
inor stiffness
to engrave disability and deformity.[1] Although many specific drugs for treatme
nt of major
inflammation and/or acute pain like steroidal anti-inflammatory agents or narcot
ic analgesics
are available but ideal NSAIDs should affect only controlled inflammation by mod
ifying
inflammatory response to diseases, but not to interfere with normal inflammatory
process.
NSAIDs effectively quell the pain and reduce the inflammation that can occur in
advanced
cases, but they do nothing to halt the disease process [2]. As awareness of the
GI side effects
associated with NSAIDs increases, safety becomes a primary requisite in treatmen
t.
Numerous articles examining the gastric and duodenal damage caused by NSAIDs hav
e been
published, however, only recently have the more distal intestinal disturbances i
nduced by
these drugs received close attention. There is often a poor correlation between
patient
reported symptoms of upper GI distress and endoscopically proven gastropathy. Th
is may
suggest afflictions of more distal parts of the intestine. The concept of select
ive and site-
3
specific damage to the upper GI tract following NSAIDs has been questioned, part
icularly by
the works of Bjarnason, who has demonstrated that patients on chronic NSAID ther
apy can
develop small and large intestinal inflammation which may lead to anaemia,
hypoalbuminemia, ucleration,‘diaphragm’ like strictures, perforation, and hemorr
hage.[3]
Medical researchers had developed a number of NSAIDs that blocked the body s pro
duction
of substances playing vital roles in pain and inflammation responses
A trend in NSAID development has been to improve therapeutic efficacy and reduce
the
severity of upper GI side effects through altering dosage forms of NSAIDs by mod
ifying
release of the formulations to optimize drug delivery. These formulations are de
signed to
increase patient compliance through a prolonged effect and reduce adverse effect
s through
lowered peak plasma concentrations [4]. The successful optimization and developm
ent of
drug entity, design of dosage form then plays important role. The design of effe
ctive drug
delivery systems has recently become an integral part of the development of new
medicines.
Hence, research continuously keeps on searching for ways to deliver drugs over a
n extended
period of time, with a well-controlled release profile. Microencapsulation is a
novel
technique to develop several novel drug delivery systems either sustained or con
trolled
manner through a various route of administration to avoid dose related adverse e
ffects
induced by repeated administration of NSAIDs. The micro particulate drug deliver
y of
NSAIDs was suggested to be the best alternatives for the safe and effective deli
very of these
drugs. The present article deals with different aspects of the microencapsulatio
n to improve
the pharmacotherapy arthritis.
4
WHAT IS ARTHRITIS?
Arthritis is a term that includes a group of disorders that affect your joints a
nd muscles.
Arthritis symptoms include joint pain, inflammation and limited movement of join
ts. When a
joint is inflamed it may be swollen, tender, warm to the touch or red. Surroundi
ng each joint
is a protective capsule holding a lubricating fluid to aid in motion. Cartilage,
a slippery
smooth substance, covers most joints to assure an even, fluid motion of the join
t. With joint
arthritis, the cartilage may be damaged, narrowed and lost by a degenerative pro
cess 0r by
inflammation making movement painful. For most people arthritis pain and inflamm
ation
cannot be avoided as the body ages. In fact, most people over the age of 50 show
some signs
of arthritis. Joints naturally degenerate over time. Fortunately, arthritis can
be managed
through a combination of medication, exercise, rest, weight-management, nutritio
n, and, in
some cases, surgery. Arthritis is not just 1 disease; it is a complex disorder t
hat comprises
more than 100 distinct conditions and can affect people at any stage of life. Tw
o of the most
common forms are osteoarthritis and rheumatoid arthritis. [5]
5
TYPES OF ARTHRITIS
Primary forms of arthritis:
Osteoarthritis.
Rheumatoid arthritis
Septic arthritis
Gout and pseudogout
Juvenile idiopathic arthritis
Ankylosing Spondylitis
Secondary to other diseases:
Lupus erythematous
Sarcoidous
Henoch-Schonlein pupura
Psoriatic arthritis
Reactive arthritis
Haemchromatosis
Hepatitis
Wegener s granulomatosis (and many other vasculitis syndromes)
Lyme disease
 Familial Mediterranean fever
Hyperimmunoglobulinemia D with recurrent fever.
TNF receptor associated periodic syndrome.
Inflammatory bowel disease (Including Crohn s Disease and Ulcerative Colitis)
6
OSTEOARTHRITIS
Osteoarthritis (OA, also known as degenerative arthritis, degenerative joint dis
ease), is a
group of diseases and mechanical abnormalities entailing degradation of joints i
.e. articular
cartilage and next to the subchondral bone. Clinical symptoms of OA may include
joint pain,
tenderness, and also stiffness, inflammation, creaking, and locking of joints. I
n OA, a variety
of potential forces; hereditary, developmental, metabolic, and mechanical may in
itiate
processes leading to loss of cartilage; a strong protein matrix that lubricates
and cushions the
joints. As the body struggles to contain ongoing damage, immune and regrowth pro
cesses can
accelerate damage. When bone surfaces become less well protected by cartilage, s
ubchondral
bone may be exposed and damaged, with regrowth leading to a proliferation of ivo
ry-like,
dense, reactive bone in central areas of cartilage loss, a process is called ebu
rnation. The
patient increasingly experiences pain upon weight bearing, including walking and
standing.
Due to decreased movement because of the pain, regional muscles may atrophy, and
ligaments may become more lax.[ 6, 7.]
7
RHEUMATOID ARTHRITIS;
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may
affect many
tissues and organs, but principally attacks the joints producing an inflammatory
synovitis that
often progresses to destruction of the articular cartilage and ankylosis of the
joints.
Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericar
dium, pleura,
and sclera, and also nodular lesions, most common in subcutaneous tissue under t
he skin.
Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivo
tal role in
its chronicity and progression. About 1% of the world s population is afflicted
by rheumatoid
arthritis, women three times more often than men. Onset is most frequent between
the ages of
40 and 50, but no age is immune. It can be a disabling and painful condition, wh
ich can lead
to substantial loss of functioning and mobility.[ 6, 7]
ANKYLOSING SPONDYLITIS
Ankylosing spondylitis (AS, from Greek ankylos, bent; spondylos, vertebrae), a f
orm of
Spondyloarthritis, is a chronic, inflammatory arthritis and autoimmune disease.
It mainly
affects joints in the spine and the sacroiliac in the pelvis, causing eventual f
usion of the spine.
8
For many with AS, but more so for women, in addition to the spine the disease ca
n affect
other joints throughout the body such as the shoulders, hips, knees, feet, as we
ll as other
joints. For some, peripheral joints are affected before there is ever any spine
pain or
inflammation, leading doctors and rheumatologists to sometimes misdiagnose someo
ne with
another rheumatic disease such as Rheumatoid Arthritis that does not affect the
spine.
Complete fusion results in a complete rigidity of the spine, a condition known a
s bamboo
spine. [8]
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs);
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of drugs commonly used
to treat
arthritis because of their analgesic anti-inflammatory, and antipyretic properti
es.
NSAIDs are among the most commonly prescribed categories of drugs worldwide in t
he
treatment of pain and inflammation in many conditions. Prostaglandins (PGs) are
an
important group of chemical mediators which are responsible for producing change
s,
symptoms and signs of inflammation. NSAIDs are heterogeneous group of compounds
that
are non- selectively by inhibiting both Cyclooxygenase enzymes (COX 1 and COX 2)
which
are responsible for the biosynthesis of the prostaglandins (PGs) and thramboxane
s from its
precursor arachidonic acid. COX 1 enzyme is constitutively present in cells. It
is a housekeeping
enzyme has a physiological function producing prostaglandins which help to keep
the stomach and blood vessels clean by making prostacyclin,whereas COX 2 is indu
cible
form and is generated at sites of inflammation. It is reported that NSAIDs provi
des pain relief
by reducing prostaglandin, bradykinins and oxygen radicals. Non selective COX in
hibitors
produces side effects on long term use and to overcome this problem, selective C
OX 2
inhibitors were developed. COX 2 inhibitors decreases COX 2 mRNA levels and modu
lates
local and systemic cytokine production in order to reduce inflammation and bone
erosion. [9]
9
CHEMISTRY OF NSAIDS;
The chemical features of NSAIDs explicitly explain different aspects of their be
havior
including kinetics mechanism of action and potential adverse effects. Members of
the NSAID
class are characterized by having several common chemical and biological feature
s. For a
drug to be an effective competitive inhibitor for arachidonic acid binding to CO
X, the drug
must possess both high lipophilic and acidic properties to mimic the natural sub
strate
chemistry. This is clearly apparent in the chemical structures of all NSAIDs suc
h as
Ibuprofen, flubiprofen, ketoprofen, naproxen, indomethacin, diclofenac, and piro
xicam. The
acidic functionality can be a propionic acid carboxylic group or an acetic acid
carboxylic
group or as an enolic group (acidic proton of 1,3 diketo group; NSAIDs with a po
lar group in
the lipophilic tail such as sulindac are not effective COX inhibitors before bei
ng metabolized
into a more lipophilic substance.In a similar manner, lipophilic drugs lacking t
he acidic
functionality, such as nabumetone are metabolized into products with acidic func
tional
groups before becoming active. For a given drug to act as an NSAID, the drug’s c
hemistry
must fulfill 2 major criteria: it must have lipophilic properties and the presen
ce of an acidic
functional group. Drugs having either weak lipophilic or weak acidic properties
are not
expected to be good anti-inflammatory agents. Acetaminophen shows weak propertie
s
regarding both lipophilicty and acidity; therefore, it is void of any anti-infla
mmatory actions.
On the other hand, acetylsalicylic acid has poor lipophilic properties but a str
ong acidic
functional group produces anti-inflammatory effects only at much higher doses (1
0 g) than its
analgesic dose of only 1g. Drugs with both strong lipophilic characteristics and
strong acidic
properties such as members of the acetic and propionic acid series show signific
ant antinflammatory
actions at much smaller doses (30 mg -100 mg).[10]
10
Pharmacokinetics of NSAID (ADME)
NSAIDs interfere with prostaglandin production by inhibiting cyclooxygenase the
mechanism may relate to the variation in response between patients. Scientific s
tudies have
shown a correlation between concentration of the drug and effect, but do not exp
lain the
differences in individual patient responses. After an oral or drug is taken, it
enters the general
circulation, is carried to its site of action, and is eliminated from the body.
These three major
processes — absorption, distribution, elimination (metabolism + excretion) make
up the
drugs pharmacokinetic profile. Pharmacokinetic properties affect how much drug e
nters the
circulation, how much is present in the blood and tissues at a given time, how q
uickly the
drug begins to act, what dosage is required, and how long the drug remains in th
e body. It is
thought that the pharmacokinetic differences among the various NSAIDs may accoun
t for the
variability in response. NSAIDs are divided into two groups: those with plasma (
blood) halflives
less than 6 hours (i.e. aspirin, diclofenac, ibuprofen) and those with half-live
s greater
than 10 hours (i.e. diflunisal, piroxicam, and sulindac). Since it takes three t
o five half-lives
to stabilize blood levels, NSAIDs with longer half-lives require a loading dose
to be given
(large dose given initially). A drug’s half-life, the time in which its blood co
ncentration is
reduced by half, is another key consideration in pharmacokinetics. A drug that i
s slowly
metabolized and slowly excreted has a relatively long half-life. This means it i
s present in the
blood for a much longer time, do not fluctuate drug-plasma concentration and its
effects can
be longer lasting.[11]
Absorption; In the first pharmacokinetic process, called absorption, a drug give
n orally
enters the general circulation. Some drugs are absorbed more rapidly and more ex
tensively
than others. These characteristics, known respectively as the rate and extent of
absorption,
11
influence how quickly a drug will act (known as its onset of action) and how muc
h drug will
be available (the concentration in the plasma at different times).Several factor
s may affect the
rate or extent of absorption of an drug; (i) The dosing form (eg, a drug given o
rally is
absorbed more slowly than one given intravenously). (ii) The presence of food in
the
stomach. (iii) The rate at which the stomach empties. (iv) The acidity of the st
omach and
intestine. (v)The drug’s first-pass metabolism in the liver (vi) The design of t
he drug’s
delivery system. Since all NSAIDs are highly lipophilic substances, members of t
he class
share similar, if not identical, absorption properties. Drug absorption after or
al administration
is generally rapid and complete. A key factor in absorption is first-pass metabo
lism. After
absorption, and before reaching the general circulation, a drug given orally is
transported to
the liver and is acted upon by liver enzymes. If drug metabolism is extensive, o
nly a small
portion of the drug ever reaches the general circulation. NSAIDs undergoes first
-pass
metabolism. Consequently has a less bioavailability: This means that a high prop
ortion of the
active ingredients are made available in the in the general circulation, capable
of exerting
therapeutic effects.[12]
Distribution:
The most significant aspect of NSAID distribution is plasma protein binding. The
chemical
nature of these agents suggests strong binding to plasma proteins. The major pla
sma protein
component is albumin, which has several basic and lipophilic residues. NSAIDs wi
th both
acidic functionality and lipophilic tails bind to albumin through both ionic and
hydrophobic
forces of interactions. NSAIDs are 95% albumin (protein) bound. The unbound frac
tion of
the NSAID is increased in patients with low albumin concentrations such as in ac
tive
rheumatoid arthritis and the elderly.
Plasma protein binding of NSAIDs may pose the potential for drug-drug interactio
n with
other drugs that bind with albumin at the same sites. Plasma protein displacemen
t is common
12
when NSAIDs are concurrently administered with other drugs such as the oral anti
coagulants,
the anticancer agent methotrexate, the oral antidiabetic agents, and thyroid hor
mones.
Displacement from albumin may increase the activity or toxicity of such drugs. T
he best
example for such a drug-drug interaction is the observed increase of the anticoa
gulant effects
by warfarin when concurrently administered with aspirin and aspirin-like drugs.[
12]
Metabolism:
Knowledge of the mechanism of action of NSAIDs, as competitive inhibitors for ar
achidonic
acid binding to COX, provides a good tool to predict whether NSAID metabolites a
re active
or not. Generally, phase-I metabolism of NSAIDs produces more polar products. Th
ese polar
metabolites are not efficient COX inhibitors because they lack the lipophilic pr
operties to
compete with arachidonic acid and prevent its binding to COX. Accordingly, it is
easy to
conclude that most of the NSAIDs are metabolized into inactive products, which i
s the case
in reality. When the original drug is polar, like sulindac (due to the ionic sul
foxide group,
phase-I metabolism results in the conversion of the sulfoxide group into the ver
y lipophilic
sulfide group by a reduction mechanism to produce the nonpolar sulfide form of t
he drug The
latter (reduced form of sulindac) is the actual inhibitor for the enzyme COX. Su
ppose the
original drug lacks the acidic functional group, such as in nabumetone phase-I m
etabolism
results in nabumetone conversion into the acetic acid derivative via an oxidativ
e degradation
process similar to that for fatty acids metabolism. Phase-I metabolism of NSAIDs
can be
affected if these drugs are co-administered with drugs that alter the metabolism
of other
drugs. Enzyme inhibitors such as cimetidine and valproic acid and enzyme inducer
s such as
carbamazepine and phenobarbital may enhance or decrease the anti-inflammatory ac
tivity of
NSAIDs depending on whether the drug is biologically activated or deactivated by
metabolism.[12]
13
Excretion:
NSAIDs are mostly excreted as phase-II glucouronides and in a few cases as sulfa
te
conjugates. In addition, small percentages of NSAIDs are excreted unchanged in u
rine. If the
drug is excreted unchanged, its rate of excretion is expected to increase if the
drug is coadministered
with agents that render the urine pH alkaline such as the antacids aluminum
hydroxide and milk of magnesia.[12]
MECHANISM OF NSAIDs;
The mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase
, which
catalyzes arachidonic acid to prostaglandins and leukotrienes. Arachidonic acid
is released
from membrane phospholipids as a response to inflammatory stimuli. Prostaglandin
s
establish the inflammatory response.
The Cyclooxygenase Pathway
NSAIDs work by interfering with the cyclooxygenase pathway. Different mechanisms
stimulate the two different types of cyclooxygenase. COX-1 is stimulated continu
ously by
normal body physiology. The COX-1 enzyme is constitutive, meaning that its conce
ntration
in the body remains stable. It is present in most tissues and converts arachidon
ic acid to
prostaglandins. These prostaglandins in turn stimulate body functions, such as s
tomach
mucous production and kidney water excretion, as well as platelet formation. The
location of
the COX-1 enzyme dictates the functions of the prostaglandins it releases. For e
xample,
COX-1 in the stomach wall produces prostaglandins that stimulate mucous producti
on. In
contrast, the COX-2 enzyme is induced. It is not normally present in cells but i
ts expression
can be increased dramatically by the action of macrophages, the scavenger cells
of the
immune system. COX-2 plays a very important role in inflammation. Cox-2 is invol
ved in
14
producing prostaglandins for an inflammatory response. COX-1 is stimulated conti
nually,
and COX-2 is stimulated only as a part of an immune response. [13]
Inflammatory Role of Prostaglandin
Prostaglandins are paracrine secretions (local hormones) - they are released fro
m cells and
bring about changes in neighboring cells that carry specific prostaglandin recep
tors in their
membranes. They are rapidly degraded locally, and generally do not reach the blo
od stream.
The influence, which prostaglandins have, depends upon the type of tissue they a
re acting
upon. Such action may be direct, or as a result of modifying the actions of othe
r signaling
molecules. Prostaglandins were released by damaged cells and nearby macrophages
and one
of their effects are to stimulate pain receptors (nociceptors). At the same time
they intensify
the effects of other chemical mediators such as histamine and bradykinin. Acting
in concert
these substances can bring about vasodilatation and an increase in the permeabil
ity of
capillaries supplying the damaged area, encouraging the migration of phagocytes
from the
blood through capillary walls into the damaged tissue. As a result of these chan
ges, the blood
supply to the area increases, the tissues swell, and pain occurs, signs of infla
mmation. [14]
Action of NSAIDs on Cyclooxygenase;
The two forms of cyclooxygenase have equal molecular weights and are very simila
r in
structure. However, the attachment site of COX-1 is smaller than the attachment
site of
COX2. Therefore, it accepts a narrower range of structures as substrates. The cy
clooxygenase
active site lies at the end of a long, narrow, hydrophobic tunnel or channel. Th
ree of the alpha
helices of the membrane-binding domain lie at the entrance to this tunnel. In va
rious ways,
they all act by filling and blocking the tunnel, preventing the migration of ara
chidonic acid to
the active site at the back of the tunnel. They do this by temporarily blocking
the attachment
15
site for arachidonic acid on the cyclooxygenase enzyme, thereby preventing it fr
om
converting arachidonic acid to prostaglandin. The exception is aspirin, which ir
reversibly
acetylates cyclooxygenase. It takes longer for the effects of aspirin to wear of
f because new
enzymes must be formed by the body to replace the altered enzymes. When COX-1 is
acetylated by aspirin, the site for arachidonic acid is blocked. However, when a
spirin
acetylates COX-2, the active site is still large enough to accept arachidonic ac
id. [15, 16]
Phospholipase A2 Lipocortin
Hydroxy fatty acids
Cyclo-oxygenese
Prostaglandin Isomerase Thromboxane Prostacyclin
Synthase synthase
Prostaglandins PGE2, PGD2 Thromboxane-A2 Prostacyclin (PGI2)
Platelet-IP Platelet comp
Aggregation Disaggregation
Vasoconstriction Vasodilatation
16
PHOSPHOLIPIDS
Stimulus Steroids
ARACHIDONIC ACID
ENDOPEROXIDES
NSAIDs
Aspirin
Ibuprofen
Flurbiprofen
Indomethacin
Piroxicam
Diclofenac
Phenylbutazone
Nefopam
Aceclofenac
Dexibuprofen
NSAIDs formulations
induces GI-disorders
Microencasulated,
enteric coated
preparetions avoids
dose related adverse
effects
Flow chart- Mechanism of NSAIDS
Classification of NSAIDs;
A) Non-selective COX-inhibitors :
1) Salicylates:-Aspirin, Difunisal
2) Pyrazolone derivatives:- Phynylbutazone, Oxyphenylbutozone
3) Indole derivatives:-Indomethacin, Etodolac, Sulindac,
4) Propionic acid derivatives:-Ibuprofen, Ketoprofen, Flurbiprofen, Dexibuprofen
.
Naproxen, Fenoprofen, Indoprofen, Benoxaprofen, Pirprofen
5) Anthranilic acid derivatives:- Mefenamic, Meclofenamic, Niflumic
6) Aryl-acetic acid derivatives:- Diclofenac, Aceclofenac, Fenclofenac.
7) Oxicam derivatives:-Piroxicam, Tenoxicam. Sudoxicam, Isoxicam, Meloxicam
8) Pyrrolo-pyrrole derivatives:-Ketorolac
B) Preferential COX-2 inhibitors: - Nimesulide, Meloxicam, Nabumetone.
C) Selective COX-2 inhibitors: - Celecoxib, Rofecoxib, Valdecoxib.
D) Analgesic-Antipyretics: - Paracetamol, Metamizol, Propiphenazone, Nefopam.
ADVERSE EFFECTS OF NSAIDS;
In generally, the different NSAIDs have a similar mechanism of action due to des
pite the
diversity of their chemical structures. Most of the conventional NSAIDs have sho
rt biological
half-lives and hence require for repeated administration 3 to 4 times a day. Thi
s leads patient
non-compliance and also fluctuation in blood level drug concentration as well as
oral and
parenteral routes. However, due to this reason and also numerous clinical report
s, postmarketing
surveillance studies have revealed that NSAIDs are associated with extensive sid
e
effects like gastric-irritation, dyspepsia, peptic ulceration, gastric bleeding,
esophagitis,
constipation, sodium and water retention, chronic renal failure, intestinal neph
ritis. CNS
17
effects etc, apart from these side effects GI-disorders are the main side effect
s caused by
repeated administration of NSAIDs especially those are involved in COX-1 inhibit
ors. [17]
Gastrointestinal alterations are associated to one degree or other with all NSAI
Ds. The
greatest consumption of NSAIDs corresponds to arthrosis-arthritis. Aspirin and s
alicylic acid
were one of the first series of damaging agents which rapidly partitioned into t
he mucosa and
caused barrier disruption, bleeding and ulcer disease.. This important that pros
taglandins have
the capacity to protect the gastrointestinal mucosa from a number of damaging ag
ents and
conditions (e.g. stress) by fortifying the barrier properties of the tissue. NSA
IDs primarily
induce gastrointestinal injury by inhibiting the COX-1 isoform of the gastrointe
stinal tract
and the biosynthesis of cytoprotective prostaglandins in the mucosa. A number of
in-vivo and
in-vitro studies have demonstrated that the gastrointestinal injurious potential
of a number of
NSAIDs can be dissociated in time, dose and route of administration from their a
bility to
inhibit COX-1. Lastly, the preclinical and clinical evidence that COX-1 selectiv
e inhibitors
are not injurious to the gastrointestinal tract and that both COX isoforms need
to be blocked
for mucosal damage to occur. [18]
Accumulation of the acid nonsteroidal anti-inflammatory analgesic compounds occu
rs
particularly in inflamed tissue, in the GI mucosa, in the renal cortex, in the b
lood and in bone
marrow owing to their acidic nature (pKa 3–5.5) and their high capacity for bind
ing proteins
(more than 90%). This property is considered to be a decisive factor not just fo
r their antiinflammatory
properties but also unwanted effects of these substances. In chronically
inflamed pulmonary tissue, NSAIDs lead to an increased production of leukotriene
s and in
this way to asthma-like reactions due to the inhibition of prostaglandin synthes
is. With nonacid,
neutral (paracetamol) or weakly basic (phenazone and derivatives) analgesics tha
t do
not accumulate in damaged tissue but reach relatively high concentrations in the
central
nervous system, such side effects are either not noticed or are only marginally
so. Consistent
18
with these findings are observations that paracetamol and phenazone are only wea
k inhibitors
of prostaglandin synthesis in the periphery. Whereas paracetamol interferes with
prostaglandin synthesis in the central nervous system [19]
NSAIDs, ibuprofen was seen to pose the least risk of gastrointestinal toxicity.
In contrast, the
relative risk (RR) of some NSAIDs compared with ibuprofen (RR=1) reached values
of up to
3.8 (piroxicam) and 4.2 (ketoprofen). The second least deleterious drug in this
study was
diclofenac. Indomethacin, naproxen, sulindac and acetylsalicylic acid (aspirin)
ranked
intermediate in this study. With other NSAIDs the relative risk was clearly lowe
r (naproxen
1.83, diclofenac 1.73, piroxicam 1.66 and ibuprofen 1.19) – the risk being maxim
um after 50
days15 The risk of important gastrointestinal damage depends on the dose and fre
quency of
administration. The great therapeutic value of these drugs has made it necessary
to develop
strategies for avoiding the gastrointestinal risks and allow continuing to assoc
iate
administration of gastric mucosa protectors and development of formulations by u
sing
different microencapsulation techniques both oral and per-oral route.
NEED NOVEL DRUG DELIVERY SYSTEMS (NDDS) FOR NSAIDs
Most of the conventional NSAIDs have a shorter half-life, which requires frequen
t dosing
and thus reduces the patient compliance and convenience. As awareness of the GI
side
effects associated with NSAIDs increases, safety becomes a primary requisite in
treatment.
For drugs with short half-lives and with a clear relationship between concentrat
ion and
response, it will be necessary to dose at regular, frequent intervals in order t
o maintain the
concentration within the therapeutic range. Higher doses at less frequent interv
als will result
in higher peak concentrations with the possibility of toxicity. For some drugs w
ith wide
margins of safety, this approach may be satisfactory. A trend in NSAIDs developm
ent has
been to improve therapeutic efficacy and reduce the severity of upper GI side ef
fects through
19
altering dosage forms of NSAIDs by modifying release of the formulations to opti
mize drug
delivery. These formulations are designed to increase patient compliance through
a prolonged
effect and reduce adverse effects through lowered peak plasma concentrations.
Oral drug delivery;
Oral drug delivery is the most desirable and preferred method of administering t
herapeutic
agents for their systemic effects. In addition, the oral medication is generally
considered as
the first avenue investigated in the discovery and development of new drug entit
ies and
pharmaceutical formulations, mainly because of patient acceptance, convenience,
and cost
effective manufacturing process. For many drug substances, conventional immediat
e release
formulations provide clinically effective therapy while maintaining the required
balance of
pharmacokinetic and pharmacodynamic profiles with acceptable level of safety to
the patient.
Since the therapy involves frequent administration of drug, chances of patient n
oncompliance
increase drastically [20]
Parenteral drug delivery;
Parenteral products are unique among dosage forms of drugs because they are inje
cted
through the skin or mucous membranes into internal body compartments. Inspite of
advantages of parenteral drug administration in RA, this route is seldomly used
due to higher
incidences of patient noncompliance and rapid clearance rate of drug which ultim
ately
compels frequent administration of drug. Moreover self medication is not possibl
e; it limits
use of this route.[21]
20
Figure 1. Drug levels in the blood with a) traditional drug dose systems and b)
controlled
drug delivery dose systems
When the new drug or existing drug is given, altering the formulation and admini
stered
through the different route, this process is called as the novel drug delivery s
ystems. NDDS
are very important consideration for all pharmaceutical and biotechnology compan
ies. At
present the drug delivery sector of global pharmaceutical market accounts for on
ly 10
percent. If the prediction of the industry experts proves right, the market for
new drug
delivery systems is likely to reach over US $54 billion by the year 2007
Over the past few decades, the rise of modern pharmaceutical technology and the
amazing
growth of the pharmaceutical industry have revolutionized the approach to drug d
iscovery
and development. The close association of people from various fields such as che
mistry,
biology, medicine and engineering in drug development research has led to the un
covering of
the cellular and molecular basis for the action of many drugs. The most common m
ode of
administration of drugs is in the form of pills or injections. These methods of
administration
21
meet the requirements of efficacy for several drugs. However, these methods are
inadequate
for many new drugs such as NSAIDs, which have short half-lives, poor permeabilit
y in
membranes and are severely toxic when delivered systemically in large doses. To
overcome
these difficulties, new modes of administration have been the focus of a great d
eal of research
over the past few decades. A controlled release drug delivery system should be a
ble to
achieve the following benefits:
(1) Maintenance of optimum therapeutic drug concentration in the blood with mini
mum
fluctuation; (2) Predictable and reproducible release rates for extended duratio
n ;(3)
Enhancement of activity duration for short half-life drugs; (4) Elimination of s
ide effects,
frequent dosing and wastage of drug; and (5) Optimized therapy and better patien
t
compliance.[22] .
Local and systemic adverse effects due to high concentrations of drug can be min
imized by
the use of controlled release delivery systems Local effects in the gastrointest
inal (GI) tract
from the release of irritant drug molecules can also be reduced, but the gastric
damage caused
by NSAIDs is only partially relieved by formulation approaches because of the in
volvement
of systemic factors in the aetiology of GI adverse events. The advantages for ea
ch drug class
must be examined. Newer dosage forms include: (i) osmotic pumps and zero order k
inetics
systems to control the release rate of the drug; (ii) bioadhesive systems and ga
stric retention
devices to control GI transit; (iii) bioerodible hydrogels; (iv) molecular carri
er systems (e.g.
cyclodextrin-encapsulated drugs) to modulate local toxicity in the GI tract; (v)
externally
activated systems; and (vi) colloidal systems such as liposomes and microspheres
. There is
evidence for improved tolerability for a variety of drugs administered in novel
delivery
systems. However, the evidence for improved tolerability is complicated by the p
otential bias
in adverse reaction reporting systems, and a lack of studies directly comparing
conventional
22
and modified release preparations. The technology now available to produce deliv
ery systems
which not only release drugs in a controlled and predetermined fashion, but whic
h can also
target to regions of the GI tract such as the colon, should allow greater contro
l of therapy and
potentially might minimize patient variables. However, the problem of variable G
I transit
times still eludes solution. Systems which rely on time to release drug might be
more
vulnerable to patient-to-patient variability than those which respond to local e
nvironments.
The effect of food intake is more apparent on single-unit, non-disintegrating do
sage forms,
although of course none so far are immune from influence. The risk of new advers
e effects
resulting from such positional therapy with novel delivery devices must be consi
dered.
Understanding the mechanisms of induction of individual adverse effects can lead
to
advances in modes of delivery to decrease the potential for adverse reactions an
d events
while maintaining therapeutic efficacy. Increased compliance can led to increase
d therapeutic
control and hence safety. Each system has to be considered on its merits. No gen
eralizations
can be made, although invariably the modulation of high peak plasma concentratio
ns
diminishes adverse effects due to rapid absorption. [23]
MICROENCAPSULATION TECHNIQUES IN NSAIDs;
Microencapsulation is a process whereby small discrete solid particles or small
liquid
droplets are surrounded and enclosed, by an intact shell. The concept of microen
capsulation
was initially utilized in carbonless copy paper. More recently it has received i
ncreasing much
attention in pharmaceutical and biomedical applications. The first research lead
ing in the
development of microencapsulation procedures for pharmaceuticals was published b
y
Bungenburg de Jong and Kass in 1931 and dealt with the preparation of gelatin sp
heres by
the use of gelatin coacervation process for coating. Drug companies have been qu
ick to
realize and exploit the enormous potential of the technology for overcoming form
ulation and
23
delivery problems in different dosage forms like tablets, capsules, topical, and
injectables.
Now a day, the pharmaceutical industries and researchers are involved and taking
most
challenging to develop newer drug delivery systems by using several coating mate
rials for the
microencapsulation of medicines. Thus microencapsulation provides the means of c
onverting
liquids to solids, of altering colloidal and surface properties, of enrolling en
vironmental
protection and of controlling the release characteristics depending on physicoch
emical
properties of coating materials. Several of these properties can be attained by
micropackaging
techniques or microparticulate techniques. [24]
Figure; 2. Several of microcapsule formulations
First, some of the more basic information on the methods of preparing microparti
culate
formulations must be discussed, with an emphasis on biodegradable microparticles
. The
terminology used to describe microparticulate formulations can sometimes be inco
nsistent
and confusing to readers unfamiliar with the field. Essentially, the term “micro
particle” refers
to a particle with a diameter of 1–1000μm, irrespective of the precise interior
or exterior
structure. Within the broad category of microparticles, “microspheres” or microb
eads
specifically refer to spherical microparticles and the subcategory of “microcaps
ules” applies
to microparticles which have a core surrounded by a material which is distinctly
different
from that of the core. The core may be solid, liquid, or even gas. Despite the s
pecific and
24
logical subcategories, many researchers use the terms interchangeably, often to
the confusion
of the reader. It is usually assumed that a formulation described as a micropart
icle is
comprised of a fairly homogeneous mixture of polymer and active agent, whereas
microcapsules have at least one discrete domain of active agent and sometimes mo
re.
Microcapsules can be divided into two broad groups. The first is Aggregate type
microcapsules, which have the active ingredient dispersed uniformly throughout a
continuous
matrix. The matrix may be a solid dry polymer or a gel swollen with solvent. In
the case
where the gel is swollen with water, the term “hydrogel” is applied. Hydrogel en
capsulation
systems of this type are generally based on water-soluble polymers, such as algi
nate, gelatin,
pectin, agar, gellan, or starch. The second is mononuclear microcapsules, which
consist of
materials that show true “shell-core” morphology. These are similar to an egg in
that they
have a solid outer shell or flexible membrane surrounding a core that may be a l
iquid, a solid,
or a gel. Some variations on microparticle structures are given in Fig. 1. As th
e domains and
sub domains of active agent within microcapsules become progressively smaller, t
he
microcapsules become microparticles. [25]
Microparticles are generally formulated by encapsulation process whereby an acti
ve
ingredient is placed into a stabilized form in order to allow it to be convenien
tly stored or
protected from unfavorable conditions until needed. The active ingredient may be
dispersed
in a protective matrix, or it may be surrounded by a coating, a shell, or a memb
rane. The
release of active ingredient(s) from the protected form may be rapid (such as by
crushing or
by ingestion), or gradual (such as by dissolution, diffusion, chemically trigger
ed or controlled
time-release, or biodegradation). In this manner, it is possible to maximize the
effectiveness
of the active ingredient by ensuring it is released at the proper time. This “co
ntrolled release”
can also be made to occur over a programmed time interval (sustained release) or
on demand
(stimulated release) combination of any biodegradable polymers.[26]
25
Research to find new or to improve microencapsulation techniques to process newl
y
discovered active molecules is in constant progress because of the limitations o
f the current
pharmacopeia. Besides this, the regulatory authorities, such as the U.S. Food an
d Drug
Administration (FDA), are restricting to greater degrees the amounts of addition
al
components allowed such as organic solvents or tensioactive molecules. For these
reasons, in
designing of new techniques one must take into account several new requirements:
The
stability and the biological activity of the drug should not be affected during
the
microencapsulation process, yield and drug encapsulation efficiency should be hi
gh,
microsphere quality and the drug release profile should be reproducible within s
pecified
limits, microspheres should not exhibit aggregation or adherence, the process sh
ould be
usable at an industrial scale, and the residual level of organic solvent should
be lower than the
limit value imposed by the European Pharmacopeia. [27]
REASONS FOR MICROENCAPSULATION;
Microencapsulation of materials is resorted to ensure that the encapsulated mate
rial reaches
the area of action without getting adversely affected by the environment through
which it
passes. Amongst the principal reasons for encapsulation are:
Separation of incompatible components
Conversion of liquids to free flowing solids
Increased stability (protection of the encapsulated materials against oxidatio
n or
deactivation due to reaction in the environment)
Masking of odor, taste and activity of encapsulated materials
Controlled release of active compounds (sustained or delayed release)
Targeted release of encapsulated materials
The ability to incorporate reasonably high concentrations of the drug.
Controlled particle size and dispersability in aqueous vehicles for injection.
.
26
Reduce GI-disorders of acidic drugs (NSAIDs)
Susceptibility to chemical modification.
Improve the bioavailability of water in-soluble drugs and patient compliance.
TECHNIQUES OF MICROENCAPSULATION;
Although a variety of techniques have been reported for microencapsulation, they
can
broadly be divided into two main categories. The first category includes those m
ethods in
which starting materials are monomers/prepolymers. In these methods chemical rea
ctions are
also involved along with microsphere formation. The second category consists of
those
methods in which starting materials are polymers. Hence, in these methods no che
mical
reactions are involved and only shape fabrication takes place. Generally the cho
ice of the
microencapsulation method depends on the physicochemical characteristics of the
drug and
polymeric/monomeric material used. Thus appropriate combination of starting mate
rials and
synthesis methods can be chosen to produce microencapsulated products with a wid
e variety
of compositional and morphological characteristics. The methods used for the pre
paration of
other active agents are adopted for the preparation of microspheres containing N
SAIDs. The
selection of method depends on the particle size required, route of administrati
on, duration of
drug release, etc. All these characteristics will ultimately relate to the other
variables like
rpm, method of crosslinking, duration of crosslinking, evaporation time, co-prec
ipitation etc.
The microspheres are separated from the reaction mixture by filtration, centrifu
gation or
freeze-drying. Recovery of the prepared microspheres depends up on the size of t
he particles
and the particle characteristics such as composition and swellability. Relativel
y large and
rigid particles are separated by filtration or decantation. Ultracentrifugation
is used for
separating smaller particles. This step is followed by washing the microspheres
in order to
remove the residual solvents, surfactant and other additives. The washed microsp
heres are
then air dried, vacuum dried, freeze dried, or reconstituted with an appropriate
medium for
27
subsequent use. Processes of preparing microspheres that enable control of well-
defined
particle characteristics such as size, size distribution, and functionality are
becoming
increasingly important for a variety of applications. However, either the partic
le size range
that is achievable, or the types of materials that can be utilized in the proces
s limit some of
the current methods of microsphere preparation. Micron size of particles is typi
cally prepared
via dispersion or suspension polymerization techniques. For suspension polymeriz
ation,
control of particle size distribution can be difficult because of the mechanical
factors that
control the particle size.[28]
Drug loading;
The active components are loaded over the microspheres principally using two met
hods, i.e.
during the preparation of the microspheres or after the formation of the microsp
heres by
incubating them with the drug. The active component can be loaded by means of th
e
physical entrapment, chemical linkage and surface adsorption. The entrapment lar
gely
depends on the method of preparation and nature of the drug or polymer (monomer
if used).
Maximum loading can be achieved by incorporating the drug during the time of pre
paration
but it may get affected by many other process variables such as method of prepar
ation,
presence of additives (e.g.cross linking agent, surfactant stabilizers, etc.) he
at of
polymerization, agitation intensity, etc.
Drug release kinetics;
Release of the active constituent is an important consideration in case of micro
spheres. The
release profile from the microspheres depends on the nature of the polymer used
in the
preparation as well as on the nature of the active drug. The release of drug fro
m both
biodegradable as well as non-biodegradable microspheres is influenced by structu
re or micromorphology
of the carrier and the properties of the polymer itself. The drugs could be
28
released through the microspheres by any of the three ways; Diffusion:- On conta
ct with
aqueous fluids in the gastrointestinal tract (GIT), water diffuses into the inte
rior of the
particle. Drug dissolution occurs and the drug solutions diffuse across the rele
ase coat to the
exterior. Erosion:-Some coatings can be designed to erode gradually with time, t
hereby
releasing the drug contained within the particle. The polymer erosion, i.e. loss
of polymer is
accompanied by accumulation of the monomer in the release medium. The erosion of
the
polymer begins with the changes in the microstructure of the carrier as water pe
netrates
within it leading to the plasticization of the matrix. Osmosis:- In allowing wat
er to enter
under the right circumstances, an osmotic pressure can be built up within the in
terior of the
particle. The drug is forced out of the particle into the exterior through the c
oating water
diffuse into the core through biodegradable or non-biodegradable coating, creati
ng sufficient
pressure that ruptures the membrane. The burst effect is mainly controlled by th
ree factors the
macromolecule/polymer ratio, particle size of the dispersed macromolecule and th
e particle
size of the microspheres. Drug release from the non-biodegradable type of polyme
rs can be
understood by considering the geometry of the carrier. The geometry of the carri
er, i.e.
whether it is reservoir type where the drug is present as core, or matrix type i
n which drug is
dispersed throughout the carrier, governs overall release profile of the drug or
governs overall
release profile of the drug or active ingredients.[28]
Polymerization techniques:
The polymerization techniques conventionally used for the preparation of the mic
rospheres
are mainly as; Normal polymerization, Interfacial polymerization. Both are carri
ed out in
liquid phase. They are carried out by using different techniques as bulk, suspen
sion,
precipitation, emulsion and micellar polymerization processes. In bulk, a monome
r or a
mixture of monomers along with the initiator or catalyst is usually heated to in
itiate
polymerization. Polymer so obtained may be moulded as microspheres. Drug loading
 may be
29
done during the process of polymerization. Suspension polymerization also referr
ed as bead
or pearl polymerization. Here it is carried out by heating the monomer or mixtur
e of
monomers as droplets dispersion in a continuous aqueous phase. The droplets may
also
contain an initiator and other additives.[29]
Alberto Gallardo et, al Prepared chemically controlled drug delivery systems or
‘polymeric
drugs’ based on copolymers of 2-hydroxyethyl methacrylate, HEMA, and five methac
rylic
derivatives which incorporate ibuprofen or ketoprofen in their chemical structur
e by means of
labile ester bonds, MAI, MAK, MAEK, MEI and MEK, have been prepared by free radi
cal
polymerization in solution at 50°C. The in vitro release experiments were carrie
d out at pH
7.4 and 9, using six different compositions for each copolymer system .The resul
ts show a
ketoprofen release rate is higher than the ibuprofen one, composition of the cop
olymer
because the release rate increases with the content of the attached drug until s
ome
composition where this effect is reverted because of the global increase in hydr
ophobicity
and pH, the release rate is noticeably higher in a strong basic medium, pH 9. [3
0]
Emulsion polymerization
According to this technique the monomer (alkyl acrylates) is added dropwise to t
he stirred
aqueous polymerization medium containing the material to be encapsulated (core m
aterial)
and a suitable emulsifier. The polymerisation begins and initially produced poly
mer
molecules precipitate in the aqueous medium to form primary nuclei. As the polym
erization
proceeds, these nuclei grow gradually and simultaneously entrap the core materia
l to form the
final microcapsules. Generally lipophilic materials (insoluble or scarcely solub
le in water) are
more suitable for encapsulation by this technique. Emulsion polymerization diffe
rs from
suspension polymerization as due to the presence initiator in the aqueous phase,
which later
on diffuses to the surface of micelles.[31]
30
Tuncay M. et, al Formulated and Invitro-Invivo evaluation of diclofenac sodium l
oaded
albumin microsphesrs for intraarticular administration to extend the duration pe
riod of the
dosage form in the knee joint. Microsphere formulations of DS which were prepare
d were
evaluated in vitro drug release. Two appropriate formulations were selected for
in vivo trials.
For the in vivo studies, Technetium-99m labelled polyclonal human immunogammaglo
bulin
(99mTc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions
by gamma
scintigraphy. After the induction of arthritis in knee joints of rabbits, the ra
dio-labelled
microspheres loaded with DS were injected directly into the articular cavity and
at specific
time points gamma scintigrams were obtained to find the residence time of the mi
crospheres
in knee joints in order to determine the most suitable formulation.[32]
Interfacial polymerization:
As the term "interfacial" implies, this technique involves the polycondensation
(condensation
polymerization) of two complementary monomers at the interface of a two phase sy
stem. For
the preparation of microcapsules, this two-phase system is mixed under carefully
-controlled
conditions to form small droplets of one phase (dispersed phase) in the other on
e (continuous
phase/suspension medium). The material to be encapsulated must be chosen in such
a way as
to be present (dissolved or dispersed) in the droplets. It is also necessary to
use a small
amount of a suitable stabilizer to prevent droplet coalescence or particle coagu
lation during
the polycondensation process and capsule formation. Interfacial polycondensation
can be
utilized to produce both monocore type or matrix type microcapsules, depending o
n the
solubility of the polycondensate in the droplet phase. Thus if the polymer is so
luble in the
droplets, matrix type microcapsules are formed. On the other hand, if the polyme
r is not
soluble, it precipitates around the droplets and leads to the formation of monoc
ore type
microcapsules. Preparation of microcapsules by interfacial polycondensation is a
pplicable to
31
a large number of polymers including polyamides, polyureas, Polyurethanes, and p
olyesters.
[33, 34]
Swati sashmal. et al was to design and evaluate NSAID loaded Nanoparticles drug
delivery
system, where Flurbiprofen (model drug) Nanoparticles with suitable size range a
re
envisaged to concentrate at inflammation sites due to increase fragility of bloo
d vessels at
those sites and increased aggregation and prostaglandin synthesis. The flurbipro
fen loaded
nanoparticles were prepared by solvent diffusion nano-precipitation method. The
in-vitro
drug release profile from nanoparticles was found to follow Higuchi square root
kinetics
implying a diffusion dependent release as is expected of an insoluble, non-swell
able nature of
PLGA. It indicated that nanoparticles formed were matrix in nature, in which flu
rbiprofen
dispersed uniformly.[35]
Spray drying and spray congealing:
These methods are based on the drying of the mist of the polymer and drug in the
air.
Depending upon the removal of the solvent or cooling of the solution, the two pr
ocesses are
named spray drying and spray congealing respectively. The polymer is first disso
lved in a
suitable volatile organic solvent such as dichloromethane, acetone, etc. The dru
g in the solid
form is then dispersed in the polymer solution under high-speed homogenization.
This
dispersion is then atomized in a stream of hot air. The atomization leads to the
formation of
the small droplets or the fine mist from which the solvent evaporates instantane
ously leading
the formation of the microspheres in a size range 1-100 μm. Microparticles are s
eparated
from the hot air by means of the cyclone separator while the traces of solvent a
re removed by
vacuum drying. The water soluble natural polymers, such as starch, gum arabic, c
hitosan,
gellan and sodium alginate are commonly used as the wall-forming materials one o
f the
major advantages of the process is feasibility of operation under aseptic condit
ions.[36, 37]
32
Moretti M.D.L. et, al Microspheres were prepared by a spray-drying technique usi
ng
solutions of ketoprofen and two polymers, cellulose acetate butyrate (CAB) and
hydroypropylmethylcellulose phthalate (HPMCP), in different weight ratios. Diffe
rent total
concentrations were used in the feed solutions: 3, 6 and 9% w/v. The spray-dried
microparticles were formulated into capsules; tablets were prepared by direct co
mpression of
the microparticles mixed with maltose and, in some cases, hydroypropylmethylcell
ulose
(HPMC). In vitro release studies were performed both at acidic and neutral pHs a
nd shows
rapid or prolonged drug release.[38]
Single emulsion technique:
The micro particulate carriers of natural polymers of natural polymers i.e. thos
e of proteins
and carbohydrates are prepared by single emulsion technique. The natural polymer
s are
dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous m
edium
like oil. Next cross linking of the dispersed globule is carried out. The cross
linking can be
achieved either by means of heat or by using the chemical cross linkers. The che
mical cross
linking agents used are glutaraldehyde, formaldehyde, di acid chloride etc. Heat
denaturation
is not suitable for thermolabile substances. Chemical cross linking suffers the
disadvantage of
excessive exposure of active ingredient to chemicals if added at the time of pre
paration and
then subjected to centrifugation, washing, separation.[39]
Bayomi, M.A. was investigated emulsion crosslinking technique using mineral oil
or
vegetable oil as oil phase and drug polymer solution as aqueous phase is simple
and widely
used method for the preparation of NSAIDs. Crosslinking can be achieved by chemi
cal agent
or heat. Viscosity of the oil phase, concentration of the crosslinking agent, du
ration of
crosslinking, etc are the different parameters, which affect the release rate an
d entrapment
efficiency.[40]
33
Double emulsion technique:
Double emulsion method of microspheres preparation involves the formation of the
multipleemulsions
or the double emulsion of type w/o/w and is best suited to water soluble drugs,
peptides, proteins and the vaccines. This method can be used with both the natur
al as well as
synthetic polymers. The aqueous protein solution is dispersed in a lipophilic or
ganic
continuous phase. This protein solution may contain the active constituents. The
continuous
phase is generally consisted of the polymer solution that eventually encapsulate
s of the
protein contained in dispersed aqueous phase. The primary emulsion is subjected
then to the
homogenization or the sonication before addition to the aqueous solution of the
poly vinyl
alcohol (PVA). This results in the formation of a double emulsion. The emulsion
is then
subjected to solvent removal either by solvent evaporation or by solvent extract
ion.[41]
Aggarwal, A et, al A new oral controlled-release drug delivery system for indome
thacin was
developed with two polymers using a multiple-emulsification technique. Powdered
drug was
dispersed in methylcellulose solution, which was emulsified in ethyl cellulose s
olution in
ethyl acetate. The primary emulsion thus formed was re-emulsified in aqueous med
ium.
During this phase, discrete microspheres were formed under optimized conditions.
The in
vitro drug release followed first-order diffusion-controlled dissolution. More t
han 85% of the
drug was released over 6 hour at pH 6.2 for all dissolution batches.[42]
Emulsion cross-linking technique;
Emulsion-crosslinking is the method of choice for the preparation of protein and
polysaccharide micro-capsules Microcapsule formation by this technique involves
dispersion
of an aqueous solution of the polymer containing core material in an immiscible
organic
solvent (suspension/dispersion medium) in the form of small droplets. The suspen
sion
medium contains a suitable stabilizer to maintain the individuality of the
34
droplet/microcapsules. The droplets are subsequently hardened by covalent crossl
inking and
are directly converted to the corresponding microcapsules. The crosslinking proc
ess is
accomplished either thermally (at >500 C) or by the use of a crosslinking agent
formaldehyde, terephthaloyl chloride, etc). Emulsion- crosslinking is a versatil
e method and
can be adopted for microencapsulation of soluble, insoluble, liquid or solid mat
erials, and for
the production of both micro and nanocapsules.[43]
Kumbar SG et al. was investigated encapsulation of diclofenac sodium into crossl
inked
chitosan microspheres. Chitosan microspheres were produced in a w/o emulsion fol
lowed by
crosslinking in the water phase by one of the crosslinking methods. The in-vitro
release
studies were performed in 7.4 pH buffer solution.. The fastest release of 81% at
500 min was
shown when heat crosslinked for 3 h. Drug release from the matrices deviated sli
ghtly from
the Fickian process. [44]
Solvent Evaporation/Solvent Extraction
Microcapsule formation by solvent evaporation/solvent extraction 53-60 is very s
imilar to
suspension crosslinking, but in this case the polymer is usually hydrophobic pol
yester. The
polymer is dissolved in a water immiscible volatile organic solvent like dichlor
omethane or
chloroform, into which the core material is also dissolved or dispersed. The res
ulting solution
is added dropwise to a stirring aqueous solution having a suitable stabilizer li
ke poly (vinyl
alcohol) or polyvinylpyrrolidone, etc. to form small polymer droplets containing
encapsulated
material. With time, the droplets are hardened to produce the corresponding poly
mer
microcapsules. This hardening process is accomplished by the removal of the solv
ent from
the polymer droplets either by solvent evaporation (by heat or reduced pressure)
, or by
solvent extraction (with a third liquid which is a precipitant for the polymer a
nd miscible with
35
both water and solvent). Solvent extraction produces microcapsules with higher p
orosities
than those obtained by solvent evaporation. Solvent evaporation/extraction proce
sses is
suitable for the preparation of drug loaded microcapsules based on the biodegrad
able
polyesters such as polylactide, poly (lactideco- glycolide) and polyhydroxybutyr
ate.[45]
Giovanni F. Palmieri et al were prepared ketoprofen controlled release microsphe
res, by
emulsion/solvent evaporation, at 15 °C, in order to avoid the formation of semis
olid
particles.. Microspheres and microcapsules were characterized by In-vitro dissol
ution studies,
and then used for the preparation of tablets. Finally, in vitro dissolution stud
ies were
performed and the release control of the tablets was pointed out. Microspheres w
ere able to
control ketoprofen release only after their transformation into tablets. Tablets
containing
eudragit RS were the most effective in slowing down drug release. (46)
Coacervation/Phase separation
Coacervation (or phase separation) is widely employed for the preparation of gel
atin and
gelatin-acacia microcapsules, as well as for a large number of products based on
cellulose
derivatives and synthetic polymers. Phase separation processes are divided into
simple and
complex coacervation. Simple coacervation involves the use of a single polymer s
uch as
gelatin or ethyl cellulose, in aqueous or organic media, respectively. Complex c
oacervation
involves two oppositely charged polymeric materials such as gelatin and acacia,
both of
which are soluble in aqueous media. In both the cases, coacervation is brought a
bout by
gradual desolvation of the fully solvated polymer molecules. Microencapsulation
by
coacervation is carried out by preparing an aqueous polymer solution (1-10 %) at
40-50 °C
into which the core material (hydrophobic) is also dispersed. A suitable stabili
zer may also be
added to the mixture to maintain the individuality of the final microcapsules. A
suitable
desolvating agent (coacervating agent) is gradually introduced to the mixture, w
hich leads to
the formation of partially desolvated polymer molecules, and hence their precipi
tation on the
36
surface of the core particles. The coacervation mixture is cooled to about 5-20
°C, followed
by the addition of a crosslinking agent to harden the microcapsule wall formed a
round the
core particles. [47, 48,]
Vanessa L. et al chitosan microspheres were prepared by the simple coacervation
method and
crosslinked using epichlorhydrin or glutaraldehyde for the controlled release of
diclofenac
sodium. Release kinetics of diclofenac sodium from these matrices was investigat
ed at pH
1.2, 6.8 and 9.0, simulating the gastrointestinal tract conditions. The results
indicated that the
release mechanism deviated slightly from Fickian transport. [49]
Fluidized bed coating;
Fluidized bed coating is used for encapsulation of solid core materials includin
g liquids
absorbed into porous solids. This technique is used extensively to encapsulate
pharmaceuticals. Solid particles to be encapsulated are suspended in a jet of ai
r and then
covered by a 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 s
uspending,
spraying and cooling is repeated until the capsule walls are of the desired thic
kness.[50]
Silva , O. S.et al studied the dissolution process of sodium diclofenac granules
coated with a
polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acidmet
hylmetacrylate
copolymer, also known as Eudragit, has been used as a pH sensitive
coating material to protect drug substances prior to delivery to the human intes
tines. The
granules coating operation was carried out in a fluidized bed with top spraying
by a doublefluid
nozzle. The released amount of sodium diclofenac was periodically determined by
UV
spectrophotometry at wavelength of 276 nm, using a spectrophotometer. The coated
product
showed gastric resistance properties confirming the feasibility of the fluidized
bed for
applying enteric coating in granules and pharmaceutical powders. [51]
37
Melt solidification;
Biodegradable microcapsules are also produced by the solidification of molten po
lymer
droplets or by polymer precipitation. A dispersion of the drug in molten polymer
is stirred in
silicone oil to produce small droplets of the polymer drug mixture. The suspensi
on mixture is
then cooled, and the resulting solidified microcapsules are separated from the o
il.49
Anant Paradkar et al has been developed melt solidification technique to obtain
sustainedrelease
waxy beads of flurbiprofen. The process involved emulsification and solidificati
on of
flurbiprofen-cetyl alcohol melt at significantly low temperature (5°C). The effe
ct of variables,
namely, the amount of cetyl alcohol and the speed of agitation, was studied usin
g 32 factorial
designs. Drug released from the beads followed zero order kinetics. Burst releas
e was shown
to a greater extent in beads containing a lower amount of cetyl alcohol. [52]
Polymer precipitation;
In the polymer precipitation process, an aqueous solution of the polymer contain
ing the drug
is dropped into a stirred solution, which acts as the precipitating medium. Here
, the polymer
droplets precipitate immediately and are thus converted into the drug loaded mic
rocapsules.
[53]
Centrifugal extrusion process;
Liquids are encapsulated using a rotating head containing concentric nozzles. In
this process,
a jet of core liquid is surrounded by a sheath of wall solution or melt. As the
jet moves
through the air it breaks, owing to, into droplets of core, each coated with the
wall solution.
While the droplets are in flight, a molten wall may be hardened or a solvent may
be

evaporated from the wall solution. Since most of the droplets are within 10% o
f the mean
diameter, they land in a narrow ring around the spray nozzle. Hence, if needed,
the capsules
38
can be hardened after formation by catching them in a ring-shaped hardening bath
.This
process is excellent for forming particles in diameter. Since the drops are form
ed by the
breakup of a liquid jet, the process is only suitable for liquid. A high product
ion rate can be
achieved of microcapsules can be produced per nozzle per hour per head.[54]
Jaleh Varshosaz et, al was to develop piroxicam enteric coated pellets using non
pareil seeds
by powder layering technique to minimize its gastrointestinal adverse effects. I
nert seeds
were prepared by incorporating sugar, Avicel PH 101 and lactose. The obtained co
res were
then treated by PVP 10 w/v % solution using centrifugal granulator (CF-granulato
r) and then
coated with micronized piroxicam using HPMC solution as binder. The piroxicam pe
llets
were finally coated with different polymers (Eudragit L30D-55, Eudragit L100, Eu
dragit
NE30D, Acryleze, or mixture of Eudragits L30D-55 and NE30D) and plasticizers (tr
iethyl
citrate and polyethylene glycol 6000). Results showed that Eudragit L30D-55 with
3%
weight gain accompanied with TEC produced suitable enteric coated pellets [55, 5
6]
Vibrational Nozzle process;
Core-Shell encapsulation or Microgranulation (matrix-encapsulation) can be done
using a
laminar flow through a nozzle and an additional vibration of the nozzle or the l
iquid. The
liquid can consists of any liquids with limited viscosities (0-10,000 mPa·s have
been shown
to work), e.g. solutions, emulsions, suspensions, melts etc. The soldification c
an be done
according to the used gelation system with an internal gelation (e.g. sol-gel pr
ocessing, melt)
or an external (additional binder system, e.g. in a slurry). The process works v
ery well for
generating droplets between applications for smaller and larger droplets depends
on the size
of orifice and vibration speed of the nozzle. [57]
Layer-by-layer adsorption Process;
39
One important method of microencapsulation is layer-by-layer deposition. In this
process
polyelectrolyte multilayer’s are prepared by sequentially immersing a substrate
in positively
and negatively charged polyelectrolyte solutions in a cyclic procedure. Core she
ll particles
with tailored size and properties are prepared using colloidal particles as the
core material
that serves as a template onto which multilayer’s are fabricated. Hollow capsule
s of organic,
inorganic or hybrid particles can be obtained by dissolving the core material. T
his technique
is both versatile and simple, with the multiplayer film thickness being controll
ed precisely by
varying the total number of layers deposited.[58]
Adi I. Arida et al investigated ketoprofen particles were encapsulated with poly
ions and
gelatin to control the release of the drug in aqueous solutions. Charged linear
polyions and
gelatin were alternatively deposited on 6 μm drug microcrystals through layer-by
-layer (LbL)
assembly. Sequential layers of poly(dimethyldiallyl ammonium chloride) (PDDA) an
d
poly(styrenesulfonate) (PSS) were followed by adsorption of two to six gelatin/P
SS bilayers
with corresponding capsule wall thicknesses ranging from 41 to 111 nm. The relea
se rate has
changed at these different pH values. At pH 7.4 the release rate of Ketoprofen f
rom the
encapsulated particles was less by 107 times compared to uncoated Ketoprofen. Th
e results
provide a method of achieving prolonged drug release and minimized adverse effec
ts of
ketoprofen. [59]
Ionotropic gelation technique Ionic-gelation may be defined as a physicochemical
process
of microdroplet hardening by chelation of polyelectrolyte with polyvalent ions.
Such a
chelation results in cross-linking the polyelectrolyte molecules while forming a
shell in the
form of a polymeric gel. The most widely used system is based on gelation of aqu
eous
sodium alginate, gellan and carrangeenan solutions by the addition of divalent c
ations such as
calcium chloride, barium chloride, potassium chloride induces the cross-linking
of the
polymers, and instantaneously formation of discrete solid microparticles. In thi
s method
40
strong spherical shape and narrow particle size with high yield microparticles a
re formed
which are used for the carriers of many NSAIDs drug to minimize the dose related
adverse
effects and prolong the drug release potential.[60]
Gonzalez-Rodriguez ML et al. reported alginate/chitosan particulate systems for
diclofenac
sodium release by ionic gelation (Ca2+ and Al3+). 25% w/v of the drug was added
to 1.2%w/
v aqueous solution of sodium alginate. The solution was stirred till a complete
solution was
formed. This solution was added dropwise to a solution containing Ca2+ or Al3+ a
nd
chitosan solution in acetic acid. The microspheres formed were left into the ori
ginal solution
for 24 hours for internal gelification. The product is separated by filtration.
The release of
sodium diclofenac was prevented at acidic pH, while it was complete in a few min
utes when
pH was raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of t
he gelifying
cation controlled the release rate of the drug.[61]
Supercritical fluid technique;
Microencapsulation has also been carried out by rapid expansion of supercritical
fluid
technique. Supercritical fluids are highly compressed gases that possess several
advantageous
properties of both liquids and gases. Most widely used ones are supercritical CO
2, alkanes
(C2 to C4) and nitrous oxide (N2O). Supercritical CO2 is widely used for its low
critical
temperature value in addition to its non-toxic and non-flammable properties. It
is also readily
available, highly pure and cost effective. It has found applications in encapsul
ating active
ingredients by polymers. Different core materials such as pesticides, pigments,
pharmaceutical ingredients, vitamins, flavors and dyes have been encapsulated by
using this
method. A wide variety of shell materials that either dissolve (paraffin wax, ac
rylates,
polyethylene glycol) or do not dissolve (proteins, polysaccharides) in supercrit
ical CO2 are
used for encapsulating core substances. In this process, supercritical fluid con
taining the
41
active ingredient and the shell material are maintained at high pressure and the
n released at
atmospheric pressure through a small nozzle. The sudden drop in pressure causes
desolvation
of the shell material, which is then deposited around the active ingredient (cor
e) and forms a
coating layer.[62, 63]
Table1; The Micro- particulate delivery of non steroidal anti-inflammatory drugs
.
NSAIDs drugs Microencapsulation
Techniques
Coating materials
Aspirin
Dose-80-100mg, Protein
bound-80-90% , Tmax-<
30min ,T1/2 - 15 min.
Complex-coacervation. Acacia, Gelatin
Solvent evaporation, Ethylcellulose
Oil-in-Water emulsification, Ethylcellulose
Spray congealing Hydrogenated Soybean oil
Diclofenc sodium
Dose-100-200mg
Protein bound-99%
Tmax-1-3h
T1/2-1.2-2h
Congealable disperse phase
method
Glycerol monostearate Tween80
Oil-in-Oil emulsificationsolvent
Low M.W.polyester
Emulsification method. Chitosan, Glutaraldehyde Aquacoats
Non-aqueous emulsion
method.
Ethylcellulose, HPMCP
Multiple-emulsion method Poly(delta-valerolactone, Acacia
Phase-separation
coacervation
Ethylcellulose, Cyclohexane,
Toluene, Petroleum ether
Solvent evaporation Polymerized rosin
42
Air suspention technique HPMC,PEG6000, Eudragit
Wet-granulation ,Thermal
change methods
Cellulose acetate phthalate,
Ethylcellulose
Ibuprofen
M.Dose-3600mg
Protein bound-99%,
Tmax-1-2 h
T1/2 - 2.0-2.5 h
Solvent Evaporation Poly(D,L-lactic acid) Ethylcellulose,
Methacrylic polymer, Eudragits,
HPMCP, Sodium alginate, Sodiu
sulphate.
Co-acervation Phase
seperation
EudragitRS100,
Emulsion Solvent- Diffusion
Technique
EudragitRL100
Ionotropic gelation Sodium alginate, Chitosan, Pectin,
Gellan gum
Spray drying Cellulose acetate phthalate, Cellulose
acetate trimelliate,
Emulsion-solvent
evaporation
Eudragit RS, RL, S100, HPMCP,
Ehylcellulose
Ionotropic-gelation method Sodium alginate, Chitosan, Pectin,
Gellan gum, Eudragit
Flurbiprofen
M.Dose-500mg
Emulsification solvent
evaporation,
EudragitRS-100
Solvent evaporation Acrylic & Methacrylic acid esters
43
Plasmabound-
99%Tmax-1-2h, T1/2-3 6h
Spray drying Sodium hyaluronate, PEG-4000
Ionotropic gelation Sodium alginate, Calcium chloride,
Pectin, Chitosan
Dexibuprofen
M.Dose-1000mg
Plasma-bound-98%
Tmax-1-2h
T1/2-1.8-3.5h
Ionotropic gelation Sodium alginate, Calcium chloride,
Chitosan, Pectin Gellan
Mefenamic acid
M.Dose-1500mg
Plasma-bound->99%
Tmax-2-4h, T1/2-2-3.5h
Spray drying Cellulose acetate phthalate, Cellulose
acetate
Emulsion-solvent
evaporation
HPMCP, Ehylcellulose
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51