Tropical Journal of Pharmaceutical Research August 2011; 10 (4): 365-373
Faculty of Pharmacy, University of Benin,
http://dx.doi.org/10.4314/tjpr.v10i4.1 Research Article Formulation and Evaluation of Bioadhesive Cyproheptadine Tablets V Chandrakala V2*, MS Srinath1, Saral A Mary2 and Kumar S Utpal2 1Department of Pharmaceutics, Government College of Pharmacy, Bangalore, Pharmaceutical Chemistry Division, 2School of Science and Humanities, Vellore Institute of Technology, Vellore, Tamil Nadu, India Abstract Purpose: To evaluate the effect of formulation variables on the bioadhesion and release properties of bioadhesive cyproheptadine hydrochloride tablets. Methods: Screening of polymers - hydroxypropyl methylcellulose, (HPMC), sodium carboxy methyl cellulose (CMC), and Carbopol 974p and 934p - in solution form were carried out by shear stress and detachment force measurement,based on Taguchi model, in order to determine their bioadhesion properties. Central composite design (CCD) was applied to optimize the combined effects of the polymers on release rate constant (K), diffusion coefficient (n), regression coefficient (R2) and detachment force of a sustained release tablet formulation of cyproheptadine hydrochloride containing also a prompt dose of the drug. Results: The shear stress of 3 % solution of HPMC was greater than that of an equivalent concentration of Carbopol 934P. The values of K, n, R2 and detachment force for the optimized formulation (F0) were 0.269, 0.696, 0.964 and 0.066 Newton (N), respectively, and showed good correlation with the predicted values, thus confirming the practicability and validity of the model. Conclusion: Gastric retention time can be increased for cyproheptadine hydrochloride by formulating it as a bioadhesive tablet that enhances the retention of the dosage form in the stomach and hence gastric absorption of the drug. Keywords: Cyproheptadine hydrochloride, Bioadhesive core tablet, Detachment force, Taguchi design, Central composite design Received: 4 August 2010 *Corresponding author: E-mail: chandra_kalav@yahoo.com, Tel: +91-8025456581 Trop J Pharm Res, August 2011;10 (4): 365
INTRODUCTION
Gastro-retentive dosage forms remain in the
Oral ingestion is the most convenient and
commonly used route of drug administration.
available in the market are oral drug delivery
alternative for maintenance of systemic drug
concentration within the therapeutic window
advantages of ease of administration and
absorbed after oral administration. It has a
between an oral pharmaceutical system and
short half life of 3 h and hence require
biological surface. It has been suggested that
frequent administration to maintain optimum
delay in gastrointestinal (GI) transit, brought
plasma concentration which cause patients’
non-compliance. These characteristics make
it a good candidate for the formulation of an
extended-release dosage form to minimize
bioavailability and duration of action. Though
utilization of drug within the therapeutic range
employed route of drug administration, it is
not suitable for drugs which are susceptible
to gut and/or hepatic metabolism as well as
EXPERIMENTAL Materials
lining the walls of various body cavities. They
consist of a connective tissue upper layer
Mederich Pharmaceuticals, Bangalore, India.
(epithelial layer), the surface of which is
mucus. The major components of all mucus
carboxymethylcellulose (CMC) were obtained
from Apotex Research Pvt Ltd, Bangalore,
India. Carbomer (Carbopol) 934p (Strides
structure-forming component of the mucus
gel, resulting in its characteristic gel-like,
cohesive and adhesive properties. It is as
Biotech Pvt Ltd, Pune, India) were also used.
thick as 1mm in humans [4].
All other chemicals and reagents used were
Although various selective antihistaminic
drugs are available in the market, their
Shear stress measurement
delivery systems may cause various hazards
Screening of the various polymers - HPMC,
dosage forms of these drugs, such as tablets,
carried out by shear stress measurement.
capsules, lotions, suspensions and syrups,
[12,13]. Two smooth, polished glass slides
often fail to achieve effective management of
were selected, one of which was fixed with an
these diseases due to peak level-associated
adhesive onto a fixed surface. The second
(upper) slide was tied with a thread, which
mouth, confusion and weight gain. In spite of
was then passed over a pulley and tied to a
their anti-allergic properties, they may
pan. The weight of the pan and frictional
produce allergic manifestations and also
force of the upper slide was nullified by
Trop J Pharm Res, August 2011;10 (4): 366
putting a weight on the pan such that the
upper slide moves freely after infinitesimal small
quantity of cyproheptadine HCl and polymer
increase of weight in the pan. One drop of each
were blended together. The ingredients were
polymer (3 % aqueous solution) was placed at
mixed in geometric proportion, after first
the center of the fixed slide and then a second
grinding separately in a mortar with a pestle, to
slide was pressed down with a weight (100g) for
fixed intervals of 5, 10, 15 and 30 min, after
mixture was granulated with sufficient ethanol to
which weights were added to the pan. The /load
make a damp mass. The damp mass was then
required to pull the upper slide or cause it to
passed through a 1 mm sieve and dried in an
slide down from the fixed slide represents the
oven at 40 0C for 30 min. The granules were
adhesion strength. Taguchi design was applied
then successively passed through sieves with
for further screening of the polymers for use in
aperture size of 250 and 90 µm, respectively.
tablet formulations based on the measurement
quantity of MCC, and compressed in a tablet
machine, using 8 mm flat punches, to make the
934P, were selected for the formulation of
tablets. Various ratios of these two polymers,
Various concentrations of polymers, based on
with respect to the weight of the drug, were then
the Taguchi design (Table 1), were screened for
optimized by Central composite design (CCD).
detachment force in core tablet formulations.
Selection of the polymers, using the Taguci OA
Formulation of Cyproheptadine tablets
The cyproheptadine hydrochloride (HCl) tablets
prepared consisted of a sustained release dose
as the tablet core, and an outer prompt dose
Taguchi OA design were subjected to CCD,
component. The sustained release core was
as in Table 2, using different ratio of HPMC
Table 1: Composition of various tablet core formulations based on Taguchi Orthogonal Array (OA) Design Ingredient Carbapol 934P Carbopol 974P Composition is given in terms of mg per tablet. Each formulation contained 11, 4, 4 and 15 mg of cyproheptadine hydrochloride, magnesium stearate, talc and microcrystalline cellulose (MCC), respectively; CMC = sodium carboxymethyl cellulose Trop J Pharm Res, August 2011;10 (4): 367
and Carbopol 934p with respect to the weight
of the drug at an α (star point or distance
variables. These response variables were
from the centre calculated by the formula 22/4)
subjected to multiple regression analysis and
value of 1.414 with three centre point to
ANOVA to find out the relation between the
resultant core formulations were evaluated
for detachment force, dissolution (n value,
optimization based on the release rate and
which characterizes release mechanism of
the drug, with n ≤ 0.45 corresponding to
Fickian diffusion mechanism; 0.45 < n < 0.89
to non-Fickian diffusion; n = 0.89 to case II
transport; and n > 0.89 to supercase II
superdisintegrant, cross carmellose sodium)
constant (K), variability of % drug release
surround the core tablet core using 10 mm
(R2) in a given concentration of the polymer,
Table 2: Application of Central composite design (CCD) to optimize polymer combination for the formulation of optimized bioadhesive core tablets Ingredient Composition is given as mg per tablet. Each formulation contained 11, 4, 4 and 15 mg of cyproheptadine hydrochloride, talc, magnesium stearate and microcrystalline cellulose (MCC ), respectively; HPMC = hydroxypropyl methylcellulose
Measurement of detachment force of
using a burette. The tablet was allowed to
stay in contact with the tissue for 30 min.
Water was then added to the beaker from a
This test was carried out using the tablet core
burette. The quantity of water required to
(i.e., the sustained release dose component)
separate the tablet from the tissue surface
to measure in-vitro bioadhesive capacity of
was noted and this value was converted to
the bioadhesive polymers to the mucosa of
detachment force (in newtons) using Eq 1.13.
rat stomach. The animals were sacrificed by
cervical dislocation. The stomach mucosa
Detachment force = (0.00981 x w)/2 …….(1)
was collected and stored in a deep freezer at
solution was added to the vial, the brim of
which was tied with rat mucosa and the other
Optimization procedure
end was fixed to a glass mortar on a hot plate
maintained at 37 0C. The adhesion force of
Taguchi design was applied to reduce the
the tablets was then measured (n = 6) as
number of experiments to optimize the range
follows. A hole was drilled in centre of the
of variable concentrations needed to obtain
tablet to be tested. One end of the thread
was passed through it and tied and the other
levels of the variable (polymer concentration)
end was passed through the pulley and tied
were used for further optimization of core
to a pan on which a beaker was placed. The
weight of the pan was nullified by suspending
the weight. Water was added to the beaker
Trop J Pharm Res, August 2011;10 (4): 368
Statistical experimental design of two factors
In vitro dissolution studies
at three different levels was used to evaluate
the influence and interactions of the three
Drug release studies on the tablets were
levels to the final responses tested. Such
three level-CCD requires a minimum number
of tests for each variable. The fact that the
apparatus (type 1, 100 rpm, 37 0C) in 900 ml
expected responses do not vary in a linear
simulated gastric fluid (0.1M HCl) without
manner with the selected variable and to
enzymes. A 5 ml aliquot was withdrawn at
enable the quantification of the prediction of
different time intervals, filtered through 0.45 µ
the responses, a central composite plan was
filter and the dissolution medium replenished
selected, where the response could be
with 5 ml of fresh dissolution fluid. The drug
error in predicting the response increases
Elico UV-Visible Spectrophotometer (model
with the distance from the centre of the
SL-159) at 290 nm after suitable dilution of
modeled region. It is advisable to limit the use
the sample. The experiments were conducted
of the models to an area bound by values
Data analysis
The parameters were carefully selected to
carry out composite factorial design (one of
To analyze the mechanism of drug release
the forms of CCD where the effect of each
and release rate kinetics from the dosage
factor is evaluated at five different levels)
based on codified values of –α, -1 , 0 +1, +α.
The value of alpha is chosen such that the
variance of the response predicted by the
Korsmeyer and Peppas release models using
Prism® and Sigma plot® software, for curve
form the centre of the modeled region. The
respectively. Finally all the response, viz, n,
K, R2, %Assay, %drug release and time of
Three replicate central point were prepared to
estimate the degree of experimental error for
quadratic regression model as shown in Eq 2
to determine the coefficients and intercept for
the factors tested at each response. The
Four key responses as mentioned earlier in
optimum formulation was constructed using
mathermatical models for evaluating relevant
ANOVA was performed to ascertain statistical
variables (maximum and minimum) boundary
significanceof the model at 95 % confidence
of each response variables are defined in the
optimization techniques. The quadratic model
0 + b1x1+ b2x2+b12x1x2 +b11x1 +b22x22 ….(2)
The shear stress of the four polymer tested is
depicted in Fig 1. As the time of contact with
where Y= response, x1 = drug: polymer ratio,
mucus is increased the shear force of the
intercept for the regression line, x1x2 is the
except for Carbopol 974p which initially
interaction and other b’s stands = for
showed a rapid increase of shear stress and
thereafter a steady state or plateau was
Trop J Pharm Res, August 2011;10 (4): 369
drug release from the formulations gave an insight into the release rate and release mechanism [8]. The final optimized composition of the core tablet (sustain release dose component), F0, is as follows: cyproheptadine HCl 11 mg, HPMC 28 mg, Carbopol 934p 4.65 mg, magnesium stearate 4 mg, talc 4 mg, MCC 15 mg, and lactose 82.97 mg. The composition of the loading (prompt) dose, which was coated around the core tablet, is: cyproheptadine HCl 4 mg, MCC 30 mg,
lactose 184 mg, magnesium strearate 10 mg,
talc 10 mg, and cross-carmellose sodium 12
Fig 1: Screening of polymers by shear stress
= HPMC; □ = Carbopol 934P; ∆ = Sodium CMC; ♦ =
DISCUSSION
The bioadhesive cyproheptadine HCl tablet
Drug dissolution and release kinetics
bioavailability and prolong therapeutic action.
In vitro parameters for the various tablet
formulations are listed in Table 3. Drug
characteristics of certain polymers can be
release throughout the study period ranged
attributed to shear stress, detachment force
from 80 to 98 % while diffusion coefficient (n)
ranged from 0.3 to 0.7, K from 0.3 to 0.5 and R2 from 0.8 to 0.9. The curve-fitting results for Table 3: Dependent variables used for optimization by CCD. Korsmeyer-Peppas model Detachment Time for drug Formulation force (N) release (h) Trop J Pharm Res, August 2011;10 (4): 370
Shear stress
response dependant variables - K, n, R2 and
The highest shear stress was shown by 3 %
solutions of HPMC and Carbopol 934P. This
may be attributed to the swelling of the
regression analysis of variance, and the
controlled hydration. Thus, shear stress
Effect of formulation variables on release
controlled rate of hydration. On the other
uncontrolled hydration and swelling with time
hydrochloride release was significant (p =
which resulted in less increase in shear
0.0478), indicating adequate fit to the surface
concentration of HPMC increased, K value
Detachment force
also increased, and this may be attributed to
the swelling of the polymers which in turn
increased the influx of water leading to
force than the other two polymers, leading to
similarly caused an increase in the value of
the exclusion of the latter from further
Effect of formulation variables on diffusion
higher friction than the individual polymers;
The model term for n was highly significant (F
higher detachment force. The exact ratio of
= 12.98), indicating adequate fit to the
the polymer combination that exhibited the
quadratic model. At low concentrations of
highest bioadhesive strength was obtained by
HPMC, n decreased while at higher
optimization using Central Composite Design
concentrations, n increased; similarly, with
increase in Carbopol 934p concentration n
the ratio 20:7.5) showed the highest drug
Effect of formulation variables on detachment
However, uniformity in mixing can be also
achieved for the other formulations if the
formulation conditions are appropriately
Detachment force was not important for the
detachment force also increased while for
Kinetic release mechanism (curve fitting)
increased and then decreased. However, the
Based on the dissolution profile, the drug
optimized mixture of these two polymers in
the tablet core showed sustained increase in
detachment force over time. This is probably
formulations as they showed high correlation
due to the fact that the rate-limiting hydration
coefficient (R2 = 0.98) Thus, drug release
Trop J Pharm Res, August 2011;10 (4): 371
Table: 4 Predicted and actual values for optimized formulation, F0 Detachment force Actual Predicted Actual Predicted Actual Predicted Actual Predicte d
interaction of Carbopol 934p was controlled
immediate therapeutic effect. Furthermore,
the application of optimization technique is a
Effect of formulation variables on R2
useful tool, particularly in evaluating several
response variables as the observed variables
The model term for R2 was significant (F =
values for the optimized formulation, thus
optimization procedure used. Consequently,
Optimization
optimization technique has been successfully
A numerical optimization technique by the
desirability approach was used to generate
the optimum setting for the formulation using
maximum adhesive force as well as favorable
drug release time, K, n and R2. When this
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