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International Journal of Drug Development and Research

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- (2012) Volume 4, Issue 4

47. Formulation and Evaluation of Mucoadhesive Buccal Bilayered Tablets of Salbutamol

Dr. N.G Raghavendra Rao1*, Gururaj S. Kulkarni2,3
  1. PG. Dept of Pharmaceutics, Jyothishmathi Institute of Pharmaceutical Science, Karimnagar - 505481, AP, India.
  2. Dept of Pharmaceutics, Vivekananda college of Pharmacy, Bangalore - 56055, KS, India.
  3. Research Scholar of Singhania University, Rajasthan, India.
Corresponding Author: Dr. N. G. Raghavendra Rao Principal and Professor Jyothishmathi Institute of Pharmaceutical Science Ramakrishna Colony, Thimmapur, KARIMNAGAR-505481, Andhra Pradesh Email: ngraghu@rediffmail.com
Received:04 November 2012 Accepted:14 November 2012
Citation: Dr. N. G Raghavendra Rao1*, Gururaj S. Kulkarni 2a, b “Formulation and Evaluation of Mucoadhesive Buccal Bilayered Tablets of Salbutamol” Int. J. Drug Dev. & Res., October- December 2012, 4(4):375-384. doi: doi number
Copyright: © 2012 IJDDR, Dr. N. G Raghavendra Rao et al. This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Salbutamol is a short-acting 2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. The salbutamol buccal mucoadhesive tablets were fabricated with objective of avoiding first pass metabolism and prolonging duration of action. Salbutamol mucoadhesive bilayered tablets were prepared by direct compression method using the bioadhesive polymers such as xanthan gum, sodium alginate and carbopol 937P along with ethyl cellulose as an impermeable backing layer. The prepared tablets evaluated for post-compressional parameter like weight variation, thickness, hardness, and friability, surface pH, mucoadhesive strength, in vitro drug release and Ex-vivo permeation study. The compatibility of drug with other ingredients was checked by FTIR studies. FTIR results revealed that there was no interaction between dug and other excipients. All the post-compressional parameter are evaluated were prescribed limits and results were within acceptable limits. The in vitro release study was carried out by using pH 6.8 buffer. The invitro drug release was in the range of 69.74% to 98.52% in eight hrs from the formulations of F1 to F6. The formulation F4 and F5 % shows the drug release 74 % and 69.74 % respectively. The results were revealed that the release of salbutamol buccal tablets was slower in formulation F4 and F5, may be due to the high concentration of xanthan gum, in comparison to other formulations. Xanthan gun, carbopol and Na-alginate were selected as the bioadhesive polymers because of their excellent bioadhesive properties. Among the all formulations studied F4 and F5 were found to be the best formulations. All the formulations showed the first order release. The stability study conducted as per the ICH guidelines and the formulations were found to be stable. The present study concludes that mucoadhesive buccal tablets of salbutamol can be a good way to bypass the extensive hepatic first-pass metabolism, provides controlled release of the drug and to improve the bioavailability of salbutamol.

Keywords

Buccal tablets, salbutamol, xanthan gum, sodium alginate, carbopol 934P.

INTRODUCTION

Buccal delivery of drug provides an alternative to the oral route of drug administration. In recent years, delivery of therapeutic agents through various transmucosal routes gained significant attention owing to their pre-systemic metabolism or instability in the acidic environment associated with oral administration [1]. Buccal delivery provides direct entry of drug into the systemic circulation, thus avoiding the hepatic first-pass effect, ensuring ease of administration, and making it possible to terminate delivery when required [2]. Attempts have been made to formulate various buccal mucoadhesive dosage forms, including tablets [3], films [4], patches [5], disks [6] and gels [7]. A suitable buccal drug delivery system should possess good bioadhesive properties, so that it can be retained in the oral cavity for the desired duration and should release the drug in a unidirectional way toward the mucosa, in a controlled and predictable manner, to elicit the required therapeutic response. This unidirectional drug release can be achieved using bi-layer tablet dosage form [6, 8]. Bioadhesive formulations have been developed to enhance the bioavailability [9, 10] of drugs that undergo substantial first-pass hepatic effect and to control the drug release to a constant rate [11].
Salbutamol is one of the old and most commonly used anti-asthmatic drug, is a short-acting 82- adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. Because of its poor bioavailability through oral route due to first pass metabolism and it satisfies the requirements of buccal drug delivery system, so we are planned in the present work, mucoadhesive tablets of salbutamol are prepared by using natural polymer xanthan gum, sodium alginate and carbopol 934P in various concentrations. Salbutamol Mucoadhesive tablets were prepared by direct compression method.

MATERIALS AND METHODOLOGY

Materials

Salbutamol was obtained from Micro labs ltd. Bangalore as a gift sample, xanthan gum and sodium alginate were from ponami and company Coimbatore and Ethyl cellulose from Medrich Labs Ltd Bangalore. Remaining chemicals are analytical grade from S.D Fine chemicals Mumbai.

Preparation of bilayered buccal tablets [12]:

Preparation of Buccal tablets of Salbutamol by direct compression method has been employed with xanthan gum in different concentrations. All the ingredients including drug, polymer and excipients were weighed accurately according to the batch formula (Table 1). The drug is thoroughly mixed with Mannitol on a butter paper with the help of a stainless steel spatula. Then all the ingredients except lubricants were mixed in the order of ascending weights and blended for 10 min. After uniform mixing of ingredients, lubricant was added and again mixed for 4 min and compressed in to tablets weight of 100 mg using 5 mm round flat punches on 10- station rotary tablet machine (Rimek). The upper punch was raised and the backing layer of ethyl cellulose was placed on the above compact; the two layers were then compressed into a Bilayered buccal tablet. Each tablet weighed 125 mg.
The prepared tablets were evaluated for weight variation [13] test was conducted by weighing 20 randomly selected tablets individually, calculating the average weight and comparing the individual tablet weights to the average. The specification of weight variation is 10%. The hardness of the tablets was determined using Pfizer hardness tester. It is expressed in kg/cm2. Six tablets were randomly picked from each formulation and the mean and standard deviation values were calculated. The tablet thickness was measured using screw gauge.
A friability test was conducted on the tablets using Friabilator. Twenty tablets were selected from each batch and any loose dust was removed with the help of a soft brush. The tablets were initially weighed (Winitial) and transferred into Friabilator. The drum was rotated at 25 rpm for 4 min after which the minitablets were removed. Any loose dust was removed from the tablets as before and the tablets were weighed again (Wfinal). The percentage friability was then calculated by,
F = [(Winitial- Wfinal)/ Winitial] X 100
% Friability of tablets less than 1% is considered acceptable.
The Drug content of prepared tablet of each batch of the formulation was determined. From each batch 20 tablets were taken, weighted and finely grounded. An amount of powder equivalent to 5 mg of powder was accurately weighted and dissolved in 6.8 phosphate buffer. The resulting solution was suitably diluted and analysed on UV spectrophotometer Shimadzu 1601 at 277 nm. The objective of study of surface pH of buccal tablet was to know whether causes irritation to mucus membrane of buccal region. The Buccal tablets were allowed swell at 37 ± 10 C for 2 hrs in 50 ml phosphate buffer (pH 6.8). The surface pH of swollen buccal tablets was measured by using pH paper.
The swelling study of tables was determined by gravimetry. The swelling rate of the bioadhesive tablets was evaluated by using 1% agar gel plate. The average weight of the tablet was calculated (W1). The tablets were placed on gel surface in a petridish placed in an incubator at 37± 1ºC. Tablets was removed at different time intervals (0.5, 1.0, 2.0, 3.0, 4.0, 5.0), wiped with filter paper and reweighed (W2). The swelling index was calculated by the formula.
Swelling index = (W2 - W1) / W
In vitro residence time [14] for tablets was determined using USP disintegration apparatus. The disintegration medium was composed of 800 ml of isotonic phosphate buffer of pH 6.8 maintained at 37°C. A segment of rabbit buccal mucosa 3 cm length was glutted to glass slab. The tablet surface was hydrated using 15 ml pH 6.8 and then hydrated surface brought into contact with the mucosal membrane. The glass slab was vertically fixed to tablets was completely immersed in the buffers solution at lowest and wash out at highest point the time necessary for complete erosion or detachment of tablets from mucosal surface was determined.
To evaluate bioadhesive strength, a tensile tester apparatus, similar to an Instron model 4301 tensile tester, was fabricated. Porcine buccal mucosa obtained from slaughter house was kept in Kerb’s buffer of pH 7.4 at 370 C for 2 hrs. The underlying mucus membrane was separated and washes thoroughly with phosphate buffer pH 6.8 solutions. The skin (mucosa side) was fixed across the opening (area: 2 cm2) of a diffusion cell filled with phosphate buffer (pH 6.8). The test was carried out in triplicate and the results expressed as mean ± standard deviation.
The in vitro dissolution tests [15-17] were performed using the basket method of USP 24. With the aid of a dissolution apparatus (TDT 08L Dissolution Tester Electro Lab) rotating at 100 rpm. The dissolution medium was 900 ml phosphate buffer (pH 6.8) and the temperature maintained was at 370 ± 10 C. Samples of the dissolution solution were withdrawn at definite time intervals. The dissolution media was then replaced by fresh dissolution fluid to maintain a constant volume. The solution was passed through a filter and then the concentration of Salbutamol in solution was measured with an Ultraviolet-Visible spectrophotometer, pharma spec1700 (Shimadzu) at a wavelength of 277 nm. The test was carried out in triplicate and the results expressed as mean ± standard deviation (SD).
Ex-vivo permeation studies [18, 19] were carried out by using sheep buccal mucosa was collected from the local slaughterhouse and immediately transported to the laboratory in cold normal saline solution. Then buccal epithelium was isolated from the underlying tissue. The buccal epithelium was used within 2 hrs upon removal. The modified Franz Diffusion cell was used to permeation studies, it consists of two compartments, one is donor compartment and another is receptor compartment .The receptor compartment was covered with water jacket to maintain temperature 37°± 1ºC. The separated buccal epithelium was mounted between two chambers and in receptor chamber phosphate buffer pH 6.8 was filled and buccal epithelium was allowed to stabilization. After stabilization of buccal epithelium, the patch was kept on buccal epithelium and donor compartment filled with phosphate buffer pH 7.4. Periodically samples were withdrawn and same volume fresh medium was replaced. The aliquots were analyzed spectrophotometrically at 277 nm.

Drug excipients interaction studies:

FTIR Studies: IR spectra for pure drug Salbutamol, Salbutamol bilayered buccal tablets F4 and F5 were recorded in a Fourier transform infrared (FTIR) spectrophotometer (FTIR 1615, Perkin Elmer, USA) with KBr pellets.
Kinetic study: To analyze the mechanism of drug release form the tablets the in vitro dissolution data were fitted to zero order (K=kt), korsmeyer and peppas model (F=ktn), higuchi (F=kÖt) release models. Where F is the fraction of drug release, k is the release constant and t is time [20-21].
Stability study: The fabricated salbutamol buccal tablets formulations were subjected for stability study [22]. The stability study was carried out according to ICH guidelines at 400 C and relative humidity at 75 % for three weeks. For stability study, the tablets were sealed in aluminum packing coated inside with polyethylene. These sample containers were placed in desiccators maintained at 75% RH. The product was evaluated for drug content, bioadhesive strength and swelling index study. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage conditions.

RESULTS AND DISCUSSION

In the present work efforts have been made to develop mucoadhesive buccal tablets of salbutamol using direct compression technique involving mucoadhesive polymers like xanthan gum, Carbopol and sodium alginate. Ethyl cellulose was selected as a backing material because this hydrophobic polymer has very low water permeability thus providing an impermeable backing layer that prevents drug loss. Magnesium stearate was included as anti adherent. Xanthan gum, CP and Na-alginate were selected as the bioadhesive polymers because of their excellent bioadhesive properties [23-25]. EC has recently been reported to be an excellent backing material, given its low water permeability, hydrophobicity, and moderate flexibility [26], so it was chosen as an impermeable backing layer.
The blend of ingredients was analyzed for physical characteristics. The results were shown in Table 2. The angle of repose of formulation blends F1 to F 6 was found to be <300 in the range of 29.42 to 26.640 which indicate excellent, The bulk density, tapped density were found in the range of 0.433 to 0.317 gm/cc, 0.52-0.47gm/cc, Carr’s index in the range of 14.56 to 17.12 % and Hausner’s ratio in the range of 1.16 to 1.28. It reveals that all the formulation blends were having good flow characteristics and flow rates.
In all the formulations, the weight variation of tablets was ranges between 148 to 150 mg. Weight variation test revealed that the tablets were within the range of pharmacopoeial limit [27]. Hardness test indicated good mechanical strength, the hardness of prepared salbutamol buccal tablets was found to be in the range of 3.28 to 4.42 kg/cm2. Thickness of the tablets was ranges from 3.25 to 3.63 mm. The friability of the buccal tablets of all the batches remained in the range of 0.54 to 0.70 %. Friability is less than 1%, indicated that tablets had a good mechanical resistance. The evaluation parameters were within acceptable range for all the formulations. The drug content of the salbutamol buccal tablets was ranges from 95.00 to 99.75%. This is within acceptable limits. The results of content uniformity indicated that the drug uniformly dispersed. In case of formulation F1 and F2, the percentage recovery low this may be due to polymer concentration. The results of weight variation, hardness, thickness, friability and drug content were shown in Table 3. The mucoadhesive strength of all the formulations (shown in Figure 1) F1 to F6 was found to be in the range of 6.42 to 8.58 gms. The bioadhesive property tablets of salbutamol containing varying proportions of polymers were determined with an insight to develop the tablets with adequate bioadhesiveness. The highest strength of the mucoadhesive bond was observed with the formulation as followed by F1 to F5 containing xanthan gum, carbopol 934 p and sodium alginate. The highest bioadhesive strength was observed in the formulation F4 and F5.The swelling of the buccal tablets observed in phosphate buffer, pH 6.8. The swelling index of the tablets was in the range 28 to 48 %. Swelling study of buccal tablets was shown in Figure 2. Swelling more pronounced in tablets F4 and F5, because of high concentration of polymer. Formulations F1 shows less, due to less concentration of xanthan gum. The surface pH of all the tablets was within a range of 6- 8 as shown in the Table 3, close to neutral pH. Appropriate swelling behavior of a buccal adhesive system is essential for uniform and prolonged release of the drug and effective mucoadhesion [28]. The surface pH of all formulations within + 0.5 units of the neutral pH and hence no mucosal irritation expected and ultimately achieve patient compliance. The surface pH of all the tablets was within ranges from 6.7 to 7.02.
The release of salbutamol from all the formulations (Figure 3) was in the range of 72.08 to 98.52 % at the end of 8 hrs. The results were revealed that the release of salbutamol buccal tablets was slower in formulation F4 and F5, may be due to the high concentration of Xanthan gum polymer, carbopol 934P and sodium alginate in comparison to other formulations. The faster release of drug found to be in the formulation F1, may be due to low concentration of Xanthan gum polymer, carbopol 934P and sodium alginate.
Among the formulations studied F4 and F5 were found to be the best (F4 buccal tablet contains xanthan gum - 40 mg, sodium alginate – 05 mg, carbopol 934 P – 10 mg, mannitol – 56, PEG 6000 – 2 mg and 5 mg PVP as core layer and EC- 25 mg and magnesium stearate - 2mg as backing layer and F5 buccal tablet contains xanthan gum - 45 mg, sodium alginate – 10 mg, carbopol 934 P – 10 mg, mannitol – 46, PEG 6000 – 2 mg and 5 mg PVP as core layer and EC- 25 mg and magnesium stearate - 2mg as backing layer). The formulation F4 shows 79.83 percentage of drug released at end 8th hr with good swelling index 54 % and bioadhesion strength 7.25. The formulation F5 showed 72.08 percentage of drug released at end 8th hr with good swelling index 62 % and bioadhesion strength 8.58.
The F4 and F5 formulations were taken as optimized formulations for in-vitro buccal permeation studies (Figure 4). Both Formulation F4 and F5 showed 68.01 and 76.91 respectively permeation drug through the buccal mucosa over a period of time 8th hrs. Hence it can be conclusively stated the both F4 and F5 formulations necessary buccoadhesive property and the desirable release characteristics. However the detailed In vivo studies of the above formulations will through more light on their viability for consideration in the clinical practice. The data obtained from in-vitro dissolution studies were fitted in different models viz. zero order, first order and Korsemeyer’s equation and the results are shown in Table 4. Kinetics drug release result reveals that all formulations follow first-order kinetics as correlation coefficient (r2) values are higher than that of zero-order release kinetics. To ascertain, the drug release mechanism the in-vitro release data were also subjected to Higuchi’s diffusion equation the r-values of all the formulations were 0.9764 to 0.9964. It suggests that the drug released by diffusion mechanism. To confirm the exact mechanism of drug release from these tablets, the data were fitted according to Korsemeyer’s equation [29-30]. Regression analysis was performed and regression values ‘R’ were 0.9764 to 0.9964 for different formulations. Slope values were in the range of 0.47 to 0.72. Slope values (0.45
The stability study conducted as per the ICH guidelines for three months and the formulations were found to be stable. No appreciable change in drug content, mucoadhesive strength and swelling index study was observed even after the evaluation for three months. Results were showed in [Table 5].
FC= Formulation code
The FTIR spectral analysis showed that there was no appearance or disappearance of any characteristic peak, which confirms the absence of chemical interaction between drug and polymers shown in Figure 5.

COCNCLUSION

From this, study it can be concluded that, mucoadhesive tablets of salbutamol are prepared by using natural polymer provides controlled release of the drug. Kinetics drug release result reveals that all formulations follow first-order kinetics. The mucoadhesive buccal tablets of salbutamol may be a good way to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of salbutamol through buccal mucosa.

ACKNOWLEDGEMENTS

Authors thanks to Micro Labs Ltd. Bangalore, for providing a gift sample of Salbutamol. The authors are also thankful to Ponami and Company Coimbatore and Med Rich Labs Ltd Bangalore for providing gift samples of Xanthan gum and Ethyl cellulose respectively. The authors are also thankful to Chairman’s of Vivekananda college of Pharmacy, Bangalore and Jyothishmathi Institute of Pharmaceutical Science, Karimnagar, providing the facilities to carry out and publish the research work.

Conflict of Interest

NIL

Source of Support

NONE

Tables at a glance

Table icon Table icon Table icon Table icon Table icon
Table 1 Table 2 Table 3 Table 4 Table 5
 

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
 
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