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Table of Contents
Year : 2018  |  Volume : 6  |  Issue : 2  |  Page : 53-59

Experimental design approach for the formulation of controlled release buccal bilayer tablets of carvedilol

1 Department of Pharmaceutics, Bhagvan Mahavir College of Pharmacy, Surat, Gujarat, India
2 Department of Pharmacy, Sumandeep Vidyapeeth, Vadodara, Gujarat, India
3 Department of Formulation Development, Zhejiang Jingxin Pharma Pvt. Ltd., Zhejiang, China

Date of Web Publication26-Feb-2019

Correspondence Address:
Vinodkumar D Ramani
Bhagvan Mahavir College of Pharmacy, BMEF Campus, VIP Road, Bharthana Vesu, Surat - 395 017, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JIHS.JIHS_19_18

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Introduction: The absolute bioavailability of carvedilol is ~25% - 35% even though it rapidly and extensively absorbed following oral administration due to a significant degree of presystemic metabolism. The purpose of this study was to develop controlled release mucoadhesive buccal bilayer tablet of carvedilol using HPMC K4M and carbomer 934 as the mucoadhesive polymer. Method: The formulation optimization was performed using 32 full factorial design to study the effect of independent variables viz. HPMC K4M (X1), carbomer 934 (X2) levels on % drug release in 8 h (Y1), mucoadhesive time (Y2) in buccal cavity and mucoadhesive strength (Y3). The tablets were evaluated for its appearance, thickness, diameter, weight uniformity, content uniformity, surface pH, swelling index and in vitro drug permeation. Results: The optimized formulation evaluated for responses which showed an in vitro drug release of 81.3% in 8 h, mucoadhesive strength 11.2 g with mucoadhesive time of 471.32 min and demonstrated case-II transport mechanism. The results of response variables were found to be very close with the predicted values. These results support the fact that 32 full factorial designs with desirability function could be effectively used in optimization of controlled release mucoadhesive buccal bilayer tablets. Conclusion: It can be concluded that buccal route can be one of the alternatives available to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of carvedilol.

Keywords: KEY WORDS: Buccal bilayer tablets, carvedilol, desirability, factorial design, mucoadhesiveBuccal bilayer tablets, carvedilol, desirability, factorial design, mucoadhesive

How to cite this article:
Ramani VD, Sailor GU, Patel MM, Parmar GR, Seth AK. Experimental design approach for the formulation of controlled release buccal bilayer tablets of carvedilol. J Integr Health Sci 2018;6:53-9

How to cite this URL:
Ramani VD, Sailor GU, Patel MM, Parmar GR, Seth AK. Experimental design approach for the formulation of controlled release buccal bilayer tablets of carvedilol. J Integr Health Sci [serial online] 2018 [cited 2022 Aug 9];6:53-9. Available from: https://www.jihs.in/text.asp?2018/6/2/53/252872

  Introduction Top

Buccal route is a preferred route of administration for drugs which having low dose, high presystemic metabolism, small molecular size and log P value of 1.60–3.30. As the oral mucosa is fairly permeable with a substantial blood supply it evades presystemic metabolism and also offers quick termination of medication in case of need.[1],[2] However, the problems of drain of drug into gastrointestinal tract through the saliva can be decreased by formulating bilayer buccal tablets which are capable of providing unidirectional drug release through buccal mucosa.

Carvedilol, [3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy) ethylamine, is a nonselective β1, β2, α1-adrenergic antagonist used in the management of hypertension and stable angina. The absolute bioavailability of carvedilol is ~25%–35% even though it is rapidly and extensively absorbed following oral administration due to a significant degree of presystemic metabolism.[3] The presence of food reduces the bioavailability of carvedilol by about 35%–40% and is unstable in acidic pH.[4] Carvedilol is a weak base having a molecular weight of 406.5 g/mol, log P value of 3.967, and pKa value of 7.8, demonstrating its ability to penetrate the buccal membrane[5],[6] and thus it can be a suitable drug candidate for the development of buccal bilayer tablet. In the present study, we report the design, development, optimization, and characterization of controlled release mucoadhesive buccal bilayer tablets of carvedilol utilizing some selective polymers such as HPMC K4M and carbomer 934.

  Experimental Top


Carvedilol was supplied from Sun Pharmaceuticals, Halol, India. HPMC K4M and carbomer 934 were received from Colorcon India Ltd. Goa, India.

Preparation of buccal tablets

The composition of the tablets is shown in [Table 1]. Initially, the mucoadhesive blend was prepared by mixing the drug and powdered excipients for 10 min and compressing using 9-mm, flat-faced punch in a single stroke using a multistation rotary punch tablet compression machine (Create Ltd, India). Following the light compression of mucoadhesive blend, the upper punch was raised and 80 mg of ethyl cellulose as backing layer was compressed over it to formulate bilayer mucoadhesive tablets. To give distinct light pink color to backing layer, 0.5% erythrosine solution was triturated with ethyl cellulose and dried in hot air oven at 50°C for about 30 min.
Table 1: 32 Full factorial design layout with coded and actual factors and their corresponding responses

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Experimental design

A 32 factorial design with two repeated center points was adopted to optimize the formulation. HPMC K4M (X1) and carbomer 934 (X2) were taken as independent variables. Responses evaluated in this study were percentage drug release in 8 h (R8) (Y1), mucoadhesion time (MT) in buccal cavity (Y2), and mucoadhesive strength (MS) (Y3). A polynomial equation was generated by this experimental design. The regression coefficients of factors and their interactions were computed from the observed experimental results.

Data analysis and validation of experimental design

The obtained response value for all factorial batches was fitted into Design Expert software (Design Expert®, Stat-Ease, Minneapolis, USA). Analysis of variance was used to validate design. Contour plot and three-dimensional (3D) response surface plots were constructed to establish the understanding of relationship of variables and its interaction.

The formulations were optimized using Design Expert® software by keeping the independent factors within the selected target range while the responses were set at the desired target. Desirability function was used to optimize the formulation while the confirmation of design validity was performed by checkpoint analysis.

Characterization of buccal tablets

Surface pH

The prepared tablets were first allowed to swell by adding 1 mL of distilled water on the surface of tablet for 2 h at room temperature. The surface pH was measured by a glass electrode (Digital pH meter-802, Systronics, Ahmedabad, India) placed on the core surface of the swollen tablet.[7]

Swelling study

One tablet of each batch was weighed (W1) and placed separately in a  Petri dish More Details containing 4 mL of phosphate buffer solution (pH 6.6). At regular intervals (0.5, 1, 2, 4, and 6 h), the tablets were removed from the Petri dishes and excess surface water was removed carefully using a filter paper. The swollen tablets were then weighed again (W2), and swelling index was calculated using Equation 1.[8]

Ex vivo mucoadhesive strength

Ex vivo MS of the tablets was measured on a modified physical balance using porcine buccal mucosa kept in Kreb's buffer at 37°C for 2 h. The underlying mucus membrane was separated and washed thoroughly with phosphate buffer solution (pH 6.8). It was then tied over the protrusion in a Teflon block using a thread. The block was then kept in a Petri dish.[9]

Two sides of the balance were made equal before the study, keeping a 5 g weight placed on the right pan. Petri dish with a Teflon block was kept below the left hand setup of the balance. The tablet was stuck on to the lower side of the hanging Teflon cylinder. Five-gram weight from the right pan was then removed. This lowered the Teflon cylinder along the tablet over the membrane with a weight of 5 g. This was kept undisturbed for 5 min. Then, the weight on the right hand side was slowly added in an increment of 0.5 g until the tablet just separated from the membrane surface. The excess weight on the right pan, i.e., the total weight minus 5 g, was taken as a measure of the MS.[10],[11]

Ex vivo mucoadhesive time

The fresh sheep buccal mucosa was tied on the glass slide, and a mucoadhesive core side of each tablet was wetted with 1 drop of phosphate buffer pH 6.8 and pasted to the sheep mucosa by applying a light force with a fingertip for 30 s. The glass slide was then put into the beaker, which was filled with 200 mL of the phosphate buffer, pH 6.8, and was kept at 37°C ± 1°C. After 2 min, a 50-rpm stirring rate was applied to stimulate the buccal cavity environment, and tablet adhesion was monitored for 8 h. The time for the tablet to detach from the sheep buccal mucosa was recorded as the MT.[8]

In vitro drug release and release kinetics

Standard USP type II dissolution apparatus was used to study the in vitro release profile using 900 mL of phosphate buffer (pH 6.8) as dissolution medium. The backing layer of the buccal tablet was fixed to the bottom of the vessel by a double-sided tape, and dissolution was carried out at a stirring speed of 50 rpm. The amount of carvedilol released was determined spectroscopically at 240 nm of 5-mL sample withdrawn at 1, 2, 3, 4, 5, 6, 7, and 8 h time intervals. The cumulative percentages of carvedilol released with respect to time for each batch were calculated.[12],[13] The data of in vitro release were fitted to different kinetic models to determine the mechanism of drug release.

Ex vivo drug permeation study

Ex vivo drug permeation study of the drug through the sheep buccal mucosa was performed using Keshary–Chien type glass diffusion cell at 37°C ± 0.2°C. The fresh sheep buccal mucosa was mounted between the donor and receptor compartments. The buccal tablet was placed with the core facing the mucosa and the compartment clamped together. The donor compartment was filled with 1 mL of phosphate buffer (pH 6.8). The receptor compartment (18 mL capacity) was filled with phosphate buffer, pH 6.8, and the hydrodynamics in the receptor compartment was maintained by stirring with a magnetic bead at 50 rpm. 2-mL sample was withdrawn at every hour (up to 8 h) and analyzed for drug content at 240 nm using a ultraviolet-visible spectrophotometer.[14],[15]

Stability study

Stability studies were carried out on the optimized formulation. Tablets were first wrapped in an aluminum foil and then placed in an amber-colored bottle. Short-term stability study was carried out at 40°C/75% ± 5% relative humidity for 6 months.[16] The tablets were evaluated for physical characteristics, mucoadhesive properties, and in vitro drug release. Results obtained were compared with data obtained for zero time at ambient temperature.

  Results and Discussion Top

Full factorial design

As per 32 full factorial design, nine batches (F1–F9) of tablets were prepared and evaluated for responses (MS, MT, and R8). The centerpoint run was replicated two times to evaluate the residuals and lack of fit. The results for the F1–F11 batches showed a wide variation and ranges between 62.9% and 100% for Y1, 181.3–514.7 min for Y2, and 9.47–11.33 g for Y3, which indicated the dependency of response on selected independent variables. The results of experimental design batches were simultaneously fitted to cubic, linear, and quadratic model using Design Expert software®. The software suggests that the best fitted model was quadratic for responses Y1, Y2, and Y3. Equations 2, 3, and 4 are the polynomial equations of full model generated for each response:

A positive value denotes an effect that favors the optimization, whereas a negative value indicates an inverse relationship between the factor and the response. Statistical validity of the polynomials was established on the basis of ANOVA which was performed to identify insignificant factors. It also indicated significant effects of the independent factors (P >F) on responses Y1 and Y2. The larger F-values for Y1= 282.44, Y2= 15630, and Y3= 162.78 suggest that the data fit to the model were significant for all responses and resulted in good correlation as high values of R2 for Y1= 0.9965, Y2= 0.9999, and Y3= 0.9939 were obtained for all dependent variables. Further, Adj-R2 and Pred-R2 values for all responses were in reasonable agreement, indicating that the data were described adequately by the mathematical model. Values of P < 0.05 indicated that model terms were significant except for response Y2, model term X12 was at P > 0.05 (P = 0.6842), and for Y3, model term X1 X2 was at P > 0.05 (P = 0.2985), indicating necessary model reduction to improve the model. The reduced model generated was tested by F statistics in portions to determine whether the coefficients b11 for and b12 for contribute significant information for the prediction of responses or not.[17] The results show that table value of F for α = 0.05 is equal to 6.61 (df = 1, 5), while the calculated value of F (Y2, FCalc= 0.1839; Y3, FCalc= 1.273) is less than the table value (FTab= 6.61), indicating that the interaction terms b11 for Y2 and b12 for Y3 do not contribute significantly to the prediction of responses and therefore can be omitted from the full model. Nonsignificant (Y1 = 0.6093, Y2= 0.4678, and Y3= 0.1785) lack of fit for all responses also implies that the models were adequate for the prediction with the range of experimental variables. Equations 5 and 6 are the polynomial equations for reduced model generated for Y2 and Y3, respectively:

The response surface (3D) and contour plots generated by Design Expert software were used to study the pattern of interaction between variables. Response surface graph for Y1[Figure 1] shows that, on increasing the concentration of either HPMC K4M or carbomer 934, there was a decrease in R8. The higher value of X2 coefficient implies that carbomer 934 has a high impact on release of drug as compared to HPMC K4M. The impact of X2 was also found at higher-order model term as shown in Equation 2.
Figure 1: Contour and three-dimensional surface plots for Y1: % drug release after 8 h (R8), Y2: Mucoadhesive time and Y3: Mucoadhesive strength

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Response surface graph for Y2 and Y3[Figure 1] show that, with increase in the concentration of either HPMC K4M or carbomer 934, an increase in MT was observed. The polynomial equations 5 and 6 show the positive sign of both the coefficients b1 and b2, indicating synergistic effect on Y2 as well as Y3. The higher value of coefficient of X2 implies that carbomer 934 has a high impact on MT as well as MS as compared to HPMC K4M. The impact of X2 was also found at higher-order model term as shown in Equations 5 and 6.

Optimization and validation of design

Desirability function approach was used to search for the optimized formulation composition with desired responses. The optimization process was performed by setting the responses Y1≥80 and Y2≥460, while no targets were selected for because all the factorial batches showed appreciable MS (Y3). On the basis of this, software suggests the various compositions of formulation starting with the highest desirability value. The desirability of optimized batch (OB) was closer to 1, indicating that this formulation was successful in achieving the desired targets. The comparison of predicted and experimental values of prepared (OB) shows low value of percent relative bias (<10%) for each response, indicating excellent lack of fit [Table 2]. These results also suggest the success of experimental design along with desirability approach for the evaluation and optimization of formulation. Validation of experimental design and polynomial equations was performed by checkpoint analysis. For that, three formulations (VB1–VB3) were selected, prepared, and evaluated for responses [Table 2]. A low value of percentage bias (<5%) in case of checkpoint batches depicted that there was reasonable agreement in the predicted and experimental values.
Table 2: Predicted and experimental values for optimized and checkpoint batches

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Characterization of tablets

Surface pH

The surface pH of all the tablets was within a range of 6.3 ± 0.17–6.9 ± 0.15, which is similar to buccal mucosal pH, specifying buccal mucosal compatibility and minimal pH-related discomfort.

Swelling study

In order to achieve prolonged and uniform drug release from mucoadhesive system, swelling property plays an important role.[18] The results of the study show that swelling index of tablets was directly proportional to the concentration of carbomer 934 and HPMC K4M and varies from 0.81 to 1.29. The tablets of batch F1 with low polymer content broke after 2 h which may be due to the erosion of polymers in medium.

Effect of formulation variable on ex vivo mucoadhesive strength

The mucoadhesive property of tablets containing varying proportion of polymers was determined with a view to develop a compact with good adhesiveness without any irritation and other problems. The results showed that increase in the amount of both polymer (carbomer 934 and HPMC K4M), bioadhesion strength increase. This was due to hydration of polymer by hydrated mucus layer which resulted in reduced glass transition temperature and increased de-coiling along with an increased motility of polymer chain.[19] This tends to increase the adhesive surface for maximum contact with mucin and flexibility for interpenetration with mucin. As shown in [Table 1], the highest MS (11.33 g) was proposed by batch F9 containing the highest levels of polymer and the least force of adhesion was proposed by batch F1, indicating that concentration of carbomer 934 had direct effect on the MS while HPMC K4M had less effect on the MS.[15]

Effect of formulation variable on ex vivo mucoadhesive time

Ex vivo MT for all tablets varied from 114 to 474 min [Table 1]. The combination of polymers directly influenced the MT. The results indicate that MT increased with increase in the amount of polymers.

Effect of formulation variable on in vitro drug release study

The drug polymer ratio plays a vital role in controlling the rate of drug release from tablets. The batch F1 showed the maximum drug release; this batch was containing less polymer content (carbomer 934 [3 mg] and HPMC K4M [5 mg]). Minimum drug release was seen with the formulation F9 containing carbomer 934 (7 mg) and HPMC K4M (15 mg). The drug release rate increased with decrease in the extent of HPMC K4M and carbomer 934 [Table 1] and [Figure 2]a. This may be due to the hydrophilic swellable nature of carbomer 934 and HPMC K4M, which can form a viscous gel layer. This gel layer controls the drug release via diffusion resulting in greater retardation of drug release.[20],[21],[22] Furthermore, the rate of drug dissolution is also affected by the presence of carbomer 934 due to dissociation of carboxyl groups at buccal pH, which results slower diffusion of drug through matrix by the formation of swollen gel. However, due to the nonionic nature of HPMC K4M, the viscosity of gel layer remains constant at buccal pH.[23]
Figure 2: (a) In vitro drug release study for F1–F9 and optimized batch, (b) Ex vivo permeation study for optimized batch

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Kinetics modeling of in vitro drug release

Drug bioavailability is greatly influenced by drug release kinetics which depends on the physicochemical properties of drug and polymer.In vitro drug release data were fitted in to Higuchi and Korsmeyer–Peppas model to determine the kinetics and mechanism of drug release from bilayer tablet formulation. The release kinetics from the optimized formulation (OB) was compared to different kinetic models. Results showed that the model was best fitted with data in Korsmeyer–Peppas model (R2 = 0.980). The value of release exponent “n” was greater than 1, suggesting super case II transport mechanism. In this kind of transport, there are two simultaneous fluxes. The first flux (glassy state) is the rate at which the diffusing material is released at an interface by relaxation of the polymer matrix.[24] In the glassy state, the matrix has a finite relaxation time, associated with the length of the polymers in relation to the entanglement network.[25] The second flux (rubbery state) is the rate at which the material diffuses away from the interface. The parameters governing the release of the dissolved material are thus the rate at which the interface moves, the diffusivity of the dissolved material in the rubbery polymer, and the total length of the diffusional path.[26] In this kind of transport, the polymer relaxation is the rate-limiting step to water transport.[27]

Ex vivo drug permeation study

Ex vivo permeation study was done to simulate the in vivo condition as close as possible. It is also a useful tool to evaluate the potential of a localized anatomical site as route for drug delivery. In optimized formulation (F12), the drug was permeated up to 67.5% ± 1.60% within 8 h through porcine buccal mucosa [Figure 2]b.[28]

Stability studies

Results of stability studies [Table 3] of optimized formulation (OB) indicate that it is stable at 40°C and 75% ± 5% relative humidity, as there was no significant difference observed for R8, MT, and MS data. This also proves that the OB was stable with excipients in the study.
Table 3: Short-term stability data of mucoadhesive bilayer tablets stored at 40°C/75% RH for 6 months

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  Conclusion Top

The mucoadhesive buccal bilayer tablets of carvedilol may be one of the alternative ways to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of carvedilol. The optimized formulation (OB) was developed using 32 full factorial design which gives optimum value of variables in the formulation to get desired responses. The experimental values of all validation batch prepared under optimized conditions were found to be very close to the predicted values, suggesting the effectiveness of the present model in the optimization of formulation. Furthermore, model fitting of the in vitro release data suggests super case-II transport mechanism according to Korsmeyer–Peppas model, indicating the role of polymer relaxation in controlled drug release. In summary, the results demonstrated the potential of 32 full factorial design with desirability functionality which could be a suitable approach for understanding formulation variables and for efficiently optimizing the formulation. The prepared tablets of carvedilol demonstrate potential to meet patient compliance with therapeutic demands in the treatment of hypertension.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]

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