Preparation and In vitro Evaluation of Buccoadhesive Tablets of Carvedilol Using Dried Mucilage Powder of Aegle marmelose

 

Nath Bipul1*, Nath LK2 and Kumar PY3

1Girijananada Chowdhury Institute of Pharmaceutical Sciences (Affiliated to Gauhati University), Gauhati-781017, Assam, (India)

2Department of Pharmaceutical Sciences, Dibrugarh University, 786004, Assam (India)

3Department of Pharmaceutical Sciences, SGRR, UTU, Dehradun-248161, UK (India)

*Corresponding Author E-mail:   bipulnath@gmail.com  

 

ABSTRACT

The purpose of this research was to develop and evaluate buccal mucoadhesive tablets of Carvedilol using dried mucilage powder of Aegle marmelose as primary mucoadhesive polymer and HPMC, NaCMC as secondary polymers. Carvedilol which undergoes extensive first pass metabolism were used as model drug. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were prepared by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of drug release. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type and its proportion. The formulations prepared using dried mucilage of Aegle marmelose gave maximum mucoadhesion, and strength decreases with decrease in its content. The buccoadhesive tablets containing 1:1 ratio of mucilaginous powder and HPMC showed suitable release kinetics, and properties for adhesion to the buccal mucosal surface. The release data seem to fit better with Higuchi model indicating that drug release from the buccoadhesive tablet was diffusion controlled.

 

KEYWORDS: Mucilage, Carvedilol, first pass effect, buccoadhesive, swelling, Higuchi model.

 

 


INTRODUCTION:

The buccal region, within the oral cavity, offers an attractive route of administration for absorption of therapeutic agents directly in to the systemic circulation, and thereby avoiding first-pass metabolism and gastrointestinal drug degradation. 1, 2 The buccoadhesive drug delivery systems have been developed basically to increase the retention of drug in the oral cavity and/or to keep a sustained release of drug towards the medium from where it is constantly removed 3,4. However, the buccal route has received much attention because of its good accessibility, robustness of the epithelium, facile removal of the dosage form, relatively low enzymatic activity, natural clearance mechanism for elimination of the drug from buccal area, satisfactory patient compliance, and improvement of bioavailability.5-7

 

Consequently, buccal drug delivery requires the use of mucoadhesive polymers as these dosage forms should ideally adhere to the mucosa and withstand salivation, tongue movement and swallowing for a significant period of time8. Various Buccoadhesive polymers like carbopol 934P, carbopol 974P, hydroxypropyl methylcellulose, Eudragit, hydroxylpropylcellulose and chitosan are extensively used 9-11.

 

Aegle marmelose (Bael fruit) contains a transparent mucilaginous pectin like substance (Marmelosin Halfordinol) having excellent mucoadhesive property. Carvedilol is a non-selective β-adrenergic antagonist used in the treatment of hypertension and stable angina pectoris. It also possesses antioxidant and antiproliferative effects, which may enhance its ability to combat the deleterious effects of sympathetic nervous system activation in heart failure.12 Carvedilol was selected as a model drug for the investigation because its oral dose is low 6.25 mg. The drug has a half life of 6-8 hours and it undergoes extensive first pass metabolism 10.

 

The aim of the present investigation is to develop and evaluate buccal mucoadhesive tablets of Carvedilol using powder mucilage of Aegle marmelose as primary mucoadhesive polymer and HPMC, NaCMC as secondary polymers. Effect of polymer type, proportion and combination was studied on the drug release rate, mucoadhesive strength of the prepared formulations and possible release mechanism proposed.

 

MATERIAL AND METHODS:

Materials:

Carvedilol was obtained as gift sample from Torrent Pharmaceutical Ltd, Ahmadabad, Gujrat, India. Mucoadhesive dried mucilaginous polymer was collected from unripe fruits of Aegle mermelose grown in Northeastern region (Assam), India. Hydroxypropylmethylcellulose (HPMC K15) and Sodium Carboxymethylcellulose (NaCMC) was procured from Central Drug House, Mumbai. (Rankem, New Delhi).  All other chemicals and reagents used in the study were of analytical grade.

 

Fig. 1. FT-IR spectra of pure drug (A), Buccoadhesive tablets containing mixture of mucilage powder, HPMC and the drug (B), Blank polymer mixture of mucilage and HPMC (C), Blank mucilage powder (D).

 

Methods:

Solubility studies:

A saturated solution of Carvedilol was prepared by shaking an excess amount in 2 ml phosphate buffer pH 6.6/distilled water at 25 ± 10°C room temperature for 24 h. The saturated solution was withdrawn, filtered and analyzed at 244 nm using UV visible spectrophotometer (Shimadzu 1601, Japan) 13.

 

Partition coefficient:

A major criterion in evaluating the ability of a drug to penetrate the lipid membranes is its apparent oil/water partition coefficient13. Mutually saturated 1-octanol and phosphate buffer solution (pH 6.6) at 37°C were used containing Carvediol (100 μg/ml). The two phases were then allowed to equilibrate at 37°C for 24 h on a magnetic stirrer. The concentration of carvedilol in the aqueous phase was determined spectrophotometrically at 244 nm.

 

Fig.2: In vitro drug release rate curve for different buccoadhesive tablets containing different proportion of mucilage powder and HPMC. FA1 (-■-), FA2 (-▲-), FA3 (-●-) showing release of drug from prepared formulations.

 

Isolation and purification of mucoadhesive polymer:

Bael fruit (Aegle marmelose, family Rutaceae) occupies an important place among other minor fruits in India. Various chemical constituents namely alkaloids, coumarins, mucilage, tannins, steroids have been isolated and identified from different parts of bael tree. The seed sac of bael fruit contains a transparent mucilaginous substance having excellent mucoadhesive property. The mucilage was collected by cutting the fruit into smaller pieces and the mucilage was collected on a glass petridish with the help of a needleless syringe and dried at room temperature. The dried mucilage is grounded in a porcelain mortar in presence of small quantity acetone. The powdered mucilage is finally washed several times with acetone and dried and stored in desiccators.

 

Formulation of buccoadhesive tablets:

Controlled-release buccoadhesive tablets were prepared by direct compression method using the formula shown in Table 1. Different ratios of natural mucoadhesive polymer, HPMC, NaCMC, fixed amount of Carvedilol and 1% magnesium stearate were passed through a No. 85 sieve and mixed in mortar with a pestle to obtain uniform mixing. The blended powder was compressed into tablets weighing appprox. 150 mg on a single punch tablet machine (Cadmach, Ahmadabad) using a flat-faced non-beveled punch and die set of 8-mm diameter13.

 


Table 1. Composition of Carvedilol buccoadhesive tablets

Ingradients

Formulation Code

FA1

FA2

FA3

FA4

FA5

FA6

Drug

6.25

6.25

6.25

6.25

6.25

6.25

Mucilage powder

72

48

36

72

48

36

HPMC

72

96

108

-------

-------

-------

NaCMC

-------

-------

--------

72

96

108

Magnesium stearate

1.5

1.5

1.5

1.5

1.5

1.5

Total weight

151.75

151.75

151.75

151.75

151.75

151.75

 

 

 

 

 

 

 

 

 

 

 

Table 2: Physical characteristics of buccoadhesive tablets of Carvedilol

Formulation Code

Thickness

(mm)

Hardness

( Kg/ cm2)

Content Uniformity

(mg)

Weight Uniformity

(mg)

Bioadhesive

Strength (gms) ±SD

FA1

2.31±0.12

10.98

4.87±0.52

148.6±12.5

26.41±0.81

FA2

2.51±0.05

8.6

4.75±0.41

149.5±6.75

21.71±1.12

FA3

2.56±0.08

8.5

4.71±0.75

150.0±5.8

18.64±0.45

FA4

2.28±0.16

6.5

4.91±0.59

147.8±13.2

37.18±0.78

FA5

2.38±0.13

5.5

4.85±0.83

148.5±10.98

32.54±0.26

FA6

2.41±0.15

5.0

4.79±0.97

150.0±8.5

29.61±0.15

 

 

 

 

 

 

 

 

 

* All values are expressed as mean ± SD, n=3

 

Table 3: Swelling index of Carvedilol buccoadhesive tablets

Formulation Code

% Swelling Index

Time (hr)

0.5

1.0

2.0

4.0

6.0

FA1

23.15±0.83

47.17±0.55

121.7±0.96

151.2±0.95

156.2±1.30

FA2

35.17±0.59

67.17±0.608

131.3±1.77

163.1±1.1

169.61±1.57

FA3

45.16±0.50

61.21±1.68

137.15±1.17

171.3±1.60

179.15±1.02

FA4

71.13±0.97

127.17±0.88

241.17±1.03

243.12±0.87

245.18±0.95

FA5

77.15±0.92

136.15±1.03

248.17±0.97

261.7±1.40

263.17±1.08

FA6

89.15±1.04

143.2±2.0

263.15±0.74

268.17±1.59

272.52±0.87

 

 

 

 

 

 

 

 

 

 

* All values are expressed as mean ± SD, n=3

 

Table 4: Evaluation of drug release data for Carvedilol buccoadhesive tablets

Formulation Code

Kinetic models

Zero Order

First Order

Higuchi

Korsemeyer-peppas

R2

k0

R2

k1

R2

kH

R2

n

FA1

0.954

6.092

0.919

0.387

0.992

23.88

0.863

0.066

FA2

0.965

5.787

0.928

0.351

0.987

23.68

0.839

0.081

FA3

0.983

4.84

0.890

0.259

0.984

20.15

0.888

0.087

FA4

0.985

9.7

0.889

1.295

0.937

38.82

0.781

0.072

FA5

0.982

8.534

0.720

0.770

0.952

34.43

0.949

0.076

FA6

0.976

6.74

0.821

0.462

0.980

26.84

0.901

0.072

 

 

 

 

 

 

 

 

 

 

* r2-Correlation coefficient, k0,k1,kH are zero order, 1st order, Higuchi rate constant respectively and n is the release exponent (0.5<n<1)

 


 

Fig.2: In vitro drug release rate curve for different buccoadhesive tablets containing different proportion of mucilage powder and HPMC. FA1 (-■-), FA2 (-▲-), FA3 (-●-) showing release of drug from prepared formulations.

 

Fig.3: In vitro drug release rate curve for different buccoadhesive tablets containing different proportion of mucilage powder and NaCMC. FA4 (-□-), FA5 (-Δ-), FA6 (-○-) showing release of drug from prepared formulations.

Evaluation of physical properties of mucoadhesive tablets:

The thickness, hardness, drug content uniformity and weight uniformity were determined in a similar manner as stated for conventional oral tablets in the accredited pharmacopoeia14

 

Drug content uniformity:

Drug content uniformity experiments were carried out by the procedure stated in the US pharmacopoeia14.

 

Swelling studies:

Each four tablets which was individually weighed (W1) were placed on a petridish containing 6 ml phosphate buffer (pH 6.6) and incubated at 37º C. At time intervals of 0.5, 1, 2, 3, 4, 5, 6 hrs one petri dish was removed from the incubator and swollen tablets were weighed out (W2). Swelling index (SI) was calculated using following formula15.

S1= (W2-W1)/W1

 

Surface pH:

The surface pH of the buccoadhesive tablet was determined in order to predict the possible irritant effects of the formulation on the buccal mucosa15. The buccoadhesive systems were allowed to swell at 37 ± 1°C for 2 h in 40 ml phosphate buffer (pH 6.6). The surface pH of the swollen buccoadhesive tablets was measured using pH paper (Rankem, New Delhi, India). Experiments were carried out in triplicate and the mean surface pH was determined.

 

In vitro mucoadhesion test:

The mucoadhesive strength of the buccoadhesive systems was measured by a modified two-arm balance using porcine buccal mucosa10. Porcine buccal mucosa was obtained from a local slaughterhouse and stored in Krebs buffer and studies were conducted within 3 h of procurement. The beaker on one side of the balance was counterbalanced by adding suitable weights to the other side. The buccoadhesive tablet was fixed with cyanoacrylate adhesive to the upper clamp. A circular piece of pig buccal mucosa was fixed to the tissue holder with cyanoacrylate adhesive immersed in tyrode solution and the temperature maintained at 37 ± 1°C. The buccoadhesive tablet was then placed on the buccal mucosa by using a preload of 50 g and kept in place for 5 min to facilitate adhesion bonding. After the preloading time, the preload was removed and water was allowed to flow into the beaker kept on the other side of the balance at a flow rate of 1 drop/sec until bucoadhesive tablet detached from the buccal mucosa. The weight (g) required to separate the system from the porcine buccal mucosa was measured using a modified two-arm balance.

 

Fourier Transform Infrared Spectroscopy (FT-IR):

Drug-polymer interactions were studied by FT-IR spectroscopy. The spectra were recorded for pure drug and physical mixture of the tablet using FT-IR (Perkin Elmer, Model No. 883). Samples were prepared in KBr disks (2 mg sample in 200 mg KBr). The scanning range was 400-4000 cm-1 and the resolution was 2 cm -1.

 

In vitro drug release study:

The in-vitro release study of the buccoadhesive tablet was carried out using USP basket-type dissolution test apparatus. Each tablet was inserted in the metallic basket and the dissolution chamber was filled with 500 ml of phosphate buffer of pH 6.6 and the whole system was stirred at 100 rpm and maintained at constant temperature (37±1 ºC). Sample were withdrawn at pre-determined time intervals and replaced with an equal volume of fresh dissolution medium. After suitable dilution, the samples were analyzed at 244 nm using Hitachi U-2001 UV-Visible spectrophotometer. The concentrations of Carvedilol in samples were corrected to compensate the drug loss during sample withdrawal, using the equation proposed by Hayton and Chen.

 

Stability in human saliva:

Each buccoadhesive tablet was kept for 4 h in Petri dish containing human saliva (pH 6.6), which was obtained from volunteers and filtered16. The dosage forms were evaluated with regard to their characteristics, like appearance, color, shape and drug content. The optimized formulation F2 was subjected to stability testing at 40±2º with 75±5% RH for one month.

 

RESULTS AND DISCUSSION:

The main aim of this work was to develop buccoadhesive tablet of a model drug Carvedilol using dried mucilage powder of Aegle marmelose owing to its excellent mucoadhesive property. The mucilage is biocompatible and solubilized readily at the salivary pH which attributed to release the drug unidirectionaly at the mucosal site for sufficient long time. Since mucilage powder cannot alone extend the drug release for prolonged period of time it is combined with some other secondary mucoadhesive polymers to extend the drug release.

 

The solubility of Carvedilol in water and phosphate buffer (pH 6.6) was found to be 17.2 ± 0.98 g/100ml and 15.46 ± 0.45 g/100ml, respectively. The apparent partition coefficient of Carvedilol in an octanol phosphate buffer (pH 6.6) system was found to be 0.083 ± 0.12.

 

Buccoadhesive tablet of Carvedilol were successfully prepared using direct compression method (Table 1). The results of physical characteristics of prepared buccoadhesive tablets were shown in Table 2. No significant difference in the weight of individual formulations was observed and the variations were within the permitted limits. The drug contents in the buccoadhesive tablets were also within the limits. Hardness of buccoadhesive tablets varied with various ratios and type of polymers and was less for tablets containing NaCMC .This is due to the fact that NaCMC is a hygroscopic material which can absorb large quantity of water from the atmospheric moisture17. So, this phenomenon is associated with a decrease in tablet hardness. The hardness of the tablets containing 1:1 ratio of mucilage powder and HPMC exhibited greater hardness which decreased by increase in the amount of HPMC. However, the differences in the tablet hardness did not affect the release of the drug from the hydrophilic matrices. Because drug is released by diffusion through the gel layer or rapid erosion of the water soluble polymers.

 

The bioadhesive property of buccoadhesive tablets of Carvedilol containing varying proportions of polymers was determined with an insight to develop the tablets with adequate bioadhesiveness without any local irritation and other problems. The bioadhesion characteristics were found to be affected by the nature of the polymer type and properties of the mucoadhesive polymers used. The polymers showed significant differences in their bioadhesion in the order of FA3>FA2>FA3>FA1>FA2>FA3 (p>0.05).The highest adhesive force was observed with the formulation containing higher amount of mucilaginous polymer and NaCMC. The reason may be ionization of mucilaginous polymer at salivary pH and also its biocompatibility with salivary mucosal surface leads to improved attachment. In addition to this, presence of NaCMC attributed to a strong interpolymer complex formation with the natural mucilaginous polymer and hence adhesive force becomes much stronger. This suggests that mucilaginous polymer have excellent bioadhesive property and hence adhesive force is decreased in the formulations as the quantity of mucilaginous polymer is decreased with respect to other polymers (Table 2).

 

Swelling index is increased as the weight gain by the tablets increased proportionately with the rate of hydration as shown in Table 3. It is observed that swelling index of the tablets containing mucilage powder and NaCMC increases with increasing amounts of NaCMC. So, higher % of swelling was seen with the formulations containing higher amounts of NaCMC and less quantity of mucilage powder. Notably, the highest swelling was observed with the formulations containing higher % of HPMC and swelling index increases with increasing amounts of HPMC. This suggests that mucilage powder has faster hydration and erosion properties and it does not contribute to the swelling behavior of the tablet formulations containing NaCMC or HPMC.

 

Surface pH of all the formulations was found to be in between 6.2 to 5.8. This result reveals that all the formulations provide an acceptable pH in the range of salivary pH 5.5 to 7.0. They did not produce any local irritation to the mucosal surface.

 

Figure 1 shows the principle absorption peaks of Carvedilol which appears at 2923.68, 1449.96, 1340.13, and 1097.31 cm–1. The identical peaks were also appeared at 2924.95, 1456.18, 1339.71 cm–1, and 1097.31 respectively in the spectra of buccoadhesive tablets prepared with different proportions of mucilaginous polymer, HPMC, NaCMC etc. These observations indicated that there were no chemical interactions between the drug and the polymers used. However, a slight shift in the spectra of drug loaded buccoadhesive tablets were noticed as compared to the spectra of pure drug, and this may be due to the physico-chemical bonding of the drug with the polymers during tablet compression.

 

In vitro release studies:

Figure 2   shows the % release of drug from the formulations containing different polymers. Tablets containing different proportion of HPMC/mucilage powder showed % drug release less than 70% and the highest release from this group was found to be 63.15%. These results were due to slower hydration rate and minimum swelling behavior of HPMC. Tablets made of different proportion of NaCMC/mucilage powder showed a higher % drug release as compared to HPMC group. The maximum drug release from this group was found to be 91.18% (Figure 3). The higher % of drug release was due to higher % of hydration of mucilage and NaCMC, which in turn led to matrix erosion. However the best release was observed with the HPMC group (Formulation F2). This can be better explained by the fact that, the concentration of mucilage powder and HPMC are the governing factors in the release rate of Carvedilol from buccoadhesive tablets. This result also suggests that a strong adhesive bond occurs at the first one hour of the swelling process, and hence a reasonable initial slow release was observed in the formulations, which become pronounced release as the time proceeds. Further, the increase in rate of drug release could be explained by the ability of the hydrophilic polymers to absorb water, whereby it promotes the dissolution of the highly water soluble drug. Moreover, the increase in hydrophilicity of both the polymers produces a synergistic effect creating more pores and channels and leaching out the drug more rapidly.

 

To study the release kinetics of Carvedilol from buccoadhesive tablets, different kinetic equations were also applied to interpret the release rate from the polymer matrices18-20. In the present study, the linear nature of the curves obtained for Higuchi model and Zero order as demonstrated by the high correlation coefficient (r2 value). When the higher correlation coefficient values are considered, the release data seem to fit better with Higuchi model (Table 4). This implies that drug release was proportional to the square root of time, indicating that drug release from the buccoadhesive tablet was diffusion controlled. Stability studies revealed that there was no significant change in drug content, bioadhesive strength and surface pH.

 

CONCLUSION:

From the study it is concluded that, dried mucilage powder of Aegle marmelose can be used as a primary mucoadhesive carrier in buccal drug delivery systems for drugs with high first-pass metabolism. The natural mucilaginous polymer produces a strong mucoadhesive bond to the buccal mucous membrane and does not cause damage to the buccal mucosa, because of its excellent biocompatibility.  The release rate of Carvedilol from tablets was significantly affected by the type and changes in the polymer mixing ratios. The buccoadhesive tablets containing 1:1 ratio of mucilaginous powder and HPMC showed suitable release kinetics, and properties for adhesion to the buccal mucosal surface and swelling properties. Evaluation of the release kinetic data reveals that buccoadhesive tablets containing different proportion of polymers exhibit Higuchi spherical matrix release indicating that drug release from the tablet was diffusion controlled.

 

Acknowledgement:

The authors greatly acknowledge Tezpur Central University, Napaam to carry out the FT-IR studies and Head, Deptt. of Pharm. Sciences, Dibrugarh University for providing necessary facilities to complete the research work. The authors are also thankful to Courtesy, Torrent Ltd, Ahmedabad, India, for sending Carvedilol as gift sample.

 

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Received on 10.05.2009       Modified on 13.07.2009

Accepted on 12.08.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 762-767