Formulation and Evaluation of Mucoadhesive Tablet of Valsartan

 

Shailesh H. Lunkad*, Dr Surajj Sarode

Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner

*Corresponding Author E-mail: jainshailesh273@yahoo.in

 

ABSTRACT:

The present work was aimed to develop novel oral antihypertensive sustained release intestinal mucoadhesive tablets of valsartan using novel natural polymer Gum olibanum and chitosan. The tablets were prepared by using different concentration of polymer of gum olibanum and chitosan by wet granulation method. Two factor three levels central composite design applied to optimize the formulation variables. In this study Gum olibanum and chitosan were selected as independent variables. The percentage drug release, Ex-vivo residence time and Mucoadhesive strength were selected as dependant variables. Prepared formulation were evaluated for various physical and chemical parameters. In- vitro drug release study was carried out for 12 hours. Formulation F2 was given as best batch by DOE software. Formulation F2 showed 96.23% drug release at 12 hours, Ex-vivo residence time was found upto 12 hours and mucoadhesive strength was found to be 26.50(Dyne/cm2). The best fit model for F2 was found to be first order with r2 value 0.9785 mechanism of drug release was found to be fickian diffusion. Hence finally we conclude that valsartan tablet is suitable for mucoadhesive drug delivery system.

 

KEYWORDS: Valsartan, Chitosan, Gum olibanum, Sustained Release, Design of Experiment, Mucoadhesive DDS.

 

 


INTRODUCTION:

Mucoadhesive Drug Delivery System:

Mucoadhesive drug delivery systems are delivery systems, which utilize the property of bioadhesion of certain polymers. Mucoadhesion can be defined as the state in which two materials adhere to each other for extended periods of time with the help of interfacial forces and when one of these materials is biological in nature, the phenomenon is known as bioadhesion or the term bioadhesion as the “attachment of a synthetic or   to mucus and/or epithelial surface”.

 

In recent years, many such mucoadhesive drug delivery systems have been developed for oral, buccal, nasal, rectal and vaginal routes for both systemic and local effects. Dosage forms designed for mucoadhesive drug delivery should be small and flexible enough to be acceptable for patients and should not cause irritation.

 

Mucoadhesive drug delivery system Having several advantages prolonged residence time enhances absorption, which results in an increase in the therapeutic efficacy of the drug. It Enormous blood supply and good blood flow rates cause rapid absorption of the drug. The drug is protected from degradation due to pH and digestive enzymes of the middle gastrointestinal tract. As mucosal membranes are relatively permeable, it allows a rapid onset of action. It Prevents first pass metabolism results in increase in drug bioavailability. Mucoadhesive dosage form reduces fluctuation of drug plasma level. Ease of drug administration therefore improved patient compliance.

 

Valsartan is BCS class IIIrd drug. It is an angiotensin receptor blocker that may be used damage hypertension and heart failure. Absolute bioavailability of valsartan is approximately 25% and elimination halflife 6 hours.

 

MATERIALS AND METHODS:

Materials:

Valsartan was obtained as a gift sample from Macleods, Vapi. Crystal of Gum Olibanum was obtained Ajanta trader’s, Ajintha. Chitosan, PVP K-30 was procured from Celogen Life Science, Mumbai. Dibasic Calcium Phosphate, Talc and Magnesium stearate was procured from Haffkine Ajintha Pharmceutical, Jalgaon.

 

Drug-excipient Interaction Study:

Infrared spectrophotometer is a useful analytical technique utilized to check the chemical interaction between the drug and other excipients used in the formulation. The sample (1mg) was powdered and mixed with 10mg of dry powdered potassium bromide. The powdered mixture was taken in a sampler and the spectrum was recorded by scanning in the wavelength region of 4000-400cm-1 using IR spectrophotometer. Check was made whether the excipients were compatible or not.

 

Standard Calibration Curve of Valsartan in Phosphate Buffer pH 6.8 at 252 nm:

An accurately weighed amount of valsartan (10 mg) was dissolved 100ml 0.1N HCl. From this stock solution, 5, 10, 15, 20 and 25μg/ml concentration of valsartan was prepared respectively. The absorbance of these solutions was measured at 252.20nm (λmax) using phosphate buffer pH 6.8 as a blank.

 

DSC Analysis:

The thermal analysis used to investigate and predict any physicochemical interaction between drug and other excipients.

 

Experimental Design by Central Composite Batches:

A Central composite was implanted for optimization of oral sustained release tablet. According to model it contains two independent variables at three level +1, 0 and -1 in table. The different independent variable include: amount of Gum olibnum (X1) and Amount of chitosan (X2), where Gum olibanum (X1) and Chitosan (X2) acts as a sustained release polymers. The different dependant responses variable: % drug Release (Y1), Ex. Vivo residence Time (Y2), Mucoadhesive Strength (Y3). The design expert software (version 7.1.5, stat-Ease Inc., Minneapolis, USA) was used to design the experiment. The software generated nine model formulations.

 

Preparation of Gum Olibanum Powder:

Olibanum is available in crystal form. The crystal form of olibanum gum was dried at 600C for 4 hours in hot air oven. Then the dried form was crushed in grinder to make it powder. Then it was passed through 100 mesh size to obtained fine powder.

 

Composition of Formulation of Core Tablet:

The tablets were prepared by wet granulation procedure. Before granulation the drug and excipients, they were shifted through sieve #60 to remove any large particles. Initially 4% PVP K-30 solution was prepared. Accurately weighed PVP K30 was taken and mixed slowly in slightly hot water with continuous stirring. Then the polymer (novel polymer), chitosan, dibasic calcium phosphate as diluent and the drug were mixed in a mortar by geometric progression for a period of 10 to 15 min with required quantity of PVP K30 solution was added and to form wet mass. The wet mass was passed through 20# sieve. The wet granules were dried in hot air oven at 50°C for 15 to 20min. Remaining ingredients like magnesium stearate and talc were added. Tablets mixture was compressed in tablet compression machine (12 station multi tooling, CIP Ahemdabad) using 14 mm punches.

 

 


Table No. 1 Formulation Composition of Central Composite Batches by Using Gum Olibanum and Chitosan In Various Concentration (F1-F9)

Formulation Code

F1

F2

F3

F4

F5

F6

F7

F8

F9

Valsartan

62

62

62

62

62

62

62

62

62

GO

12.93

20

25

27.07

20

15

25

15

20

Chitosan

10

10

15

10

17.07

15

5

5

2.93

DCP

111.07

104

94

96.93

96.93

104

104

114

111.07

Mg. Stearate

2

2

2

2

2

2

2

2

2

Talc

2

2

2

2

2

2

2

2

2

Total Wt.

200

200

200

200

200

200

200

200

200

*All quantities are in mg, GO= Gum Olibanum, DCP= Dicalcium Phosphate

 


Preparation of Coated Tablets:

Prepared core tablets were press coated with cellulose acetate phthalate (CAP) in different ratios (core tablet weight: weight of CAP) i.e. 1:1, 1:1.5, 1:2, 1:2.5 and 1:3 using 11 mm biconvex punch. The optimized coating ratio was found to be 1:2. The resultant weight of each tablet was 600 mg.

 

Evaluation of Physicochemical Parameters:

1.     Preformulation:

The preformulation study i,e. bulk density, tapped density, compressibility index, hausner’s ratio and angle of repose were carried out. The results of preformulation studies were shown in table no.3.

 

2.     Post Compression Parameters:

a)    Drug Content: Twenty tablets were weighed and powdered by using mortar and pestle. An amount equivalent to 62 mg valsartan was shaken with 100 ml phosphate buffer solution (pH 6.8) and sonicated for about 30 min. The solution was filtered through Whatman filter paper and the content of valsartan was determined by measuring absorbance at 252 nm on double beam UV spectrophotometer (Shimadzu-1800) after suitable dilution. Uniformity of content was calculated by using formula.

 

Uniformity of content=×100

 

The results were shown in table no.4.

 

b)    Weight Variation: Twenty tablets were randomly selected from each formulation and weighed individually to check for weight variation. The following percentage deviation in weight variation according to USP was allowed. The results were shown in table no.4

 

c)     Tablet Hardness: Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Mosanto hardness tester. It was expressed in Newton’s (N). Ten tablets were randomly selected from each formulation and hardness of the same were determined.

 

d)    The average value was also calculated and measured in terms Kg/cm2. The results were shown in table no.4.

 

e)     Friability: The friability of tablets was determined using Roche friabilator. It is expressed in percentage (%). About 6 g tablets (Initial weight) were transferred into friabilator. The friabilator was operated at 25rpm for 4 minutes or 100 revolutions. The tablets were dedusted and weighed again (Final Weight).

 

% Friability =  × 100

 

The results were shown in table no.4.

 

f)     Thickness: Twenty tablets were randomly selected from formulations and thickness was measured using Vernier calipers individually. It was expressed in millimeter and average was calculated. The results were shown in table no.4.

 

g)    Ex-Vivo Residence Time: The disintegration test apparatus is used for the study of Ex-vivo residence time of tablets. The intestinal mucosa is collected and is cut in to 2×2 size pieces. These pieces are placed on the glass sides and tied with rubber bands. The formulations are placed on the tissue and kept aside for few minutes. Then all glass slides are fitted to the disintegration test apparatus and the apparatus is allowed to start this process is continued for 12 hours. The residence time of of each formulation is noted as Ex-vivo residence time. The results were shown in table no.4.

 

h)    Measurement of Ex-Vivo Mucoadhesive Strength: Mucoadhesive strength was determined by using modified physical balance method, for which Goat stomach mucosa was collected from local slaughter house and stored in Krebs solution. Mucosa was sticked on glass slide using double sided sticker which was already sticked on the bottom of 100 ml beaker, and this beaker was placed in1Ltr beaker which already contained 0.1N HCl of pH 1.2. Tablet were sticked on lower side of left pan of double pan balance using double sided sticker, in both pan of the balance empty beaker were placed and their weight were adjusted, near to the right sided pan arrangement of burette were made for drop wise addition of water, as shown in figure. The mucosal and tablet surface was wetted with few drop of 0.1N HCl and on the left pan tablet 5 gm weight was placed for 5min. to allow the initial contact of mucoadhesion. Then drop wise water was added in beaker of right pan till the detachment of tablet from the mucous membrane was observed. Then weight of water present in right pan beaker was determined, using following formula.

 

i)        Mucoadhesive strength = (Wt. of the beaker + Wt. of the water) – Wt. of the empty beaker.

 

After determination of mucoadhesive strength Force of adhesion was calculated using formula

 

Force of adhesion (N) = Mucoadhesive strength/100 × 9.81

 

The results were shown in table no.4.

 

j)        In-Vitro Drug Release Study: Tablets of all optimized batches were subjected to dissolution rate studies. In- vitro dissolution studies were carried out in dissolution apparatus (Electrolab Model: TDL-08L) to determine the drug release from various formulation. The 37±0.5oC temperature was maintained throughout the study. Studies were carried out in 900 ml of pH 1.2 acid buffer for initial 2Hrs and in pH 6.8 Phosphate buffer up to 12hrs at 50 rpm. 5ml sample were withdraw at 1, 2, 3, 4, 6, 8,10,12 hrs and immediately replace by equal volume of dissolution medium equilibrated at the same temperature to maintain a volume. The sample withdrawn was passed through whatmann filter paper. The dissolution data recorded was analysed to calculate the amount of drug release and percentage cumulative drug release at different time interval. % cumulative drug release Vs time graph Plotted. The results were shown in table no. 5.

 

Kinetic Analysis of Dissolution Data:

To study the mechanism of drug release from the matrix tablets, the release data were fitted to zero-order, first order and Higuchi equations. The dissolution data was also fitted to the well-known exponential equation. Results for kinetic analysis of dissolution data was shown in table no.6.

 

Stability Studies:

The stability studies of the mucoadhesive tablet were conducted according to ICH guidelines by storing the tablet at 40±20 C and 75±5% RH for 1 month. The sample were withdrawn at 30 days and evaluated for Ex-vivo mucoadhesive strength, drug content and % drug release of valsartan in 12 hours and drug content. The in-vitro drug release study was performed after 30 days and compared with fresh batch. The results were shown in table no. 7.

 

RESULT AND DISCUSSION:

FTIR- IR spectrum of physical mixture of valsartan, novel polymer, Chitosan (1:1:1) are shown in Figure 2.  From IR spectra of drug and physical mixture, no significant change in peak pattern was observed. Hence, it was concluded that, absence of drug excipients interaction and drug was compatible with excipients used in the present work.

 

 

Figure No. 1 FTIR Spectrum of Valsartan

 

Figure No. 2 FTIR Spectrum of Overlay

 

UV-visible spectroscopy:

 

Figure No. 3 UV Spectrum of Valsartan

 

Standard Calibration Curve:

 

Figure No. 4 Standard Calibration Curve of Valsartan in Phosphate Buffer (pH 6.8)

 

Differential Scanning Calorimetry:

The DSC graph valsartan and valsartan with polymer was shown in figure no 5 and 6 The melting point of valsartan (1070C) and Mixture (1060C) Matches with the standard value(1050-1100C). The DSC graph of valsartan was also showed the melting point at 1070C indicate that there is no interaction of drug polymer.

 


Figure No. 5 DSC Graph of Valsartan

 

Figure No. 6 DSC Graph of Valsartan+ Gum Olibanum + Chitosan

 


Characterization of Natural Polymer Gum Olibanum:

The results of physicochemical properties of Gum olibanum are shown in Table No. 2. The values of angle of angle of repose, Carr’s index, hausner’s ratio indicated that the polymer having good flow property and compressibility.

 

Table No. 2 Results for Physicochemical Evaluation of Gum Olibanum Powder

Sr. No.

Physicochemical Parameter

Results

1

Carr’s Index

14.27 ± 1.07

2

Loss on Drying (%)

3

3

Total Ash (%)

7

4

Acid Soluble Ash (%)

1

5

Bulk Density (gm/cm3)

0.5429±0.017

6

Tapped Density (gm/cm3)

0.6333±0.025

7

Hausner’s Ratio

25.96±1.96

8

Angle of Repose (degree)

1.16±0.015


Evaluation of Optimized Batches of Valsartan Mucoadhesive Tablets:

Preformulation Parameter:

Table No. 3 Evaluation of Precompression Parameters of Optimized Batches of Mucoadhesive Tablet of Valsartan.

Batch

Bulk Density (gm/ml)

Tapped Density (gm/ml)

Hausner’s Ratio

Carr’s Index (%)

Angle of Repose (Degree)

F1

0.606±0.004

0.720±0.001

15.82±0.011

1.185±0.74

29.54±0.21

F2

0.620±0.002

0.704±0.005

11.91±0.011

1.133±0.67

27.45±0.33

F3

0.591±0.015

0.714±0.004

17.17±0.207

1.065±1.88

27.48±0.26

F4

0.68±0.01

0.758±0.003

11.26±0.021

1.114±2.54

27.70±0.19

F5

0.674±0.012

0.751±0.007

10.33±0.010

1.114±0.08

28.26±0.11

F6

0.605±0.005

0.745±0.006

18.73±0.005

1.230±0.37

29.14±0.41

F7

0.623±0.001

0.756±0.020

17.58±0.036

1.231±2.38

27.33±0.15

F8

0.643±0.032

0.760±0.017

15.63±0.089

1.183±5.83

27.34±0.47

F9

0.653±0.017

0.693±0.005

15.70±0.087

1.059±2.95

26.6±0.491

 

From the above results it is concluded that results for all the optimized batch were found within range.

Post Compression Parameter

Table No. 4 Results of Physical Evaluation of Optimized Batches of Mucoadhesive Tablet of Valsartan

Batches

Weight Variation

Hardness (kg/cm2)

Ex-vivo Residence Time (Hrs)

Ex-Vivo Mucoadhesion Force (Dyne/cm2)

Friability (%)

Drug Content (%)

F1

199

5.94

<12

21.3

0.468

98.90±1.98

F2

199.3

6.74

12

26.50

0.451

97.03±1.91

F3

200.3

6.07

>12

26.89

0.565

96.30±2.56

F4

200

5.46

>12

26.20

0.366

98.09±1.26

F5

199.6

6.36

>12

27.8

0.434

99.96±1.15

F6

199

6.30

<12

22.3

0.418

96.30±1.13

F7

199.6

6.63

<12

25.25

0.250

97.60±2.50

F8

199.6

6.82

<12

21.46

0.383

99.26±2.50

F9

200.3

6.93

<12

20.24

0.532

100.5±0.57

 

From the above results it can be conclude that weight variation, hardness, % friability and drug content were found within limit as per official standard. Result of ex-vivo residence and mucoadhesive strength were found to be 12 hours and 26.50 dyne/cm2 respectively for batch F2.

 

Table No. 5 Result of In Vitro Drug Release Study of Optimized Batches of Mucoadhesive Tablet of Valsartan

Time (Hrs)

% Drug Release

F1

F2

F3

F4

F5

F6

F7

F8

F9

1

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

0

0

0

0

3

37.21

28.18

24.9

23.12

23.10

25.14

25.5

30.12

30.12

4

48.40

40.10

34.70

30.27

28.90

39.36

32.14

44.50

45.90

6

67.50

53.26

47.30

44.83

44.30

54.61

46.90

60.05

60.54

8

85.57

70.20

56.92

58.10

56.95

71.85

59.90

75.23

76.37

10

94.28

83.27

64.30

70.30

69.38

98.90

72.30

93.50

92.90

12

-

96.23

80.14

83.20

82.50

-

86.94

-

-

 


Figure No. 7 In-Vitro Dissolution Study of Central Composite Batches (F1-F5)

 

Figure No. 8 In-Vitro Dissolution Study of Central Composite Batches (F6-F9)


In-vitro drug release study was conducted and % drug release for formulation F2 was found to be 96.23% at 12 hours and followed first order kinetics (r2= 0.9785).

 

Table No 6. Mathematical Model Fitting of Optimized Batch F2

Batch code

r2

Release Exponent (n)

Zero order

First order

Higuchi’s model

Korsmeyer Peppas

F2

0.9581

0.9785

0.5273

0.7098

0.3

 

Stability Testing:

Table No. 7 Results for Stability Testing of Optimized Batch F2

Evaluation Parameter

Optimized Batch F2

Initial

After Storage at 400C / 75% RH for 1 Month

% Drug Release at end of 12 hr

96.23

95.89

% Drug Content

97.03

96.90

Ex- Vivo Mucoadhesive Strength

26.5

26.5

 

Data Analysis and Optimization:

The designing and optimization of the mucoadhesive tablet of valsartan was done by applying central composite design. The quantitative effect of formulation variables on response was illustrated by the Response Surface Methodology. Based on the conclusion of the preliminary studies, the data used to select the concentration of independent variable and the central composite batches were design expert software. The experimental values for the response Y1(% Drug Release), Y2(Ex-Vivo Residence Time) and Y3(Ex-Vivo Mucoadhesive Force) were curve fitted in quadratic model. The regression equation for the response fitted in quadratic model was generated. Only statistically significant (p < 0.05) coefficients were included in the regression equations.

 

Regression Equation for the Quadratics Model:

Percentage Drug Release at 12 Hours:

Final equation in coded form

 

% Drug Release at 12 hours (Y1) = +96.23 + 35.59X1 + 13.73X2 – 1.70X1X2 – 27.23X12 – 27.40X22

 

From the regression analysis, both the coefficients X1 and X2 bear positive sign for % Drug Release of tablets. Additions more amount of Gum Olibanum, % drug release time of tablet were increases while increase amount in the amount of Chitosan.

 

Ex-Vivo Residence Time:

Final equation in coded form

 

Ex-vivo residence time (Y2) = +12.00 + 1.16X1 + 0.91 X2 + 0.25X1X2 – 0.44X12 – 0.44X22

 

From the regression analysis, both the coefficients X1 and X2 bear positive sign for Ex-vivo residence time of tablets. Additions more amount of Gum Olibanum, ex-vivo residence time of tablet were increases while increase amount in the amount of Chitosan.

Ex-Vivo Mucoadhesive Force:

Final equation in coded form

 

Ex-Vivo mucoadhesive Force (Y3) =+26.50 + 1.91X1 + 1.65X2 + 0.20X1X2 – 1.35X12 – 1.22X22

 

From the regression analysis, both the coefficients X1 and X2 bear positive sign for Ex-vivo mucoadhesive force of tablets. Additions more amount of Gum Olibanum, Ex-vivo mucoadhesive of tablet were increases while increase amount in the amount of Chitosan.

 


Figure No. 9 3D Contour Plot Showing Influence of Gum Olibanum and Chitosan on the % Drug Release of Valsartan in 12Hours, Ex-vivo Residence time of Valsartan at 12 hours and Ex-vivo Mucoadhesive Strength of Valsartan at 12 hours and Overlay Plot


 

Table No. 8 Summary of Results of Analysis of Variance

ANOVA for Y1 (Percentage Drug release at 12 Hrs)

Source

DF

Sum of Square

Mean Square

F value

P- Value Prob> f

Model

5

20839.20

4167.84

13.19

0.0019 – Significant

Residual

7

2211.18

315.88

---

---

Cor total

12

23050.38

---

---

---

ANOVA for Y2 (Ex-vivo Residence time)

Source

DF

Sum of Square

Mean Square

F value

P- Value

Prob> f

Model

5

19.84

3.97

19.99

0.005 – significant

Residual

7

1.39

0.20

---

---

Cor total

12

21.23

---

---

---

ANOVA for Y3 (Ex-Vivo Mucoadhesive Force)

Source

DF

Sum of Square

Mean Square

F value

P- Value

Prob> f

Model

5

71.74

14.31

11.50

0.029 – Significant

Residual

7

8.71

1.24

---

---

Cor total

12

80.25

---

---

---

 


CONCLUSION:

Mucoadhesive tablets of Valsartan with good mucoadhesive strength can be successfully prepared by the wet granulation technique using natural polymer i.e. gum olibanum and chitosan as mucoadhesive polymer. It was concluded that the rate of drug release from all the formulations primarily was good. The coating was done by Press coating method using cellulose acetate phthalate as a polymer. The proposed mucoadhesive formulation found to be successful with respect to parameters evaluated such as weight variation, friability, hardness, drug content, mucoadhesive strength, Ex-vivo residence time and In-vitro drug release study. According to ex-vivo mucoadhesive force the formulation containing high concentration of gum olibanum and chitosan showing better results. According to ex-vivo residence time, F2 (formulation containing medium concentration of gum olibanum and chitosan) showing best result for 12 hours among all the formulations. In in-vitro drug release study formulation (F2) containing medium concentration of gum olibanum and chitosan showing better sustained release among all the formulations i.e. 96.23%. All the formulations following first order release and follow diffusion type of sustained release. After the stability study there should be no change in the parameters of the formulation containing gum olibanum and chitosan. Hence finally we conclude that valsartan tablet is suitable for mucoadhesive drug delivery system.

 

ACKNOWLEDGEMENT:

Authors specially wish to express their sincere thanks to Department of Pharmaceutics, Shree Sureshdada Jain Institute of pharmaceutical Education and Research jammer, Dist. Jalgaon, Maharashtra for providing the laboratory facilities to carry out this research work.

 

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Received on 04.07.2019         Accepted on 28.08.2019

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2019; 9(4):229-237.

DOI: 10.5958/2231-5691.2019.00037.6