INTRODUCTION:

The unique environment of the oral cavity offers its potential as a site for drug delivery. Because of the rich blood supply and direct access to systemic circulation, the oral mucosal route is suitable for drugs, which are susceptible to acid hydrolysis in the stomach or which are extensively metabolized in the liver (first pass effect). Such delivery systems which involve administration of drug via the buccal mucosa to the systemic circulation are termed as buccal drug delivery system.^1,2

The total area of the oral cavity is about 100cm 2. Out of this about one third is the buccal surface, which is lined with an epithelium of about 0.5mm thickness.

The oral mucosal surface is constantly washed by the saliva (daily turn out is about 0.5 to 2 liters). The continuous secretion of saliva results in rapid removal of released drug. Conversely, the thin mucin film which exists on the surface of the oral mucosa, may provide an opportunity to retain a drug delivery system in contact with the mucosa for prolonged periods if it is designed to be mucoadhesive. Such systems ensure a close contact with absorbing membrane, thus optimizing the drug concentration gradient across the biological membrane and reducing the differential pathway. Therefore, the buccal (oral) mucosa may be a potential site for controlled or sustained drug delivery.³

MATERIAL AND METHODS;

Gliclazide was a gift sample from Hetero company, Bangalore. Carbopol-940 was gift sample from DIVIS laboratory HPMC K15 LV ,Sodium alginate Guar gum was gift sample fromexmed pharma Chennai. Mannitol, Talc, Magnesium stearate from S D fine chemical Ltd, Chennai.

FORMULATION DEVELOPMENT:

1. Pre-formulation Studies:

Pre-formulation may be described as a phase of the dosage form development process that consists of characterization of the physical, chemical and mechanical properties of new drug substances, in order to develop stable, safe & effective dosage forms. Here Pre-formulation studies were conducted for the both the drug and excipients.

Melting Point:

Melting point of the drug was determined by capillary tube method. In this method, small amount of the drug was fill in the capillary and one end of the capillary was packed. The capillary tubes were placed in the digital melting point apparatus and temperature was increased then and note down the temp. When drug was start to melt. Repeat these procedures at least three time and take average of them.

Drug- polymer Compatibility Studies:

Infrared spectra of pure drug and mixture of drug and excipients were recorded by KBr method using Fourier transform infrared spectrophotometer. In the present study, the potassium bromide disc method was employed. The powdered sample was intimately mixed with dry powdered potassium bromide. This mixture was then compressed into transparent pellet under high pressure press at a pressure of 1000 psi. The characteristic peaks were recorded.

Optimization using full factorial design:

A 23 full factorial design was created to determine and optimize the effect of the three formulation factors using t90% as response factor. In this present research work gliclazide mucoadhesive buccal tablets optimized has been done by statistically using 23 full factorial designs. In this study, three variables factors were evaluated each at two levels, and investigational were performed at all eight possible combinations. In which three variables was kept at two levels, one is low level and another one is high level.

Preparation of mucoadhesive buccal tablets of gliclazide:

FORMULATION TABLE;

S.No.	Ingredients (mg)	H1	H2	H3	H4	S1	S2	S3	S4	G1	G2	G3	G4
1	Gliclazide	80	80	80	80	80	80	80	80	80	80	80	80
2	Carbopol-940	20	20	20	20	20	20	20	20	20	20	20	20
3	HPMC E15 LV	10	30	60	80	-	-	-	-	-	-	-	-
4	Sodium alginate	-	-	-	-	10	30	60	80	-	-	-	-
5	Xanthum gum	-	-	-	-	-	-	-	-	10	30	60	80
6	Mannitol	80	60	30	10	80	60	30	10	80	60	30	10
7	Talc	5	5	5	5	5	5	5	5	5	5	5	5
8	Magnesium stearate	5	5	5	5	5	5	5	5	5	5	5	5
9	Total weight	200	200	200	200	200	200	200	200	200	200	200	200

Evaluation parameters of mucoadhesive buccal tablets:

1. Pre-compression Parameters:

a. Bulk Density:

BD=M/BV

Where, BD=Bulk density, M=Weight of sample in grams, BV=Final volume of blend.

b. Tapped Density (TD):

(TD)=M/TV

Where TD =Tapped density, M=Weight of powder in grams, TV=Tapped volume of powder.

c. Angle of Repose:

It is defined as maximum angle possible between surface of pile of powder and the horizontal plane. It is an indicative of flow properties of powder.

Tan ᶿ = h/r,

Where, h=height in cms, r=radius in cms.

d. carr’s index or compressibility index:

CI= TD-BD/TD X 100 Where,

TD=Tapped density of powder, BD=Bulk density of powder, It is expressed in “percentage”

e. Hausner’s Ratio:

It is defined as the ratio of tapped density to the bulk density. It is calculated by the formula as follow^4-7

Hausner’s ratio= TD/BD

Where, TD= Tapped density, BD=Bulk density.

2. Post Compression Parameters:

a. Hardness Test:

The hardness of tablets was measured using Pfizer hardness tester. It is expressed in kg/cm2 Three tablets were randomly picked from each formulation and the mean and standard deviation values was calculated.

b. Thickness and diameter:

Thickness and diameter of the prepared tablets were evaluated with the help of Vernier callipers and screw gauge. It is expressed in mm.

c. Friability Test:

Friability (%) =Initial weight – final weight × 100 Initial weight

d. Weight variation:

The weight variation test was performed as per procedure of IP. The weight of each of 20 individual tablets, selected randomly from each formulation was determined by using electronic balance. The weight data from the tablets were analyzed for sample mean and percent deviation.^8,9.

e. Determination of Drug Content:

The prepared formulations were analysed for drug content. Five mucoadhesive tablets were taken and the contents are powdered. About 200 mg of the formulation was taken in to a 100 ml volumetric flask. Phosphate buffer 6.8 was added to volumetric flask and shaken well. Further, the volume was made up to the mark with phosphate buffer 6.8. The drug content was determined by measuring the absorbance at 229 nm using UV spectrophotometer¹⁰

f. Swelling Index:

Swelling Index = [W2––W1] X100 W1

g. Surface pH:

The microenvironment pH (surface pH) of the buccal tablets was determined in order to investigate the possibility of any side effects in- vivo. As an acidic or alkaline pH may cause irritation to the buccal mucosa, it was decided to keep the surface pH as close to neutral as possible. A combined glass electrode was used for measurement of surface pH. The tablet was allowed to swell by keeping it in contact with 4 ml of distilled water (pH 6.5±0.05) for 2 h at room temperature. The pH was measured by bringing the electrode in contact with the surface of the tablets and allowing it to equilibrate for 1 min.¹¹

h. In-vitro Drug Release Study:

The USP type II dissolution apparatus was used to study the release of drug from buccal tablets. The dissolution medium consists of 900ml of phosphate buffer pH 6.8. The release was performed at 37±0.5°C, at a rotating speed of 50rpm. The samples were filtered through whatman filter paper and were analysed spectrophotometric ally at 229nm against phosphate buffer pH 6.8 as blank.¹²

j. Ex-vivo mucoadhesive time:

The Ex-vivo mucoadhesion time was examined after application of the buccal tablet on freshly cut sheep buccal mucosa. The fresh sheep buccal mucosa was tied on the glass slide, and a mucoadhesive core side of each tablet was wetted with 1 drop of phosphate buffer pH 6.8 and pasted to the sheep buccal mucosa by applying a light force with a fingertip for 30 seconds. The glass slide was then put in the beaker, which was filled with 200mL of the phosphate buffer pH 6.8 and kept at 37 ± 1ºC. After 2 min, a slow stirring rate was applied to simulate the buccal cavity environment, and tablet adhesion was monitored for 8 h. The time for the tablet to detach from the sheep buccal mucosa was recorded as the mucoadhesion time^13.

RESULTS:

Characterization of active Pharmaceutical Ingredient:

In Preformulation studies, characterization of API was performed and it was found that all are within the range specified in the pharmacopoeia. Physical appearance of drug was examined by various organoleptic properties.

Color : White crystalline powder;

Odor : Odorless;

Taste : Tasteless;

State : Fine to granular powder.

Melting point:

Melting point of the Gliclazide was determined by Capillary Fusion method. One side closed capillary filled with drug and put into the Melting Point Apparatus and finally the temperature was noted as at which solid drug changed to into liquid. It was found to be 180^oC.

Figure 1: Calibration curve of Gliclazide

Ftir Compatability Studies:

Figure 2: FTIR spectra of Gliclazide+HPMC K15 L

Figure 3: FTIR spectra of Gliclazide+HPMC K15 L

Precompression Parameter of Powder Blend:

Table 2: Precompression parameter of powder blend.

S.No	Formulation Code	Angle of repose (θ)^*	Bulk Density^* g/cm³	Tapped Density^* g/cm³	Hausner’s ratio^*	Carr’s index^* %
1	H1	26.27±0.55	0.50±0.14	0.59±0.03	1.19±0.01	15.84±0.72
2	H2	25.18±0.97	0.49±0.19	0.56±0.05	1.17±0.02	15.03±0.76
3	H3	26.41±0.60	0.50±0.18	0.62±0.06	1.18±0.02	16.19±0.83
4	H4	27.26±0.60	0.49±0.11	0.60±0.07	1.18±0.02	15.33±0.63
5	S1	25.04±0.62	0.50±0.22	0.58±0.07	1.14±0.01	13.28±0.87
6	S2	25.88±0.66	0.50±0.23	0.57±0.08	1.17±0.01	14.74±0.41
7	S3	26.04±0.45	0.51±0.22	0.61±0.07	1.18±0.02	15.48±0.97
8	S4	25.03±0.45	0.50±0.22	0.58±0.06	1.17±0.01	13.31±0.62
9	G1	25.37±0.75	0.50±0.23	0.57±0.06	1.14±0.01	12.67±0.47
10	G2	26.33±0.50	0.50±0.19	0.58±0.050	1.16±0.01	13.73±0.99
11	G3	25.12±0.66	0.50±0.18	0.57±0.04	1.16±0.02	14.57±0.65
12	G4	25.20±0.68	0.41±0.14	0.59±0.02	1.19±0.01	15.64±0.89

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

Post compression Parameters

Table No 3 : Results of Post-compression parameters

S.No	Formulation Code	*Thickness^(mm)**	*Hardness^(kg/cm²)**	Friability(%)	Weight variation^(%)**
1	H1	3.32±0.15	5.16±0.40	0.85	0.073±0.43
2	H2	3.40±0.10	4.91±0.49	0.83	0.068±0.55
3	H3	3.44±0.41	5.41±0.37	0.84	0.047±0.46
4	H4	3.51±0.14	5.16±0.60	0.72	0.022±0.52
5	S1	3.25±0.15	5.33±0.51	0.65	0.068±0.48
6	S2	3.30±0.11	5.58±0.37	0.85	0.020±0.54
7	S3	3.17±0.09	5.50±0.54	0.65	0.020±0.65
8	S4	3.26±0.16	5.16±0.60	0.73	0.096±0.57
9	G1	3.23±0.12	5.25±0.41	0.52	0.068±0.57
10	G2	3.36±0.10	5.66±0.40	0.82	0.019±0.63
11	G3	3.28±0.12	5.50±0.44	0.75	0.020±0.16
12	G4	3.43±0.14	5.25±0.52	0.61	0.071±0.56

Table.4 Results of % of drug content, surface pH, swelling index, bioadhesive strength

S.No	Formulati Code	(%)Drug content^*	SurfacepH^**	Bioadhesive strength^(gm)*	%Swelling index^* after 8 hrs**
1	H1	99.45±0.95	6.35±0.32	15.46±0.35	187.33±5.50
2	H2	100.24±0.60	6.56±0.45	15.83±0.30	189.66±5.03
3	H3	99.43±0.85	6.48±0.33	16.23±0.25	192.33±5.50
4	H4	99.09±0.67	6.45±0.50	16.51±0.36	193.66±6.02
5	S1	99.73±0.95	6.53±0.41	18.86±0.11	135.66±6.02
6	S2	99.62±0.52	6.21±0.46	19.26±0.15	137.85±7.02
7	S3	99.78±0.73	6.25±0.37	19.86±0.25	141.21±8.18
8	S4	99.94±0.78	6.35±0.36	20.36±0.11	145.61±9.84
9	G1	100.11±0.70	6.33±0.40	22.30±0.25	103.00±6.24
10	G2	99.32±0.39	6.61±0.35	22.40±0.10	106.00±5.56
11	G3	99.10±0.58	6.55±0.33	23.21±0.17	109.66±6.02
12	G4	100.31±0.98	6.58±0.21	23.63±0.75	113.33±7.50

^*Mean ± SD, n = 20. ^**Mean ± SD, n = 6. ^***Mean ± SD, n = 3

Fig. 4: In-vitro drug release profile of formulations H1 – H

Fig.5. In-vitro drug release profile of formulations G1 – G4

Ex vivo permeation studies through porcine buccal mucosa:

The aim of this study was to investigate the permeability of buccal mucosa to Gliclazide. It is based on the generally accepted hypothesis that the epithelium is the rate-limiting barrier in the buccal absorption.

Figure. 6: Ex-vivo permeation of Gliclazide drug solution through the porcine buccal mucos

DISCUSSION:

FTIR results indicate that there was no chemical incompatibility between drug and excipients used in formulation. The powder blends were also evaluated for various pre-compression parameters. The results are shown in Table No.4. All the powder blend resulta are within the limits as per IP 1996. Hence, powder mixture was found suitable for direct compression method. The thickness of the batch from H1-H4, S1-S4, G1- G4 was found to be in the range of 3.17-3.51 mm and hardness was found to be 4.91-5.66 kg/cm² as. Thus tablets were having good mechanical strength. The friability of all the formulated tablets of Gliclazide was found to be between 0.52 - 0.85% are reported in Table No.4 and all the formulated tablets of Gliclazide confirmed that% friability within the official limits (i.e., not more than 1 %).The values of the mucoadhesive strength of Gliclazide mucoadhesive buccal tablets are given in Table No.6. In all the formulations, as the polymer concentration increased, the mucoadhesive strength also increased. The in-vitro release of Gliclazide from mucoadhesive buccal tablet was found to vary according to the type and ratio of polymer used. The release of Gliclazide was decreased with increasing concentration of HPMC K15 LV, sodium alginate, guar gum. The percentage of the drug released from the formulations H1, H2, H3, H4 was found to be 82.94±0.54%, 78.26±0.99%, 74.21±0.86 %, 71.70±0.53% respectively. The percentage of the drug released from the formulations S1, S2, S3, S4 was found to be 92.00±0.56%, 88.12±0.60%, 83.09±0.47%, 80.60±0.48% respectively. The percentage of the drug released from the formulations G1, G2, G3, G4 was found to be 75.43±0.47%, 72.62±0.58%, 69.44±0.39%, 60.89±0.34% respectively.

The formulation H4 is considered as a optimized formulation because of its better sustained release 71.70±0.53%. The data for in-vitro drug release of formulations was shown in the Table No.7-9. The in- vitro drug release profiles were shown in Figure No.7-9 . From the results mentioned in the table-11 it was evident that selected formulation was showing good Flux and permeability coefficient values. The selected formulations H4 formulation was showing maximum flux value and permeability coefficient value i.e., 389.42 (µg.hrs-1cm-2) and 0.111 (cm/h).

CONCLUSION:

An optimised mucoadhesive buccal formulation consisting of HPMC E 15 LV, xanthan gum, sodium alginate was successfully developed with an increased drug release rate, swelling index, and avoid the first pass metabolism. Thus, the study confirmed that the mucoadhesive buccal tablet formulation could be used as a possible alternative to the traditional oral formulation. 23 full Factorial design showed that the direct compression method was suitable for the preparation of gliclazide buccal tablets. The prepared buccal tablets physical characteristics were evaluated, and they acquiesce with the official Pharmacopoeial limits. zero-order, first order, Higuchi, Korsmeyer- Peppas models are computed with drug release data. The criterion for selecting the most appropriate model was from the goodness-or fittest.

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Received on 22.05.2021 Modified on 15.07.2021

Asian J. Pharm. Tech. 2021; 11(4):261-266.

DOI: 10.52711/2231-5713.2021.00043