STUDIES ON CORE IN COAT GASTRORETENTIVE TABLETS USING POROUS CARRIERS WITH CELLULOSIC POLYMERS AND NATURAL GUMS
Putta Rajesh Kumar, Hiremath Doddayya and S. Rajendra Reddy
Department of Pharmaceutics, N.E.T. Pharmacy College, Raichur -584103, Karnataka, India.
Keywords: Floating tablet, porous carrier, xanthan gum, guar gum and duodenal ulcer.
Abstract

The present study was aimed to develop a gastroretentive tablet that could deliver antibiotic in stomach from the coat tablet for localized action and acid liable anti secretory agent in duodenum from the enteric coated core. During tablet formulation Studies on rheological characteristics of Clarithromycin coat granular blends showed their free flowing nature and ease for compression to tablet. The compressed tablets exhibited uniform post compressional characteristics. Evaluation of floating parameters indicated results suits for the tablets to formulate core in coat tablets for release of Clarithromycin in gastric pH and esomeprazole in alkaline pH to treat peptic ulcer disease associated with h pylori bacteria. The formulations exhibited uniform rheological and post compressional properties. The drug content was found to be uniform and consistent in all formulations. The tablet showed density < 1 facilitated tablets floating ability over 0.1N HCl with minimum floating lag time. In vitro release studies showed that T6C6 formulation exhibited better release for both the drugs in simulated gastric and intestinal fluids for 12 h. The study revealed the role of porous carriers, cellulosic polymers and natural gums on drug release profiles of esomeprazole core in clarithromycin coat gastroretentive tablets in duodenal ulcer treatment.

Article Information

Identifiers and Pagination:
Year:2012
Volume:4
First Page:73
Last Page:85
Publisher Id:JAppPharm (2012 ). 4. 73-85
Article History:
Received:November 16, 2011
Accepted:January 5, 2012
Collection year:2011
First Published:January 20, 2012

INTRODUCTION

            Development of oral controlled release systems formulation of drug in a gel forming polymer such as semi synthetic derivatives of cellulose, it swells in the gastric fluid with a bulk density less than one [1]. Floating drug delivery systems have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate from floating system due to extended gastric residence time leads to better control over fluctuations in plasma drug concentration. Peptic ulcers are defects in gastric or duodenal mucosa extend through muscularis mucosa as indicated in figure 1. An ulcer may develop if there is an alteration in balance between acid amount and mucus defense results in damage of lining in the stomach or duodenum by excess acid.

            The patients suffering from peptic ulcers with h pylori infection requires medication that addresses immediate symptomatic relief followed by rapid ulcer healing effect. The medications currently available were conventional separate dosage forms and are erratically absorbed in the stomach. Clarithromycin has a t1/2 of 3.5±0.5 h with an oral bioavailability of 50% and Esomeprazole has a half life of 1.25±0.25 h and has a bioavailability of 48% when administered orally. Esomeprazole has been clinically successful in a dose 20 mg bid [2-4]. Clarithromycin at a dose of 500 mg bid, has been reported to inhibit h pylori in humans [5-6]. Hence treatment of peptic ulcer disease with antibiotic Clarithromycin, along with proton pump inhibitor esomeprazole, would be beneficial and effective. Based on above rationale, this investigation is planned to develop floating type of ‘coat’ tablets containing clarithromycin, to release antibiotic in stomach and increase its residence time. Further small enteric coated tablets of esomeprazole to release the drug in small intestine, will be developed as a ‘core’ tablet. The clarithromycin ‘coat’ surrounds the esomeprazole ‘core’ so that both the drugs are dispensed as one unit and to release one medicament in stomach and the other in small intestine.

 

MATERIALS AND METHODS

Active pharmaceutical ingredient and Reagents:

Esomeprazole magnesium trihydrate were procured from Aurobindo pharma limited. Croscarmellose sodium, Crospovidone, Sodium starch glycolate gifted by Danmed Pharmaceuticals Pvt Ltd, Hyderabad. Lactose DC and Mannitol DC were procured from SD Fine Chemicals Limited. Eudragit L 30 D55, Colorcon (Acryl EZE) was supplied by Medreich Limited, Bangalore. Clarithromycin obtained from Limited, Bangalore. Polypropylene, Calcium silicate, Aerosil purchased for from Sigma Aldrich, Bangalore. Xanthan gums, Guar gum, HPMC K4M, MCC were purchased from INR chem and yarrow chemicals, Mumbai.

Formulation of esomeprazole core tablet by direct compression and enteric coating [7]: The esomeprazole core tablets were prepared by direct compression technology. The uniform blend of powder containing esomeprazole and direct compressible vehicles was studied for rheological characteristics. The blend of powder was then compressed to tablets using 6 mm flat punches. To protect esomeprazole from gastric acid and to deliver in duodenum the core tablets were coated with enteric coating polymer, Acryl EZE.

Preparation of clarithromycin coat granules by wet granulation for compression coating [8-9]: The ingredients with drug, porous carrier, effervescent agent and matrix carrier for a batch 250 tablets were accurately weighed, passed through # 100 sieve and blended uniformly. The powder blends CTP1 to CTP4, D1 and D2 were wet granulated with distilled water and starch paste (15% w/w) as binder. The wet mass obtained was passed through # 16 sieve then dried in an oven at 40°C for 4 h and passed through sieve # 20. Later, talc and magnesium stearate as required were added and blended. The coat granules were studied for flow properties and used for compression coating over esomeprazole cores. Then the powder blends of various batches formulations 5 to 20 were prepared and are wet granulated with guar gum (1.5% w/w) as binder in water to produce wet mass. Further ingredients of S4 to S10 formulations were wet granulated with (1.5% w/w) each of xanthan gum, guar gum and HPMC K4M as binder in water to produce wet mass. Later for formulations T4 to T6 the powder blends of ingredients were wet granulated with (1.5% w/w) each of guar gum, xanthan gum and HPMC K4M as binder in water to produce wet mass. The wet mass of respective coat formulations was then passed through mesh # 14, dried in an oven for 4 h. Later the dried coat granules were passed through mesh # 16. Later, talc and magnesium stearate as required were incorporated as glidant and lubricant and blended thoroughly. The granules were studied for their rheological parameters and further used for compression coating over esomeprazole core tablets.

Preparation of core in Coat tablet [10]: First half of the weight of coat tablets containing clarithromycin granules was placed into the die cavity (13mm) and then enteric coated core tablets of esomeprazole (6 mm) was placed into the same die cavity, the core tablet was adjusted and centered. The remaining half of the coat granules was placed over the core tablet so that the core is completely and uniformly surrounded by the coat granules and was then punched in a 10 station tablet press (PP1D, Chamunda) at 4-6 kg/cm2 hardness. In each batch 300 tablets were manufactured. These tablets were studied for compression characteristics and later, in vitro dissolution studies were carried out.

Evaluation of rheological properties of powder/granular bed [10]: (Prabhakar Reddy Veerareddy., 2010).

Bulk density [10]: Bulk density was determined (Konark instruments, India) by placing the powder/granules blend in a measuring cylinder and the total volume was noted. The weight of powder/granule bed was determined in a Dhona 200 D electronic balance. Bulk density was calculated by using the formula. Bulk density = Total weight of powder / granules / Total volume of powder / granules. Average of three densities of powder/granule were taken and tabulated. (n=3). Similarly Tappped density was also studied.

Compressibility index [10]: Compressibility index was determined by placing the powder/granules in a measuring cylinder and the volume (V0) was noted before tapping. After 100 tapping again volume (V­) was noticed. Compressibility index = (1- V/ V0) X 100. Where V0 = volume of powder/granules before tapping and V = volume of powder/granules after 100 tappings. (n = 3).

Angle of repose (°q) [10]: Angle of repose was determined by measuring the height and radius of the heap of the powder/granule bed. A cut stem funnel was fixed to a stand and bottom of the funnel was fixed at a height of 3 cm from the plane. Powder/granule was placed in the funnel and allowed to flow freely. With the help of vernier calipers (Mitutoyo, Japan) the height and radius of the heap were measured and noted. Average of triplicate reading were noted (n = 3). Tan ø = h /r. where h = height of heap of powder/granule bed and r = radius of heap of powder/granule bed.

Evaluation of compressional characteristics of the tablets [11]:

Thickness test [11]: The tablets were evaluated for their thickness using a micrometer (Mitutoyo, Japan). Average of three readings were taken and the results were tabulated (n = 3).

Diameter test [11]: The tablets were evaluated for their diameter using a micrometer (Mitutoyo, Japan). Average of three readings were taken and tabulated (n = 3).

Hardness test [11]: The tablets were evaluated for their hardness using Pfizer hardness tester. Average of three reading were taken and tabulated (n = 3).

Determination of drug content [12]: Ten core tablets of esomeprazole was crushed into powder in a mortar and 100 mg of powder was taken in a volumetric flask containing distilled water and kept aside with constant shaking for 24 hours to extract the total drug present in the tablet. Then the absorbance of the solutions was measured after suitable dilution at 203.5 nm against drug devoid methanol as blank. Averages of triplicate readings were taken. Similarly Coat tablets of Clarithromycin was crushed into powder in a mortar and 100 mg of powder was taken in a volumetric flask containing dry ethanol and kept aside with constant shaking for 24 hours to extract the total drug present in the tablet. Then the absorbance of the solutions was measured after suitable dilution at 211 nm against drug devoid dry ethanol as blank. Averages of triplicate readings were taken.

Density measurement [13]: The apparent density of the tablets was calculated from their volumes and masses. The volumes V of the tablets were calculated from their height h and radius r using micrometer. Volume of the tablets was calculated by using the following equation V = Õ x r2 x h. Average of three readings were taken and tabulated (n = 3).

Buoyancy lag time [14]: The buoyancy of tablets was studied at 37 ± 0.5 °C, in 100 ml of 0.1N HCl. A glass beaker containing 100 ml of 0.1N HCl was taken, in which a tablet was placed for observation. The duration of time taken to float the tablet was observed visually. Average of three readings were taken and tabulated (n = 3).

Duration of floating time [15]: (Pare A et al., 2008). A glass beaker containing 100 ml of 0.1N HCl was taken, in which a tablet was placed for observation. The total duration for which a tablet remains floating was recorded as duration of floatation. Average of three readings were taken and tabulated (n = 3).

In vitro dissolution studies [16]: (Mukesh C. Gohel et al., 2006) A modified dissolution apparatus was fabricated from a 100 ml glass beaker, by attaching an S-shaped side arm (glass tube) and capable of holding 70 ml of dissolution medium (simulated gastric fluid/simulated intestinal fluid). The medium was stirred on a magnetic stirrer. A burette was mounted above the beaker to deliver the dissolution medium at a flow rate of 2 ml/min. The tablet was put in the modified beaker containing 70 ml of dissolution medium and the medium was stirred at 75 rpm. The temperature of the medium was maintained at 37 ± 0.5 ºC. From the burette, simulated gastric fluid was added at a rate of 2 ml/min. Samples of 1 ml were collected at predetermined time intervals for 2 h. The dissolution was further carried out with the same tablet by replacing the dissolution media with buffer pH 9.0 for 10 h and samples of 1 ml were withdrawn analyzed spectrophotometrically. All the studies were carried out in triplicate, (n = 3).

 

RESULTS

 

Table 1. Rheological parameters of preliminary Clarithromycin coat formulations.

 

F. Code

Angle of repose (Øo)

Bulk

density±SD

Tapped

density±SD

C.I±SD

(%)

Hardness±SD

Before glidant±SD

After glidant±SD

Ctp I

26.33±0.28

25.40±0.36

0.43±0.01

0.50±0.02

14.33±0.05

5.03±0.15

Ctp II

25.50±0.50

23.03±0.15

0.39±0.02

0.48±0.02

15.00±0.50

4.06±0.11

Ctp III

32.20±0.34

29.96±0.40

0.33±0.01

0.44±0.05

13.90±0.36

3.80±0.10

Ctp IV

27.63±0.32

25.70±0.43

0.42±0.06

0.47±0.02

12.00±0.50

3.70±0.10

D1

27.16±0.76

25.20±0.20

0.40±0.01

0.50±0.01

14.03±0.55

4.03±0.15

D2

26.06±0.70

24.80±0.55

0.41±0.01

0.52±0.01

14.73±0.32

4.10±0.26

5

25.40±0.55

24.66±0.57

0.38±0.02

0.47±0.04

15.03±0.45

5.06±0.20

6

28.73±0.46

26.33±0.57

0.37±0.02

0.50±0.02

14.00±0.50

5.20±0.17

7

26.56±0.81

24.70±0.52

0.41±0.02

0.51±0.02

14.50±0.81

4.80±0.34

8

25.23±0.28

23.60±0.43

0.43±0.02

0.52±0.02

14.50±0.50

5.00±0.20

9

26.83±0.28

25.03±0.55

0.41±0.03

0.52±0.03

14.10±0.36

4.20±0.17

10

25.73±0.64

24.06±0.90

0.43±0.01

0.55±0.05

14.20±0.75

4.70±0.26

11

26.50±0.50

24.66±0.57

0.41±0.01

0.51±0.06

14.03±0.35

4.30±0.26

12

26.13±0.80

24.93±0.60

0.42±0.01

0.55±0.04

15.00±0.88

4.80±0.26

13

28.10±0.96

26.16±0.58

0.43±0.07

0.52±0.02

14.43±0.49

5.20±0.17

14

26.50±0.50

24.76±0.40

0.40±0.03

0.50±0.01

15.03±0.45

5.40±0.26

15

28.23±0.86

26.50±0.50

0.41±0.01

0.53±0.01

15.06±0.40

4.16±0.15

16

27.03±0.55

25.43±0.66

0.40±0.01

0.52±0.02

15.06±0.30

5.00±0.10

17

26.00±0.50

25.03±0.55

0.38±0.01

0.50±0.06

14.06±0.60

4.80±0.20

17C

25.96±0.55

24.66±0.20

0.40±0.01

0.50±0.01

14.06±0.92

5.03±0.15

18

24.46±0.47

24.73±0.30

0.40±0.08

0.50±0.01

14.20±0.34

5.20±0.20

19

27.00±0.60

25.76±0.25

0.42±0.01

0.52±0.02

14.96±0.40

5.43±0.15

20

26.56±0.25

24.06±0.11

0.42±0.08

0.55±0.01

14.26±0.41

4.83±0.05

S4

26.98±0.15

25.30±0.28

0.35±0.03

0.41±0.05

14.20±0.02

5.50±0.20

S5

27.34±0.40

25.76±0.28

0.31±0.02

0.35±0.50

12.70±0.02

5.80±0.10

S6

28.17±0.43

26.16±0.64

0.38±0.02

0.45±0.36

14.50±0.02

5.60±0.17

S7

27.56±0.55

25.80±0.55

0.36±0.01

0.42±0.02

15.01±0.88

5.51±0.34

S8

28.00±0.46

26.41±0.07

0.38±0.08

0.43±0.04

14.21±0.49

5.60±0.20

S9

27.50±0.81

25.84±0.72

0.40±0.03

0.45±0.02

12.00±0.45

5.20±0.17

S10

26.90±0.28

25.50±0.50

0.43±0.02

0.52±0.02

15.00±0.40

5.60±0.26

 





















Table 2. Floating parameters of preliminary Clarithromycin coat formulations - I.


F code

Tablet Floating lag time and Duration of Floating studies observations

Ctp I

Tablet sank to the bottom; swollen mass formed and disintegrated in 6 sec but did not float to the surface.

Ctp II

Tablet sank to the bottom , swelled by slight erosion, floating lag time is 38 min and duration of floating was >24 hr.

Ctp III

Tablet sank to the bottom hydrated, floating lag time is 3 min and duration of floating is 16 hrs.

Ctp IV

Tablet sank to the bottom hydrated and swollen, floating lag time is 10 min, duration of floating is > 24 hrs.

D1

Tablet sank to the bottom hydrated, swelled and eroded but did not float to the surface.

D2

Tablet sank to the bottom hydrated, swelled and eroded but did not float to the surface.

5

Tablet sank to the bottom swelled and eroded but did not float to the surface.

6

Tablet floated after 3 sec to surface with effervescence, Core tablet released after 15 min and sank to bottom, coat tablet completely eroded in 22 min

7

Tablet floating lag time is 5 sec, core tablet released after 5 min and sank to bottom, coat tablet eroded in 17 min.

8

Tablet floating lag time is 3 sec, core tablet released after 8 min and sank to bottom, coat tablet eroded in 15 min.

9

Tablet floating lag time is 2 sec, core tablet released after 7 min and sank to bottom, coat tablet eroded in 22 min.

10

Tablet floating lag time 3 sec, core tablet released after 11 min and sank to bottom, coat tablet eroded in 29 min.

11

Tablet floating lag time 2 sec, core tablet released after 8 min and sank to bottom, coat tablet eroded in 23 min.

12

Tablet floating lag time is 3 sec, erosion of particles with effervescence and sank to bottom, core tablet released after 10.5 min, coat tablet eroded in 28 min.

13

Tablet sank to the bottom hydrated and swelled but did not float to the surface.

14

Tablet sank to the bottom hydrated, swelled with simultaneous erosion, about a half of tablet without core floated to surface after 5 min , eroded with simultaneous effervescence and particles sank to bottom, coat tablet eroded in 22 min

15

Tablet sank to the bottom hydrated and swelled but did not float to the surface.

16

Tablet sank to the bottom hydrated, swelled with simultaneous erosion due to effervescence about a half of tablet without core floated to surface after 3 min , eroded with effervescence and particles sank to bottom, coat tablet eroded in 15 min

 

Table 3. Floating parameters of preliminary Clarithromycin coat formulations - II.

17

Tablet floating lag time is 3 sec with hydration and swelling of tablet, duration of floating is 30 min, after 30 min tablet sank to the bottom and intact for 6 hrs

17C

Tablet sank to the bottom, swelled and eroded but did not float to the surface.

18

Tablet sank to the bottom, hydrated, swelled and eroded with effervescence in 5 min, but did not float to the surface.

19

Tablet sank to the bottom, swelled hydrated with slight erosion of surface, but did not float to the surface.

20

Tablet sank to the bottom, hydrated swelled and slightly eroded and but did not float to the surface.

S4

Tablet sank to the bottom, swelled and disintegrated, but did not float to the surface.

S5

Tablet sank to the bottom, swelled and not disintegrated, but did not float to the surface.

S6

Tablet floating lag time is 4 sec, duration of floating is 1 h 50 min, core released 1 h 22 min

S7

Tablet floating lag time is 3 sec, duration of floating 15 min with slight erosion, core released after 9 min.

S8

Tablet floating lag time is 2 sec, core released after 2min. Effervescence, erosion, tablet eroded in 5 min, but did not float to the surface.

S9

Tablet floating lag time is 35 min; duration of floating is 55 min and no erosion of tablet.

S10

Tablet floating lag time is 3 sec, Tablet swelled; core released after 4 min, coat tablet eroded in 7 min, but did not float to the surface.

  

Table 4. Rheological parameters of T4 to T6 Clarithromycin coat formulations granules:

F. code

Angle of repose (Øo) ± SD

Bulk

Density

± SD

Tapped

Density

± SD

Carr’s

compressibility

 Index± SD

Before

Adding glidant

After

Adding glidant

T 4

24.967

±0.351

23.600

±0.361

0.386

±0.004

0.434

±0.009

11.633

±0.321

T 5

23.867

±0.321

22.767

±0.208

0.527

±0.002

0.623

±0.005

14.767

±0.208

T 6

27.000

±0.500

26.167

±0.569

0.311

±0.011

0.392

±0.007

14.767

±0.208

 

 

 

 

 

 

 

 

  

Table 5. Tablet Floating lag time and Duration of Floating studies, core release studies of T4 to T6 core in coat formulations.

Parameters

T4 C4

T5 C5

T6 C6

Floating lag time (sec)

05

20

135

Duration of floating (h)

24

2.25

15

Core tablet

(min)

Exposed

90

--

150

Released

--

55

--

 

Table 6. Post compressional parameters of core in coat tablets of Esomeprazole magnesium trihydrate and Clarithromycin:

 

Formu

lation

code

Weight

Variation

(mg±SD)

Diameter

(mm±SD)

Thickness

(mm±SD)

Hardness

(kg/cm2) ±SD

Fria bility (%)

Apparent

Density (g/cc)

DC in dry ethanol

(mg±SD)

T4 C4

602.37

±0.882

13.45

±0.010

4.28±

0.005

5.50±

0.100

0.842

0.990

245.33

±0.115

T5 C5

604.49

±0.758

13.48

±0.026

4.31±

0.010

5.93±

0.156

0.800

0.986

246.67

±0.306

T6 C6

605.14

±0.849

13.49

±0.035

4.27±

0.005

5.86±

0.111

0.906

0.985

248.34

±0.111

 

 

 


Table 7. In vitro release studies of clarithromycin and esomeprazole magnesium trihydrate from SGF and SIF in modified dissolution apparatus in media SGF pH 3 (2h) and SIF pH 9 (10 h).

 

Time

(min)

T4C4

T5C5

T6C6

Clarithromycin  in SGF

Cum. amt

of drug (mg)

% drug

release

Cum. amt

of drug (mg)

% drug

release

Cum. amt

of drug (mg)

% drug

release

0

0

0

0

0

0

0

1

2.053

0.82

3.827

1.53

6.067

2.43

3

10.36

4.14

14.65

5.86

18.29

7.32

5

22.86

9.15

29.12

11.65

34.34

13.74

10

42.00

16.80

47.13

18.85

53.57

21.43

15

67.57

27.03

79.42

31.77

91.56

36.62

30

124.5

49.80

139.1

55.66

165.1

66.04

45

173.8

69.55

183.5

73.43

206.08

82.43

60

197.5

79.03

208.9

83.59

224.2

89.71

90

230.8

92.33

235.4

94.19

239.7

95.91

120

244.0

97.63

246.0

98.41

248.0

99.23

121

0.000

0.000

0.000

0.000

0.000

0.000

123

0.000

0.000

0.000

0.000

0.000

0.000

Esomeprazole Magnesium Trihydrate  in SIF

125

0.000

0.000

0.000

0.000

0.000

0.000

130

0.000

0.000

0.000

0.000

0.000

0.000

135

0.000

0.000

0.000

0.000

0.000

0.000

150

0.029

0.147

0.195

0.974

0.360

1.801

165

0.406

2.030

0.764

3.822

1.196

5.980

180

1.709

8.543

1.804

9.021

3.144

15.71

210

2.914

14.57

3.044

15.22

5.883

29.41

240

4.654

23.26

5.199

25.99

7.849

39.24

300

6.618

33.08

8.157

40.78

10.50

52.51

360