Development and Evaluation of Mucoadhesive Buccal Tablet of Simvastatin

 

Ashish Jayant Saraf*, Sudhir Pange, Satyajit Deshmukh, Rahul Hajgude

K. T. Patil College of Pharmacy, Osmanabad-413501, Maharashtra, India

*Corresponding Author E-mail: ashish.saraf9@gmail.com

 

 

ABSTRACT:

Mucoadhesive buccal tablets of Simvastatin were prepared with an objective of enhanced bioavailability using Carbopol 934P in varying concentration with secondary polymers like Sodium alginate, Sodium CMC, HPMC K4M, Xanthan gum by direct compression method. Preformulation studies confirmed identity and purity of the drug by means of IR Spectroscopy and Melting point determination. An analytical method was developed for Simvastatin. The tablets were evaluated for hardness, thickness, weight variation, friability and drug content concluded that all these parameters were in acceptable range of pharmacopoeial specification. The tablets were studied for surface pH, swelling index, in vitro drug release, ex vivo residence time, mucoadhesive strength, ex vivo permeation. The surface pH of the tablet was from 6.16 to 6.66 which fall in the range of salivary pH and all the tablets showed ex vivo residence time of 3.24 to 6.35 h indicated good adhesive capacity of tablet. The buccal tablet showed good swelling of >65% up to 8 h maintaining the integrity of polymers. The in vitro release of simvastatin was extended only for 6-7 h, if Carbopol 934P in combination with secondary polymer Xanthan gum was used. While the tablets contained Carbopol 934P along with Sodium alginate, Sodium CMC, HPMC K4M prolonged the released up to 8 h. Hence Carbopol 934P along with sodium alginate, Sodium CMC, HPMC K4M could be used to prepared prolonged released buccal tablet. The in vitro release of batches containing Carbopol 934P with sodium CMC show maximum drug release 97.11% which obeyed Korsemeyer-Peppas release kinetics with Non fickian transport mechanism of release due to more hydrophilic nature of polymer and drug. All the tablets showed good mucoadhesive strength of 7.60 to 30.10 g with high force of adhesion. The ex vivo permeation concluded that Carbopol enhanced the flux and permeability coefficient of simvastatin from the tablets. More flux observed in batches containing Carbopol 934P with Sodium CMC.

 

KEYWORDS: Carvedilol Simvastatin, primary and secondary polymers, in vitro drug release, mucoadhesion, ex vivo permeation.

 

 


INTRODUCTION:

Delivery of drugs through various transmucosal routes has gained significant attention owing to their presystemic metabolism or instability in the acidic environment associated with the oral environment. Amongst the various absorptive mucosae, mucosa of the oral cavity is viewed as a convenient and easily accessible site for the delivery of therapeutic agents. Rich blood supply, robust nature, short recovery times after stress or damage, lower enzymatic activity of saliva, facile removal of formulation, better patient acceptance and compliance are some other prominent meritorious visages of buccoadhesive systems. Simvastatin is hydrolyzed to the corresponding β-hydroxyacid form.

 

This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, this enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. In additionally simvastatin reduces very-low density lipoproteins (VLDL) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C). Simvastatin used to treatment of hypercholesterolemia with a bioavailability <5% due to first pass metabolism. In this study an attempt was made to develop a simvastatin buccal tablet to avoid presystemic metabolism. Plasma half life of Simvastatin is 3 h, molecular weight 418.6.

 

Rational blends of Carbopol 934P as Primary Polymer with Sodium alginate, Sodium CMC, Hydroxypropylmethyl cellulose (HPMC K4M) and Xanthan gum were chosen as the Secondary Polymers to formulate buccal bioadhesive tablets of drug. The polymers were selected as it is documented to provide regulated drug release and bioadhesion.

 

MATERIAL AND METHOD:

Materials:

Simvastatin was received as a gift sample from Watson Pharma, Mumbai. Carbopol 934P, Sodium alginate was received as a gift sample from FDC Ltd, Mumbai. Carboxy methyl cellulose sodium, HPMC K4M, Xanthan Gum, Microcrystalline Cellulose, Lactose, Citric acid, Magnesium stearate, Saccharin sodium, Dodecyl sodium sulphate was received as gift sample from Micro Labs Ltd, Bangalore. All chemicals were used of analytical reagent grade.

 

Methods:

1) Preformulation Studies of Simvastatin:

Melting point1:-

The melting point was determined by melting point apparatus. The melting point was determined by introducing a small amount of substance in the capillary attached to graduated thermometer and constant heat was applied to the assembly suspended in the paraffin bath. The drug sample was tested in temperature range 135-138°C and point at which drug melts was noted.

 

Infra red spectroscopy:-

This study was done to check whether any compatibility related problems are associated with drug and the excipients used for the formulation of buccal tablet. The drug and excipients must be compatible with one another to produce product that is stable, efficacious, attractive and easy to administer and safe.

 

IR spectroscopy was employed to ascertain the compatibility between Simvastatin and the selected polymers by using Bruker IR and the spectrum analysis was done.

 

2) Development of Analytical Method for Simvastatin2:-

Calibration curve of Simvastatin in phosphate buffer pH 6.8 solution

UV spectrophotometry is widely employed for routine drug analysis. Therefore the objective of the present investigation was to develop an UV spectrophotometric method of analysis of Simvastatin

Determination λmax of Simvastatin

Standard stock solution was prepared by dissolving Simvastatin in methanol to make final concentration of 1000 µg/ml. Different aliquots were taken from stock solution  and diluted with pH 6.8 phosphate buffer to prepare the series of concentration from 5-15 µg/ml. This solution was subjected to scanning between 200–400 nm against blank and absorption maximum was determined 247 nm.

 

Standard calibration curve of Simvastatin

Standard stock solution: A stock solution containing 1 mg/ml (1000 mcg/ml) of pure drug was prepared by dissolving 100 mg of Simvastatin in sufficient methanol to produce 100 ml solution in a volumetric flask.

 

Stock solution: From the standard stock solution, 1 ml of the stock solution was further diluted to 10 ml with phosphate buffer pH 6.8 into a 10 ml volumetric flask and diluted up to the mark with phosphate buffer pH 6.8(100mcg/ml ). Aliquots of 0.5, 1.0, 1.5, 2.0 and 2.5ml of stock solution were pipette out into 10ml volumetric flasks. The volume was made up to the mark with phosphate buffer pH 6.8. These dilutions give 5,10,15,20 and 25 mcg/ml concentration of Simvastatin respectively. The absorbance was measured in the UV-Visible spectrophotometer at 247 nm using Phosphate buffer pH 6.8 as blank and graph of concentration versus absorbance was plotted.

 

3) Preparation of Simvastatin tablet

Direct compression method was employed to prepare buccal tablets of Simvastatin using different concentration of Carbopol 934P as primary polymer with different ratio of Sodium alginate, Carboxymethycellulose sodium, HPMC K4M and xanthan gum as secondary polymers. All the ingredients including drug, polymer and excipients were weighed accurately according to the batch formula (table.1) the drug and all the ingredients except lubricants were taken on a butter paper with the help of a stainless steel spatula and the ingredients were mixed in the order of ascending weights and blended for 10 min in an inflated polyethylene pouch. After uniform mixing of ingredients, lubricant was added and again mixed for 2 min.  The prepared blend of each formulation was compressed by using 8 mm punches.

 


 

Table (1): Formulation of single mucoadhesive buccal tablet of Simvastatin

Formulation Ingredients

Quantity (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

Simvastatin

10

10

10

10

10

10

10

10

10

10

10

10

Carbopol 934P

25

20

15

25

20

15

25

20

15

25

20

15

Sodium Alginate

35

40

45

---

---

---

---

---

---

---

---

---

Carboxymethylcellulose sodium

---

---

---

35

40

45

---

---

---

---

---

---

Hydroxy propyl MethylCellulose

---

---

---

---

---

---

35

40

45

---

---

---

Xanthan gum

---

---

---

---

---

---

----

---

---

35

40

45

Microcrystalline cellulose

50

50

50

50

50

50

50

50

50

50

50

50

Lactose

25

25

25

25

25

25

25

25

25

25

25

25

Citric acid

2

2

2

2

2

2

2

2

2

2

2

2

Magnesium  stearate

2

2

2

2

2

2

2

2

2

2

2

2

Saccharin Sodium

1

1

1

1

1

1

1

1

1

1

1

1

Total

150

150

150

150

150

150

150

150

150

150

150

150

 


4) Evaluation of mucoadhesive buccal tablets of Simvastatin:-

Weight variation test 3, 4:-

The weight variation test was performed as per procedure of IP. The weight (mg) of each of 20 individual tablets, selected randomly from each formulation was determined by dusting each tablet off and placing it in an electronic balance. The weight data from the tablets were analyzed for sample mean and percent deviation.

 

Tablet hardness 3, 4:-

Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in Kg/cm2. Three tablets were randomly picked from each formulation and the mean and standard deviation values were calculated.

 

Friability 3, 4:-

Friability is the measure of tablet strength. It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or attrition.

 

Roche friabilator was used for testing the friability using the following procedure Twenty tablets were weighed accurately and laced in the tumbling apparatus that revolves at 25 rpm dropping the tablets though a distance of six inches with each revolution. After 4 min, the tablets were weighed and the percentage loss in tablet weight was determined.

% Friability =

(Initial weight of the tablets – Final weight of the tablets)

 

X 100

Initial weight of the tablets

% Friability of tablets less than 1% is considered acceptable.

 

Tablet thickness 3, 4:-

The thickness of three randomly selected Simvastatin buccal tablets from each formulation was determined in mm using a Vernier caliper.

 

Uniformity of drug content 4, 5, 6:-

Five tablets were accurately weighed and powdered. A quantity of the powder equivalent to 10 mg of Simvastatin was weighed accurately and extracted in methanol by shaking for 20 min. After filtration through whatmann filter paper no.1 and sufficient dilution with Phosphate buffer 6.8 pH, samples were analyzed spectrophotometrically at 247 nm. This procedure was repeated thrice. Amount of drug present was determined from the standard curve of Simvastatin.

 

Surface pH study7:-

 The surface pH of the buccal tablets is determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may irritate the buccal mucosa, we sought to keep the surface pH as close to neutral as possible. A combined glass electrode is used for this purpose. The tablet is allowed to swell by keeping it in contact with 1 ml of phosphate buffer pH 6.8 for 2 h at room temperature. The pH is identified by bringing the electrode into contact with the tablet surface and allowing equilibrating for 1 min.

 

Swelling index8:-

The swelling index of the buccal tablet was evaluated in phosphate buffer pH 6.8  The initial weight of the tablet was determined and then tablet was placed in 15 ml phosphate buffer pH 6.8 in a petri-dishes  and then was incubated at 37 ± 1o C. The tablet was removed at different time intervals (0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 h) blotted with filter paper and reweighed (W2).  The swelling index is calculated by the formula:

Swelling index = 100 (W2-W1) / W1.

Where, W1 = Initial weight of the tablet

     W2 = Final weight of tablet.

 

In-vitro drug release 1, 4, 5, 6, 9:

The study was carried out in USP tablet dissolution test apparatus-II (Electrolab TDT-08L), employing paddle stirrer at 50 rpm and 500 ml of phosphate buffer pH 6.8 as dissolution medium containing 0.5% dodecylsodium sulphate, maintained at 37±2°C.

 

The tablet was supposed to release drug from one side only hence a one side of tablet was fixed to glass disk with cyanoacrylate adhesive. The disk was placed at the bottom of the dissolution vessel. At different time interval 5 ml of sample was withdrawn and replaced with fresh medium with help of auto sampler, the samples were filtered through filter and analyzed for Simvastatin after appropriate dilution at 247 nm using Shimadzu-1800 UV-Visible spectrophotometer up to 8 hours.The graphs of % cumulative release versus time were plotted.

 

Ex vivo residence time 10,11:

Prior to the study approval was obtained from Institutional Animal Ethics Committee (Reg. No.1347/ac/10/ CPCSEA).The in vitro residence time for buccal tablet was determined using a modified USP disintegration apparatus. The medium was composed of 200 ml of phosphate buffer pH 6.8 maintained at 37°C ± 1°C.

 

A segment of sheep buccal mucosa 4 cm length was glued to glass slab. The tablet surface was hydrated using phosphate buffer pH 6.8 and then the hydrated surface was brought into contact with the mucosal membrane. The glass slab was vertically fixed to the tablet was completely immersed into the buffer solution at the lowest point and was out at the highest point. The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded.

 

Mucoadhesion strength12, 13, 14:-

Prior to the study approval was obtained from Institutional Animal Ethics Committee (Reg. No.1347/ac/10/CPCSEA). Mucoadhesion strength of the tablet was measured on a modified physical balance employing the method as described by Gupta et al using sheep buccal mucosa as model mucosal membrane. Fresh sheep buccal mucosa was obtained from a local slaughter house and was used within 2 h of slaughtering. The mucosal membrane was washed with distilled water and then with phosphate buffer pH 6.8. A double beam physical balance was taken and to the left arm of balance a thick thread of suitable length was hanged and to the bottom side of thread a glass stopper with uniform surface was tied. The buccal mucosa was tied tightly with mucosal side upward using thread over the base of inverted 50 ml glass beaker which was placed in a 500 ml beaker filled with phosphate buffer pH 6.8 kept at 37o C such that the buffer reaches the surface of mucosal membrane and keeps it moist. The buccal tablet was then stuck to glass stopper from one side membrane using an adhesive.

 

The two sides of the balance were made equal before the study, by keeping a weight 5gm on the right hand pan. A weight of 5 g was removed from the right hand pan, which lowered the glass stopper along with the tablet over the mucosal membrane with a weight of 5 g. The balance was kept in this position for 5 min. Then, the weights were increased on the right pan until tablet just separated from mucosal membrane. The excess weight on the right pan i.e. total weight minus 5 g was taken as a measure of the mucoadhesive strength. The mean value of three trials was taken for each set of formulations. After each measurement, the tissue was gently and thoroughly washed with phosphate buffer and left for 5 minutes before placing a new tablet to get appropriate results for the formulation. After calculating mucoadhesion strength the force of adhesion and bond strength parameters were calculated from following equations as;

 

Force of Adhesion (N) =Mucoadhesive Strength× 9.8

                                                            1000

 

Ex vivo drug permeation 15 , 16:-

Prior to the study approval was obtained from Institutional Animal Ethics Committee (Reg. No.1347/ac/10/CPCSEA). In vitro permeation of Simvastatin from mucoadhesive buccal tablets through the excised sheep buccal mucosal membrane was studied using modified Keshary Chien (K-C) type of diffusion cell. Fresh sheep buccal mucosa was obtained from a local slaughterhouse and used within 2 h of slaughter. The tissue was stored in phosphate buffer pH 6.8 at 4oC after collection. The epithelium was separated from the underlying connective tissue with a surgical technique and the thickness of membrane was found (0.025 cm) and then the delipidized membrane was allowed to equilibrate for approximately one hour in receptor buffer to regain lost elasticity. The Keshary- Chein cell with receptor side volume of 25 ml and diffusion area of 4.90 cm2 was used.

 

The isolated sheep buccal mucosa was mounted between donor and receptor compartment of diffusion cell. The selected prepared buccal tablet of Simvastatin was placed over the membrane to the donor side, and the compartment was clamped together in such a way that the membrane side will be in contact with receptor medium. The donor compartment of diffusion cell was filled with 1 ml of phosphate buffer pH 6.8 and the receptor compartment (15 ml capacity) was filled with phosphate buffer pH 7.4 and stirring was kept at slow uniform speed with magnetic stirrer. At predetermined time intervals 1 ml sample was from the receptor compartment and replaced with an equal volume of phosphate buffer pH 6.8 to maintain sink condition. The amount of Simvastatin in samples was estimated by the UV spectrophotometer at 247nm.

 

RESULT AND DISCUSSION:

By carried out Preformulation studies the drug was subjected to various tests it was confirmed that the drug was pure and found good solubility in methanol and its melting point 1360c within prescribed range. The drug-polymer interaction was studied using IR spectroscopy for selected combination of drug with different polymers used. The IR spectrum of pure drug and physical mixture of drug polymers and excipients were studied. IR techniques have been used here to study the physical and chemical interaction between drug and excipients used. In the present study, it has been observed that IR spectrum of drug and polymers showed that major frequencies of functional groups of pure drug remain intact in granules containing different polymers; hence there was no chemical interaction between Simvastatin and the polymers used in the study. No significant changes in peak pattern in IR spectra of pure drug and optimized formulation indicates that there was no interaction between pure drug and excipients.


 

 

Table (2): Evaluation parameters of mucoadhesive buccal tablets of Simvastatin

Formulations

Hardness (kg/cm2)

Thickness(mm)

Weight variation(mg)

Friability(%)

Drug content (%)

Surface pH

F1

4.5±0.10

3.00±0.10

151.7±0.43

0.58

98.81±0.10

6.30±0.19

F2

4.4±0.05

2.97±0.06

151.2±0.23

0.67

97.86±0.06

6.40±0.12

F3

4.3±0.10

2.83±0.15

153.3±0.49

0.54

96.90±0.04

6.17±0.04

F4

4.6±0.20

3.00±0.00

151.3±0.31

0.55

99.52±0.06

6.66±0.13

F5

4.5±0.10

2.97±0.06

149.7±0.76

0.51

99.04±0.90

6.25±0.24

F6

4.5±0.10

2.97±0.16

151.5±0.40

0.67

98.33.±0.09

6.25±0.04

F7

4.6±0.10

3.03±0.06

151.5±0.71

0.46

98.62±0.05

6.25±0.29

F8

4.5±0.06

3.03±0.06

152.3±0.49

0.72

96.91±0.08

6.34±0.34

F9

4.6±0.06

3.03±0.06

149.5±1.13

0.56

96.19±0.02

6.18±0.13

F10

4.4±0.01

3.03±0.00

150.3±1.22

0.52

96.67±0.04

6.16±0.14

F11

4.4±0.06

3.00±0.00

148.7±0.59

0.56

95.19±0.02

6.37±0.28

F12

4.4±0.10

2.97±0.06

151.8±1.56

0.40

95.24±0.05

6.41±0.10

 


 


 

Table (3): Swelling data of mucoadhesive buccal tablets of Simvastatin

Time (h)

 

Percentage weight change

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

0.5

22.07±

0.02

19.12±

0.08

15.08±

0.23

9.68±

0.44

7.12±

0.42

5.64±

0.19

23.42±

0.23

19.48±

0.56

16.13±

0.17

12.23±

0.45

7.13±

0.18

6.12±

0.18

1

42.05±

0.03

38.23±

0.12

31.14±

0.17

15.42±

0.68

13.48±

0.82

12.32±

0.82

43.53±

0.12

37.73±

0.08

32.28±

0.19

44.22±

0.51

38.72±

0.29

34.12±

0.27

2

55.14±

0.01

51.21±

0.17

41.13±

0.09

32.13±

0.52

28.25±

0.67

21.34±

0.28

56.48±

0.09

53.83±

0.10

41.53±

0.25

59.58±

0.17

54.12±

0.17

43.85±

0.19

3

59.11±

0.08

54.28±

0.31

48.08±

0.32

49.32±

0.12

43.27±

0.27

35.13±

0.40

58.53±

0.34

55.25±

0.29

50.34±

0.42

60.83±

0.19

58.18±

0.23

52.82±

0.31

4

62.18±

0.04

58.53±

0.21

55.21±

0.07

56.24±

0.89

54.31±

0.34

52.18±

0.34

61.21±

0.17

57.27±

0.27

53.52±

0.45

63.42±

0.32

60.26±

0.28

59.15±

0.19

5

75.08±

0.19

69.22±

0.09

58.23±

0.26

68.14±

0.13

63.42±

0.25

61.8±

0.29

64.68±

0.08

59.88±

0.52

55.84±

0.32

65.73±

0.41

62.03±

0.19

61.18±

0.43

6

82.18±

0.14

75.34±

0.23

65.09±

0.24

72.7±

0.12

69.53±

0.41

66.28±

0.53

71.52±

0.16

62.98±

0.18

59.52±

0.21

69.84±

0.08

68.84±

0.32

65.17±

0.36

7

87.89±

0.07

81.28±

0.32

72.18±

0.12

89.23±

0.39

83.18±

0.32

78.32±

0.42

73.79±

0.24

65.47±

0.17

61.6±

0.43

75.23±

0.23

72.08±

0.24

68.16±

0.19

8

89.05±

0.20

85.13±

0.07

78.34±

0.08

95.28±

0.25

93.08±

0.43

91.48±

0.12

75.8±

0.45

69.53±

0.25

65.65±

0.49

78.21±

0.17

75.07±

0.36

70.17±

0.19

(n=3, Mean± SD

 


The IR spectrum of simvastatin with Carbopol 934P in combination with Sodium alginate, Sodium CMC, HPMC K4M, Xanthan gum suggested that the characteristics peak of Simvastatin was undisturbed and also the characteristic peak of each polymer was unaffected. Hence the IR study reveals that Simvastatin was in the free form and no drug-polymer and polymer-polymer interactions took place during formulation development.

 

The calibration curve for the estimation of Simvastatin was constructed in phosphate buffer pH 6.8 at 247 nm. The method obeyed Beer-Lambert’s law in the steady range of 5-25 mcg/ml with a high ‘r’ value of >0.99 and low standard deviation suggested that the method was reproducible and hence suitable for estimation of Simvastatin.

 

The Preformulation studies were carried out with an aim to establish drug profile, confirm its identity and purity and to generate a data base for further formulation and evaluation work. Thus Preformulation studies confirmed identity and purity of the drug by means of IR and Melting point determination.

 

Fig. (1): Effect of polymer concentration on swelling behavior of mucoadhesive buccal tablets of Simvastatin

The hardness of prepared mucoadhesive buccal tablets was from 4.3 to 4.6 kg/cm2. The thickness of the tablets was from 2.83 to 3.03 mm. All the prepared tablets complies the Indian Pharmacopoeial standard for weight variation and friability. The drug content was from 95.19 to 99.52% suggested uniform mixing of drug. The surface pH for all the buccal tablets was from 6.16 to 6.66 which were nearer to salivary pH (5.6 to7 pH) suggesting that the prepared buccal tablets can be used without the risk of mucosal irritation and discomfort.

 

The swelling study of prepared buccal tablets was performed in phosphate buffer pH 6.8 and the results were presented as percentage weight change with respect to time in Table 3 and in fig.1. The swelling behaviour of a bioadhesive system is an important property for uniform and prolonged release of drug and bioadhesion. The swelling behaviour depends upon nature of polymer, concentration of polymer and pH of the medium. The swelling of all the tablets was increased as the time proceeds because the polymer gradually absorbs water due to hydrophilicity of the polymer. The outermost hydrophilic polymer layer hydrates/swells first and as the hydrated layer progressively dissolves or disperse, the hydration swelling  process will continuous towards new expose surfaces thus maintaining the integrity of dosage form. Swelling index increased as the weight gain by tablet increased proportionally with rate of hydration. In swelling study it was found that the amount of Carbopol play important role in swelling of matrix and leads to the drug diffusion. The swelling was getting affected in the formulations contained secondary polymer along with Carbopol as a primary polymer. The highest swelling of 91.48% to 95.28% for formulations which contained Sodium CMC while 78.34%  to 89.20 % for formulations which contained sodium alginate because Sodium CMC and Sodium alginate were more water soluble and rapidly get hydrated above 50% within 4 hours.

 


Table (4): In vitro release data of simvastatin from mucoadhesive buccal tablets

Time (h)

In vitro release

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

0.5

9.69±

0.25

5.94±

0.54

4.69±

0.91

9.69±

0.77

7.19±

0.19

2.19±

0.52

13.57±

0.78

10.94±

0.54

9.69±

0.54

3.44±

0.55

2.19±

0.53

2.19±

0.39

1

13.54±

0.11

9.75±

1.19

8.49±

0.27

18.54±

0.67

13.51±

0.73

9.71±

0.09

24.96±

0.34

21.05±

0.27

17.29±

0.31

9.72±

0.12

9.09±

0.40

7.59±

0.27

2

22.42±

1.56

19.85±

1.21

13.57±

0.47

31.23±

0.09

23.65±

0.19

21.52±

0.63

35.08±

0.19

27.51±

0.40

24.96±

0.36

16.07±

0.67

13.55±

0.31

12.41±

0.38

3

31.40±

0.77

30.05±

0.49

19.96±

0.21

41.54

0.50

36.39±

0.20

27.52±

0.59

48.56±

0.40

42.79±

0.37

38.97±

0.29

29.99±

0.07

25.07±

0.26

23.41±

0.33

4

48.96±

0.53

40.60±

1.77

26.41±

0.65

51.95±

0.81

46.75±

0.46

34.05±

0.29

60.29±

0.27

53.22±

0.57

48.1±

0.37

46.54±

0.43

42.95±

0.95

37.65±

0.25

5

59.59±

0.74

56.82±

0.62

41.67±

0.25

63.72±

0.79

59.72±

0.51

48.14±

0.10

65.26±

0.49

59.99±

0.39

53.58±

0.39

55.75±

0.39

52.00±

17

50.53±

0.42

6

71.43±

0.58

68.92±

1.17

53.34±

1.54

77.11±

0.52

74.06±

0.95

63.61±

0.12

73.4±

0.43

68.08±

0.66

61.6±

0.47

73.81±

0.19

70.02±

31

63.4±

53

7

79.63±

0.54

74.59±

0.78

72.62±

0.56

88.73±

0.43

84.78±

0.53

79.24±

0.51

77.86±

0.26

74.59±

0.49

69.7±

0.84s

78.28±

0.73

74.33±

0.30

71.78±

0.97

8

90.41±

0.78

82.82±

0.19

79.58±

0.54

97.11±

0.41

93.11±

0.67

90.02±

0.73

86.11±

0.44

80.71±

0.07

76.63±

0.52

--

--

--

 

 


The swelling index for the formulations contained Xanthan gum and HPMC K4M was less among the secondary polymers used due to formation of highly viscous mucilaginous layer over the surface of the tablet. It was observed that swelling index increased by increasing Carbopol content of prepared tablet. Maximum swelling was seen in formulation F4, F5 and F6 containing Sodium CMC as secondary polymers.

 

Fig.(2) Effect of Polymer concentration on in vitro release Simvastatin from mucoadhesive buccal tablets

 

The in vitro release of Simvastatin was performed in phosphate buffer pH 6.8. The in vitro release data was represented in Table 4 and illustrated in fig.2. The in vitro release of Simvastatin was mainly affected by drug polymer ratio, nature and amount of polymer and the dissolution medium. The in vitro release of Simvastatin was also depends on swelling behaviour of the polymers used. Carbopol is more hydrophilic. It can swell rapidly, therefore decrease of carbopol content delay the drug release from core. The addition of secondary polymers like Sodium alginate, Sodium CMC, HPMC K4M and Xanthan gum along with Carbopol as primary polymers in formulations F1 to F12 prolonged the release of Simvastatin from 7 to 8 h.

The buccal tablets containing Sodium CMC showed a maximum release of 90.02 % to 97.11% within 8 hours due to more swelling of polymer, the more amount of drug diffused out from the polymer matrix in faster rate. Sodium alginate showed release of 79.58% to 90.41% within 8 hours due to fact that sodium alginate gets rapidly swelled and form IPN complex with Carbopol as it is an anionic polymer. HPMC K4M showed released of 76.63% to 86.11% within 8 hours because HPMC with a grade of K4M has a hydrophilic gel forming matrix which was used as a release retardant. The formulations containing Xanthan gum showed release of 71.78 to 78.28 % within 7 h depicted that Xanthan is a highly swellable polymer and rapidly get eroded in aqueous media. The kinetics of drug release shows that, in vitro release data was subjected to zero order, first order, Higuchi, Korsemeyer-Peppas and Hixson crowell in order to establish the drug release mechanism and kinetics of drug release from the buccal tablets. When the data was subjected to zero order and first order kinetic model, a linear relationship was observed with high ‘r2’ value for zero order model as compared to first order model suggested that the formulations were zero order controlled release. Higuchi’s model was applied to the in vitro release data, linearity was obtained with high ‘r2’ value suggested that the drug release from tablet followed diffusion mechanism as all the polymers used were gel based matrix type. When the in vitro release data was subjected to Hixson crowell cube root model and erosion model a good linearity was observed with high ‘r2’ values suggested that the geometrical shape of tablet diminished proportionally over the time due to polymer erosion. In order to define a perfect model which will represent a better fit for the in vitro release data, Korsemeyer-Peppas model was applied which will define exact release mechanism when more than one type of release phenomenon was observed. Good linearity with high ‘r2’ value was observed with Korsemeyer-Peppas model. The value of release exponent ‘n’ calculated as a slope defines the release mechanism. The value of ‘n’ obtained for all the tablet formulation was >0.5 and <1.0 suggested that the drug release followed non-fickian anomalous diffusion due to the higher affinity of hydrophilic polymers towards water. Formulations contained more Carbopol 934P concentration along with Sodium CMC that was F4 showed maximum drug released up to 97.11% showed Korsemeyer-Peppas model as best fit model, having “n” value 0.82 hence Non fickian transport.

 

Table (5) Evaluation of mucoadhesive buccal tablets of Simvastatin for ex vivo residence time

Formulation Code

Ex vivo Residence Time (h)

F1

5.55±0.29

F2

5.30±0.50

F3

5.18±0.21

F4

6.35±0.76

F5

6.05±0.37

F6

5.45±0.26

F7

6.05±0.51

F8

5.40±0.19

F9

5.25±0.32

F10

4.28±0.71

F11

3.47±0.41

F12

3.24±0.34

 (n=3, Mean±SD)

 

Figure (3): Effect of Polymer concentration on ex vivo residence time of mucoadhesive buccal tablet of Simvastatin

 

The prepared mucoadhesive buccal tablets were evaluated for ex vivo residence time using sheep buccal mucosa and the results were tabulated in Table 5. Ex vivo residence time is the time necessary for complete detachment or erosion of tablet from mucosal surface without losing integrity. This test reflects the adhesive capacity of polymer used in formulation. All the tablet formulations showed a residence time of 3.24 to 6.35 h. As all the polymers used were hydrogel forming hydrophilic matrix and get swelled to adhere to the mucus surface. The ex vivo residence time relates directly to the swelling index. The polymers sodium alginate, Sodium CMC and HPMC K4M along with Carbopol 934P showed a maximum of >5 h residence time with prolonged drug release indicated best formulation as controlled release system. As the concentration of Carbapol increased there was significant increased in residence time as shown in figure 3.

 

Table (6) valuation of mucoadhesive buccal tablet of Simvastatin For mucoadhesive strength

Formulation Code

Mucoadhesive Strength(gm)

Force

of Adhesion(N)

F1

12.40±0.27

0.122

F2

9.30±0.45

0.091

F3

7.60±0.60

0.075

F4

30.10±0.85

0.295

F5

24.50±0.30

0.240

F6

27.20±0.15

0.267

F7

20.00±0.47

0.196

F8

19.40±0.75

0.190

F9

17.70±0.69

0.174

F10

14.60±0.84

0.143

F11

12.10±0.23

0.119

F12

9.80±0.25

0.096

(n=3, Mean±SD)

 

Figure (4): Effect of Polymer concentration on mucoadhesive strength of mucoadhesive buccal tablets of Simvastatin

 

The Mucoadhesive strength of prepared mucoadhesive buccal tablet was studied using sheep buccal mucosa and the mucoadhesive parameters are represented in Table 6. Mucoadhesion is considered to occur in four major stages wetting, interpenetration, adsorption and formation of secondary chemical bonds between mucus membrane and polymers. The mucoadhesive strength is affected by molecular weight of polymer, contact time with membrane and degree of swelling of the polymer. The mucoadhesion of prepared tablets was increased as the degree of swelling increased. The mucoadhesive strength was influenced by addition of secondary polymers like Sodium alginate, Sodium CMC, HPMC K4M, Xanthan gum. The maximum 30.10 gm mucoadhesive strength was observed with formulation containing Sodium CMC while 12.40 gm with sodium alginate and 20 gm with HPMC K4M along with Carbopol 934P . The highest mucoadhesive strength was due to pronounced swelling upon hydration of these polymers. The lowest mucoadhesive strength was 14.60 gm was observed with formulation containing Xanthan gum because of swelling and rapid detachment upon hydration. As the concentration of Carbopol increased in the entire tablet formulation there was significantly increased in mucoadhesive strength as represented in fig. 4, which was due to the reason as explained previously.


Table( 7): Ex vivo permeation data of Simvastatin through buccal mucosa after 5 h

Formulation Code

Amount permeated at 5 h, Q5 (mcg/cm²)

Flux, JSS (mcg/cm²/hr)

Release rate constant, k

(mcg/cm²/h0.5)

Permeability coefficient, kp (cm/h)

Diffusion coefficient, D (cm2/h)

F1

3477.12

652.07

1928.03

0.065

8.66

F2

3325.94

626.94

1873.88

0.063

9.19

F3

3250.35

597.98

1762.21

0.059

8.50

F4

3590.51

670.01

2012.51

0.067

9.30

F5

3522.48

653.76

1957.31

0.065

9.11

F6

3363.73

623.42

1856.42

0.062

8.90

F7

3401.53

626.14

1858.61

0.063

8.72

F8

3288.15

605.41

1797.35

0.061

8.72

F9

3167.20

584.85

1737.89

0.058

8.77

F10

3212.56

605.95

1830.63

0.061

9.63

F11

3016.02

560.43

1666.29

0.056

8.85

F12

2789.26

528.64

1576.54

0.053

9.11

 


 

Figure(5): Effect of Polymer concentration on ex vivo permeation of Simvastatin from mucoadhesive buccal tablets through buccal mucosa

 

Ex vivo permeation study for prepared buccal tablet was performed using sheep buccal mucosa. From the permeation data different permeation parameters like flux (JSS), permeability coefficient (kp), diffusion coefficient (D), amount drug permeated at 5 h (Q5) and release rate constant (k) were calculated and represented in Table7. The flux obtained was between 528.64 to 670.01mcg/cm2/h with permeability coefficient of 0.053 to 0.067 cm/h. The secondary polymer used with primary polymer significantly affect the ex vivo permeation as shown in fig 5. For better permeability all formulation contained citric acid as permeability enhancer, F4 which contained Sodium CMC showed better permeabity due to more flux that was 670 mcg/cm²/hr.

 

CONCLUSION:

Preformulation studies confirmed identity and purity of the drug by means of IR and Melting point determination. Prepared tablets were found to be good and were free from chipping and capping. All the prepared tablets were in acceptable range of weight variation, hardness, thickness, friability and drug content as per pharmacopoeial specification.The surface pH of prepared buccal tablets was in the range of salivary pH, suggested that prepared tablets could be used without risk of mucosal irritation. The buccal tablets showed good swelling up to 8 h in phosphate buffer pH 6.8 maintaining the integrity of formulation which is required for bioadhesion. The increased in Carbopol 934P  concentration significantly increases the swelling. The in vitro release of simvastatin was extended only for 6-7 h, if Carbopol 934P in combination with secondary polymer Xanthan gum was used. While the tablets contained Carbopol 934P along with Sodium alginate, Sodium CMC, HPMC K4M prolonged the released up to 8 h. Hence Carbopol 934P along with sodium alginate, Sodium CMC, HPMC K4M could be used to prepared prolonged released buccal tablet. Carbopol is more hydrophilic, it can swell rapidly, therefore decrease of Carbopol content delays drug release from tablet core. The in vitro release of F4 batch show maximum drug release 97.11% which contained Sodium CMC with Carbopol 934P obeyed Korsemeyer-Peppas release kinetics with Non fickian transport mechanism of release due to more hydrophilic nature of polymer and drug. All the tablets showed good residence time of 3.24 to 6.35 h, indicated good adhesive capacity of polymers used. Formulations contained Sodium CMC with Carbopol 934P showed more residence time in that formulation F4 showed maximum means 6.35 h residence time. All the tablets showed good mucoadhesive strength of 7.60 to 30.10 g with high force of adhesion. The mucoadhesive strength was also depend upon  the addition of secondary polymers like Sodium alginate, Sodium CMC, HPMC K4M, Xanthan gum, such as increased secondary polymers concentration showed decrease in bioadhesion which might be due to low viscosity. As the concentration of Carbopol 934P increased there was significantly increased in Mucoadhesion. Formulations containing Sodium CMC with Carbopol 934P showed maximum mucoadhesive strength in that formulation F4 showed maximum means 30.10 gm Mucoadhesive strength. The ex vivo permeation concluded that Carbopol enhanced the flux and permeability coefficient of simvastatin from the tablets. More flux observed in batch F4 containing Carbopol 934P and Sodium CMC.

 

Formulation F4 were found to be the best formulations to achieve the aim of this study, Hence formulation F4 was optimized and selected as final resultant batch. Hence, the mucoadhesive buccal tablets of simvastatin can be prepared with enhanced bioavailability and prolonged therapeutic effect for the better management of cholesterol. The study conducted so far reveals a promising result suggesting scope for pharmacodynamic and pharmacokinetic evaluation.

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Received on 18.02.2013       Modified on 01.03.2013

Accepted on 10.03.2013      © RJPT All right reserved

Research J. Pharm. and Tech. 6(4): April 2013; Page   406-414