INTRODUCTION:

Controlled drug delivery system is the one which delivers the drug at a predetermined rate, locally or systematically, for specified period of time^[1]. Gastro retentive formulations could be designed based on approaches like: a) floating; b) high density system; c) bioadhesion; d) lowered motility of the GIT by concomitant administration of drugs or pharmaceutical excipient; e) swellable and expandable system ^[2]. GRDDS is suitable for drugs with an absorption window in the stomach or the upper small intestine, for drugs which act locally in the stomach and for drugs that are poorly soluble or unstable in the intestinal fluid ^[3].

Various approaches to formulate gastroretentive drug delivery system (GRDDS) are explored and mucoadhesion is one of them ^[3]. Mucoadhesive formulation is one of the most commonly used approaches for controlled and site specific drug delivery ^[4].

Bioadhesion is defined as an ability of a material to adhere a particular region of the body for extended period of time not only for local targeting of drugs but also for better control of systemic delivery ^[1]. Adhesiveness of the dosage form is based on the bioadhesive power of the polymer ^[5]. The mechanism by which mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the establishment of the adhesive interactions) ^[6]. Prolong gastric retention time (GRT) improves bioavailability, reduced drug waste and enhance solubility for drugs that are less soluble in high pH environment ^[7]. Bioadhesive system control drug release could improve the treatment of diseases and help to maintain an effective concentration of the drug at the site of action ^[8].

EXPERIMENTAL:

Material:

Ondansetron HCl was procured from Celogen Life Sciences, Mumbai. Carbopol, chitosan, xanthan gum and HPMC K100M were procured from Celogen Life Sciences, Mumbai, Lactose, magnesium stearate and talc was procured from Haffkine Ajintha Pharmaceutical Ltd., Jalgaon.

Preparation of mucoadhesive tablet:

Mucoadhesive tablets each containing 32mg of ondansetron HCl were prepared by wet granulation method employing HPMC K100M, chitosan, carbopol, Xanthan gum as mucoadhesive materials as shown in the formulae given in table. A batch of 60 tablets was prepared in each case a blend of 1.92s gm of ondansetron HCl with required amount of polymers. Which were then granulated along with 5% w/w PVP K30 in water as abinder solution.Firstly all ingredients weigh accurately. Ondansetron HCl, HPMC K 15 M/HPMC K 100M/Chitosan/Carbopol 934p/Xanthan gum, Lactose, Magnesium stearate, Talc were sifted separately through 60#sieve. Ondansetron HCl, HPMC K15M/HPMC K 100M/Chitosan/Carbopol 934p/Xanthan gum and Lactose were taken in small polythene bag and mixed slowly for 5 min. Mixed material was put in mortar and binder solution is added to prepare a dump mass. The mass was dump passing through sieve 8#. That wet granules were dried at room temperature. Dried granules were passed through 16#. The granules were ready for lubrication. Sifted granules were transferred to polythene bag and magnesium stearate and talc also sifted through 60#sieve and added to above granules, mixed for 2 minutes.

Compression of mucoadhesive tablet:

Mucoadhesive tablet were prepared manually using multi-tooling punching machine (CIP). 9mm biconcave punch was selected. Then granules were compressed in to 250 mg tablets of hardness 4-5 kg/cm².

Sr.No.	Ingredients	A1	A2	A3	A4	A5	A6	A7	A8
1	Ondansetron HCl	32	32	32	32	32	32	32	32
2	Lactose	42.5	42.5	42.5	42.5	42.5	42.5	42.5	42.5
3	HPMC K100M	160	-	-	-	80	80	80	-
4	Carbopol934p	-	160	-	-	80	-	-	80
5	Chitosan	-	-	160	-	-	80	-	80
6	Xanthan Gum	-	-	-	160	-	-	80	-
7	PVP K30	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
8	Magnesium stearate	1	1	1	1	1	1	1	1
9	Talc	2	2	2	2	2	2	2	2
Average weight		250	250	250	250	250	250	250	250

*Note: All Quantities Were in mg

Evaluation of Ondansetron HCl Mucoadhesive Tablet:

1. Hardness Testing:

Hardness for sustained release tablet in order to maintain the physical strength as well as desired release, because has indirect effect on the release of SR tablet. The tester consists of a barrel containing a compressible spring held between two plungers. The lower plunger was placed in contact with the tablet, and zero reading was taken. The upper plunger was then forced against a spring by turning a threaded bolt until a tablet fracture. As a spring compressed, a pointer rides along agauge in the barrel to indicate the force. The force of fracture is recorded, and the zero force reading was deducted from it. 10 tablets of each formulation A-1 to A-8 were taken and the hardness was determined. After which the standard deviation was determined by using MS-Excel. Hardness is expressed in kg/cm^{2 [9, 10]}.

2. Friability:

A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up. Friability is expressed in percentage. A number of tablets were weighed. It was placed in the apparatus where they were exposed to rolling and repeat shock as they fall 6 inches in each turn within the apparatus. After 4 minutes of this treatment or 100 revolutions (25rpm), the tablets are weighed and the weight compared with the initial weight ^{[10, 11]}.

%friability=(Initial weight-Final weight/Initial weight) X100

3. Weight Variation:

It is an important property to determine the drug content present in each tablet. Twenty tablets were select randomly from each batch and weighed individually. Average weight was calculated from the total weight of all tablets. The individual weights were compared with the average weight. The acceptable%of weight variation as per USP is+7.5 % that is>130mg to<324 mg. Tablet meet the USP test if no more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit ^[9,10,11].

Weight variation parameters ^[11]

Average weight of tablet	Percentage deviation
130 mg or less	±10
>130 mg-<324 mg	±7.5
324 mg or more	±5

*In all the formulations, the tablet weight is 250 mg, hence ±7. 5% maximum difference allowed.

4. Drug Content: -

Then 10 tablets from each formulations from A1-A8 were taken, crushed and then accurately weight was taken according to the 16mg of pure drug and dissolved in the suitable solvent and the values were observed in spectrophotometer (UV-VIS-1800 Shimadzu, Japan) at 248nm, these will be the values of sample, after that with the help of the following formula content uniformity was calculated^[11].

Content Uniformit=(Absor bance of sample)/absorbance of standard) X100

5. In-Vitro Swelling Studies:

The degree of swelling of mucoadhesive polymer is an important factor affecting adhesion. For conducting the study, a tablet was weighed and placed in a petri dish containing 5 ml of 0.1 N HCl pH 1.2 in 6 h at regular intervals of time, the tablet was taken carefully by using filter paper. The swelling index was calculated using the following formula^[12,
16].

Swelling Index(S.I)=(Wt-Wo)/WoX100

Where S.I=swelling index,

W_t=swollen weight of tablet at time t,

W_o=weight of the initial tablet

6. In-vitro Dissolution Studies:

The USP dissolution test apparatus (apparatus II paddle type) was used to study the drug release from the tablets. The dissolution medium was 900 ml of 0.1N HCl buffer pH 1.2. The release was performed at 37±0.5°C, with a rotation speed of 50 rpm. 5ml samples were withdrawn at predetermined time intervals and replaced with fresh medium to maintained sink condition. The samples were analyzed after appropriate dilution by UV spectrophotometer at 248 nm and drug release was determined from standard curve^{[9, 11, and 15]}.

%Drug Released=(Sample abs/Std.abs.)X

Standrard dilution X Test dilution X

(Purity/Label Claim)

Dissolution Parameters:

· Dissolution medium: 900 ml of 0.1 N HCl pH 1.2

· Rotation of paddle: 50 rpm

· Temperature of medium: 37±0.5°c

· Sample volume withdrawn: 5ml sample

· λ max : 248 nm

· Time interval: 0, 1, 2, 3, 4, 6, 8, 10 and 12hrs.

Dissolution acceptance criteria for sustained release formulation

Time (hr.)	% Drug Release
1^st hour	15-25%
3^rd hour	25-50%
5^th hour	50-80%
8^th hour	>80%

Measurement of Ex-Vivo Mucoadhesive Strength:

A double beam physical balance was taken, the left pan was removed. To left arm of balance a thick thread of suitable length was hanged. To bottom side of thread a glass stopper with uniform surface was tied. A clean glass mortar was placed below hanging glass stopper. In this mortar was placed a clean 500 mi glass beaker, within which was placed another glass beaker of 50 ml capacity in inverted position and weighed with 50g to prevent floating. The temperature control system involves placing thermometer in 500 ml beaker and intermittently adding hot water in outer mortar filled with water. The balance was so adjusted that right hand side was exactly 5g heavier than the left. The balance adjusted as described above was used for the study.The bovine check pouch excised and washed was tied tightly with mucosal side upward using thread over the base of inverted 50 ml glass beaker. This beaker suitably weighed was lowered into 500 ml beaker, which was then filled with 0.1N HCl kept at 37⁰C such that the buffer reaches the surface of mucosal membrane and keeps it moist.This was then kept below left hand side of balance. The mucoadhesive tablet was then stuck to glass stopper through its backing membrane using an adhesive (Feviquick). The 5g on right side is removed; this causes application of 5 g of pressure on mucoadhesive tablet overlying moist mucosa.The balanced was kept in this position for 3 min and then slowly weights were increased on the right pan, till tablet separates from mucosal membrane.The gives mucoadhesive strength in grams. The mean value of three trials was taken for each set of formulations.After each measurement, the tissue was gently and thoroughly washed with isotonic phosphate buffer and left for 5 min before reading a new tablet of same formulation to get reproducible multiple results for the formulation^{[12, 15, 17]}.

RESULTS AND DISSCUTION:

1) Determination of Wavelength:

Ondansetron hydrochloride solution (100µg/ml) was prepared in 0.1 N HCl. These solutions were scanned under UV/VIS spectrophotometer (Shimadzu 1800)^{[13, 14]}.

UV spectrum of ondansetron HCl

2. Standard Calibration Curve of Ondansetron HCl in 0.1 N HCl:

Weigh accurately 50 mg of Ondansetron HCl, transfer it to 50 ml volumetric flask, add 0.1 N HCl, dissolve it to get 1000 µg/ml. From that solution, pipette out 1ml, transfer into 10 ml volumetric flask and make up the volume up to 10ml with0.1NHCl to get 100 µg/ml concentration of Ondansetron HCl. Then prepare a various concentration solution like 5, 10, 15, 20, 25 µ/ml solution. Measure the absorbance of solutions at 248 nm by using UV spectrophotometry. 0.1N HCl taken as blank solution for estimation. Plot a graph by taking concentration on X–axis and absorbance on Y–axis. This plot gives a straight line and linearity was determined^{[13, 14]}.

Standard calibration curve of ondansetron HCl

3) DSC AND FTIR Estimation of ondansetron HCl:

FTIR Spectrum of Ondansetron HCl

DSC graph of Ondansetron HCl

4) Drug Excipient Compatibility Study:

1) DSC Study:

The melting point of Ondansetron HCl (178.5⁰C) matches with the standard value (178.5-179.5). The DSC graph of Ondansetron HCl was also showed the melting point at 178.5 indicate that is as pure.

DSC graph of Ondansetron HCl with polymers

2) FTIR Study:

FTIR spectrum of Ondansetron HCl with HPMC K100M, Ondansetron HCl with Chitosan, Ondansetron HCl with carbopol and Ondansetron HCl with Xanthan gum.The FTIR spectrums of all these samples were compared to that of pure Ondansetron HCl spectrum. It indicates that there was no interaction with excipients^{[13, 14].}

FTIR spectrum of Ondansetron HCl + HPMC K100M

FTIR spectrum of Ondansetron HCl+Chitosan

FTIR spectrum of Ondansetron HCl + Carbopol 934p

FTIR spectrum of Ondansetron HCl+Xanthan gum

Precompression evaluation parameter of ondansetron HCl granules:

Batches	Parameters
Batches	BD (g/ml)*	TD (g/ml)*	CI (%)*	HR*	*Angle of repose (degree)**
A1	0.30±0.01	0.33±0.02	11.17±0.56	1.28±0.01	38.47±0.2
A2	0.29±0.01	0.31±0.01	21.08±0.5	1.32±0.01	35.85±0.03
A3	0.32±0.003	0.35±0.001	14.21±0.7	1.26±0.02	37.23±0.04
A4	0.29±0.002	0.34±0.004	20.49±0.33	1.29±0.01	32.93±0.02
A5	0.32±0.00	0.40±0.004	18.16±0.3	1.21±0.006	30.88±0.1
A6	0.30±0.01	0.35±0.01	14.93±0.03	1.18±0.00	29.85±0.03
A7	0.34±0.01	0.43±0.01	19.80±0.2	1.23±0.02	22.69±0.04
A8	0.33±0.01	0.39±0.013	17.18±0.45	1.21±0.006	31.07±0.05

*Where, All values are mean±SD, n=3

Evaluation parameter of Ondansetron HCl Mucoadhesive Tablet

Table: Evaluation of Mucoadhesive Tablet

Sr. No.	Evaluation Parameters	Batches
Sr. No.	Evaluation Parameters	A1	A2	A3	A4	A5	A6	A7	A8
1.	Appearance	White colored round shaped uncoated tablet
2.	Weight variation(mg)	0.249	0.248	0.246	0.253	0.245	0.249	0.247	0.252
3.	Thickness (mm)	3.75	3.7	3.86	3.82	3.9	3.7	3.8	3.78
4.	Hardness(kg/cm²)	4.2	4.4	4.3	4.3	4.2	4.4	4.4	4.5
5.	Friability (%)	0.73	0.51	0.55	0.61	0.81	0.52	0.67	0.71
6.	Drug content (%)	97.41	96.28	97.16	95.93	97.11	98.67	97.37	95.34
7.	Mucoadhesive strength(gm)	35	40	42	25	24	45	30	34

The value of bulk density indicates good packing character. The compressibility index of formulation A3 and A6 below 15%, indicating good flow properties of granules. The hausner’s ratio of the formulation A6 in the range 1.12-1.18 showed good flow property. The angle of repose of formulation A6 was in between 25⁰ to 30⁰ which indicate good flow properties of granules^{[9, 10, 15, 17 ]}.

7. In-vitro swelling study:

Time (hr) Batch no.	Swelling Index
Time (hr) Batch no.	1	3	6	8
A1	0.624	1.041	1.250	1.27
A2	0.558	0.987	1.024	1.029
A3	0.672	1.122	1.347	1.306
A4	0.120	0.616	0.946	1.265
A5	0.220	0.558	1.140	1.181
A6	0.258	0.695	1.210	1.485
A7	0.228	0.605	1.000	1.043
A8	0.561	0.674	0.901	0.942

Swelling behavior of mucoadhesive tablet

Ex-vivo mucoadhesive strength

8. In-vitro dissolution mucoadhesive table

Batches Time hr	% Drug Release
Batches Time hr	A1	A2	A3	A4	A5	A6	A7	A8
1	14.62	13.52	17.57	11.4	13.21	15.62	12.88	15.62
2	28.86	24.56	30.15	22.45	21.45	23.34	22.03	24.77
3	35.88	31.96	43.93	32.98	29.13	32.54	30.92	33.87
4	45.26	39.84	57.77	39.98	35.52	42.86	36.12	42.11
5 9 12 Batches Time(hr) 1 2 % Drug Release	58.16	47.94	66.34	47.1	43.01	52.89	44.57	51.89
6	66.2	56.99	69.8	56.68	53.38	63.95	55.49	60.48
8	78.48	75.44	77.13	70.48	70.48	85.98	75.99	78.29
12	94.23	93.49	95.83	90.28	91.47	97.71	92.84	95.62

Fig 1: In-vitro drug release profile of mucoadhesive tablet formulation A1–A4

Fig 2: In-vitro drug release profile of mucoadhesive tablet formulation A5-A8

CONCLUSION:

In present research work the ondansetron HCl mucoadhesive tablet were successfully prepared by wet granulation method using mucoadhesive polymers like chitosan, carbopol, xanthan gum and HPMC K100M in different concentration. Drug-excipient compatibility study was performed by using FTIR and DSC. No drug-excipient incompatibility was observed in both FTIR and DSC. Precompression study of ondansetron HCl granules was performed like bulk density, tap density, compressibility index, Hausner’s ratioand angle of repose. Among these formulations A6 indicates that good flow property. Post compression study was also performed. Various parameters such as general appearance, tablet dimension, friability, hardness, weight variation, uniformity content, swelling index, in-vitro drug release and mucoadhesive strength were determined. Among this formulation A6 gaves best result. A6 formulation was showed better mucoadhesive strength, swelling in increasing and from the dissolution data of A6 formulation was observed better in vitro drug release.

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Received on 07.06.2018 Accepted on 18.08.2018

Asian J. Pharm. Tech. 2018; 8 (3):132-138 .

DOI: 10.5958/2231-5713.2018.00021.1