Formulation and Evaluation of Silymarin Floating Drug Delivery System

 

Vinay Kumar D.1, Palanichamy S.2, Kumara Swamy G. 3*, Ashok Kumar U.3

1School of Pharmacy, JNTU, Kakinada, A.P.   2Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, Tamil Nadu.             3Trinity College of Pharmaceutical sciences, Peddapalli, Karimnagar (Dist) - 505172. A.P, India.

*Corresponding Author E-mail: kumaraswamy.gandla@gmail.com

 

ABSTRACT:

A Gastroretentive floating controlled drug delivery system containing Silymarin was prepared in the form of tablets and evaluated for its processing parameters, in vitro release in 0.1 N HCl. Eight formulations were prepared by using rate controlling polymers such as HPMC K4M and Eudragit RS100, alkalizing agent sodium bicarbonate and solubilizing agent poly vinyl Pyrrolidone (PVP K30). Floating tablets were prepared by direct compression method. The preformulation studies and tablet evaluation tests were performed and results were within the limits.  Tablets remained buoyant over 20 hours in the release medium and the amount of sodium bicarbonate found to be significant for not only to remaining buoyant without causing disintegration of the tablet. The different ratios of polymers 15% and 20% showed the significant difference in the drug release with increasing in the concentration of solubilizing agent PVP K30. All the formulations exhibited diffusion dominant drug release. Stability studies for all formulations were conducted for a period of 60 days at 4º±2ºC, 27º±2ºC and 45º±2ºC respectively and the formulations showed no significant changes in physical appearance, drug content and      in-vitro drug release even after 60 days.

 

KEYWORDS: Floating drug delivery system, controlled drug release, low-density polymers, Silymarin.

 


 

INTRODUCTION:

Silymarin, a flavonolignan from ‘milk thistle’ (Silybum marianum) is used in the treatment of liver diseases. The half-life of Silymarin is 4-6 hrs. Since, it has a very low bioavaliability of 20%-50% and poor water solubility, multiple doses are needed to maintain a constant plasma concentration for a good therapeutic response and improved patient compliance. To overcome these problems, Silymarin has been formulated as floating drug delivery system (FDDS) to increase the gastric retention time which in turn improve the bioavailability of drug. It releases the drug over an extended period in the stomach and upper gastrointestinal tract (GIT), thus enhancing the opportunity for absorption. Various approaches have been proposed to control the gastric residence of drug delivery system in the upper GIT including FDDS, high density DDS, mucoadhesive systems, swelling and expanding DDS, modified shape systems and other delayed gastric devices1,2

 

FDDS is a gastroretentive dosage form (GRDF), which can prolong the gastric residence time (GRT) to produce an acceptable drug bioavaliability. FDDS is suitable for drugs having absorption window in the stomach or upper small intestine and for drugs that are poorly soluble or unstable in the intestine in the intestinal fluid.

 

FDDS should have lower bulk density than gastric fluid and thus it floats on gastric fluid for a prolonged period of time and releases the drug slowly at controlled manner. Therefore it was proposed to develop Silymarin as FDDS to enhance the absorption of drug using two polymers namely Hydroxy propyl methyl cellulose K4M (HPMC K4M) and Eudragit RS100 with different concentrations.

 

MATERIAL AND METHODS:

Silymarin, Hydroxy propyl methyl cellulose (HPMC K4M) and Eudragit RS100 were obtained as gift sample from Micro Labs, Hosur. Polyvinyl pyrrolidone (PVP K30) was obtained from Granules India Ltd., Hyderabad. Other reagents and solvents were of analytical grade.

 

Preparation of Silymarin floating tablets:

The drug, polymers (at different ratios), PVP K30, sodium lauryl sulfate (SLS), sodium bicarbonate (NaHCO3) and lactose were blended thoroughly in a motor and pestle and then passed through sieve no. 100. The powder blend was mixed with talc (2%) and tablets were prepared by direct compression method with hardness 6 kg/cm2 using a single punch-tableting machine (Minipress-I)3. Eight formulations were prepared and coded them from F1 to F8. The details of composition of each formulation are shown in Table-1.

 

EVALUATION OF GRANULES (OR) POWDER BLEND:

Preformulation studies such as angle of repose (n=5), bulk density (n=5), tapped density (n=5), compressibility index (n=5) and Hausner’s ratio (n=5) were determined for their micromeritic properties.

 

EVALUATION OF FLOATING TABLETS:

To design tablets and tablets production quality, the formulated tablets were evaluated for hardness test (n=5) (using Monsanto Hardness Tester)4, friability test (n=5) (using Roche Friabilator)5 and weight variation test (n=5)6.

 

Buoyancy / Floating test:

The time interval between introduction of tablet into the dissolution medium and its floatation to the top of the dissolution medium was termed as buoyancy lag time (BLT). The duration upto which the tablet floats on the dissolution medium was taken as duration of buoyancy (DB). Both BLT and DB were determined using USP 24 type II dissolution apparatus in 900ml of 0.1N HCl at 37°±1°C 7.

 

Drug content:

Five tablets from each formulation were taken and grinded into fine powder. From this equivalent to 100mg of Silymarin powder was weighed and dissolved in sufficient quantity of methanol and diluted with 0.1 N HCl. The samples (n=5) were analysed spectrophotometrically at 286nm3.

 

IR Spectral Analysis:

Drug-polymers interactions was studied by using FTIR (Shimadzu, Japan, Model-8400s)8.        IR Spectral Analysis of pure Silymarin, Silymarin + HPMC K4M (20%), Silymarin + Eudragit RS 100 (20%) and Silymarin + HPMC K4M (20%) + Eudragit RS 100 (20%) were carried out. The peaks and the patterns produced by the pure durg were compared with peaks and patterns of pure drug with combination of polymers.

 

Dissolution studies:3

In vitro drug release of all the formulations were carried out using USP–type II dissolution apparatus (paddle type).  The dissolution medium, 900 ml 0.1N HCl solution, was placed into the dissolution flask maintaining the temperature of 37 + 0.5oC and rpm of 50.  One Silymarin tablet was placed in the dissolution apparatus.  The apparatus was allowed to run for 7 hours.  Samples measuring 10 ml were withdrawn every 30mts intervals upto 7 hours.

 

The fresh dissolution medium (37oC) was replaced every time with the same quantity of dissolution medium to maintain the same volume of dissolution medium. Collected samples were diluted upto 100ml with 0.1N HCl and analyzed at 286nm using 0.1N HCl as blank.  The cumulative percentage drug release was calculated.

 

Drug release kinetics (Curve Fitting Analysis):9-11

To analyze the mechanism of the drug release rate kinetics of the dosage form, the data obtained were fitted into zero order, first order, Higuchi’s model and Korsmeyer’s equation release models. The model with the highest correlation coefficient was considered to be the best model. The value of ‘n’ in the Korsmeyer’s model indicates the release mechanism.

 

Stability studies:12

It was carried out to evaluate the stability of the drug. All the formulations were stored at 4°±2°C, 27°±2°C (RH 65%+5%) and 45°+2°C (RH 75%+5%) temperatures for 60 days.  Two tablets were taken from all the stored samples at the intervals of 15th, 30th, 45th and 60th days. The drug content analysis and in vitro release studies were carried out to determine the percentage of Silymarin released using U.V. spectrophotometric at 286nm. Stability studies are used to find out whether any chemical degradation of Silymarin formulations takes place or not.

 

RESULTS AND DISCUSSIONS:

The Silymarin floating tablets using two polymers and in combination of polymers with different ratios were prepared by direct compression method. Before compression of the powder, preformulation studies such as Bulk density, Tapped density, Angle of repose, Compressibility index and Hausner’s ratio were determined for all formulations. The results of bulk density and tapped density were ranged from 0.314 to 0.416 and 0.352 to 0.470 respectively. Angle of repose and Compressibility index (Carr’s index) (%) ranged from 29.05° to 33.27° and 11.57 to 13.74 respectively (Table-2). These ranges are acceptable limits for powder bled to show good flow properties while formulating tablets.

 

The tablets were prepared and evaluated for the hardness, friability, weight variation, drug content and buoyancy determination. The hardness of the tablets was ranged from 6.0 to 6.2. The friability, weight variation and percentage of drug content for all the formulations were found to be within the acceptable range. The buoyancy lag time of all formulations was ranged from 96 to 174 sec. and duration of buoyancy was more than 20 h (Table-3). These results exhibited satisfactory floatable ability because of their low density and internal voids.

 

IR spectrum of pure Silymarin and Silymarin with combination of polymers showed no significant interactions between the drug and polymers and they are compatible with each other. The in-vitro dissolution studies of all the formulations are performed and shown  in  Table-4. The percentage drug release at the end of 7 h from   F1, F2, F3, F4, F5, F6, F7 and F8 were found to be 40.26%, 36.16%, 45.21%, 39.67%, 34.15%, 43.95%, 35.29% and 44.43% respectively. As the ratio of the polymers     (HPMC K4M and Eudragit RS100) increased from 15% to 20%, the percentage drug release was decreased that is in formulation F2 (36.16%) and F5 (34.15%) when compared to the formulations F1 (40.26%) and F4 (39.67%). The formulations F3, F6 and F8 (i.e., 45.12%, 43.95% and 44.43%) showed slightly higher percentage drug release when compared to the formulations F2, F5 and F7 (i.e., 36.16%, 34.15% and 35.29%) due to solubilization property of PVP K30 and increased concentration of PVP K30 from 4% to 8% 7.


Table-1: Formulations of Silymarin floating tablets

S. No.

INGREDIENTS

FORMULATIONS OF SILYMARIN FLOATING TABLETS*

F1

F2

F3

F4

F5

F6

F7

F8

01.

SILYMARIN

280

280

280

280

280

280

280

280

02.

HPMC K4M

75

100

100

--

--

--

50

50

03.

EUDRAGIT RS 100

--

--

--

75

100

100

50

50

04.

NaHCO3

70

70

70

70

70

70

70

70

05.

PVP K30

20

20

40

20

20

40

20

40

06.

SLS

3

3

3

3

3

3

3

3

07.

TALC

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

08.

LACTOSE

45

20

--

45

20

--

20

--

* Weight of one tablet is 500mg.

F1 - HPMC K4M (15%w/w) and PVP K30 (4%w/w); F2 - HPMC K4M (20%w/w) and PVP K30 (4%w/w); F3 - HPMC K4M (20%w/w) and PVP K30 (8%w/w); F4 – Eudragit RS100 (15%w/w) and PVP K30 (4%w/w); F5 – Eudragit RS100 (20%w/w) and PVP K30 (4%w/w);

F6 – Eudragit RS100 (20%w/w) and PVP K30 (8%w/w); F7 – HPMC K4M (10%w/w), Eudragit RS100 (10%w/w) and PVP K30 (4%w/w);

F8 – HPMC K4M (10%w/w), Eudragit RS100 (10%w/w) and PVP K30 (8%w/w)

 

 

Table-2: Evaluation of Silymarin powder blend

S. No.

PARAMETERS

PHYSICAL CHARECTERISTICS OF SILYMARIN POWDER BLEND

F1

F2

F3

F4

F5

F6

F7

F8

01.

BULK DENSITY* (gm/cc)

0.358 ±0.025

0.314

±0.039

0.374

±0.018

0.380

±0.076

0.357

±0.104

0.393

±0.085

0.416

±0.067

0.376

±0.068

02.

TAPPED DENSITY* (gm/cc)

0.400 ±0.017

0.352

±0.054

0.425

±0.062

0.424

±0.098

0.402

±0.087

0.447

±0.064

0.470

±0.015

0.427

±0.057

03.

BULKINESS* (cc/gm)

2.79 ±0.019

3.18

±0.064

2.67

±0.095

2.63

±0.108

2.80

±0.095

2.54

±0.038

2.40

±0.044

2.66

±0.014

04.

ANGLE OF REPOSE* (Ө)

29º58’ ±0.534

33º23’

±0.351

33º27’

±0.259

30º96’

±0.190

29º05’

±0.251

29º35’

±0.483

31º26’

±0.604

30º96’

±0.365

05.

COMPRESSIBILITY INDEX* (%)

11.73 ±0.794

12.10

±0.542

13.63

±0.387

11.57

±1.054

12.60

±0.864

13.74

±0.573

12.98

±0.652

13.56

±1.004

06.

HAUSNER’S RATIO*

1.11 ±0.154

1.12

±0.288

1.13

±0.121

1.11

±0.854

1.12

±0.432

1.13

±0.548

1.12

±0.742

1.13

±0.240

* All values are expressed as mean ± standard deviation, n =5

 

Table-3: Evaluation of Silymarin floating tablets

S. No.

PARAMETERS

PHYSICAL CHARECTERISTICS OF SILYMARIN FLOATING TABLETS

F1

F2

F3

F4

F5

F6

F7

F8

01.

Hardness* (kg/cm2)

6.1

±0.42

6.0

±0.25

6.2

±0.31

6.1

±0.36

6.1

±0.74

6.0

±0.52

6.0

±0.36

6.2

±0.18

02.

Friability* (%)

0.29

±0.12

0.20

±0.18

0.26

±0.21

0.17

±0.11

0.20

±0.15

0.28

±0.11

0.20

±0.17

0.22

±0.20

03.

Uniformity of Weight* (mg)

0.500

±0.21

0.500

±0.43

0.499

±0.30

0.498

±0.42

0.500

±0.34

0.499

±0.26

0.499

±0.17

0.499

±0.29

04.

Drug Content* (%)

99.10

±0.255

100.0

±0.498

99.40

±0.352

99.70

±0.647

100.21

±1.205

98.80

±0.654

98.80

±0.354

100.0

±0.412

05.

Thickness* (mm)

3.5

±0.05

3.8

±0.03

3.4

±0.03

3.5

±0.07

3.7

±0.06

3.6

±0.08

3.7

±0.03

3.8

±0.03

06.

Buoyancy

Lag Time*(sec.)

113

±4.58

129

±2.68

174

±3.47

150

±5.10

165

±5.02

140

±1.65

96

±2.84

109

±3.00

07.

Duration of Buoyancy (hrs.)

>20

>20

>20

>20

>20

>20

>20

>20

* All values are expressed as mean ± standard deviation, n =5

 

 


However, when the drug release of F1 and F2 (using HPMC K4M) is compared with the F4 and F5 (using Eudragit RS100) showed less drug release due to the less water permeability of Eudragit RS100 when compared with HPMC K4M13.

 

The results of four kinetic models namely zero order equation, first order equation, Higuchi’s equation and Korsmeyer’s equation are presented in the Table-5. All formulations follow the first order release rate (R2: 0.8814 to 0.9423). Higuchi’s equation proved that (R2= 0.9544 to 0.9829) the diffusion is the dominant mechanism in all the formulations10. In Korsmeyer’s equation if n=0.45 or n<0.45, it is Fickian diffusion. Kosmeyer’s plot proved that the n values are <0.45 for all the formulations. Therefore all formulations follows Fickian release mechanism11.

 

Stability studies were performed for all the formulations. All the formulations were stored at 4°±2°C, 27°±2°C (RH 60+5%) and 45°+2°C (RH 75+5%) for 60 days. After an interval of 15th, 30th, 45th and 60th days the samples were withdrawn and tablet evaluation tests were conducted. There was no colour change and there were no deviations in all tests. There was no deviations in the percentage of drug release also. It showed that all formulations remain stable for 60 days.


Table-4: Cumulative percentage of drug release from the Silymarin formulations

S. No.

TIME (hrs)

F1

F2

F3

F4

F5

F6

F7

F8

01.

0.5

19.12

±1.21

14.72

±1.56

18.28

±1.22

17.89

±1.24

12.50

±1.69

17.87

±1.02

13.72

±1.04

17.51

±1.15

02.

1.0

20.97

±1.65

16.61

±1.64

20.79

±1.45

19.82

±1.65

14.72

±1.24

20.40

±1.04

15.53

±1.05

19.91

±1.08

03.

1.5

22.16

±1.42

18.38

±1.51

23.22

±1.61

21.48

±1.84

16.78

±1.65

22.93

±1.12

17.84

±1.34

22.05

±1.22

04.

2.0

23.33

±1.24

20.02

±1.20

25.36

±1.07

23.23

±1.77

18.74

±1.31

24.59

±1.64

19.21

±1.54

24.29

±1.54

05.

2.5

24.79

±1.65

22.06

±1.64

27.79

±1.54

24.88

±1.22

19.97

±1.08

26.73

±1.35

21.36

±1.42

26.53

±1.02

06.

3.0

27.01

±1.35

23.52

±1.84

29.65

±1.24

26.63

±1.35

21.63

±1.08

28.19

±1.55

22.80

±1.94

28.77

±1.20

07.

3.5

28.68

±1.02

25.27

±1.77

31.79

±1.36

28.10

±1.54

23.48

±1.65

31.00

±1.92

24.77

±1.02

31.00

±1.31

08.

4.0

30.43

±1.06

26.73

±1.64

33.44

±1.62

29.94

±1.20

24.61

±1.55

32.28

±1.34

25.63

±1.31

32.57

±1.54

09.

4.5

31.89

±1.92

28.29

±1.55

35.10

±1.54

31.21

±1.14

26.27

±1.33

34.41

±1.75

27.35

±1.45

34.03

±1.22

10.

5.0

33.16

±1.08

30.04

±1.32

37.23

±1.20

32.57

±1.05

28.21

±1.42

36.55

±1.98

29.80

±1.20

36.07

±1.31

11.

5.5

34.81

±1.35

31.31

±1.20

39.57

±1.00

34.22

±1.06

29.78

±1.65

38.11

±1.44

30.34

±1.05

38.49

±1.64

12.

6.0

36.46

±1.11

33.05

±1.04

41.61

±1.64

35.49

±1.00

31.33

±1.33

40.15

±1.35

32.17

±1.34

40.35

±1.20

13.

6.5

38.69

±1.25

34.61

±1.24

43.08

±1.08

37.62

±1.84

32.70

±1.20

42.29

±1.08

33.42

±1.24

42.01

±1.05

14.

7.0

40.26

±1.09

36.16

±1.64

45.21

±1.34

39.67

±1.15

34.15

±1.61

43.95

±1.95

35.29

±1.64

44.43

±1.84

* All values are expressed as mean ± standard deviation, n =5

 

Table-5: Curve Fitting Analysis

FORMULATION

ZERO ORDER

  R2

FIRST ORDER

 R2

HIGUCHI’S PLOT

  R2

KORSMEYER’S PLOT

R2

n

F1

0.8383

0.8814

0.9544

0.3302

0.176

F2

0.8867

0.9224

0.9810

0.3890

0.296

F3

0.8841

0.9284

0.9814

0.3720

0.312

F4

0.8459

0.8926

0.9641

0.3443

0.272

F5

0.9100

0.9423

0.9877

0.5385

0.384

F6

0.8840

0.9256

0.9795

0.3709

0.240

F7

0.8961

0.9145

0.9844

0.5207

0.256

F8

0.8930

0.9335

0.9829

0.3820

0.336

R2= regression coefficient; n= slope

 


CONCLUSION:

The present study was carried out to develop the floating drug delivery system using HPMC K4M and Eudragit RS100 polymers as carriers. The results of experimental studies of Silymarin floating tablets proved that the powder blend showed good flow properties, tablet evaluation tests are within the acceptable limits, IR spectral analysis proved that there was no drug-polymer interaction, percentage drug release was controlled and the formulations were stable after storing at different temperatures for 60 days. Thus, results of the current study clearly indicates, a promising potential of the Silymarin floating system as an alternative to the conventional dosage form.

 

ACKNOWLEDGMENT:

The authors are thankful to Micro laboratories Ltd., Hosur. for providing gift sample of Silymarin and polymers. The authors are also grateful to the correspondent, Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, Tamil Nadu for providing necessary facilities to conduct the experimental studies.

 

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Received on 25.10.2010          Modified on 12.11.2010

Accepted on 18.11.2010         © RJPT All right reserved

Research J. Pharm. and Tech. 4(3): March 2011; Page 393-397