Glimepiride And Valdecoxib Combination Mucoadhesive Tablets Biology Essay

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Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. The objective of this study was to extend the GI residence time of the dosage form and control the release of Glimepiride and Valdecoxib using mucoadhesive tablet to achieve controlled plasma level of the drug which is especially in diabetes mellitus patients with NSAIDs therapy. Direct compression method was used to prepare tablets. All the formulations were shown good pre compression and post compression parameters. The optimized formulation was subjected to accelerated stability studies.

Keywords: Glimepiride, Valdecoxib, mucoadhesive tablet, evaluation.

INTRODUCTION

Glimepiride is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from pancreas and is typically prescribed to treat type II Diabetes (non-insulin dependent diabetes mellitus). The drug is selected as model for designing sustained release because of its short biological half-life (3.4±0.7 hours) necessitates that it can be administered 2 or 3 doses with 2.5 to 10 mg per day.

Valdecoxib, a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties was chosen as a model drug due to its high first pass metabolism. It undergoes both P450 and non-P450 dependent (glucuronidation) metabolism. The mechanism of action is believed to be due to inhibition of Prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2).

Mucoadhesive Glimepiride tablets were prepared by using Sodium carboxy methyl cellulose (SCMC) and Hydroxy propyl methyl cellulose (HPMC), carbopol and Poly vinyl pyrrolidone. There is no availability of Glimepiride and Valdecoxib mucoadhessive tablets commercially. So an attempt has been made to develop a combination sustained release mucoadhessive formulation of anti-diabetic drug with NSAID.

MATERIAL AND METHODS

Materials

Glimepiride and Valedicoxib were obtained from Dr. Reddy's laboratories, Hyderabad, India. HPMC K4M, Carbopol-934P, Povidone, magnesium stearate were procured from SD fine chemicals, Mumbai, India and all other ingredients used were of analytical grade.

experimental methods:

Pre formulation Studies for Drug Excipients Compatibility:

The pure drug and formulation (F4) were separately mixed with IR grade potassium bromide in a ratio (1:100) and pellets were prepared by applying 10 metric ton of pressure in hydraulic press. The pellets were then scanned over range of 4000-400cm-1 in FTIR instrument.

Preparation of mucoadhesive Tablets:

Mucoadhesive tablets were prepared in 3 steps

Step-I: Preparation of Core Layer's Mixture:

Glimepiride, Valdecoxib, Hydroxy propyl Methyl Cellulose, Carbopol-940, Sodium Carboxy Methyl Cellulose-H, Polyvinyl Pyrrolidone-K30 and Magnesium stearate were mixed well by using glass mortar and pestle. This mixture was used for the preparation of core layer of the tablet. The composition of core layer was represented in Table 1.

Step-II: Preparation of Backing Layer's Granules:

Carbopol 934P, Poly vinyl pyrrolidone, Magnesium stearate, Saccharin sodium were mixed well using glass mortar and pestle. In a separate glass beaker, solution of Amaranth was prepared using ethanol as a solvent. By gradually adding the color solution to a dry mixture; a wet mass/lump was prepared. Peppermint oil was added to this lump and mixed properly. Then this lump was passed through the sieve (Sieve No.40). Then wet granules were dried in a Hot Air Oven at a temperature 500C for 20 minutes. To this dried granules, magnesium stearate lubricant was added. These granules were used for the preparation of backing layer of the tablet. The composition of backing layer was represented in table 2.

Step-III: Compression:

For this purpose an I.R. hydraulic press and Die Punch Set having diameter of 10mm was used. Firstly, the mixture of drug and polymers (weighed quantity-150mg) was compressed using a pressure of 50kg/cm2 for 5 seconds. Then upper punch was removed and then granules of backing layer (weighed quantity -75mg) were added over the first layer and compressed at a pressure of 200kg/cm2 for 15 seconds. By this way, the bilayer tablet was prepared.

EVALUATION OF TABLETS

Pre-compression parameters

Compatibilities study

The compatibility of drugs and excipients used under experimental condition were studied. The syudy was performed by taking 2 mg sample in 200 mg KBr(using Perkin Elmer, spectrum-100, Japan). The scanning range was 400 to 4000 cm-1 and the resolution was 1cm-1. This spectral analysis was employed to check the compatibility of drugs with the excipients used.

Physical evaluation of tablets:

Thickness

The thickness of the tablets was determined using a thickness screw gauge (Mitutoyo, New Delhi, India). Five tablets from each batch were used and average values were calculated.

Uniformity of Weight Test

To study weight variation, 20 tablets of each formulation were weighed using an electronic balance (Denver APX-100, Arvada, Colorado) and the test was performed according to the official method.

Hardness and Friability

For each formulation, the hardness and friability of 10 tablets were determined using the Monsanto hardness tester (Cadmach, Ahmedabad, India) and the Roche friabilator (Campbell Electronics, Mumbai, India), respectively.

Swelling behavior of matrix tablets

The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behavior of formulation GAP-1, GAP-2, GAP-3, GAP-4 and GAP-5 were studied. One tablet from each formulation was kept in a Petri dish containing phosphate pH 7.4. At the end of 2 hours, the tablet was withdrawn, kept on tissue paper and weighed, repeated for every 2 hours till the end of 12 hours. The % weight gain by the tablet was calculated by eq.1.

S.I = {(Mt-M0) / M0} X 100 ------ (1)

Where, S.I = Swelling Index, Mt = Weight of tablet at time 't' and

M0 = Weight of tablet at time 0.

Uniformity in drug content:

The formulated tablets were tested for uniformity in Glimepiride and Valdecoxib contents by using UV/ Visible spectrophotometer (Elico SL 210) at 226 nm and 243 nm for Glimepiride and Valdecoxib respectively.

Surface pH

The surface pH of the mucoadhesive tablets was determined in order to investigate the possibility of any side effects in vivo. An acidic or alkaline pH may cause irritation to the mucosa. A combined glass electrode was used for this purpose. The tablet was allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.5 ± 0.05) for 2hr at room temperature. The pH was measured by bringing the electrode in contact with the surface of the tablet and allowing it to equilibrate for 1min.

Moisture absorption studies of mucoadhesive tablet

A 5% w/v solution of Agar prepared in hot water and transferred into petri dishes and allowed to solidify. Five pre weighed tablets from each formulation were placed in vacuum oven overnight to remove moisture and laminated on one side with a water impermeable backing membrane. The tablets were placed on the surface of the agar and incubated at 37°C for one hour. Then the tablets were removed and weighed and the percentage of moisture absorption was calculated by using eq. 2.

% Moisture absorption = {(final weight - initial weight)/initial weight} x100 ---- (2)

Mucoadhesive Force Measurement

Mucoadhesive force measurement of tablets was done by modifying balance method. The right pan was replaced with a glass beaker container and on the left side beaker with a copper wire. Teflon block of 1.5 cm diameter and 3 cm height was adhered strongly with the glass beaker. The two sides were then adjusted, so that the left hand side was exactly 5 g heavier than the right. Stick the stomach on the teflon block with help of the cynoacrylate glue and fill the beaker with acidic buffer till the tissue remains in a moist condition. Stick the tablet to beaker and put on the tissue for 15 minutes. After 15 minutes add water slowly into right beaker until the tablet detaches.

Weigh the water required for the tablet detachment. Calculate Actual weight for detachment and force of adhesion in dynes by following eq.2.

Actual weight for detachment (W) = weight for detachment (g) ……………….(2)

Matrix Erosion

Each tablet weighed (W1) were immersed in a phosphate buffer pH 6.8 for predetermined time (1, 2, 4, 8 and 12 hours). After immersion, tablets were wiped off by the excess of surface water by the use of filter paper. The swollen tablets were dried at 60°C for 24 hours in an oven and kept in a desiccator for 48 hours prior to be reweighed (W2). The matrix erosion was calculated using the formula given in the eq.3.

(W1 - W2)

Matrix Erosion = ----- - 100 ………. (3)

W1

Dissolution Studies:

The dissolution of the mucoadhessive tablets were performed using USP XXIII dissolution apparatus (paddle method) using 500 ml of phosphate buffer (pH 7.4) as the dissolution medium, which was maintained at 37±0.50C and stirred at 50 r.p.m. Tablet was glued with Cyanoacrylate adhesive (Evobond) from backing layer side to the glass slide and it was placed at the bottom of jar of dissolution apparatus to avoid movement of tablet. Aliquots of 5ml of samples were withdrawn with a bulb pipette at different time intervals of 30, 60, 120, 180, 240, 300 and 360 minutes and replaced with equal volume of phosphate buffer (pH 7.4) at each withdrawal, filtered it through Whatmann Filter Paper No.1.

The samples were then analysed using double beam uv visible spectrophotometer (Elico SL 210) at 226 nm and 243 nm for Glimepiride and Valdecoxib respectively. The cumulative amount of drug released at various time intervals was calculated. This test was done in triplicates.

Accelerated Stability Studies

To assess the drug and formulation stability, stability studies were done according to ICH and WHO guidelines. Optimized formulation (F4) was sealed in aluminum packaging coated inside with polyethylene, and then kept in stability chamber maintained at 45°C and 75% RH for 3 months. At the end of studies, samples were analyzed for the drug content, in-vitro dissolution, floating behavior and other physicochemical parameters

RESULTS AND DISCUSSIONS

Pre-compression parameters

FTIR Spectrum:

Infrared Spectrum of Valdecoxib, Glimepiride and the formulation blend (F4) were showed in Fig. 1, 2 and 3 respectively. The uninterrupted characteristic peaks of Valdecoxib, Glimepiride were observed in the FTIR spectrum of the blend. This indicates the excipients used were not having any negative interactions with the drugs used.

Post compression parameters

Thickness:

Tablets were evaluated for their thickness using Vernier Callipers. The results are shown in Table 3.

Uniformity of Weight Test:

The tablets of all the formulations were passed the uniformity in weight test-IP . The results were shown in Table 3.

Hardness and Friability:

The hardness of formulated tablets was more than 5 kg/cm2 and the friability was less than 1% indicates the formulated tablets were found to have good mechanical strength. The results were shown in Table 3.

Swelling behavior of matrix tablets:

The swelling index of the formulated tablets was evaluated and the results were provided in Fig. 4. The values were 65.8, 71.8, 80.2, 86.5 and 85.9% respectively. The highest hydration (swelling) was observed with the formulation F4. The swelling index increases by increasing the contact time as the polymers gradually absorbs the water due to hydrophilic nature with resultant swelling.

Uniformity in drug content:

The values of Glimepiride and Valdecoxib content in the formulations was represented in Table 4.

Moisture absorption studies of mucoadhesive tablet

The values of Moisture absorption of formulated tablets were shown in table 4.

Mucoadhesive strength Measurement:

The values of In-vitro mucoadhesive strength were shown in Table 4. The values were ranged from 14.52 ± 1.29 to 19.51 ± 2.25g. This indicates Hydroxy Propyl Methyl Cellulose, Carbopol-940, Sodium Carboxy Methyl Cellulose-H and Polyvinyl Pyrrolidone-K30 exhibited good mucoadhesive strength. Among various formulations, F4 was found to be best.

Surface pH:

The surface pH of formulated tablets were ranged from 6.11 ±2.25 to 6.99 ± 5.69 and represented in table 4.

Matrix Erosion:

The % matrix erosion of formulated tablets was ranged from 4.01±0.38 to 11.01±0.02% and the values were represented in table 5.

Dissolution Studies:

The plot result from in-vitro dissolution study was shown in Fig. 5 and 6.

Accelerated Stability Studies

The optimized formulation (F4) was tested for drug content, Surface pH, mucoadhesion strength and Swelling Index before and after accelerated stability studies. The study proved that the formulations retain their characteristic parameters before and after accelerated stability studies. The values were shown in table 6.

Table 1: composition of mucoadhesive tablets core layer

Ingredients (mg)

Formulations

F1

F2

F3

F4

F5

Glimepiride

2

2

2

2

2

Valdecoxib

20

20

20

20

20

Hydroxy Propyl Methyl Cellulose

5

10

15

20

25

Carbopol-940

10

20

30

40

50

Sodium Carboxy Methyl Cellulose-H

5

10

15

20

25

Polyvinyl Pyrrolidone-K30

2

4

6

8

10

Spray dried Lactose

102

80

58

36

14

Magnesium stearate

4

4

4

4

4

Total Weight = 150 mg

Table 2: Composition of mucoadhesive tablet backing layer

S. No

Ingredients

Quantity (mg)

1.

Magnesium stearate

30

2.

Carbopol-940

10

3.

Polyvinyl Pyrrolidone K30

25

4.

Amaranth

0.06

5.

Peppermint oil

5

6.

Saccharin sodium

5

Total Weight = 75 mg

Table 3: Evaluation of physical parameters of different mucoadhesive tablets

Formulation

Weight variation test

Thickness

(mm)

Friability (%)

Hardness (kg/cm2)

n=5

Average Weight (mg)

IP Weight Variation Test

F1

499±1.28

Passes

2.7±0.01

0.52±0.09

6.8±0.67

F2

498±2.27

Passes

2.2±0.02

0.16±0.01

5.8±0.19

F3

500±3.59

Passes

2.8±0.06

0.35±0.04

7.2±0.28

F4

501±5.68

Passes

2.9±0.03

0.66±0.05

8.1±0.19

F5

498±4.55

Passes

2.7±0.04

0.78±0.01

5.9±1.02

Table 4: Evaluation parameters of different mucoadhesive tablets

Formulations

% Drug content

Surface

pH

% water absorption

Mucoadhession strength (g)

Glimepiride

Valdecoxib

F1

100.15±3.62

99.35±4.49

6.56 ± 6.62

45.25 ±2.20

15.26 ±0.12

F2

99.62±5.59

99.99±6.66

6.99 ± 5.69

52.33 ±2.25

16.29 ±2.25

F3

99.15±6.59

100.02±3.33

6.59 ± 1.29

45.28 ±4.35

14.52 ±1.29

F4

99.10±4.44

100.59±5.52

6.12 ± 1.55

56.29 ±3.26

19.51 ±2.25

F5

100.95±6.31

98.98±6.59

6.11 ± 2.25

49.28 ±2.25

15.54 ±1.25

Table 5: Matrix Erosion of formulated tablets

Formulation

% matrix erosion

2hour

4 hour

6 hour

8 hour

12 hour

F1

4.01±0.38

5.89±0.52

6.38±0.25

7.95±0.06

9.50±0.05

F2

5.25±0.16

6.12±0.21

7.15±0.06

8.16±0.05

9.95±0.06

F3

5.62±0.56

6.39±0.15

7.89±0.19

8.99±0.15

10.29±0.04

F4

4.69±0.06

6.22±0.54

7.80±0.52

9.25±0.25

10.23±0.02

F5

4.55±0.55

7.01±0.62

7.88±0.23

8.95±0.45

11.01±0.02

Table 6: Summary of parameters before and after stability studies

Parameter

Before stability studies

After stability studies

Drug content (%)

Glimepiride= 99.10

Glimepiride= 99.05

Valdecoxib= 100.59

Valdecoxib= 100.50

Surface pH

6.12

6.11

Mucoadhession strength (g)

19.51

19.50

Swelling Index (%)

86.5

86.5

Fig 1: Infra-Red Spectrum of Valdecoxib

Fig 2: i.r. Spectrum of Glimepiride

Fig 3: i.r. Spectrum of formulation blend

Fig.4: Swelling Index of formulated tablets

Fig.5: In-vitro drug release from formulated tablets (Glimepiride)

Fig.6: In-vitro drug release from formulated tablets (Valdecoxib)

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