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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: [email protected], 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 REFERENCES
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