formulation and in vitro evaluation of mucoadhesive ...

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PHARMANEST

An International Journal of Advances in Pharmaceutical Sciences Volume 5|Issue 6|November-December 2014|Pages 2499-2510

Original Research Paper FORMULATION AND IN VITRO EVALUATION OF MUCOADHESIVE BUCCAL TABLETS OF FLUVASTATIN BANJERLA RAJU*, V. UMA MAHESHWAR RAO, H. SUJITHA, KALAKUNTLA SAIKRISHNA, CH. VENKATESHWARLU, LEELA KEERTHI CMR College of Pharmacy, Kandlakoya, Medchal, Hyderabad

Author for Correspondence: [email protected] Received: 05-09-2014 Accepted: 09-10-2014

Revised: 20-09-2014 Available online: 10-11-2014

ABSTRACT Buccal drug delivery has been considered as an alternative to oral dosing for compounds subjected to degradation in the gastrointestinal tract or to hepatic first pass metabolism. An attempt has been made to develop buccoadhesive tablets comprising of drug containing bioadhesive layer and drug free backing layer to release the drug for extended period of time with reduction in dosing frequency. Various formulations of Fluvastatin buccal tablets were prepared by direct compression method using bioadhesive polymers like Carbopol 940, (HPMC)Methocel K15 and Karaya gum, The physical characteristics, swelling index, surface pH, in-vitro bioadhesion strength and in-vitro release of formulated tablets were shown to be dependent on characteristics and composition of bioadhesive materials used. The maximum bioadhesive strength was observed in tablets formulated with karaya gum alone and strength decreases with its content. The tablets were evaluated for in vitro release in pH 6.8 phosphate buffer upto 12 hours using standardized apparatus. In order to determine the model of release, the data was subjected to Krosmeyer and Peppas diffusion model. All the formulations followed non- Fickian release mechanism. Carbopol 940P and Methocel K4m can be used to design effective and stable buccoadhesive tablets of Fluvastatin.

Key Words:

Buccal, Fluvastatin, HPMC K15, Carbopol, Karaya gum, HMG CoA Reductase Inhibitor.

INTRODUCTION Among the various routes of drug delivery, oral route is the most suitable and most widely accepted one by the patients for the delivery of the therapeutically active drugs. But, after oral drug administration many drugs are subjected to presystemic clearance in liver, which often leads to a lack of correlation between membrane permeability, absorption and bioavailability. Within the oral route, the oral cavity is an attractive site for drug delivery due to ease of administration and avoids possible drug degradation in the gastroretentive tract as well as first pass hepatic metabolism. Hyperlipidemia is a major cause of atherosclerosis and its associated disorders like coronary heart diseases, ischemic cerebrovascular diseases etc. Recognition of hypercholestermia as a risk factor has led to the development of drugs that reduces cholesterol levels. Statins are the most effective antihyperlipidemic agents. Statins act as competitive inhibitors of HMG-CoA reductase which catalyzes the step of cholesterol synthesis. Statins also reduces the triglycerides levels caused by elevated VLDL levels. All the statins are subjected to extensive first past metabolism by liver and gut wall enzymes, resulting in low systemic availability of the parent compound. Fluvastatin is also administered in its active form as a sodium salt and is almost completely absorbed, but 50-80% of the absorbed drug undergoes first pass metabolism whereby it is converted to its inactive metabolites which have a very short elimination half life.

MATERIALS AND METHODS: Drug : Fluvastatin. Polymers like carbopol , HPMC, karaya gum. Exipients like Talc ,Magnesium Stearate, MCC etc. brought from the commercial labs. Method: direct compression method Step1: Weigh all the ingredients in required quantity Step2: Transfer all ingredients into a mortar, triturate for 10minutes until to get fine powder and sieve the material. (#60) Step3: then transfer the material into blender for proper distribution of drug in blend for 10minutes. Step 4: then addition of lubricant, mix well. Step5 : Perform the micromeritic properties (Precompression studies). Step6: Compression Pre-compression parameters: a) Bulk density (BD): It is the total mass per bulk volume of powder. It is measured by pouring the weighed amount of powder (passed through standard sieve # 20) into a measuring cylinder and then t h e initial volume is noted. This initial volume is called the bulk volume. From this, the bulk density is calculated according to the formula mentioned below. It is expressed in g/cc and is given by BD = m/Vo Where, m=mass of the powder

PHARMANEST - An International Journal of Advances in Pharmaceutical Sciences Volume 5|Issue 6| November-December 2014 Available online: http://www.pharmanest.net

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Vo= bulk volume of the powder

θ = Angle of repose h = Height of the heap r = Radius of the heap Post-compression parameters: Tablet Thickness: In this three tablets are randomly taken and then their thickness and diameter are measured by using vernier calipers or by calibrated screw gauze. Weight Variation Test: Twenty tablets are selected and weighed individually. Then the average weight and standard deviation is calculated. Test passes when not more than two tablets deviate from the average weight. Hardness: It is expressed in kg/cm2 and is measured using Monsanto hardness tester by randomly picking three tablets. Hardness helps in knowing the ability of tablet to withstand mechanical shock during handling. Friability: Ten tablets are selected, weighed and then placed in friabilator, which is rotated for 4 minutes at 25 rpm. After 4 minutes, the tablets are weighed again. %F= [1-(Wt/W)]*100 If % Friability of tablets is less than 1% is considered acceptable. In Vitro Dissolution Studies: Dissolution study is performed using USP paddle apparatus. Study is carried out at 37oC temperature and 50 rpm. At various time intervals, 5 ml sample is withdrawn and is replaced with same amount of buffer solution. Drug Content Uniformity: Ten tablets are taken and powdered, equivalent weight of drug dose is measured and transferred to volumetric flask and then buffer is added. Absorbance is determined using U.V spectrophotometer. Swelling Study: Initially tablet is weighed (W0) and placed in a glass beaker, containing 200 mL of 0.1 N HCl. This is placed in a water bath maintained at 37 ± 0.5oC. At different time intervals, the tablet is taken out and the excess of liquid is carefully blotted by using a filter paper. The swollen tablet is reweighed (Wt). The swelling index (SI) is calculated using the formula. SI=(Wt -W0/W0)*100 Wt (Weight of swollen tablet) W0 (Initial weight of tablet)

b) Tapped density (TD): It is the total mass per tapped volume of powder. The volume is measured by tapping the powder for 500 times. Again the tapping is done for 750 times and the tapped volume is noted (the difference between these two volumes should be less than 2%). If it is more than 2%, tapping is continued for 1250 times and tapped volume is noted. It is expressed in g/cc and is given by: TD = m/Vi Where, m= mass of the powder. Vi = tapped Volume of the powder c) Hausner’s Ratio (H.R): It is the measurement of frictional resistance of the drug. The ideal range should be 1.2 – 1.5, and is determined by dividing tapped density to bulk density. H.R = T.D / B.D d) Compressibility Index (C.I): The flowability of t h e powder m a t e r i a l can be evaluated by comparing the Bulk density (BD) to the Tapped density (TD) of powder and the rate at which it gets packed down. Compressibility index is calculated using the following formula; C.I = 100 X (1 – 1/H.R.) e) Flow properties (angle of repose): This is the maximum angle possible between the surface of a pile of powder or granules and the horizontal plane. The angle of repose of granules is determined by u s i n g funnel method. The funnel is fixed at a particular height (2.5 cm) on a burette stand. The powder sample is then passed through the funnel until it forms a heap. Further addition of granules is stopped as soon as the heap touches the tip of the funnel. A circle is drawn across it without disturbing the pile. The radius and height of the heap is then noted. The same procedure is repeated for three times and the average value is taken. The angle of repose is calculated by using following equation. Tan θ =h/r –1 θ = tan (h/r) Where Table.1.Formulation chart of Buccal tablets (Total weight of tablet is 200mg) Ingredients Fluvastatin HPMC K15 Carbopol Karaya gum Talc Mg.stearate MCC

F1 40 30

F2 40 40

2 4 124

2 4 114

Total

200

200

F3 40 50

F4 40

F5 40

F6 40

F7 40

F8 40

F9 40

30

40

50

2 4 104

2 4 124

2 4 114

2 4 104

30 2 4 124

40 2 4 114

50 2 4 104

200

200

200

200

200

200

200


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RESULTS Determination of λmax

Fig.1.UV Spectrum of Fluvastatin 240nm

Table.2.Standard plot of Fluvastatin S.No

Vol of SSII In ml

Vol Made Upto

Conc In μg/ml

Absorbance At 240nm

1

0

50 ml

0

0.00

2

1

50ml

2

0.198

3

2

50ml

4

0.407

4

3

50ml

6

0.600

5

4

50ml

8

0.801

6

5

50ml

10

0.986

7

6

50ml

12

1.156

Fig.2.Standard graph of Fluvastatin in Phosphate buffer pH6.8 Evaluation of precompression parameters of Fluvastatin The precompression properties for all the batches were determined and the results were shown in the tables 2 and 3. All the batches were found to be within the acceptable limits.


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Table.3.Angle of repose as a measure of flow properties of Fluvastatin Formulation FM1 FM2 FM3 FM4 FM5 FM6 FM7 FM8 FM9

Angle of Repose(θ) (± SD) 23.2±0.11 23.7±0.08 24.7±0.16 24.7±0.12 24.2±0.09 25.1±0.11 24.2±0.12 23.7±0.09 24.2±0.13

Comment Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent

Table.4.Pre Compression Parameters Indicating Flow Properties of Fluvastatin

Formulation

Bulk Density (g/cc) (± SD)

FM1 FM2 FM3 FM4 FM5 FM6 FM7 FM8 FM9

0.301±0.07 0.306±0.09 0.304±0.09 0.314±0.12 0.308±0.14 0.304±0.08 0.318±0.09 0.304±0.12 0.312±0.15

Drug – Excipient compatibility studies: The compatibility between the drug and polymer was compared by FT-IR spectra. The position of peak in FT-IR spectra of pure Fluvastatin is compared with those in FT-IR spectra of Fluvastatin plus excipients.

Tapped Density (g/cc) (± SD) 0.35±0.05 0.34±0.09 0.36±0.11 0.35±0.08 0.35±0.09 0.35±0.08 0.36±0.13 0.34±0.09 0.36±0.11

Carr’s Index (%) (± SD)

Hausner ratio (± SD)

14.1±0.06 11.7±0.05 15.5±0.09 10.2±0.06 12.3±0.13 13.3±0.08 11.9±0.11 11.3±0.05 13.8±0.05

1.16±0.05 1.11±0.07 1.18±0.05 1.11±0.09 1.13±0.06 1.15±0.09 1.13±0.07 1.12±0.05 1.16±0.07

Hence, it can be concluded that drug can be used with the selected polymer without causing instability in the formulation. The data obtained is shown in fig 2 & 3. The spectra are reported in Figures below.

Fig.3. FT-IR Spectra of pure drug Fluvastatin


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Fig.4.FTIR spctra of Optimised formula Table.5.Post Compression Parameters % Drug Content Formulation Code F1

97.12±0.005

Wt variation 199±1.24

Thickness (mm)

Hardness 2 (kg/cm )

% Friability

2.71±0.017

7.6±0.34

0.47±0.002

F2

97.00±0.05

198±1.20

2.72±0.020

7.26±0.23

0.51±0.005

F3

97.60±0.01

199±1.25

2.72±0.020

6.13±0.11

0.52±0.005

F4

97.20±0.005

198±1.123

2.71±0.017

7.86±011

0.52±0.005

F5

97.40±0.05

199±1.12

2.72±0.020

7.46±0.11

0.53±0.015

F6

97.00±0.04

198±1.23

2.71±0.017

7.13±0.11

0.54±0.016

F7

97.52±0.15

199±1.12

2.72±0.020

7.66±0.11

0.51±0.005

F8

97.56±0.17

197±1.12

2.71±0.017

5.66±0.23

0.52±0.005

F9

97.28±0.10

198±1.23

2.73±0.005

4.93±0.11

0.56±0.018

Determination of Swelling Index: The swelling index was determined for the prepared tablets. Swelling index increased as the weight gain by the tablets increased proportionally with the rate of hydration as shown in table below. The swelling indices of

tablets with Carbopol and HPMC increased with increasing amounts of Carbopol. Maximum swelling was seen with the formulation (F9, F10, F8 AND F1) containing NaCMC and/or Carbopol, the values increased with increasing amounts of NaCMC and/or Carbopol.


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Table.6.Result of percentage swelling index tablet formulations F1-F9 Percentage (%) Swelling Index Formulation

0.5 hour

1 hour

2 hour

4 hour

6 hour

Code F1

50.01±0.098

90.71±1.10

90.71±1.10

260±0.78

275.00±1.89

F2

42.12±0.084

77.04±1.51

170.96±1.99

200±2.12

220.05±2.22

F3

36.98±1.01

65.14±1.33

135.96±1.33

175.59±1.12

180.07±1.11

F4

46.14±0.088

82.96±0.052

185.58±1.01

225.54±1.23

250.20±1.99

F5

338.36±0.99

72.16±1.05

162.04±1.21

193.66±1.34

213.16±2.01

F6

34.31±0.65

59.53±0.78

130.42±1.57

171.33±0.95

177.00±0.00

F7

42.61±0.95

77.96±1.01

179.0±0.58

217.18±1.04

240.01±1.11

F8

55.66±1.16

100.56±1.47

219.84±1.99

267.53±2.01

280.00±1.66

F9

60.12±0.69

110.03±0.95

225.17±0.49

283.19±1.41

295.00±1.59

Dissolution studies: The prepared tablets were subjected to dissolution studies in order to know

the amount drug release. As the concentration of polymer increased, the drug release decreased.

Table.7.Results of % Drug release of tablet F1-F9

*Standard deviation, n = 3


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Fig.5.Percentage drug release of Formulations F1-F9 Zero order of kinetics:

Fig.6.Zero order kinetics of F9 Formulation

Fig.7.First order plot of F9 Formulation

Fig.8.Higuchi order plot of F9 Formulation

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Fig.9.Peppas Order Plot of F9 Formulation Table.8.Order of kinetic values of Formulation F9 Order of Kinetics

Zero

First

Higuchi

Peppas

Regression Values

0.962

0.92

0.953

0.739

In vitro mucoadhesion studies: Increasing the polymer concentration caused an increase in the bioadhesive strength. Adhesion was reported to be affected by hydration. Hydration of the muccoadhesive polymer is essential to initiate the muccoadhesive bonding process. The cohesive force arises when water from the space between the mucosa

and the polymer is taken up; this plays a vital role in the establishment of an effective muccoadhesive bond. The bioadhesive characteristics were found to be affected by the nature and proportions of the bioadhesive polymers used. The highest adhesion force i.e. highest strength of muccoadhesive bond was observed with formulation F9 containing only.

Table.9.Results of Mucoadhesive strength Detachment weight in gms Formulation

Balancing

Trial l

Trial II

Trial

Average Bioadhesive

Code

weight

F1

6.55gm

22.85

22.50

23.00

23.11

16.56gm

F2

6.55gm

29.99

30.50

30.00

30.16

23.61gm

F3

6.55gm

27.95

28.10

28.00

28.01

21.46gm

F4

6.55gm

36.11

36.00

36.25

36.12

29.57gm

F5

6.55gm

28.97

28.50

29.00

28.82

22.27gm

F6

6.55gm

28.97

28.00

28.40

28.46

21.90gm

F7

6.55gm

32.03

32.30

32.00

32.17

25.62gm

F8

6.55gm

21.84

21.50

22.00

21.78

15.23gm

F9

6.55gm

41.21

41.21

41.00

41.14

III

Strength

34.59gm

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Table.10. Results of Force of Adhesion Formulation Code

Force Of Adhesion (N)

F1

0.15

F2

0.23

F3

0.21

F4

0.29

F5

0.21

F6

0.21

F7

0.25

F8

0.14

F9

0.33

DISCUSSION In the present investigation an attempt was made to design Mucoadhesive buccal tablets containing Fluvastatin. It has short biological half life of 3 hours, and is used orally in dose of,20,40,80 g twice or thrice a day.The conventional dosage forms available are associated with low bioavailability problems due to extensive first pass metabolism & characterized by short biological half life, due to which frequency of dosing is increased, which results in patient incompliance. The present investigation was aimed at avoidance of first pass metabolism of Fluvastatin by preparing mucoadhesive tablets for delivery of the drug via buccal route. Fluvastatin is an antilipemic agent that competitively inhibits hydroxyl methyl glutarylcoenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Fluvastatin belongs to a class of medications called statins and is used to reduce plasma cholesterol levels and prevent cardiovascular disease. It is also the first entirely synthetic HMG-CoA reductase inhibitor and is structurally distinct. PREFORMULATION STUDIES: SPECTROSCOPIC STUDIES: Determination of λmax A solution of 10µg/ml of Fluvastatin was scanned in the range of 200 to 400nm. The drug exhibited λmax at 240nm in Phosphate buffer pH 6.8 and had good reproducibility. Correlation between the concentration and absorbance was found to be nearer to 1, with a slope of 0.999. COMPATIBILITY STUDIES: Drug polymer compatibility studies were carried out using Fourier Transform Infra Red spectroscopy to establish any possible interaction of Fluvastatin with the polymers used in the formulation. The FT-IR spectra of the formulations were compared with the FT-IR spectra of the pure drug.The results indicated that the characteristic absorption peaks due to pure Fluvastatin have appeared in the formulations, without any

Among the non-invasive routes buccal administration has a promising potential and is a viable alternative for systemic medication of drugs. The buccal cavity offers a large surface area, highly vascularised mucosal layer for efficient absorption; also blood is drained directly from buccal cavity into the systemic circulation, thereby avoiding the first pass effect, combined with other features like ease and convenience of administration. Mucoadhesive tablets have the ability to increase the drug residence in the buccal cavity, control the rate of drug clearance as well as protect the drug form enzymatic degradation (in stomach). The mucoadhesive buccal tablets release the drug in a sustained manner, leading to reduced fluctuations in the plasma level which results in reduced toxicity and adverse reactions. In the present study, mucoadhesive tablets were prepared by direct compression method, using different polymers like Carbopol, HPMC K15M & Karaya gum, in different ratios in O r d e r t o release the drug in unidirectionally.

Calibration curve of Fluvastatin in phosphate buffer pH 6.8: Figure 2 shows the calibration curve data of Fluvastatin in Phosphate buffer pH 6.8 at 240nm. Figure 2 shows the standard calibration curve with a regression value of 0.999, slope of 0.098 in Phosphate buffer pH 6.8. The curve was found to be linear in the concentration range of 212 µg/ml. significant change in their position, indicating no chemical interaction between fluvastatin and polymers. Evaluation of blend materials of Buccal tablets: The preformulation studies of Fluvastatin were evaluated for various physical properties individually and the values are present in the table no. (Table no: 3 and 4. Fluovastatin shows good flow properties.)

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

  

Angle of repose was found to be between o o 22.2 – 25.1 , which is well within the specified limit of 20º - 30º and the type of flow is good. Bulk density was found to be between 0.301– 0.318g/ml. Tapped density was found to be between 0.343 – 0.361g/ml. Carr’s index was found to be in the range



of 10.2 – 15.5. All the granules are well within the specification limit. Hausner’s ratio was found to be between 1.11 – 1.16. With this the granules were found to be free flowing material and showed suitability to be compressed as tablets of expected weight.

PREPARATION OF MUCOADHESIVE BUCCAL TABLETS CONTAINING FLUVASTATIN: The required amount of ingredients were weighed variation in all the formulations were within the accurately (table no.1) and mixed thoroughly using limit. mortar and pestle. The tablets were produced by DETERMINATION OF THICKNESS: DIRECT PUNCHING METHOD.The tablets so The prepared formulations were evaluated for produced were subjected to post compression thickness and the thickness of all the tablets were parameters. reported in the table 5. It was found that all DETERMINATION OF DRUG CONTENT: the tablets possessed uniform thickness with The prepared formulations were analysed for drug minor differences. content and the data is reported in Table 5. The DETERMINATION OF HARDNESS: drug content was found to be within the limits not The prepared tablets were evaluated for the less than 98.91and not more than101.10%. Which hardness and were reported in the table 5. It was show that the drug was uniformly distributed in all observed that all the tablets had hardness within the formulations the limit. DETERMINATION OF WEIGHT VARIATION: DETERMINATION OF FRIABILITY: The prepared formulations were analysed for The prepared tablets were subjected to friability average weight and the data was reported in and the results are reported in the table 5. The the table 5. The weight variation was calculated friability was found to be within the limit. using average weight. It was found that weight DISSOLUTION STUDIES: The prepared tablets were subjected to dissolution studies in order to know the amount of drug released and the results of percentage drug release are shown in table 7. As the concentration of polymer increased, the drug release decreased. In vitro drug release studies revealed that release of Fluvastatin from different formulations varies with characteristics and composition of matrix forming polymers. The release rate decreased with increasing concentration of and HPMC K15M in F1-F3 respectively. Carbapol940 in F4-F6& karaya gum in F7-F9 fomulations. Hydrophilic polymers would leach out and hence, create more pores and channels for the drug to diffuse out of the device. Formulation F9 containing karaya gum gets best results . DRUG RELEASE KINETICS: In order to understand the mechanism of drug release and release rate kinetics of the drug from dosage form, the in-vitro drug diffusion data obtained was fitted to various mathematical models such as zero order, First order, Higuchi matrix, and Krosmeyer- Peppas model model using software (PCP- Disso-V2). Thevalues are CONCLUSION The main objective of the present study was to formulate and evaluate the sustained release buccal tablets of Fluvastatin Carbopol, HPMC K15M and Karayagum were selected as buccoadhesive polymers on the basis of their matrix forming properties and mucoadhesiveness. The prepared tablets were evaluated for various parameters such as compatibility studies, drug content, weight variation, hardness, thickness, friability, swelling studies, microenvironment pH, in vitro drug release studies, in vitro

compiled. The obtained values of n lie between 0.5 and 1.0 in all formulations except for F9, indicating non Fickian release kinetics, which is indicative of drug release mechanisms involving a combination of both diffusion and chain relaxation. IN VITRO MUCOADHESION STUDIES: Results of the Mucoadhesion and Force of Adhesion are tabulated in table no 9 and 10. Increasing the polymer concentration caused an increase in the bioadhesive strength. Adhesion was reported to be affected by hydration. Hydration of the muccoadhesive polymer is essential to initiate the mucoadhesive bonding process. The cohesive force arises when water from the space between the mucosa and the polymer is taken up; this plays a vital role in the establishment of an effective mucoadhesive bond. The bioadhesive characteristics were found to be affected by the nature and proportions of the bioadhesive polymers used. The highest adhesion force i.e. highest strength of mucoadhesive bond was observed with formulation F9 containing only .

mucoadhesion strength and Release rate kinetics. The following conclusions were drawn from the results:  From the FT-IR spectra it was observed that similar characteristic peaks appear with minor differences (within limit) for the drug and its formulations. Hence it may be concluded that there was no chemical interaction between the drug and excipients used.  All the formulations passes test for weight

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variation content uniformity and showed acceptable results with respect to drug content and percentage friability (0.47-0.56%).  S w e l l i n g index was calculated with respect to time. Swelling index increased as the weight gain by the tablets increased proportionally with rate of hydration. The swelling indices of tablets with Carbopol and HPMC increased with increasing amounts of Carbopol. Maximum swelling was seen with formulations (F9, F10, F8 and F1) containing NaCMC and or Carbopol, the values increased with increasing amounts of NaCMC and or Carbopol.  Analysis of drug release mechanism showed that the drug release followed non-Fickian diffusion and the best fit model was found to be st 1 order.  The bioadhesion characteristics were found to be affected by the nature and proportions of bioadhesive polymers used. The highest

adhesion force i.e. highest strength of muccoadhesive bond was observed with formulation F1 containing only Carbopol this followed by F4 and F7 formulations containing Carbopol: HPMC K4M and Carbopol: HPMC K15M, respectively. Adhesion force decreased as another polymer is mixed with Carbopol. Tablets containing NaCMC showed least adhesion force than tablet of all other formulations, which is due to low viscosity of NaCMC. These observations indicate that the bioadhesive strength of Carbopol is much more than NaCMC.  After all the evaluation tests formulation coded F9 was selected for stability studies and the results revealed no significant change in % drug content and physical characters. Stability studies indicated that the selected formulation was stable.  Based on the results of evaluation tests and stability tests formulation F9 was concluded as best formulation for buccal drug delivery system.

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HOW TO CITE THIS ARTICLE Banjerla Raju*, V. Uma Maheshwar Rao, H.Sujitha, Kalakuntla Saikrishna, CH. Venkateshwarlu, Leela Keerthi. (2014 November 10). Formulation and in vitro Evaluation of Mucoadhesive Buccal Tablets of Fluvastatin. PHARMANEST,5(6),2499-2510. http://www.pharmanest.net