INTRODUCTION:
The vital role of novel
drug delivery system that improve the therapeutic effectiveness of integrated
drugs by providing extended, controlled delivery and or targeting the drug to
desired site. Extended release formulations make the drug available over
extended time period after oral administration. The extended release product
will optimize therapeutic effect and safety of a drug at the same time
improving the patient convenience and compliance. By incorporating the dose for
24 hrs into one tablet/capsule from which the drug is released slowly. This
formulation helps to avoid the side effects associated with low and high
concentrations. The ideal drug delivery system should show a constant
zero-order release rate and maintain the constant plasma concentrations.1,2,3
The design of oral
extended release delivery systems is subjected to several interrelated
variables of considerable importance such as the type of delivery system, the
disease being treated, the patient, the length of therapy and the properties of
the drug. Matrix tablets are considered to be the commercially feasible
extended action dosage forms that involve the least processing variables,
utilize the conventional facilities and accommodate large doses of drug. These
remains an interest in developing novel formulations that allow for extended
the drug release using readily available, inexpensive excipient by matrix based
formulation.4,5 During the last two decades there has been
remarkable increase in interest in extended release drug delivery system. This
has been due to various factors like the prohibitive cost of developing new
drug entities, expiration of existing international patients, discovery of new
polymeric materials suitable for prolonging the drug release, and the
improvement in therapeutic efficiency and safety achieved by these delivery
systems. The basic goal is to achieve a steady state blood level that is
therapeutically effective and non-toxic for an extended period of time. The
design of proper dosage form is an important element to accomplish this goal.6,7
Extended release, extended action, prolonged action, controlled release,
extended action, timed release and depot dosage form are term used to identify
drug delivery system that are designed to achieve prolonged therapeutic effect
by continuously releasing medication over an extended period of time after
administration of a single dose. In the case of oral extended released dosage
form, an effect is for several hours depending upon residence time of
formulation in the GIT. Conventional drug therapy requires periodic doses of
therapeutic agents. These agents are formulated to produce maximum stability,
activity and bioavailability. For most drugs, conventional methods of drug
administration are effective, but some drugs are unstable or toxic and have
narrow therapeutic ranges.8,9,10
Advantages:
Extended
release products having many advantages.
1.
The extended release formulations maintain therapeutic concentrations over
prolonged periods.
2.
The use of extended release formulations avoids the high blood concentration.
3.
Extended release formulations have the potential to improve the patient
compliance.
4.
Reduce the toxicity by slowing drug absorption.
5.
Increase the stability by protecting the drug from hydrolysis or other
degradative changes in gastrointestinal
tract.
6.
Minimize the local and systemic side effects.
7.
Improvement in treatment efficacy.
8.
Minimize drug accumulation with chronic dosing.
9.
Minimum drug usage.
10.
Improvement the bioavailability of some drugs.
Ex: Divalproex sodium
11.
Improvement of the ability to provide special effects.
Ex: Morning relief of arthritis through
bed time dosing.
Disadvantages:
1.
High cost of preparation.
2.
The release rates are affected by various factors such as, food and the rate
transit through the gut.
3.
Extended release formulation contains a higher drug load and thus any loss of
integrity affects the release
characteristics of the dosage form.
4.
The larger size of extended release products may cause difficulties in
ingestion or transit through gut.
5.
Reduced potential for dosage adjustment.
Drug properties, which are suitable for, extended
release formulation:2,3
a) Physiochemical Properties of the drug
1. Aqueous solubility: (>0.1mg/ml).
2. Partition co-efficient: (1000:1 octanol:water
system).
3. Drug stability in vivo: (High enough, sodrug
remain stable during release from system).
4. Protein binding: (Drug with high protein binding
will not required release modification).
5. Drug pKa and ionization
at physiological pH: (pKa for acidic Drug= 3.0 - 7.5, pKa for Basic Drug = 7.0
- 11.0).
6. Mechanisms and sites of
absorption: (Mechanism of absorption should not be active type and absorption
window should not be narrow).
7. Molecular size and
diffusivity: (Molecule size should be small (100-400 D so it can be easily
diffused through polymer matrix).
8. Dose size: (<300mg).
b) Biological Properties of Drug
1. Distribution: (Drug. with
large volume of distribution is not suitable).
2. Metabolism: (Drug. should
be metabolized with intermediate speed).
3. Half-life of drug: (2 - 8
hrs).
4. Margin of safety: (High
enough so dose dumping does not cause any serious side effect).
5. Plasma concentration
response relationship: (Drug. having linear relationship is better candidate).
Drug selection for oral extended release drug delivery
systems:
The biopharmaceutical
evaluation of a drug for potential use in controlled release drug delivery system
requires knowledge on the absorption mechanism of the drug form the G.I. Tract,
the general absorbability, the drug’s molecular weight, solubility at different
pH and apparent partition coefficient.10,11,12
Table 1: Physicochemical
Parameters for drug selection.
|
Parameter
|
Preferred value
|
|
Molecular
weight/ size
|
500
daltons
|
|
Solubility
|
>
0.1mg/ml for pH 1 to pH 7.8
|
|
Apparent
partition coefficient
|
High
|
|
Absorption
mechanism
|
Diffusion
|
|
General
absorbability
|
From
all GI segments
|
|
Release
|
Should
not be influenced by pH and enzymes
|
The pharmacokinetic
evaluation requires knowledge on a drug’s elimination half- life, total
clearance, absolute bioavailability, possible first- pass effect, and the
desired steady concentrations for peak and trough.11
Table 2: Pharmacokinetic
parameters for drug selection.
|
Parameter
|
Comment
|
|
Elimination
half life
|
Preferably
between 2 and 8 h
|
|
Total
clearance
|
Should
not be dose dependent
|
|
Elimination
rate constant
|
Required
for design
|
|
Apparent
volume of distribution Vd
|
The
larger Vd and MEC, the larger will be the required dose size.
|
|
Absolute
bioavailability
|
Should
be 75% or more
|
|
Intrinsic
absorption rate
|
Must
be greater than release rate
|
|
Therapeutic
concentration Css av
|
The
lower Css av and smaller Vd, the loss
among of drug required
|
|
Toxic
concentration
|
Apart
the values of MTC and MEC, safer the dosage form. Also suitable for drugs
with very short half-life.
|
Terminology:
Modified Release dosage form
may be classified as
A. Delayed release
B. Extended release
·
Sustained release
·
Controlled release
·
Prolonged release
C. Site-specific and
receptor targeting.
·
Organ targeting
·
Cellular targeting
·
Sub cellular targeting13
Delayed release:
A delayed-release dosage
form is designed to release the drug at a time other than promptly after
administration. The delay may be time based or based on the influence of
environmental conditions, like gastrointestinal pH.14
Extended release:
The U.S. Food and Drug
Administration (FDA) defines an “extended-release dosage form as one that
allows a reduction in dosing frequency from that necessitated by a conventional
dosage form, such as a solution or an immediate-release dosage form”.14
Sustained release:
Sustained release indicates
an initial release of drug sufficient to provide a therapeutic dose soon after
administration, and then a gradual release over an extended period.14
Controlled release:
Dosage forms release drug at
a constant rate and provide plasma concentrations that remain invariant with
time.14
Prolonged release:
Prolonged release indicates
that the drug is provided for absorption over a longer period of time than from
a conventional dosage form. However, there is an implication that onset is
delayed because of an overall slower release rate from the dosage form.14
Site-specific and receptor targeting:
Targeted release describes
drug release directed toward isolating or concentrating a drug in a body
region, tissue, or site for absorption or for drug action.15
Release rate and dose consideration:
The dosage forms can be
considered to release their active drugs into an absorption pool immediately.
Conventional dosage forms include solutions, capsules, tablets, emulsions, etc.
Figure
1: The absorption pool
represents a solution of the drug at the site of absorption.
The absorption pool
represents a solution of the drug at the site of absorption.
Where,
Kr = First order rate
constant for drug release
Ka = First order rate
constant for drug absorption.
Ke = First order rate
constant for drug elimination.
For immediate release dosage
forms Kr >>>Ka or alternatively absorption of drug across a biological
membrane is the rate-limiting step in delivery of the drug to its target area.
For non-immediate release
dosage forms, Kr <<<Ka, that is, release of drug from the dosage form
is the rate limiting step. This cause the above kinetics Figure to reduce to.
Figure
2: Drug release from the dosage
form.
Thus, the effort to develop a
delivery system that release drug slowly must be directed primarily at altering
the release rate by affecting the value of Kr. The ideal goal in designing a
controlled release system is to deliver drug to the desired site at a rate
according to needs of the body, i.e. a self-regulated system based on feedback
control but this is a difficult assignment.
The pivotal question is at
what rate should drug be delivered to maintain a constant blood drug level?
This constant rate should be analogous to that achieved by continuous
intravenous infusion where a drug is provided to the patient at constants rates
just equal to its rate of elimination. This implies that the rate of delivery
must be independent of the amount of drug remaining in the dosage form and
constant over time. That is, release from the dosage form should follow
zero-order kinetics, as shown below
Kr° = Rate in =
Rate out = Ke Cd Vd
Where,
Kr° = Zero order rate
constant for drug release (amount/time)
Ke = First order rate
constant for overall drug elimination time.
Cd = Desired drug level in
the body (amount/volume)
Vd =Volume space in which the
drug is distributed.
To achieve a therapeutic
level promptly and sustain the level for a given period of time, the dosage
from generally consist of two parts: an initial primary dose, Di, which release
drug immediately and a maintenance or sustaining dose, Dm. The total dose, W,
thus required for the system is
W = Di + Dm
To maintain drug blood levels
with the therapeutic range over the entire time course of therapy, most
controlled release drug delivery systems are, like conventional dosage forms,
administered as multiple rather than single doses. For an ideal
controlled-release system that releases drug by zero-order kinetics, the
multiple dosing regimens are analogous to that used for a constant intravenous
infusion. For those controlled-release systems having release kinetics other
than zero-order, the multiple dosing regimens are more complex.16
Design and Formulation of Oral Sustained Release Drug
Delivery System
The oral route of
administration is the most preferred route due to flexibility in dosage form,
design and patient compliance. But here one has to take into consideration, the
various pH that the dosage form would encounter during its transit, the
gastrointestinal motility, the enzyme system and its influence on the drug and
the dosage form. The majority of oral sustained release systems rely on
dissolution, diffusion or a combination of both mechanisms, to generate slow
release of drug to the gastrointestinal milieu. Theoretically and desirably a
sustained release delivery device, should release the drug by a zero-order
process which would result in a blood level time profile similar to that after
intravenous constant rate infusion.
Extended (zero-order) drug
release has been attempted to be achieved with various classes of extended drug
delivery system
1. Diffusion extended
system.
i) Reservoir type.
ii) Matrix type.
2. Dissolution extended
system.
i) Reservoir type.
ii) Matrix type.
3. Methods using
Ion-exchange.
4. Methods using osmotic
pressure.
5. pH independent
formulations.
6. Altered density
formulations.
Diffusion Extended System
Basically diffusion process
shows the movement of drug molecules from a region of a higher concentration to
one of lower concentration. The flux of the drug J (in amount/ area -time),
across a membrane in the direction of decreasing concentration is given by Fick‟s law.
J= - D dc/dx.
D = diffusion coefficient in
area/ time
dc/dx = change of
concentration 'c' with distance 'x' In common form, when a water insoluble
membrane encloses a core of drug, it must diffuse through the membrane. The
drug release rate dm/ dt is given by.
dm/ dt= ADKΔ
C/L
Where; A = Area.
K = Partition coefficient of
drug between the membrane and drug core.
L= Diffusion path length
(i.e. thickness of coat).
Δc= Concentration
difference across the membrane.17
Reservoir Type
In the system, a water
insoluble polymeric material encases a core of drug (Figure 3.). Drug will
partition into the membrane and exchange with the fluid surrounding the
particle or tablet. Additional drug will enter the polymer, diffuse to the
periphery and exchange with the surrounding media.
Figure
3: Diffusion Extended drug
release: Reservoir system.
Description:
Drug core surrounded by
polymer membrane which controls release rate.
Advantages:
Zero order delivery is
possible, release rates variable with polymer type.
Disadvantages:
System must be physically
removed from implant sites. Difficult to deliver high molecular weight
compound, generally increased cost per dosage unit, potential toxicity if
system fails.18
Matrix Type
A solid drug is dispersed in
an insoluble matrix. and the rate of release of drug is dependent on the rate
of drug diffusion and not on the rate of solid dissolution.
Higuchi has derived the
appropriate equation for drug release for this system
Q = Dε/ T [2
A –εCs] Cst˝
Where; Q = Weight in gms of
drug released per unit area of surface at time t.
D = Diffusion coefficient of
drug in the release medium.
ε = Porosity of the
matrix.
Cs = Solubility of drug in
release medium.
T= Tortuosity of the matrix.
A = Concentration of drug in
the tablet, as gm/ ml.19
Description:
Homogenous dispersion of
solid drug in a polymer mixture.
Advantages:
Easier to produce than
reservoir or encapsulated devices, can deliver high molecular weight compounds.
Disadvantages:
Cannot provide zero order
release, removal of remaining matrix is necessary for implanted system.
Diffusional mechanism is the system where a partially soluble membrane encloses
a drug core. Dissolution of part of membrane allows for diffusion of the
constrained drug through pores in the polymer coat. The release rate can be
given by following equation.
Release rate = AD
/ L = [C1- C2]
Where;
A = Area.
D = Diffusion coefficient.
C1 = Drug concentration in
the core.
C2 = Drug concentration in
the surrounding medium.
L = Diffusional path length.
Thus diffusion extended
products are based on two approaches the first approach entails placement of
the drug in an insoluble matrix of some sort. The eluting medium penetrates the
matrix and drug diffuses out of the matrix to the surrounding pool for ultimate
absorption. The second approach involves enclosing the drug particle with a
polymer coat. In this case the portion of the drug which has dissolved in the
polymer coat diffuses through an unstirred film of liquid into the surrounding
fluid. 20
Dissolution Extended Systems:
A drug with a slow
dissolution rate is inherently extended and for those drugs with high water
solubility, one can decrease dissolution through appropriate salt or derivative
formation. These systems are most commonly employed in the production of
enteric coated dosage forms. To protect the stomach from the effects of drugs
such as Aspirin, a coating that dissolves in natural or alkaline media is used.
This inhibits release of drug from the device until it reaches the higher pH of
the intestine. In most cases, enteric coated dosage forms are not truly
sustaining in nature, but serve as a useful function in directing release of
the drug to a special site.
Reservoir Type:
Drug is coated with a given
thickness coating, which is slowly dissolved in the contents of
gastrointestinal tract. By alternating layers of drug with the rate controlling
coats as a pulsed delivery can be achieved. If the outer layer is quickly
releasing bolus dose of the drug, initial levels of the drug in the body can be
quickly established with pulsed intervals. Although this is not a true extended
release system, the biological effects can be similar. An alternative method is
to administer the drug as group of beads that have coating of different
thickness. The maintenance of drug levels at late times will be achieved from
those with thicker coating.
Matrix Type:
These are common type of
dissolution extended dosage form. It can be either a drug impregnated sphere or
a drug impregnated tablet, which will be subjected to slow erosion. Two types
of dissolution extended pulsed delivery systems. i) Single bead type device
with alternating drug and rate-controlling layer. ii) Beads containing drug
with differing thickness of dissolving coats. Amongst extended release
formulations, hydrophilic matrix technology is the most widely used drug
delivery system due to following advantages. iii) Provide desired release
profiles for a wide therapeutic drug category, dose and solubility. iv) Simple
and cost effective manufacturing using existing tableting unit operation
equipment. v) Broad regulatory and patient acceptance. vi) Ease of drug release
modulation through level and choice of polymeric systems and function coatings.21
Methods Using Ion Exchange:
It is based on the formation
of drug resin complex formed when anionic solution is kept in contact with
ionic resins. The drug from these complexes gets exchanged in gastrointestinal
tract and released with excess of Na+ and Cl- present in gastrointestinal
tract.
Anion Exchangers: Resin+ -
Drug- + Cl- goes to Resin+- Cl-+ Drug-
Cation Exchangers: Resin--
Drug+ + Na+ go to Resin- - Na+ + Drug+
These systems generally
utilize resin compounds of water insoluble cross linked polymer. They contain
salt forming functional group in repeating positions on the polymer chain. The
release rate can be further extended by coating the drug resin complex by
microencapsulation process. 22
Methods Using Osmotic Pressure
A semi permeable membrane is
placed around a tablet, particle or drug solution that allows transport of
water into the tablet with eventual pumping of drug solution out of the tablet
through a small delivery aperture in tablet coating.
Two types of osmotically
extended systems are:-
Type A contains an osmotic
core with drug.
Type B contains the drug in
flexible bag with osmotic core surrounding.23
pH– Independent Formulations
The gastrointestinal tracts
present some unusual features for the oral route of drug administration with
relatively brief transit time through the gastrointestinal tract. Since most
drugs are either weak acids or weak bases, the release from extended release
formulations is pH dependent. A buffered extended release formulation is
prepared by mixing a basic or acidic drug with one or more buffering agent,
granulating with appropriate pharmaceutical excipients and coating with
gastrointestinal fluid permeable film forming polymer. When gastrointestinal
fluid permeates through the membrane, the buffering agents adjust the fluid
inside to suitable constant pH thereby rendering a constant rate of drug
release.24
Altered Density Formulations:
It is reasonable to expect
that unless a delivery system remains in the vicinity of the absorption site
until most, if not all of its drug content is released. Several approaches have
been developed to prolong the residence time of drug delivery system in the GI.
High Density Approach:
In this approach the density
of the pellets must exceed that of normal stomach content and should therefore
be at least 1-4gm/cm3.
Low Density Approach:
Globular shells which have
an apparent density lower than that of gastric fluid can be used as a carrier
of drug for extended release purpose. 25
Polymers Used in Preparations of Extended Release
Dosages:
Hydrogels
·
Polyhydroxyethylmethylacrylate (PHEMA)
·
Cross-linked polyvinyl alcohol (PVA)
·
Cross-linked polyvinylpyrrolidone (PVP)
·
Polyethyleneoxide (PEO)
·
Polyacrylamide (PA)
Soluble Polymers
·
Polyethyleneglycol (PEG)
·
Polyvinyl alcohol (PVA)
·
Polyvinylpyrrolidone (PVP)
·
Hydroxypropylmethylcellulose (HPMC)
Biodegradable Polymers
·
Polylactic acid (PLA)
·
Polyglycolic acid (PGA)
·
Polycaprolactone (PLA)
·
Polyanhydrides
·
Polyorthoesters
Non Biodegradable Polymers
·
Polyethylene vinyl acetate (PVA)
·
Polydimethylsiloxane (PDS)
·
Polyetherurethane (PEU)
·
Polyvinyl chloride (PVC)
·
Cellulose acetate (CA)
Mucoadhesive Polymers
·
Polycarbophil
·
Sodium carboxymethyl cellulose
·
Polyacrilic acid
·
Tragacanth
·
Methyl cellulose
·
Pectin
·
Natural gums
·
Xanthan gum
·
Guar gum
·
Karaya gum26
In vitro performance of oral ER formulations:
Dissolution testing
Dissolution testing is an official evaluation method
for solid oral dosage forms. Several Pharmacopoeial standard dissolution media
and apparatuses are well documented. The method was initially developed for IR
solid oral dosage form and then extended to modified release solid oral dosage
forms as well as other novel/special dosage forms.27
The application of dissolution testing was
conventionally known as a tool for ensuring batch to batch consistency. It is
also an essential mean for deciding on a candidate formulation in product
development. The tests should be sensitive enough to demonstrate any small
variable in manufacturing of a product as well as the type and level of excipients
used. Therefore, it is possible that an
over discriminatory test, although in vivo irrelevance might be suitable for
these purposes.27
The value of dissolution test was later shifted to
bioavailability prediction. Challenges in selecting the test conditions which
reflect in vivo drug release have been of interested to many
researchers.28,29 The
tests may not be Pharmacopoeial standard, they should, however, be sensitive, reliable and discriminatory with
regard to the in vivo drug release characteristics.27,30 The
ultimate goal of the dissolution test is to predict the in vivo performance
of products from in vitro test by a proper correlation, so called in
vitro/in vivo correlation (IVIVC).31
In certain cases, dissolution tests can be used for providing
bio-waivers for lower strengths of a product once the higher strength is
approved. The waivers can also be granted to some categories of postapproval
changes, based on the appropriate bioavailability/ bioequivalence test
procedure. 32,33
Bio-relevant dissolution
testing:
A) Physiological properties of the gastrointestinal
tract
Physiological conditions vary wildly along the
gastrointestinal (GI) tract. Not to mention inter subject variability, various
factors within an individual, such as disease states, physical activity level,
stress level and food ingestion, considerably influence the GI conditions.34
The effects of this variability on the performance of ER systems are even more
pronounced given that the dosage forms are designed to remain in the GI tract
for the substantially longer period of time and transit through various
conditions compared with IR systems. Inhomogeneous distribution of fluid in the
small and large intestine is one of many factors that potentially
contribute to the variability of drug release and absorption. Physiological
properties in various GI compartments with and without effect of food are
presented in table 3 and table 4.
Gastric emptying time of a solid dosage form changes
dramatically with the effect of co administered food. One out of twelve
capsules taken three hrs before meal and all twelve capsules taken immediately
after meal remained in the stomach for at least one hrs, while in the fasted
state, the majority of the capsules had left the stomach within one hrs.35
The total time for a dosage form to empty from the stomach in the fasted state
depends on the size of the dosage form, i.e. the longer time is needed for the
larger, as well as the motility cycle of the stomach which is two hrs in
average. The emptying for most non-disintegrating solid dosage forms with
larger than one millimetre diameter occurred in the late phase II or phase III
of the cycle. Co-administered food even further altered the emptying
time depending on the calorie content. A delay for several hrs to empty a
relatively large solid dosage form can also occur as the food will be first
cleared from the stomach and return to the normal gastric motility cycle in the
fasted state. The dosage form is then emptied under the phase III activity.34
Unlike the gastric emptying, transit time in the small intestine in both fasted
and fed states are not significantly different, regardless of the type of
dosage forms.34,36 The pH and osmolality of the stomach and the
upper small intestine is greatly influence by coadministered food. In healthy
humans, their values for the stomach increased from pH 1.7/ 140 mOsm kg-1 up to
pH 6.4/559 mOsm kg-1 within thirty minutes postprandial and then gradually
decreased to pH 2.7/217 mOsm kg-1 after 3.5 hrs. Composition and quantity of
the meal significantly affected the time require to re-establish the fasting
gastric pH more than did the pH value of the meal.
For example, two hrs was required after a 651
mOsm/1000 kcal (pH 5.6) meal whereas only one hrs was needed for a 540 mOsm/458
kcal meal (pH 6). As the average time for restoring the pH of the
stomach was two to three hrs, dosage forms with pH-dependent controlled
release, such as an enteric coated tablet, may fail to control the release when
taken with or soon after meal.37
Unlike the stomach and the small intestine, the
movement of luminal contents in the colon did not always occur longitudinally,
but also laterally in order to assist the mixing of the contents and to
facilitate absorption. A food effect study with radiography revealed the
remaining of some of the radio-opaque markers after 36 h at the ascending
colon, whilst some of them taken only 12 hrs before the study were found at the
end of the transverse colon. the transit time of a dosage form was,
therefore, considered as no effect of food intake.
Effect of food on the bioavailability of drugs and
dosage forms:
The presence of food within the GI tract can
significantly influence the bioavailability of drugs, both by the nature of
food and the drug formulations. Factors deserving critical attention for
predicting bioavailability under fed conditions are;
a) An increase in solubilisation capacity by higher
concentrations of bile salts and fatty acids. This factor can alter the release
profiles of lipophilic drugs or from dosage forms that drug released is
controlled by hydrophilicity.38
b) A prolonged gastric emptying time (increased
GI-residence time), thus increasing the total time available for dissolution
and improve the bioavailability.39,40,41
This factor, however, can also inversely affect acid labile drugs that
would expose to the acidic environment of the stomach for a significantly
longer period of time.
c) An elevation of the pH in the stomach altered the
release pattern of pH-dependent controlling formulations as well as affected
the dissolution rate of drugs with pH dependent solubility.39
d) Changes in the physical and biochemical barrier
function of the GI tract. The increased fluidity of the intestinal wall by lipid
as well as the increased leakiness of tight junctions by high concentration of
glucose can enhance the permeability of the small intestine.42,43
e) Stimulation of intestinal lymphatic transport.43
CONCLUSION:
On the basis above
discussion, it can be concluded that extended release dosage forms provide an
advantage over conventional dosage forms by optimizing bio-pharmacokinetic and
pharmacodynamic properties of the drugs in such a way that it reduces dosing
frequency to an extent that once daily. The extended release formulations are a
promising way to improve the patient’s compliance by reducing dosing intervals
and minimizing adverse effects. The dosage form is very useful and comes with
reasonable cost compare to conventional dosage forms.
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