Formulation and In Vitro Evaluation of Indomethacin Matrix Tablet with pH Modulated Release Kinetics

 

Panigrahy R.N.*, Kar S.K. and Mahale A.M.

Department of Industrial Pharmacy, Sudhakarrao Naik Institute of Pharmacy, Pusad, Dist-Yavatmal, Maharashtra

*Corresponding Author E-mail: rabi.papu@gmail.com

 

ABSTRACT:

Controlled release preparations have been reported to reduce the gastro irritant and ulcerogenic effects of Non-steroidal Anti inflammatory drugs. In the present study, an attempt was made to develop matrix tablet-based controlled release formulations of Indomethacin, using ethyl cellulose as the rate-controlling polymer. In order to prevent initial release of the drug in the acidic environment of the stomach, Eudragit L 100-55 was incorporated in the matrix in varying amounts. It was found that with increasing the proportion of ethyl cellulose in the matrix, the drug release initial release of the drug in the first 2-3 h followed by enhanced release rate in alkaline medium owing to the high solubility of Eudragit L 100-55 at basic pH which led to creation of a porous matrix. It was concluded that combination of Eudragit L 100-55 with ethyl cellulose in the matrix base can be an effective means of developing a controlled release formulation of Indomethacin with very low initial release followed with controlled release up to 14-16 h.

 

KEYWORDS: Indomethacin; ethyl cellulose; matrix tablet; Eudragit L 100-55.

 


INTRODUCTION:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective in the treatment of rheumatoid and osteoarthritis1, but their long term use results in gastrointestinal (GI) toxicity in a large number of cases like ulceration and stricture formation in esophagus, stomach and duodenum leading to severe bleeding, perforation and obstruction. Indomethacin, like other drugs of this group, also has a wide spectrum of gastrointestinal side effects ranging from mild dyspepsia to gastric bleeding. Due to its short plasma half-life (1-3 h) and GI toxicity parole, Indomethacin is an ideal candidate for preparing extended or controlled release drug products that can potentially avoid drug release in upper position of the GI tract1. Several matrixes based controlled release products of Indomethacin have been reported based on the use of either hydrophilic (HPMC or Carbopol) and/or hydrophobic polymers (EC)2. The reported controlled release formulations of Indomethacin did not involve any attempt to prevent drug release in the upper GI tract. Eudragit L 100-55 (EUDRAGIT L100-55) is a commonly employed enteric coating polymer in pharmaceutical industry in combination with cellulose acetate butyrate.

 

EUDRAGIT L100-55 has been employed for preparing enteric matrix microspheres by emulsiosolvent evaporation technique3.In the present study, it was envisaged to design controlled release formulation of Indomethacin with pH dependent release profile so as to minimize initial drug release in stomach that will reduce the possible gastro irritant and ulcerogenic effects of the drug. At the same time, there would be no compromise on the biopharmaceutical profile of the drug as Indomethacin is reported to be well absorbed throughout the GI tract13.

 

MATERIALS AND METHODS:

Indomethacin and Eudragit L 100-55 were obtained as gift samples from Themis pharmaceutical Limited, Mumbai, and Colorcon India, Mumbai. India, respectively. Eudragit L100-55 was obtained as gift samples from Evonik Degussa; Mumbai. Ethyl cellulose was obtained as gift samples from Research lab, Mumbai, India. All other chemicals and reagents used were either of analytical or pharmaceutical grades.

 

Analytical method:

Indomethacin in pure form and designed formulation was analyzed using in-house developed and validated UVspectrophotometric method using Shimadzu1700 UV/Vis spectrophotometer. The method involved analysis of the drug at 320 nm in 7.4 pH phosphate buffer using 1 cm matched quartz cells4, 5.

Preparation of matrix tablets:

Different matrix embedded formulations of Indomethacin were prepared by wet granulation technique using varying proportion of polymers (Table 1). Accurately weighed quantities of pre-sieved drug and polymer(s) were mixed thoroughly and granulated with ethyl alcohol. The wet granules were sieved through20 sieves and the final granules were blended with 1% talc and 0.5%magnesium stearate and compressed using 8 mm punches on single station tablet press (Cadmach, Ahmadabad, India).6, 7, and 8.

 

Physicochemical characterization of tablets:

The designed formulations were studied for their physicochemical properties such as weight variation, hardness, friability, and assay9. For estimation of drug content (Table 2). 10 tablets were crushed and powdered. The aliquot of powder equivalent to 10 mg of drug was weighed and dissolved in methanol: phosphate buffer pH 7.4 (1:10) mixture. The resultant solution was filtered and suitably diluted with phosphate buffer (pH 7.4) and analyzed using the UV method discussed earlier. From the absorbance value, drug content was calculated on average weight basis. In vitro release studies In vitro dissolution studies were carried out using USP Type II (paddle method) apparatus (Electro lab TDT-08L, Mumbai, India) at 75 rpm (Table 3 and 4) 6, 7, 8 and 10.. The dissolution was carried out for the first 2 h in distilled water (500 ml).Then, 200 ml of phosphate buffer concentrate (4.75 g of KH2PO4 and 1.07 g of NaOH in distilled water was added to raise the total media volume to 700 ml and pH to 7.4 for the remaining period. At predetermined time intervals, a 10ml sample was withdrawn and replaced with fresh dissolution media. The samples were filtered, suitably diluted, and analyzed using the UV method discussed earlier. The release studies were conducted in duplicate and the mean values along with the SD were plotted against time. (Fig.1, 2, 3, 4 and 5).


 

 

Table No. 1 Formulation Chart of Indomethacin matrix tablets

Batch/ Ingredients (mg)

Drug

Ethyl cellulose

Eudragit L 100-55

Lactose

Mg. stearate

Talc

Total weight

F1

75

3.75

 

118.25

1

2

200

F2

75

7.5

 

114.5

1

2

200

F3

75

11.25

 

110.75

1

2

200

F4

75

3.75

9.375

108.875

1

2

200

F5

75

3.75

18.75

99.5

1

2

200

F6

75

7.5

18.75

95.75

1

2

200

F7

75

7.5

28.125

86.375

1

2

200

F8

75

11.25

28.125

82.625

1

2

200

F9

75

11.25

37.5

73.25

1

2

200

 

 

Table No. 2 Standard Physical Tests for Matrix Tablet

Formulation

Hardness (kg/cm2)

Percent friability

Thickness (mm)

Content uniformity (%)

Wt. variation

F1

5.8±0.2

0.61±0.02

3.37±0.03

99.23%

Passes

F2

6.2±0.3

0.55±0.03

3.28±0.06

100.16%

Passes

F3

6.1±0.3

0.54±0.01

3.29±0.02

99.41%

Passes

F4

6.2±0.4

0.52±0.03

3.27±0.01

99.37%

Passes

F5

6.3±0.2

0.51±0.03

3.26±0.03

100.13%

Passes

F6

65±0.1

0.48±0.04

3.23±.03

99.74%

Passes

F7

6.5±0.2

0.52±0.05

3.22±0.01

100.26%

Passes

F8

6.3±0.3

0.51±0.02

3.25±0.04

99.63%

Passes

F9

6.4.±0.2

0.49±0.03

3.23±0.02

99.85%

Passes

All the values represent mean ± Standard deviation (n=3)

 

 

Table No.3: In vitro Dissolution Data of F1, F2, F3, F4, and F5:

Time in Hours

% Cumulative drug release

Batch code

F1

F2

F3

F4

F5

0

0

0

0

0

0

1

6.31±0.403

5.42±0.41

4.91±0.376

4.22±0.31

3.85±0.206

2

11.09±0.451

10.34±0.349

9.17±0.312

7.82±0.303

6.64±0.269

3

15.27±0.424

13.61±0.423

12.21±0.434

14.48±0.329

12.97±0.332

4

18.64±0.489

17.73±0.471

15.48±0.348

19.63±0.481

19.79±0.398

5

24.86±0.439

22.77±0.398

21.71±0.46

26.11±0.513

27.47±0.451

6

31.25±0.513

29.89±0.557

27.46±0.462

31.89±0.454

33.39±0.56

7

37.83±0.449

35.11±0.465

34.69±0.511

40.64±0.412

41.27±0.354

8

43.97±0.536

41.57±0.42

38.33±0.381

48.89±0.449

52.64±0.407

9

48.31±0.534

45.34±0.522

43.84±0.335

54.33±0.389

59.77±0.514

10

52.27±0.421

48.12±0.376

47.39±0.522

61.81±0.573

67.29±0.418

11

55.07±0.563

53.61±0.494

50.41±0.501

67.27±0.321

74.87±0.477

12

59.85±0.419

56.02±0.389

56.11±0.455

72.49±0.576

80.35±0.475

13

62.19±0.407

60.84±0.445

58.82±0.407

78.84±0.534

85.64±0.601

14

66.48±0.429

65.19±0.459

63.55±0.475

83.52±0.407

89.42±0.511

All the values represent mean ± Standard deviation (n=3)

Table No.4 In vitro Dissolution Data of F6, F7, F8, and F9:

Time in Hours

% Cumulative drug release

Batch code

F6

F7

F8

F9

0

0

0

0

0

1

3.27±0.231

2.85±0.276

2.04±0.141

1.15±0.129

2

5.79±0.262

4.68±0.205

4.07±0.198

2.21±0.123

3

12.05±0.317

10.94±0.193

10.52±0.273

8.49±0.229

4

17.09±0.351

15.24±0.385

14.64±0.336

13.95±0.412

5

24.54±0.466

23.47±0.262

20.41±0.453

21.25±0.448

6

30.97±0.534

31.81±0.351

28.57±0.554

30.29±0.618

7

36.95±0.561

38.38±0.295

36.28±0.591

36.64±0.469

8

44.73±0.611

46.96±0.313

42.79±0.386

45.12±0.462

9

53.85±0.479

55.63±0.325

52.96±0.375

54.37±0.417

10

61.19±0.404

64.47±0.641

61.34±0.609

63.88±0.516

11

68.47±0.418

72.14±0.549

69.12±0.467

73.21±0.4569

12

74.25±0.373

80.64±0.522

77.47±0.541

81.88±0.547

13

82.56±0.493

87.81±0.499

84.29±0.443

90.69±0.527

14

88.09±0.478

93.38±0.408

90.34±0.754

97.47±0.341

All the values represent mean ± Standard deviation (n=3)

 


 

Fig No. 1 :  In vitro Dissolution Profile of Formulation F1, F2and F3

 

Fig No. 2: In vitro Dissolution Profile of Formulation F1, F4and F5

 

Figure No. 3:   In vitro Dissolution Profile of Formulation F2, F6and F7

 

Fig No. 4 : In vitro Dissolution Profile of Formulation F3, F8and F9

 

Figure No. 5 :  In vitro Dissolution Profile of Formulation F9

 

Effect of simulated GI fluid pH (without enzymes) on release:

The release profile was also studied in a medium of changing pH (Table 5)1, 6, 7, 8. The initial condition was 350 ml of 0.1N HCl (pH 1.2) for 0–2 h. At the end of second hour, the pH of the media was raised to 4.5 and the total dissolution media volume to 600ml. At the end of fourth hour, pH was raised to 7.4 by adding 300 ml phosphate buffer concentrate (2.18 g of KH2PO4 and1.46 g of NaOH in distilled water). The study was further continued till the end in 900 ml volume. At predetermined time intervals, a 5ml sample was withdrawn and replaced with fresh dissolution media. After appropriate dilutions, the samples were analyzed by the UV method discussed earlier. The corresponding release profiles are presented in Figure.

 

Table No. 5. Effect of GI Simulated Conditions on Release Profile of F9:

Time in Hours

% Cumulative drug release

Batch code

F9

0

0

1

0.53±0.059

2

1.07±0.103

3

4.26±0.215

4

7.71±0.227

5

15.92±0.379

6

24.79±0.411

7

31.48±0.469

8

39.51±0.485

9

48.86±0.499

10

59.07±0.413

11

67.94±0.422

12

75.49±0.448

13

84.21±0.503

14

91.37±0.513

All the values represent mean ± Standard deviation (n=3)

 

Model Fitting:

The model fitting for % cumulative release was done using Microsoft excel 2003 to find the best fits kinetic equation for the dissolution profile

 

Kinetics of Drug Release:

In order to understand the mechanism and kinetics of drug release11, 12, 13, the results of the in-vitro dissolution study of the batches were fitted with various kinetic equations like

i. Zero order           (% release =K t),

ii. First order           (log %Unreleased =Kt),

iii. Higuchi’s model   (%Release =Kt0.5) and

iv. Peppas Korsmeyer Equation        (% Release=Ktn)

(Or)  empirical equation (Power law expression) of

Mt / Mµ  = K t

Where,

Mt                  = amount of drug release at time t

Mµ               = amount of drug release at infinite time

K             = constant characteristics, and

n               = Diffusion exponent

If   n        = 0.45 indicates Fickian diffusion mechanism                                    (Higuchi matrix)

n              = 0.45 to 0.89 indicates Anomalous Transport or               Non Fickian transport.

N             = 0.89 indicates Case II Transport

n              > 0.89  Super case –II transport

Coefficient of correlation (R2) values were calculated for the linear curves obtained by regression analysis of the above plots.(Table 6,7,8 and 9).

 

Table No. 7    Estimated Values of n and k by Regression of log (Mt / M) of log (t)

Batch No.

N

K

r2

Model Fitting

F1

1.197

3.427

0.9915

Zero order

F2

1.201

3.235

0.995

Zero order

F3

1.233

2.864

0.996

Zero order

F4

1.393

2.5

0.995

Zero order.

F5

1.468

2.259

0.9918

Zero order

F6

1.486

1.99

0.9909

Zero order

F7

1.554

1.963

0.9877

Zero order

F8

1.6

1.503

0.9870

Peppas

F9

1.785

1.035

0.9880

Peppas

 

 

Table No. 8  Kinetic Data of Indomethacin Matrix Tablets in GI Simulated Conditions:

Formulation Code

Zero Order

(R2)

First order

(R2)

Matrix Model

(R2)

Korsemeyer- peppas model (R2)

F9

0.9683

0.8408

0.8123

0.9752

 

 

Table No. 9  Estimated Values of n and k by Regression of log (Mt / M) on log (t) of F9 in GI Simulated Conditions:

Batch No.

N

K

r2

Model Fitting

F9

1.983

1.757

0.9752

Peppas

 

 

Batch reproducibility and stability on storage:

Three batches of each formulation were prepared and their respective dissolution rates were evaluated under the same conditions14. The best formulation of each type was studied after 6 months and 1 y for the effect of storage in ambient conditions on the stability and release profiles of drug from the different formulations respectively. The tablets were sealed in airtight cellophane packets and were stored in ambient conditions. (Temp 25 oC and RH 65%)

The In vitro release profile for each was studied as per the specification enlisted in previous sections and compared with its initial release profile.

 

RESULTS AND DISCUSSION:

Physical appearance, hardness, friability, weight variation and drug content uniformity of different tablet formulations were found to be satisfactory. The manufactured tablets showed low weight variation and high degree of drug content uniformity. Indomethacin, a weak indole acetic acid derivative with a pKa of 4.5 is practically insoluble in simulated gastric fluid. Therefore, dissolution studies were carried out in distilled water for the first two hours followed by phosphate buffer pH (7.4) for the remaining period of study. This medium was considered as most19suitable as the drug was freely soluble at this pH and it also mimics the alkaline environment of small intestine. The selection of wet granulation technique for matrix tablet preparation was based on previously reported study which suggested that wet granulation results in harder tablets with lower matrix porosity that give very low release rates when compared to direct compression .In our study, the use of ethyl alcohol as granulating agent was based on the partial solubility of EC in this granulating solvent which resulted in providing the necessary adhesion between the various matrix components and precluded the use of a separate binder. All the formulation were subjected to in-vitro dissolution studies and results are shown in table and figure no..The results revealed  release profiles of matrix tablets of Indomethacin containing varying proportion of ethyl cellulose (5%, 10%, 15% w/w of drug ) i.e. F1, F2 and F3 showed 66.48, 65.19 and 63.55 % of drug release in 14 hours. This showed that as concentration of ethyl cellulose as matrix former increases the rate of drug release decreases on account of formation of strong matrix with reduced porosity. As the presence of only ethyl cellulose in the matrix would not give the desired release profile of low initial drug release followed by increased release rate, EUDRAGIT L100-55 was included in the matrix. It was expected that presence of these pH dependent polymers would provide pH modulated release characteristic with very low drug release in acidic environment of upper GIT (Stomach and initial Duodenum) followed by higher release rate in alkaline pH of small intestine on account of formation of a porous matrix due to dissolution of Eudragit L 100-55. The release profile of F4and F5 containing fixed proportion of ethyl cellulose (5% w/w of drug) with Eudragit L 100-55 12.5% and 25% respectively showed 78.13, 85.69% respectively. The F4 and F5 show more release then F1 which may be due to increased erosion of matrix as the polymer concentration increases. Similarly the release profile of F6 and F7 containing fixed proportion of ethyl cellulose 10% w/w of drug with Eudragit L 100-55 at 25% and 37.5% w/w of drug respectively showed 81.37, 88.13, % respectively in 14 hours . There is increase in the drug release in comparison to only ethyl cellulose (10% w/w of drug) based matrix tablets which may be due to increased erosion of Eudragit L 100-55 based formulation. Formulation F8, F9, contains fixed proportion ethyl cellulose (15 % w/w of drug) with varying proportion of Eudragit L 100-55. (37.5% w/w of drug and 50% w/w/ of drug) showed 88% and 94%, respectively in 14 hours. The increased release with increase in concentration of pH dependent polymers in comparison to tablet containing ethyl cellulose alone may be attributed to increase erosion of Eudragit L 100-55 containing tablets at pH 7.4..The results showed that formulation F9 showed very low initial drug released in first two hours in compared to other formulation while in 14 hours they release the drug almost completely. Hence these formulations were selected for further studies till simulated GI conditions of changing pH. The results shown in table and figure revealed that the formulations when subjected to GI simulated condition release about 2.21% of drug during first 2 hours in .1N HCl or 1.2 pH. For the next 2 hours the release slightly increases in both the formulation due to slightly acidic condition of the medium simulated duodenal pH of 4.5. The released after 4 hours is 10.88% respectively after words when the pH of the medium is raised to pH 7.4 the release of the drug from both the formulations increases quite rapidly due to increased erosion of Eudragit L 100-55 in the alkaline conditions of small intestine. The data obtained from in vitro dissolution studies and dissolution studies in GI simulated conditions were fitted in different models like zero order, First order, higuchi model and korsemeyer peppas model. The zero order plots were found to be fairly linear as indicated by their high regression values. To conform the exact mechanism of drug release from these matrix tablets the data was fitted according to korsemeyer empirical equation of Mt / Mµ  = Ktn   Regression values r2 were found 0.8722 to 0.9909 for different formulations. The mean diffusional exponent values (n) was found to be ranged from 1.197 to 1.983 indicated all the formulation follows super case II transport i.e. swelling and erosion simultaneously occur during the release. Since both swelling and erosion occur simultaneously, zero order release is achieved from these matrices. This behavior is responsible for maintaining zero order release in which the increase in diffusion path length due to swelling is balanced with the decrease in diffusion path length due to matrix erosion. Overall a constant diffusion path length is maintained. Thus it was found that drug release from Indomethacin matrix tablet follows zero order models. No significant difference was observed in the release profile of different batches of each matrix formulation, indicating that the manufacturing process employed was reliable and reproducible. Also, the release kinetics remained unaltered up to one year of storage and there were no changes in the tablet characteristics, suggesting that ibuprofen was stable in EC matrices.

 

CONCLUSION:

In conclusion, matrix embedding technique using EC as the retardant has successfully extended the release of ibuprofen from its tablet formulations. In the present case, we found that the incorporation of EUDRAGIT L100-55 in the matrix not only helped to provide good initial retardation in the release but also helps to enhance the overall release rate of the drug after a suitable lag time. The manufacturing method employed is simple and easily adaptable in the conventional tablet-manufacturing units.

ACKNOWLEDGEMENTS:

I am thankful to Themis Pharmacueticals Ltd., Mumbai. For providing gift samples of Indomethacin. I am thankful to Evonik Degussa, Mumbai Colorcon, Goa, and Research-Lab Fine Chem. Industries, Mumbai for providing gift samples of Eudragit L 100-55, and Ethyl cellulose respectively.

 

REFERENCES:

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Received on 07.12.2010          Modified on 03.01.2011

Accepted on 17.01.2011         © RJPT All right reserved

Research J. Pharm. and Tech. 4(4): April 2011; Page 600-605