Formulation and Evaluation of Bilayered Buccal Adhesive Tablets of Carvedilol

Sirisha Y. and Venkateswara Rao T.

Bapatla College of Pharmacy, Bapatla Educational Society, Bapatla, Guntur District, Andhrapradesh-522101

ABSTRACT:

Carvedilol is a non selective α and β receptor blocker which undergoes extensive hepatic first pass metabolism by liver and has poor oral bioavailability of 25% - 30%. In the present investigation Carvedilol was formulated as a bilayered buccal adhesive tablets in order to avoid the first-pass effect and decrease the drug loss using different polymers and excipients. Twelve formulations were made using different concentrations (17%w/w, 35%w/w, 53%w/w) of Carbopol934P, HPMC (3500-6000cps), HPC and Guar gum. The formulations were tested for %weight variation, hardness, Friability, %Drug content, in-vitro drug release, surface pH, Swelling index and Mucoadhesive strength. Mucoadhesive strength was determined by the modified balance method in grams and was found to be between 27.75±0.234gm to 75.94±0.146gm and Surface pH was found to be 7. In-vitro release studies revealed that as polymer concentration increases from 17% to 53%w/w, rate of drug release was retarded and the data was fitted into pharmacokinetic models. Among all other formulations, formulations (F_4,F₈and F₁₁) containing 17%w/w HPMC, 35%w/wHPC and 35%w/w Guar gum were found to be best as the release was retarded upto 8.5 hours and they have good mucoadhesive strength and they follow zero order with non-fickian diffusion mechanism.

KEYWORDS: Bilayered buccal tablets, Carvedilol, Carbopol934P, HPMC, HPC, Guar gum

INTRODUCTION:

Buccal preparations have been developed to allow prolonged localized therapy and enhanced systemic delivery. The ability to maintain a delivery system at a particular location for an extended period of time has great appeal for both local as well as systemic drug bioavailability. Drug absorption through a mucosal surface is efficient because mucosal surfaces are usually rich in blood supply, providing rapid drug transport to the systemic circulation and avoiding degradation by gastrointestinal enzymes and first pass hepatic metabolism.

Carvedilol is a non selective α,β receptor blocker used in the treatment of hypertension and stable angina pectoris. It has biological half life of 2-6hr. It undergoes extensive hepatic first pass metabolism and intestinal metabolism with 25-30% oral bioavailability. An alternative to the oral route is needed for the effective drug delivery. In the present investigation Bilayered Carvedilol buccal adhesive tablets were designed and developed as these offers a wide range of advantages viz. avoidance of first pass metabolism, prevention of drug degradation by gastointestinal enzymes, provides rapid drug absorption, self-placement of a dosage form and improves patient compliance..

Materials:

Carvedilol, gift sample from Aurobindo pharma ltd,Himachal pradesh, Carbopol934P from Siri’s pvt ltd.Vijayawada, HPMC(3500-6000cps) from S.D fine chemicals Mumbai, HPC from Dr.Reddy’s Hyderabad, Guargum, Ethyl cellulose from Qualigens fine chemicals Mumbai, Spraydried lactose obtained from Reddy’s laboratories Hyderabad and Talc.

Methods:

Estimation of Carvedilol :

The following methods are available for the estimation of Carvedilol :

High Performance Liquid Chromatography, Liquid Chromatography, Capillary Electrophoresis, Spectrophotometric method, Spectrofluorimetric method and Mass Spectrometry.

A spectrophotometric method based on the measurement of extinction at 242.5 nm in 0.5%w/v SLS was used in the present study for the estimation of Carvedilol.

Standard solution:

25 mg of Carvedilol was dissolved in 5ml methanol in a 25ml volumetric flask and the volume was made up to 25ml with 0.5%w/v SLS solution.

Procedure:

The standard solution of Carvedilol was subsequently diluted with 0.5%w/vSLS solution to obtain a series of dilutions containing 2, 4, 6, 8 and 10 µg of Carvedilol per 1 ml of solution. The absorbance of the above dilutions was measured in Shimadzu double beam UV spectrophotometer at 242.5 nm using the 0.5%w/vSLS solution as a blank. The concentrations of Carvedilol and the corresponding absorbance values are given Table 1. The absorbance values were plotted against concentrations of Carvedilol as shown in Fig 1.

Fig .1:Calibration curve for the estimation Of Carvedilol:

Table.1: Calibration Curve For The Estimation Of Carvedilol:

Concentration (µg /ml)	Absorbance ((± s.d))
0	0
2	0.184±0.0002
4	0.390±0.0001
6	0.582±0.0014
8	0.764±0.0016
10	0.988±0.0001

PREFORMULATION STUDIES:

Infrared (IR) spectral studies were conducted for the samples to estimate if any interaction between the drug and polymers. In-vitro permeation studies were conducted to determine the permeability of drug.

Infrared Spectroscopic Analysis:

Infrared (IR) spectra were obtained using the KBr disk method (2 mg sample in 200 mg KBr). The scanning range was 400 to 4000 cm-1 and the resolution was 1 cm^-1.

In-vitro buccal permeation studies²:

In-vitro diffusion study of pure drug was carried out using fresh sheep buccal mucosa. It was studied using Franz diffusion cell. The donor compartment was filled with 6ml of 0.5%w/v sodium lauryl sulphate solution (SLS) containing 20% methanol. 6.25mg of drug was dissolved in the above solution. The receptor compartment consists of 15ml of 0.5%w/v SLS solution to maintain sink conditions. The whole assembly was maintained at 37±1^oc. Three ml of samples were withdrawn from the receptor compartment and replaced with same amount of fresh medium. The withdrawn samples were then diluted suitably and estimated for drug spectrophotometrically at 242.5nm and the % cumulative drug diffused was calculated.

Formulation of mucoadhesive buccal tablets of Carvedilol:

The composition of the tablet formulations were shown in Table 2. Required amount of drug, polymers and diluents except Ethyl cellulose were blended in mortar with a pestle to obtain uniform mixture. Then mixture was then mixed with Talc. The blended powder was then slightly compressed initially and then required quantity of EC(backing layer) was added and compressed into tablets employing direct compression technique using 16 station rotary tablet machine (Cadmach, India) with 9 mm round shaped flat punches.

Micrometric studies on the physical mixtures:

Loose bulk density, tapped bulk density and the angle of repose for the physical mixtures were determined by fixed funnel method and by density apparatus. Carr’s index and Haussner’s ratios were calculated by the following formulas.

Compressibility index (I) was calculated as follows:

I = V₀-V_t/ V₀× 100

Where V₀ - bulk volume

V_t - tapped volume

Haussner’s ratio = Tapped density / Bulk density

Table 2 : Formulation of Carvedilol Buccal Adhesive Tablets using Carbopol934P, HPMC(3500-6000cps), HPC-M and Guar gum

*S. NO*	INGREDIENTS	*Quantity per single tablet(mg)*
*S. NO*	INGREDIENTS	F₁	F₂	F₃	F₄	F₅	F₆	F₇	F₈	F₉	*F₁₀*	*F₁₁*	*F₁₂*
1.	Carvedilol	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25
2.	Carbopol934P	35.437	70.875	106.31	-	-	-	-	-	-	-	-	-
3.	HPMC(3000-5600cps)	-	-	-	35.437	70.875	106. 31	-	-	-	-	-	-
4.	HPC-M	-	-	-	-	-	-	35.437	70.875	106.31	-	-	-
5.	Guar gum	-	-	-	-	-	-	-	-	-	35. 437	70. 875	106.31
6.	Spray dried Lactose	106.31	70.875	35.437	106.31	70.875	35. 437	106.31	70.875	35. 437	106.31	70. 875	35. 437
7.	Talc	2	2	2	2	2	2	2	2	2	2	2	2
8.	Ethyl Cellulose	50	50	50	50	50	50	50	50	50	50	50	50
Total tablet weight (mg)		200	200	200	200	200	200	200	200	200	200	200	200

Evaluation studies on carvedilol buccal tablets:

All the prepared mucoadhesive buccal tablets were evaluated for following official and unofficial parameters.

Weight Variation³:

Formulated tablets were tested for weight uniformity, 20 tablets were weighed collectively and individually. From the collective weight, average weight was calculated. The percent weight variation was calculated by using the following formula.

Hardness:

The hardness of tablets was measured by Monsanto hardness tester. The hardness was measured in terms of kg/cm².

Friability⁴:

The Roche friability test apparatus was used to determine the friability of the tablets. Twenty pre-weighed tablets were placed in the apparatus and operated for 100 revolutions and then the tablets were reweighed. The percentage friability was calculated according to the following formula.

Surface pH²:

The tablets were allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.5 ± 0.05) for 2hr at room temperature. The pH was measured by bringing the electrode in contact with the surface of the tablet and allowed it to equilibrate for 1min.

% Drug Content²:

Three tablets were taken in separate 100 ml volumetric flaks containing 100 ml of 0.5%w/v SLS and were kept for 24 hrs undisturbed. The solutions were then filtered, diluted suitably and analyzed at 242.5 nm using UV- spectrophotometer. The average of three tablets was taken as the content of drug in one tablet unit.

Swelling index²:

Tablets were weighed (W1) and placed separately in Petri dishes containing 20 ml of 0.5w/v SLS solution. At regular time intervals tablets were removed and the excess water on their surface was carefully removed using filter paper. The swollen tablets were reweighed (W2) and the index of swelling was calculated by the following formula

Swelling Index (S.I) = [(W2-W1)/W1] x 100

In-vitro mucoadhesive strength⁴:

Adhesive properties of Carvedilol mucoadhesive buccal tablet formulations were carried out by using modified balance method described by Gupta et.al. Sheep buccal mucosa were collected from the slaughter house and stored in 0.5%w/v SLS buffer solution. The sheep buccal mucosa was attached to the back of right pan of the balance by using cellophane tape. The balance was now balanced properly using sufficient weights. A tablet to be tested was attached to the base of a glass slide using cynoacrylate glue. The right pan which was attached to the tablet with mild force and weights were added slowly to the left pan and the weight in grams at which the tablet detaches form the sheep mucosal surface was noted.

In-Vitro Release Studies⁵:

In-vitro drug release studies of carvedilol buccal adhesive tablets were performed in 500 ml of 0.5%w/v SLS at 37+0.5^oC using USP type II dissolution apparatus with a paddle speed of 50 rpm. The tablet was attached to a glass slide with instant adhesive and placed at the bottom of dissolution vessel. Aliquots (5ml each) were withdrawn at regular time intervals and replaced with fresh medium to maintain sink conditions. The samples were filtered, with appropriate dilutions with the above solution and were analysed spectrophotometrically at 242.5

RESULTS:

Table 3: physic chemical evaluation of the formulations formulated with Carbopol 934P, HPMC, HPC and Guar gum

Formulation	%weight variation	Hardness kg/cm²	% Friability	Surface pH	% Drug content	Mucoadhesive Strength (g)	Swelling index At 6^thhr
F₁	0.395±0.081	4.7±0.156	0.36±0.066	7.21±0.153	98.57±0.065	27.75±0.234	25.88±0.178
F₂	0.427±0.185	4.9±0.172	0.58±0.018	6.29±0.033	102.22±0.083	33.65±0.186	33.33±0.322
F₃	0.436±0.306	4.8±0.211	0.65±0.047	6.73±0.218	101.37±0.21	44.43±0.099	38.09±0.096
F₄	0.417±0.356	4.7±0.132	0.54±0.017	6.37±0.082	101.26±0.051	35.73±0.241	76.19±0.220
F₅	0.411±0.274	4.9±0.12	0.37±0.022	5.95±0.113	99.24±0.161	48.71±0.056	125.00±0.225
F₆	0.423±0.362	4.8±0.234	0.42±0.025	6.24±0.034	100.33±0.024	54.35±0.135	147.62±0.224
F₇	0.409±0.307	4.6±0.352	0.47±0.026	5.82±0.036	99.46±0.088	35.42±0.065	38.15±0.222
F₈	0.417±0.256	4.5±0.224	0.63±0.017	5.94±0.047	100.19±0.052	48.47±0.078	50.76±0.244
F₉	0.423±0.264	4.4±0.122	0.56±0.072	6.46±0.261	98.82±0.073	59.94±0.146	52.38±0.118
F₁₀	0.427±0.270	4.7±0.102	0.36±0.025	6.11±0.032	99.65±0.011	35.66±0.203	85.71±0.16
F₁₁	0.435±0.166	4.5±0.212	0.53±0.023	6.25±0.242	100.82±0.043	55.36±0.175	175.41±0.217
F₁₂	0.408±0.248	4.8±0.116	0.62±0.024	6.74±0.045	101.33±0.06	60.89±0.134	200.05±0.255

Table 4 In-vitro release kinetics of Carvedilol buccoadhesive tablets formulated with Carbopol934P, HPMC(3000-5600cps), HPC and Guargum

Formulation	Correlation coefficient					Release rate
Formulation	Zero order	First order	Higguchi	Peppas	Hixson- Crowell	k₀ (mg/hr)	%D.E	T₅₀ Hr	T₉₀ Hr	Exponential coefficient (n)
F₁	0.9259	0.8485	0.9728	0.9845	0.9602	4.5758	66.23	0.3	1.7	0.3219
F₂	0.9273	0.8402	0.9764	0.9886	0.9382	2.7588	57.53	1.4	3.2	0.4932
F₃	0.9551	0.8443	0.9759	0.9778	0.9379	2.4543	54.53	1.7	3.7	0.5543
F₄	0.9479	0.7657	0.9462	0.9560	0.8863	1.5479	48.44	4.7	8.4	0.5233
F₅	0.9659	0.7568	0.9727	0.9931	0.9643	1.3944	50.98	4.1	13.5	0.5759
F₆	0.9588	0.8456	0.9778	0.9845	0.9542	1.3591	44.31	5.6	18.1	0.5124
F₇	0.9722	0.8022	0.9606	0.9804	0.9140	2.4108	57.27	2.4	5.7	0.5194
F₈	0.9639	0.7295	0.9384	0.9439	0.8789	1.5073	48.13	4.9	8.3	0.5494
F₉	0.9705	0.9537	0.9403	0.9718	0.9393	1.2813	43.43	6.4	10.9	0.5542
F₁₀	0.9659	0.8353	0.9736	0.9817	0.9405	1.7936	53.80	2.8	5.7	0.5902
F₁₁	0.9879	0.7904	0.9677	0.9848	0.9216	1..5250	49.76	3.9	7.8	0.6067
F₁₂	0.9416	0.9153	0.9187	0.9257	0.9345	1.1735	35.30	6.9	12.2	0.5096

RESULTS AND DISCUSSION:

The designed buccal mucoadhesive controlled release tablets Carvedilol were found to possess good physico- chemical properties and results were presented in Table 3.The prepared tablets were smooth white in colour. %Weight variation and hardness falls well within the acceptance criteria. Friability was 1%w/w indicating the suitability for manufacturing of tablets by this method. The percent drug content of developed formulations was between 98% to 101%. The mucoadhesive strength of designed formulations were presented in Table 3. It was found that mucoadhesive strength depends upon the polymer type, polymer concentrations and polymer viscosity. If the concentration of polymer was low the no. of penetrating chains per unit volume of mucous is low, so it results in weaker interaction with mucous. Formulation containing higher concentrations of Guar gum (51%w/w) shows superior mucoadhesive strength of 60.89g when compared to other polymers like carbopol934P, HPMC and HPC as reported in table 3.

In vitro release study data indicates that duration of release of drug is dependent on polymer concentrations used in the formulations. Increase in the polymer concentration increases the viscosity and that leads to decrease in the diffusion of the drug and it results in reduction in drug release rate. The Invitro release kinetics and plots of cumulative percent drug release v_S time were shown in Table 4 and figure 2, 3, 4and5 respectively. Increasing polymer concentration from 17% to 51%w/w of tablet weight resulted in controlled drug release from 2 to 8 hours. The maximum % drug release was shown by F₁₁and drug release from tablets was fitted into various kinetic models and obeyed zero order kinetics and non-fickian transport mechanism.

CONCLUSION:

It can be concluded that the designed buccoadhesive tablets of Carvedilol showed controlled release upto 8.5hrs for formulations F_4,F₈and F₁₁with good mucoadhesive strength upto 60.89g. All the physic chemical parameters are in acceptable limits and the formulations follows zero order kinetics and non-fickian anomalous transport mechanism. Thus bilayer buccal adhesive tablets of Carvedilol were successfully developed to overcome the disadvantages of oral administration of carvedilol tablets

ACKNOWLEDGEMENTS:

The authors express their gratitude to Aurobindo pharma ltd. Himachal pradesh for providing gift sample of Carvedilol. The authors are thankful to Bapatla Educational Society, Bapatla for providing facilities to carry out research.

REFERENCES:

1. Paudel KR1, Rauniar GP, Bhattacharya SK and Das BP. “Recent advancement in drug delivery system”. Kathmandu University Medical Journal (2008), Vol. 6, No. 2, Issue 22, 262-267.

2. Sonia Pandey, Aarti Gupta, Jitendra Singh Yadav and D.R.Shah.”Formulation and invitro evaluation of bilayered buccal tablets of Carvedilol”. Indian J.Pharm. Educ. Res. 44(3), Jul-Sep, 2010.

3. Indian Pharmacopeia 1996, Ministry of Health and Family Welfare, the Controller of Publications, New Delhi, 2, 750, 1996.

4. USP 27/NF 22, United States Pharmacopeial Convention, Rockville, 2621,2004.

5. Vamshi vishnu Yamsani and M. E. Bhanoji Rao. Development and in-vitro evaluation of buccoadhesive tablets of Carvedilol tablets. Acta Pharm. 57 (2007) 185–197.

Received on 15.07.2011

Modified on 24.07.2011

Accepted on 01.08.2011

Research J. Science and Tech. 3(6): Nov.-Dec. 2011: 335-339