Formulation and Evaluation of Buccal Tablets of Diclofenac Sodium using Semi-Synthetic Polymers

 

Venkatalakshmi Ranganathan*, Tan Siew Hui, Prasanthi Sri

 

ABSTRACT:

The purpose of this research work is to formulate and evaluate diclofenac sodium buccal tablets using semi-synthetic polymers such as hydroxypropyl methyl cellulose K4M (HPMC K4M), methyl cellulose (MC) and sodium carboxyl methyl cellulose (SCMC) along with ethyl cellulose (EC) as the backing membrane. The drug excipient compatibility study was carried out by Fourier transform infrared spectroscopy. The diclofenac sodium buccal tablets were formulated by direct compression method. The prepared diclofenac sodium buccal tablet were evaluated for general appearance, hardness, weight variation, thickness, swelling studies, drug content, friability test, in vitro disintegration test, in vitro dissolution test, in vitro drug release kinetic and ex vivo residence time.

 

 

INTRODUCTION:

In buccal drug delivery system, the drug is deliver within or through the buccal mucosa and this provides several advantages such as avoidance of hepatic metabolism, drug degradation in the gastrointestinal tract and drug related side effects.

 

Diclofenac sodium, a non-steroidal anti-inflammatory drug which has been use to relief pain and sign and symptoms of rheumatic disorder. Diclofenac sodium is a drug that almost completely absorbed in gastrointestinal tract. In the liver, there is only 50% of the diclofenac sodium able to reach the systemic circulation as an unchanged drug. There are five diclofenac metabolites found in human plasma, urine, and/or bile and 4'­hydroxy- diclofenac is the major metabolite. Diclofenac sodium is an ideal candidate for sustained release buccal formulation as it has short biological half-life which is between 1 to 2 hours, hepatic metabolism and drug related side effects such as peptic ulceration, irritation and gastric bleeding.

 

Formulating diclofenac sodium buccal tablet will allows the drug to reach the systemic blood circulation, bypass the hepatic first pass metabolism as well as reduce the gastrointestinal side effects. Buccal drug delivery system will able to enhance the bioavailability of drug, effectiveness of drug, reduce the dose of drug and minimise the drug related side effects¹.

 

MATERIALS AND METHODS:^2-6

Diclofenac sodium and brilliant blue was purchased from Sigma-Aldrich (US). HPMC K4M, Mannitol, talcum, EC and polyvinylpyrrolidone K30 (PVP-K30) was purchased from R&M Chemicals (India). SCMC was purchased from HiMedia Labs (India). MC was purchased from MP Biomedicals (US). Diclofenac sodium was used as active ingredient, HPMC, MC, SCMC as mucoadhesive polymer, mannitol as diluent, PVP-K30 as binder, talcum as lubricant, EC as backing layer and brilliant blue as colouring agent to differentiate the primary layer and backing layer.

 

Drug – Excipient Compatibility Study by Fourier Transform Infrared Spectroscopy (FT-IR):

Diclofenac Sodiumand all formulations were subjected for FT-IR analysis. The sample was placed on the sample compartment and scanned over a range of 4000-400 cm. The FT-IR spectrum were analyzed for purity and drug- polymer interaction. The results were showed in Figure 1 to Figure 7.

 

Construction of Diclofenac Sodium Calibration Curve:

10 mg of diclofenac sodium was weighed accurately and dissolved in 100 ml volumetric flask contain 100 ml phosphate buffer pH 6.8 to prepare standard stock solution of 0.1 mg/ml. From the standard stock solution, aliquot was further dilute in a 10 ml volumetric flask and the final concentration was 10,20,30,40,50 and 60 µg/ml with phosphate buffer pH6.8. The absorbance of standard solution was determined by using UV spectrometer at 276 nm. The results were showed in Figure 8.

 

Formulation of Diclofenac Sodium Buccal Tablets:^3-6

Diclofenac sodium buccal tablets were prepared by using direct compression method. All the ingredients were weighed accurately according to the batch formula and mixed homogenously.150 mg of the mixture was compressed using a single punch tablet compression machine. The upper punch was raised and 50 mg of the backing layer EC was placed and compress to form diclofenac sodium buccal tablets. The composition of diclofenac sodium buccal tablets was shown in Table 1.

 

Table 1: Composition of diclofenac sodium buccal tablets

Formulation (mg/tab)	F1	F2	F3	F4	F5	F6
Diclofenac sodium	50	50	50	50	50	20
HPMC K4M	50	-	-	25	-	25
MC	-	50	-	25	25	-
SCMC	-	-	50	-	25	25
Mannitol	40	40	40	40	40	40
PVP-K30	8	8	8	8	8	8
Magnesium stearate	2	2	2	2	2	2
EC	50	50	50	50	50	50
Total	200	200	200	200	200	200

 

Evaluation of Diclofenac Sodium Buccal Tablets^2-7

a)   General Appearance:

The prepared buccal tablets was evaluated for shape, size, colour and surface texture.

 

b)   Hardness:

Five tablets from each formulation were selected randomly and measured using Monsato hardness tester.

 

c)    Weight Variation:

Twenty tablets were weighed individually and recorded. The average weight of twenty tablets were calculated and recorded.

 

d)   Thickness:

Ten tablets were selected randomly and the thickness of each tablets were measured using verniercaliper and the average thickness as well as individual thickness were recorded.

 

e)    Friability:

The friability of prepared buccal tablets were determined by using Roche friabilator which set to operate at 25 rpm and run up to 100 revolutions. The percentage of friability was calculated by the following formula:

 

% friability = [(Winitial – Wfinal) / Winitial] * 100

Where,

Winitial is initial weight, Wfinal is final weight

 

f)    Drug content:

Drug content was performed by selecting six tablets from each formulation randomly and powdered.200 mg of the powder was weighed and dissolved in 100 ml of phosphate buffer pH 6.8. 1 ml of the solution was measured and diluted with phosphate buffer up to 100 ml and analysed using a UV spectrometer at 276 nm against blank reagent. The drug content was calculated by the following formula:

 

 

g)   Swelling studies:

Swelling study was performed by weighing three buccal tablet from each formulation individually and placed separately in petri dishes with 6 ml of phosphate buffer pH 6.8 and incubated at 37±1 °C. The tablet was removed from the petri dish at different time interval (0, 5, 10, 15, 20, 25, 30 minutes). Excess surface water was removed carefully and the swollen tablet was then reweighed again. The swelling index was calculated by using the following equation:

 

Swelling Index = [(W2 – W1) / W2] * 100

Where,

W1 is initial weight of tablet, W2 is the weight of swollen tablet

 

h)   In vitro dissolution study:

In vitro dissolution study was performed by using USP dissolution type apparatus II and dissolution medium was 500 ml of phosphate buffer pH 6.8. It was performed at 37±0.5 °C with a rotating speed of 50 rpm. 5 ml of the samples was withdrawn at predetermined time intervals and volume was replaced with 5 ml of fresh medium. The samples was filtered by 0.2 µm filter paper and it was analysed by UV spectrophotometer at 276 nm.

i)     Ex vivo mucoadhesive time:³

Fresh porcine buccal mucosa was obtained from a local slaughterhouse and it was immersed in a phosphate saline buffer solution. The mucosal membrane was separated by removing the underlying fat and loose tissues using fine-point forceps and surgical scissors. Later, it was washed with distilled water and then with phosphate buffer pH 6.8 at 37 ºC.

 

The fresh porcine buccal mucosa was cut into pieces and wash with phosphate buffer pH 6.8. The fresh porcine buccal mucosa was tied on the glass slide. The glass slide was placed into a beaker contain 250 ml of phosphate buffer pH 6.8. The diclofenac sodium buccal tablet was attached to the porcine buccal mucosa and it was keep at 37 ± 0.5ºC. Ex vivomucoadhesive time of prepared buccal tablets were evaluated by accessing time required for the buccal tablet to detach from the procaine mucosa membrane in beaker.

 

j)    In vitro drug release kinetics:

In vitro drug release kinetics of diclofenac buccal tablets were further analysed by fitting into various mechanical model such as zero order, first order, Higuchi’s model and Korsmeyer-Peppas model equation.

 

RESULTS AND DISCUSSION:

Drug Polymer Interaction:

The FT-IR spectrum of diclofenac sodium and the drug polymer mixtures was show in Figure 1 to Figure 10. All the major frequency peaks value and functional group were complemented with the mixture of drug and polymers. This ensure that there was no chemical interaction between mixture of drug and polymers.

 

 

Figure 1: FT-IR spectra of Diclofenac sodium

 

Figure 2: FT-IR spectra of Diclofenac Sodium and HPMC

 

Figure 3: FT-IR spectra of Diclofenac Sodium and MC

 

Figure 4: FT-IR spectra of Diclofenac Sodium and SCMC

 

 

Figure 5: FT-IR spectra of Diclofenac Sodium, HPMC and MC

 

 

Figure 6: FT-IR spectra of Diclofenac Sodium, MC and SCMC

 

 

Figure 7: FT-IR spectra of Diclofenac Sodium, HPMC and SCMC

 

Figure 8: Standard Calibration Curve of Diclofenac Sodium

 

Physiochemical Properties of Diclofenac Sodium Buccal Tablets:

All tablets were in round shape, uniform colour: white for primary layer, greyish blue for backing membrane and have smooth surface texture. All tablets have uniform thickness ranging from 3.185 ± 0.050 to 3.241 ± 0.008 cm. The hardness of prepared tablets were ranging from 4.2 ± 0.65 to 5.6 ± 0.42 kg/cm² and formulation F4 have the highest mechanical strength of 5.6 ± 0.42 kg/cm².

 

The friability for all six formulation was found to be less than 1.0% which indicates that the prepared tablets is able to withstand rigors of handling and transportation. The weight variation for all formulation was in the range of 199.5 ± 6.86 to 206 ± 8.83 mg. The results of drug content uniformity lies between 81.5 to 101.54% and the drug content uniformity was in the order of F2 > F5 > F4 >F6 > F3 >F1. The results for hardness, thickness, weight variation, friability and drug content was shown in Table 2.

 

Table 2: Post- compression Parameter of Diclofenac Sodium Buccal Tablets

 

Swelling Studies:

The swelling index for all formulation after 6 hours was in the order of F3 > F5 > F2 > F4 > F6 > F1 and the result was show in figure 9 and Figure 10. According to H. Omidian and K. Park, 2008 polymer SCMC has free swelling capacity of 10 to 40 g/g whereas HPMC and MC has free swelling capacity of 5 to 20 g/g. Thus, F3 containing SCMC has better swelling index of 46.50% as compare to F5 containing SCMC and MC 41.75%, F2 containing MC 37.62%, F4 containing HPMC and MC, F6 containing HPMC and SCMC 20.63% and F1 containing HPMC 15.17%. Based on the results that obtained, it can concluded that as the time proceed, all the buccal tablets swells due to the hydrophilicity of the polymer which will gradually absorb water.

 

 

Figure 9: Swelling Index of Diclofenac Sodium Buccal Tablets

 

Figure 10: Swelling Index of Diclofenac Sodium Buccal Tablets after 6 hours

 

 

Formulation 1

 

 

Formulation 2

 

Formulation 3

 

 

Formulation 4

 

 

Formulation 5

 

 

Formulation 6

Figure 11: Swelling Index of Diclofenac Sodium Buccal Tablets after 6 hours

 

In vitro dissolution study:

The cumulative % of drug release of formulation F1 to formulation F6 were in the range of 78.2 to 96.2% in 8 hours respectively. The rate of drug release for formulation with one polymer was in the order of F3 > F2 > F1. According to research that done by R Indira Prasanna et al., 2011 showed that formulation containing SCMC has higher swelling index and higher drug release when compare to formulation containing HPMC. This indicates that there is a relationship between the swelling index and drugrelease rate of polymer. However, this does not showed in formulations containing two polymers.

 

Figure 12: In vitroDissolution of Diclofenac Sodium Buccal Tablets

 

Ex vivo mucoadhesive time:

Buccal tablet with high mucoadhsive time will allow more drug to be absorbed. The ex vivo mucoadhesive time for all formulation was in the order of F4 > F5 > F6 > F2 > F3 > F1. Formulation F2 show better mucaodhesive time as compare to formulation F3 and. Meanwhile, formulation F4 show better mucaodhesive time as compare to formulation F5 and formulation F6. In general, it can be concluded that formulation containing two polymers show better mucoadhesive time as compared to formulation with one polymer. The results of ex vivo mucoadhesive time for all formulation show in Table 4.

 

Table 4: Ex vivo mucoadhesive time for Formulation 1 to Formulation 6

Formulation Code	Ex vivoMucoadhesive Time (mins) (n=2)
F1	74.0
F2	131.5
F3	111.0
F4	479.5
F5	460.5
F6	427.0

 

 

 

Figure 13: Ex vivo mucoadhesive time of Diclofenac Sodium Buccal Tablets

In vitro drug release kinetic study:

The mechanism of drug release of diclofenac sodium buccal tablets during the dissolution study using phosphate buffer pH 6.8 as dissolution medium were determined using zero order, first order, Higuchi’s model and Korsmeyer-Peppas model. Zero order is used to describe that the drug release rate is constant and independent of concentration of drug whereas first order is used to describe that the drug release rate is dependent on the concentration of drug. Higuchi’s model is used to describe the release of drug as a diffusion process based on the Fick’s law and Korsmeyer-Peppas equation is used to describe the drug release behaviour form hydrophilic matrix. Table 5 showed the interpretation of diffusional release mechanisms from polymeric films.

 

 

Table 5: Interpretation of diffusional release mechanisms from polymeric films

Release exponent (n)	Drug Transport Mechanism
0.5	Fickian diffusion
0.45 < n = 0.89	Non-Fickian diffusion
0.89	Case II transport
Higher than 0.89	Super case II transport

 

 

Figure 14: Zero Order for Diclofenac Sodium Buccal Tablets

 

Kinetics Model that show highest regression value, R2 value was considered as the best fit model. Table 6 showed the kinetic drug release for formulation F1 to formulation F6. Based on the data that obtained, it can concluded that all formulation followed first order of drug release as the R2 value is higher when compared to zero order. Besides, the R2 value of Higuchi’s model of all formulation were in the range of 0.923 to 0.971. The release exponent, n for all formulation were in the range of 0.736 to 0.769 which is within the category, 0.45 < n = 0.89. This indicate that diclofenac sodium buccal tablets follows non-Fickian diffusion. In overall, the drug release kinetics for all the formulation was first order and the mechanism of drug release was non-Fickian diffusion.

 

Figure 15: First Order for Diclofenac Sodium Buccal Tablets

 

 

Figure 16: Higuchi’s Model for Diclofenac Sodium Buccal Tablets

 

 

Figure 17: Korsmeyer-PeppasModel for Diclofenac Sodium Buccal Tablets

 

Table 6: Kinetic Drug Release for Formulation F1 to Formulation F6

Formulation		F1	F2	F3	F4	F5	F6
Zero Order	R2	0.902	0.872	0.763	0.871	0.847	0.785
	k0	0.175	0.162	0.170	0.153	0.191	0.180
First Order	R2	0.97	0.940	0.911	0.929	0.965	0.941
	k1	-0.002	-0.002	-0.003	-0.001	-0.003	-0.003
Higuchi’s Model	R2	0.971	0.960	0.923	0.953	0.955	0.929
	k (min-1/2)	4.301	4.232	4.665	4.004	4.814	4.880
Korsmeyer-Peppas Model	R2	0.992	0.994	0.978	0.988	0.986	0.979
	n	0.745	0.736	0.756	0.737	0.761	0.769

 

 

CONCLUSION:

In the study, diclofenac sodium buccal tablets were prepared by direct compression using semi-synthetic polymers such as HPMC, MC and SCMC. Among the six formulations, formulation F5 which contain MC and SCMC was found to be the most desired formulation. FT-IR studies did not show any interaction between the drug and polymers. Besides, it also show good swelling properties, high mucoadhesive time in the procaine buccal mucosa and the in vitro drug release of formulation F5 promising sustained release of drug for more than 8 hours. Moreover, the drug release kinetics for formulation F5 was first order and the mechanism of drug release follow non-fickian diffusion.  Thus, further explore the potentially of buccal drug delivery system is needed to enhance the bioavailability of drug, avoidance of hepatic first pass metabolism and gastro-intestinal degradation as well as avoidance of adverse effect of drug.

 

ACKNOWLEDGEMENTS:

Authors are thankful to MAHSA University Selangor, Malaysia for providing facilities for carrying out this research project.

 

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Received on 24.08.2017         Modified on 26.09.2017

Accepted on 05.10.2017      © RJPT All right reserved