Development and In vitro Evalution of Buccoadhesive tablets of Propranolol
Aparna Bommanchu1, Manga Kanukuntla*
Department of Pharmaceutics, Malla Reddy College of Pharmacy, Affiliated to Osmania University, Hyderabad.
*Corresponding Author E-mail: bommanchuaparna.01@gmail.com
ABSTRACT:
Buccal tablets of propranolol were prepared by direct compression method using different hydrophilic polymers such as hydroxypropyl methylcellulose, sodium carboxy methylcellulose and Carbopol. All the prepared formulations showed satisfactory mass uniformity, thickness and favourable drug content. The friability of all the formulation was below 1%, which is an indication of good mechanical resistance of tablets. Among all the formulations, F4 showed maximum swelling index and in vitro release. Drug release mechanism was determined by plotting release data to Higuchi and Korsmeyer-Peppas model. All the formulations are best fitted to Higuchi model and according to this model the drug releases from theses tablets may be controlled by diffusion. The surface pH of all formulations was found to be almost in neutral pH and no mucosal irritation was expected. The accelerated stability studies indicated that, the selected formulation (F4) showed almost same drug content, mass uniformity and residence time. No colour change or no changes in texture were observed when tablets were tested in simulated saliva solution (pH 6.8).
KEYWORDS: Buccal Drug Delivery, Higuchi and Korsmeyer-Peppas Model, Stability Studies, In Vitro Release.
INTRODUCTION:
Among the various transmucosal routes, buccal mucosa has excellent accessibility, an expanse of smooth muscle and relatively immobile mucosa, hence suitable for administration of retentive dosage form. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability.1,2 It had been a great challenge to the pharmaceutical sciences in order to enhance localised drug delivery or to deliver ‘difficult’ molecules (proteins and oligonucleotides) into the systemic circulation.
Mucoadhesive systems remain in close contact with the absorption tissue, the mucous membrane releasing the drug at the action site leading to increase in bioavailability.3
The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation.4 Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules.5 However, the need for safe and effective buccal permeation absorption enhancers is a crucial component for a prospective future in the area of buccal drug delivery.6
Technically, an ideal buccal adhesive system must have the following properties: (1) maintains its position in the mouth for a few hours, (2) releases the drug in a controlled fashion, and (3) provides drug release in a unidirectional way toward the mucosa. Various buccal adhesive dosage forms, such as discs, microspheres, and bilayered tablets, have been thoroughly prepared and reported by several research groups.7,8 Limited studies, however, exist on novel devices that are superior to those of conventional buccal adhesive systems for the delivery of therapeutic agents through buccal mucosa. Mucoadhesive polymers have been utilised in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosa. These dosage forms include tablets, patches, tapes, films, semisolids and powders.
MATERIALS:
Propranolol was obtained as a gift sample from Lincoln Pharmaceutical Ahmedabad, India. Hydroxypropyl methylcellulose (HPMC K-4M), sodium carboxy methylcellulose (Na CMC) and Carbopol 934-P was obtained from Sigma Chemicals. Aspartame was obtained from Strides Arco Labs, Bangalore, India. Mannitol, magnesium stearate and ethyl cellulose were supplied from Loba Chemie Mumbai, India.
METHODS:
Formulation:
Mucoadhesive buccal tablets containing Propranolol were prepared by direct compression method. The ingredients of the core layer were weighed accurately and mixed by trituration in a glass mortar and pestle for 15 minutes. All the ingredients were screened through sieve no. 100. The above mixture was then compressed using 6 mm punch on 10 stages rotary tablet compression machine. In order to obtain constant tablet weight the mannitol was added as filler excipient in the core layer. After compression of tablets, the upper punch was removed carefully without disturbing the set up.
Table.1 Formulation Compositions
|
Compositions |
Formulation Code |
|||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
|
|
Propranolol(mg) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
Carbopol 934P (mg) |
12.5 |
16.7 |
25 |
33.3 |
12.5 |
16.7 |
25 |
33.3 |
|
HPMC K4M (mg) |
37.5 |
33.3 |
25 |
16.7 |
- |
- |
- |
- |
|
Na CMC (mg) |
- |
- |
- |
- |
37.5 |
33.3 |
25 |
16.7 |
|
Mannitol (mg) |
32 |
32 |
32 |
32 |
32 |
32 |
32 |
32 |
|
Magnesium stearate (mg) |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
Aspartame (mg) |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
|
Ethyl cellulose (mg) |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
Thickness Uniformity:
The thickness of films was measured by using Digimatic Micrometer. The thickness of each tablet was determined at six different places and their average was calculated. The standard deviation of thickness was computed from the mean value.9,10
Drug Content Uniformity:
To check the uniformity of the drug in the tablet, six tablets were taken out from each batch. Each film was then placed in volumetric flask containing 10ml of distilled water and shaken to extract the drug from tablet. One milliliter of above resulting solution was withdrawn, after suitable dilution with distilled water and analyzed UV spectrophotometrically at 289 nm using distilled water as blank. The mean and standard deviation of drug content of three randomly selected films were calculated. The same procedure was adopted for all the batches and drug content was noted.11
Weight Uniformity:
Tablets were taken from each batch. The weight of each tablet was taken and the weight variation of six tablets was calculated. The standard deviation of weight was computed from the mean value.12
Percentage Moisture Loss:
Test Percentage moisture loss test was determined by keeping the tablets in a desiccators containing anhydrous calcium chloride. After 3 days, the tablets were taken out, re-weighed and the percentage moisture loss was calculated using the following formula.12
Percentage Moisture Loss = (Initial weight - Final weight)/ Initial weight) x 100
Percentage Moisture Uptake/absorb:
The weighed tablets were kept in desiccators at room temperature for 24 hrs containing saturated solution of potassium chloride in order to maintain 84% RH. After 24 hrs the tablets were reweighed and determine the percentage moisture uptake from the below mentioned formula.13
Percentage moisture uptake = [Final weight - Initial weight/ Final weight] ×100
Swelling index:
Buccal tablets are weighed individually (W1) and placed separately in Petri-dish containing phosphate buffer pH 6.8. The buccal tablets are then removed from the petri dish and excess surface water is removed using filter paper. The buccal tablets are reweighed (W2) and swelling index (SI) was calculated as follows:14
S.I. = (W2-W1)/W1
Whereas:
S.I. = Swelling index
W2 = Final weight
W1 = Initial weight
In vitro diffusion study:
In vitro diffusion study was performed by using modified franz diffusion cell across cellophane membrane. Phosphate buffer solution (PBS) of pH6.8 was used as medium for diffusion study. Buccal tablets were placed on the membrane, which was placed between donor and receptor compartments of Franz diffusion cell. Cellophane membrane was brought in contact with PBS of pH 6.8 filled in receptor compartment. Temperature was maintained at 37oC with stirring at 50 rpm using a magnetic bead stirrer. 1ml of sample was withdrawn from a receptor compartment at pre-determined interval and was replaced with fresh PBS of pH 6.8. With suitable dilution, samples were measured for absorbance at 289 nm using UV visible spectrophotometer.15,16
Stability Study:
Stability studies were carried out on formulation, according to ICH guidelines by storing replicates of tablets (packaged in aluminum foil) in a humidity chamber, with a relative humidity of 75± 5% and a temperature of 40±0.5 °C. At periodic intervals the samples were taken out at 0, 15, 45 and 90 days and the period for their degradation of the tablet was checked. Samples were also analyzed for drug content.17-19
RESULTS AND DISCUSSION:
Weight Variation Hardness Thickness, Friability and Drug Content:
The physico-chemical characteristics of the Propranolol buccal tablets are shown in Table 2. All the formulation showed almost uniform mass, thickness and showed favorable drug content between 98.23 and 100.65%. The weight of the tablets was varied between 118.1 ± 1.33 and to 120 ± 2.18 mg and thickness ranged between 4.44 ± 0.05 and 4.54 ± 0.04 mm. The hardness and friability lies between 6.9 ± 0.19 and 7.18 ± 0.15 Kg/cm 2, and 0.34 ± 0.15 and 0.47 ± 0.05 % respectively. In all the formulation, friability fallen below 1%, which is an indication of good mechanical resistance of tablets.
Maximum mucoadhesion strength and residence time. The mucoadhesive strength of the formulation F4 was found to be maximum of 1.15 Newton. This may be due to fact that positive charges on surface of Carbopol 934-P, could give rise to strong electrostatic interaction with mucous or negatively charged mucous membrane. The residence time of buccal tablets ranged between 7-11 hour and noted this much time required for buccal tablets to detach from the buccal mucosa.
In Vitro Dissolution:
In vitro release of Propranolol buccal tablets is shown in Figure 5. The formulations F4 showed a maximum release of 98.12% after 8 hours. Similarly it shows maximum swelling index as well. It is apparent that the higher release of Propranolol occurred from the tablets contain higher proportion of Carbopol 934P. Initially in dry state Propranolol is distributed uniformly throughout the polymer matrix. After coming in contact with dissolution and as gelation takes place the release of Propranolol occurs from the surface of the swollen matrix. The movement of Propranolol to the surface is governed by the viscosity of the external hydrogel phase. Also Carbopol in its non-neutralized form does not become gel completely, as it still remain in coiled form. As the proportion of Carbopol increases, viscosity also decreases in the same order. Thus, a higher release with larger proportion of Carbopol.
Table 2. Physico-Chemical Characteristics of The Propranolol Buccal Tablets
|
Formulation Code |
Weight Variation |
Hardeness |
Thickness |
Friability |
Drug Content |
|
(mg)* |
(Kg/cm2)** |
(mm)*** |
(%) *** |
(%) *** |
|
|
F1 |
120 ± 2.18 |
7.18 ± 0.15 |
4.49 ± 0.06 |
0.39 ± 0.05 |
98.69 ± 0.21 |
|
F2 |
118.1 ± 1.33 |
6.98 ± 0.18 |
4.44 ± 0.05 |
0.34 ± 0.15 |
98.23 ± 0.10 |
|
F3 |
120.15 ± 2.08 |
7 ± 0.16 |
4.48 ± 0.06 |
0.41 ± 0.08 |
99.77 ± 0.35 |
|
F4 |
118.4 ± 2.14 |
6.9 ±0.19 |
4.54 ± 0.04 |
0.44 ± 0.13 |
100.28 ± 0.79 |
|
F5 |
120.15 ± 1.09 |
7.08 ± 0.29 |
4.47 ± 0.01 |
0.42 ± 0.08 |
99.67 ± 0.19 |
|
F6 |
118.3 ± 1.45 |
7.16 ± 0.15 |
4.52 ± 0.03 |
0.34 ± 0.22 |
98.58 ± 0.15 |
|
F7 |
119 ± 1.52 |
7.04 ± 0.23 |
4.45 ± 0.02 |
0.36 ± 0.05 |
99.79 ± 0.07 |
|
F8 |
119.4 ± 2.14 |
7.16 ± 0.15 |
4.49 ± 0.02 |
0.47 ± 0.05 |
100.65 ± 0.40 |
*Mean ± SD, n = 20, **Mean ± SD, n = 5, ***Mean ± SD, n = 10
Table 3. The Swelling Index of Propranolol Buccal Tablets
|
Time (hr) |
|
|
|
Formulation code |
|
|
|
|
|
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0.5 |
46.0 |
40.7 |
45.3 |
50.3 |
11.3 |
16.3 |
17.7 |
18.7 |
|
1 |
73.0 |
77.7 |
71.7 |
79.7 |
24.7 |
29.3 |
38.7 |
42.3 |
|
2 |
112.3 |
113.3 |
104.7 |
132.3 |
62.0 |
68.3 |
68.3 |
79.0 |
|
3 |
130.7 |
148.3 |
138.3 |
152.7 |
68.3 |
74.3 |
84.7 |
94.7 |
|
4 |
141.0 |
156.7 |
155.0 |
192.0 |
90.0 |
95.3 |
103.3 |
107.0 |
|
5 |
152.3 |
170.3 |
175.0 |
205.7 |
101.3 |
106.0 |
115.0 |
125.0 |
|
6 |
165.3 |
171.7 |
194.0 |
208.7 |
127.3 |
130.0 |
135.3 |
135.7 |
|
7 |
171.0 |
183.0 |
205.3 |
215.0 |
138.3 |
149.3 |
151.3 |
155.7 |
|
8 |
184.0 |
190.0 |
213.7 |
225.7 |
162.7 |
171.7 |
176.7 |
181.7 |
Table 4. Surface pH of Buccal Tablets
|
Formulation Code |
Surface pH |
|
F1 |
7.1 |
|
F2 |
6.8 |
|
F3 |
6.4 |
|
F4 |
6.2 |
|
F5 |
7.0 |
|
F6 |
6.8 |
|
F7 |
6.5 |
|
F8 |
6.2 |
Table 5. Stability Studies of Selected Propranolol Buccal Tablet
|
Evaluation Parameter |
1st Month |
2nd Month |
3rd Month |
4th Month |
5th Month |
6th Month |
|
|
Weight Variation (mg)* |
117.3 ± 1.11 |
117.0 ± 1.02 |
116.1 ± 2.10 |
115.2 ± 1.11 |
115.0 ± 0.98 |
115.0 ± 1.0 |
|
|
Residence Time (Hours)** |
10.2 ± 0.52 |
10.0 ± 0.81 |
9.9 ± 0.45 |
9.6 ± 0.32 |
9.6 |
± 1.2 |
9.5 ± 0.99 |
|
Drug Content (%) *** |
99.99 ± 0.12 |
99.52 ± 0.22 |
98.99 ± 0.42 |
98.20 ± 0.12 |
98.1 |
± 0.89 |
98.00 ± 1.20 |
CONCLUSION:
Buccal tablets of propranolol were prepared using different hydrophilic polymers such as hydroxypropyl methylcellulose, sodiumcarboxy methylcellulose and Carbopol in different ratios and combinations, to study the effect of these polymers on the physio chemical characters, swelling index and in vitro drug release of propranolol from the propranolol buccal tablets. Initially we have prepared all the formulations by altering the polymer quantity randomly and from these formulations eight formulations (i.e. F1, F2, F3, F4, F5, F6, F7 and F8) were selected as best formulations for further studies. Among all the eight formulations, F4 showed maximum swelling index, bioadhesive strength, residence time and in vitro drug release also. The surface pH indicates that Carbopol alone is not suitable in designing mucoadhesive tablets and a combination of Carbopol with other polymers produces tablets with neutral pH that are safe for mucosal membrane. The swelling behaviour of Carbopol is high in all the formulation wherever Carbopol is used as more quantity and showed maximum release of Propranolol from the prepared Propranolol buccal tablet. The release studies indicated that the prepared Propranolol buccal tablets improved the bioavailabity by avoiding the first pass metabolism. Novel mucoadhesive buccal tablets of Propranolol were developed to overcome the first-pass metabolism and subsequent low bioavailability of the Propranolol. The in vitro studies have shown that this is a potential drug delivery system for Propranolol with a considerably good stability and release profile.
REFERENCES:
1. Y. Krishna Reddy, Juveria Tasleem. Formulation and Evaluation of Bioadhesive Buccal Drug Delivery of Sumatriptan Succinate Tablets. Asian J. Pharm. Res. 2020; 10(2):105-109.
2. Puja Saha, Pratik Swarup Das. Formulation Development and Evaluation of Buccal Patches of Aceclofenac for Gingivitis. Res. J. Pharm. Dosage Form. & Tech. 2017; 9(4): 163-167.
3. M. N. L. Aishwarya, V. Prudhvi Raj, Subhashis Debnath, M. Niranjan Babu. A Review on Buccal Drug Delivery System. Res. J. Pharm. Dosage Form. & Tech. 2017; 9(3): 109-113.
4. Chetan M Patel, Sejal N Patel, Nikhil P Patel, DM Patel, CN Patel. Formulation and Evaluation of Buccal Adhesive Drug Delivery System of Lercanidipine. Research J. Pharma. Dosage Forms and Tech. 2010; 2(2):164-168.
5. Namita S. Bhosale, Aniket S. Gudur, Rishi Ramesan, Dipasha D. Rane, Pranil D. Arolkar, Afrin S. Darwajkar, Pratiksha P. Mestry, Vijay A. Jagtap. A Comprehensive Review on Buccal Drug Delivery System. Asian Journal of Pharmacy and Technology. 2023; 13(2):139-5.
6. Jani Devdatt, Nagesh C., Megha Hiroji, Chandrashekhar S., Nirav Patel. Formulation and Evaluation of Buccal Films of Timolol maleate. Research J. Pharma. Dosage Forms and Tech. 2012; 4(3): 177-184.
7. Nagaveni P., Sirisha. S, C. Appa Rao. A Complete Review on Mucoadhesive Buccal Tablets. Research Journal of Pharmaceutical Dosage Forms and Technology. 2021; 13(2):121-6.
8. Gnanprakash, D Dhachinamoorthi. Buccal Drug Delivery System – An Overview. Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 653-663.
9. M. A. Shende, P. K. Gupta. Formulation Development of Propranolol Hydrochloride Sustained Release Prunus amygdalus Gum Based Mucoadhesive Buccal Matrices. Asian.J.Pharm.Tech. 2017; 7(4).
10. Harikrishnan V, Madhusudhan S and Santhiagu A. Evaluation of a Novel, Natural Badam Gum as a Sustained Release and Mucoadhesive Component of Tizanidine HCl Buccal Tablets. Asian J. Pharm. Tech. 2015; 5(2): 71-78.
11. Nikam AP and Ratnaparkhi MP. Formulation and Evaluation of Losartan Potassium Sustained Release tablets. Research J. Pharm. and Tech. 2014; 7(11):1219-1225.
12. Ashok, T., Ganesh, K.G., Manasa, B., Subaldebnath, C., Santosh, K., and Chiranjib, B. Design and evaluation of controlled release mucoadhesive buccal tablets of candesartan. Journal of Pharmaceutics and Cosmetology. 2011; 1: 125-130.
13. R. Nagaraju, P. Subhash Chandra Bose, G. Ravi, Damineni Saritha, Valluru Ravi. A Review on Current status of Buccal drug delivery system. Research J. Pharm. and Tech. 2020; 13(6): 2954-2962.
14. Annapurna Uppala, Naga Swapna V, Neelima Devi R, Glory Sheren G, Kishore Kumar B. Research J. Pharm. and Tech. 2015; 8(9): 1269-1275.
15. Vaidya, V.M., Manwar, J.V., Mahajan, N.M., and Sakarkar. D.M. Design and in vitro evaluation of mucoadhesive buccal tablets of terbutaline sulphate. Int. J. Pharm. Tech. Res. 2009; 1: 588-597.
16. Shivam, T., and Jain, N. Buccal control drug delivery system A Review. International Journal of Pharmaceutical Science and Research, 2011; 2: 13-24.
17. Krupashree KG, Parthiban S, Vikneshwari K, Senthil Kumar GP, Tamizmani T. Formulation and in-vitro evaluation of mucoadhesive buccal tablets of gliclazide. Asian J. Res. Biol. Pharm. Sci. 2015; 3: 1–13.
18. S. Velmurugan, P. Srinivas. Formulation and in vitro evaluation of Losartan potassium mucoadhesive buccal tablets. Asian J Pharm Clin Res. 2013; 6(3): 125-130.
19. Vaidya, V.M., Manwar, J.V., Mahajan, N.M., and Sakarkar. D.M. Design and in vitro evaluation of mucoadhesive buccal tablets of terbutaline sulphate. Int. J. Pharm. Tech. Res. 2009; 1: 588-597.
|
Received on 19.08.2023 Revised on 08.05.2024 Accepted on 26.10.2024 Published on 18.12.2024 Available online on December 21, 2024 Asian J. Pharm. Tech. 2024; 14(4):311-314. DOI: 10.52711/2231-5713.2024.00050 ©Asian Pharma Press All Right Reserved
|