design and development of bioadhesive buccal drug delivery system of carvedilol

7/29/2019 Design and Development of Bioadhesive Buccal Drug Delivery System of Carvedilol

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Amol Harsulkar et al., IJSID, 2012, 2 (6), 580-597

International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

580

DESIGN AND DEVELOPMENT OF BIOADHESIVE BUCCAL DRUG DELIVERY SYSTEM OF CARVEDILOL

Amol Harsulkar1* and S.A. Sreenivas2

1Research scholar, Pharmaceutical Sciences Department, J.J.T. University, Jhunjhunu, Rajasthan, India; 2Grurunanak Institute o

Pharmacy, Ibrahimpatnam. Dist. RR, Hydrabad, AP, India

INTRODUCTION

INTRODUCTION

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries An International peerReview Journal for Science

Research Article Available online through www.ijsidonline.info

Received: 02-12-2012

Accepted: 04-01-2013

*Corresponding Author

Address:

Name:

Amol Harsulkar

Place:

Rajasthan, India

E-mail:

amol3harsulkar

@rediffmail.com

ABSTRACT

Oral mucosal drug delivery is an alternative method of systemic drug delivery tha

offers several advantages over both injectable and enteral methods. Because the ora

mucosa is highly vascularized, drugs that are absorbed through the oral mucosa directly

enter the systemic circulation, bypassing the gastrointestinal tract and first-pas

metabolism in the liver. Hence, the present study is focus on the development and

evaluation of bio adhesive buccal tablet using Carvedilol a nonselective -adrenergi

blocking agent with 1-blocking activity and bioadhesive polymers for the controlle

release of the drug from tablet in the buccal cavity, to increase the bioavailability o

carvedilol. Bioadhesive buccal tablets of carvedilol were prepared by direct compression

method using different polymers such as Methocel K4M, Methocel K15M, Sodium-carboxy

methylcellulose and Carbopol. The different concentrations of carbopol and other

polymers were used; also combinations of these were prepared in different proportions

The tablets were evaluated for different parameters like weight variation, thickness

friability, content uniformity, hardness, swelling index, mucoadhesive strength, in-vitr

release study and stability studies on selected formulation. From the results it can b

concluded that the formulation C3 containing concentration of 35% the Methocel K4M give

promising results for sustained release of carvedilol, as release profile indicated the mos

promising formulation as the extent of drug release was high as compare to othe

formulations with adequate swelling and bioadhesion properties also stability data for thi

optimized formulation shown good stability up to two months.

Keywords: Carvedilol, Bio-adhesive, in-vitro, bioavailability, swelling index.


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INTRODUCTION

Oral route is perhaps the most preferred to the patient and the clinician alike. However, peroral administration of

drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit

oral administration of certain classes of drugs especially peptides and proteins. The oral cavity, on the other hand, is highly

acceptable by patients, the mucosa is relatively permeable with a rich blood supply, it is robust and shows short recovery

times after stress or damage [1], and the virtual lack of Langerhans cells makes the oral mucosa tolerant to potential

allergens[2].Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over

both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral

mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver

Buccal delivery of drugs at first glance, seems to offer a combination of advantages of transdermal and peroral delivery. A

buccal devise offers the easy application and removal of transdermal delivery without the excellent barrier properties of the

stratum cornium and with less immune activity than the epidermis.

Bioadhesive Drug Delivery System:

Bioadhesive drug delivery system is defined as drug delivery system, which utilizes property of bioadhesion of certain

water-soluble polymers, which become adhesive on hydration and hence can be used for targeting a drug to a particular

region of the body for extended period of time. The bioadhesive delivery system includes the following [3,4] i) Buccal drug

delivery system ii) Oral drug delivery system iii) Rectal drug delivery system iv)Vaginal drug delivery system. v) Occular

drug delivery system vi) Nasal drug delivery system.

The present study was carried out about the bioadhesive buccal drug delivery system, which offers a great potentia

for commercial application as an alternative to conventional drug therapy. The oral mucosa is composed of an outermost layer

of stratified squamous epithelium (Figure 1). Below this lies a basement membrane, a lamina perporia followed by the

submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in

that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the

superficial layers, where cells are shed from the surface of the epithelium [5, 6, 7, 8].

Fig. No. 1: - Structure of buccal mucosa [6]

As the carvedilol has high first pass effect, low aqueous solubility, but high lipid solubility. Carvedilol is a nonselective

-adrenergic blocking agent with 1-blocking activity [9, 10, 11,]. The main route of carvedilol absorption seemed to be

transcellular. The pka between 7.7 to 7.9, pH 7.1(weak base) and half-life is 6 hrs. Carvedilol has one major side effect o


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orthostatic hypotension due to rapid achievement of drug serum concentration. Therefore all the properties mentioned here

makes the carvedilol a good candidate for mucoadhesive controlled release buccal drug delivery system to avoid first pass

metabolism of carvedilol, thereby increasing the bioavailibity of the carvedilol. Therefore mucoadhesive buccal route is the

route of choice for formulation development of carvedilol.

So, the current work is focus on the development and evaluation of bioadhesive buccal drug delivery system in the form

of Bioadhesive buccal tablet using different bioadhesive polymers for the controlled release of the drug carvedilol from tablet

in the buccal cavity, to increase the bioavailability of carvedilol and reducing the chances of orthostatic hypotension.

MATERIALS AND METHODS

Materials:

Drug: - Carvedilol (6.25 mg)

Polymers: - Carbopol 974P, Methocel K4M, Methocel K15M, Sodium CMC.

Diluents: - Lactose

Lubricants: - Magnesium Stearate, Talc.

Methods:

Table No. 1: - Composition of carvedilol bioadhesive buccal tablets.

Ingredients C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11

Carvedilol (mg) 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

Carbopol 974P(mg) 10 7.5 ---- ---- ---- 7.5 5 2.5 7.5 5 2.5

Methocel K4M (mg) ---- ---- 35 ---- ---- 27.5 30.0 32.5 ---- ---- ----

Methocel K15M (mg) ---- ---- ---- 35 ---- ---- ---- ---- 27.5 30.0 32.5

Sodium CMC (mg) ---- ---- ---- ---- 35 ---- ---- ---- ---- ---- ----

Lactose (mg) 81 78.5 56 56 56 56 56 56 56 56 56

Magnesium Stearate (%) 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75

Talc (%) 2 2 2 2 2 2 2 2 2 2 2

Table No. 2: - Composition of carvedilol bioadhesive buccal tablets.

Preparation of Bioadhesive Buccal Tablets of Carvedilol:

Bioadhesive buccal tablets of carvedilol was prepared by direct compression method using different polymers such as

Methocel K4M, Methocel K15M, Sodium-carboxy methylcellulose, which are hydrophilic polymers and carbopol was used as

the base polymer which is hydrophobic polymer but show good bioadhesion. The different concentrations of carbopol and

other polymers were used; also combinations of these were prepared in different proportions. Compositions of various

formulations are shown in Table No. 1 & 2. All the ingredients of the mucoadhesive buccal tablet of carvedilol was weighed

and mixed in mortar with the help of pastel, then in the last 0.75% magnesium stearate and 2% talc was added for lubrication

Ingredients C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23

Carvedilol (mg) 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

Carbopol 974P (mg) 7.5 5 2.5 ---- ---- ---- ---- ---- ---- ---- ---- ----

Methocel K4M (mg) ---- ---- ---- 17.5 11.7 23.3 17.5 11.7 23.3 ---- ---- ----

Methocel K15M (mg) ---- ---- ---- 17.5 23.3 11.7 ---- ---- ---- 17.5 11.7 23.3

Sodium CMC (mg) 27.5 30.0 32.5 ---- ---- ---- 17.5 23.3 11.7 17.5 23.3 11.7

Lactose (mg) 56 56 56 56 56 56 56 56 56 56 56 56

Magnesium Stearate

(%)

0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75

Talc (%) 2 2 2 2 2 2 2 2 2 2 2 2


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Then the blended material was slightly compressed on the 6 mm flat-faced punch. The total weight of the formulation was

maintained 100 mg.

EVALUATION OF BIOADHESIVE BUCCAL TABLET:

All the prepared bioadhesive buccal tablets were evaluated for following official and unofficial parameters.

1. Hardness

Method: - Hardness was measured using Pfizer hardness tester. For each batch three tablets were tested.

Result: - The measured hardness (Kg.) of tablets of each batch is shown in the table no 4.

2. Friability [12]

Method: Twenty tablets were weighed and placed in the Roche friabilator. The apparatus was rotated at 25 rpm for 4

minutes. After revolutions the tablets were dedusted and weighed again. The percentage friability was measured using the

formula,

% F = {1-(Wo/W)} 100

Where, % F = friability in percentage; Wo = Initial weight of tablet; W = weight of tablets after revolution

Result: The results of measured % friability were shown in Table no. 4.

3. Weight variation [13]

Method: Twenty tablets were randomly selected form each batch and individually weighed. The average weight and standard

deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more then two of the individual

tablet weight deviate from the average weight by more than the percentage shown in Table no. 4, and none deviate by more

than twice the percentage shown.

Table 3: - Limits of percentage deviation allowed under weight variation test.

Table of % deviation allowed under weight variation test.

Average weight of tablet (X mg) Percentage deviation

X < 80 mg 10

80 < X < 250 mg 7.5X > 250 mg 5

Result: - The average weight and standard deviation of the tablets of each batch given in Table 4.

4. Thickness Uniformity

Method: Three tablets were selected randomly from each batch and thicknesses were measured by using screw gauge.

Result: Thickness values are shown in Table no 4.

5. Content uniformity [14]

Method: -Twenty tablets from each batch were weighed accurately and powdered powder equivalent to 6.25 mg carvedilol

was shaken with 50 ml of methanol in 50ml volumetric flask and from this standard solution 4 ml was pipette out and than

dilute upto 100 ml phosphate buffer (pH 6.8). Resulting solution was filtered and the absorbance of filtrate was recorded on

spectrophotometer at 242 nm and content of carvedilol was calculated. Results are shown in table No 4.

In Vitro Mucoadhesion Study [15, 16, 17, 18]

The term bioadhesion implies attachment of a drug carrier system to a specific biological location. Invitro

bioadhesive strength of tablets was measured using modified physical balance. Porcine buccal mucosa was used as a model

membrane and phosphate buffer pH 6.8 was used as moistening fluid. Bioadhesive studies were performed in triplicate and


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average bioadhesive strength was determined. From the mucoadhesive strength, force of adhesion was calculated. Force o

adhesion (N) = (Bioadhesive strength/100) x 9.81. Results are summarized in Table No 5.

Table No 4: - Evaluation of physical parameter of prepared bioadhesive buccal tablets of carvedilol.

Batch

Code

Evaluation parameter

Uniformity ofWt. (gm)

(Mean + S.D.)

Drug content (%)

(Mean + S.D.)

Friability

(%)

Hardness(kg/cm2)

(Mean + S.D.)

Thickness(mm)

(Mean + S.D.)C 1 101.0 + 5.13 99.48 + 0.40 0.19 6.7 + 0.49 2.61 + 0.059

C 2 101.38 + 5.00 99.46 + 0.35 0.21 6.8 + 0.14 2.60 + 0.057

C 3 101.44 + 4.82 100.05 + 0.32 0.41 8.2 + 0.19 2.58 + 0.054

C 4 101.21 +1.56 100.12 + 0.41 0.31 8.6 + 0.10 2.58 + 0.051

C 5 101.01 +0.71 98.92 + 0.32 0.75 7.4 + 0.46 2.64 + 0.091

C 6 101.81 + 0.11 98.97 + 0.19 0.15 7.2 + 0.12 2.61 + 0.057

C 7 101.62 + 0.52 99.98 + 0.31 0.32 7.1 + 0.12 2.62 + 0.051

C 8 100.34 + 3.85 100.42 + 0.32 0.33 6.9 + 0.34 2.57 + 0.052

C 9 101.12 + 4.89 102.45 + 0.51 0.48 7.3 + 0.42 2.60 + 0.057

C 10 100.17 + 1.62 100.69 + 0.05 0.50 7.5 + 0.29 2.61 + 0.010

C 11 100.48 + 1.71 98.35 + 0.31 0.41 8.1 + 0.42 2.60 + 0.057

C 12 100.88 + 1.59 99.43 + 0.23 0.42 7.8 + 0.32 2.60 + 0.010

C 13 100.85 + 1.24 103.23 + 0.21 0.39 7.6 + 0.19 2.60 + 0.000

C 14 100.92 + 1.95 98.99 + 0.22 0.27 7.3 + 0.21 2.59 + 0.015

C 15 99.54 + 2.14 99.63 + 0.26 0.42 7.4 + 0.10 2.58 + 0.051

C 16 101.85 + 2.16 101.10 + 0.50 0.39 7.5 + 0.10 2.62 + 0.050

C 17 100.89 + 1.99 103.91 + 0.03 0.27 7.5 + 0.11 2.61 + 0.048

C 18 100.83 + 2.33 99.56 + 0.00 0.36 7.1 + 0.12 2.60 + 0.057

C 19 100.15 + 1.63 98.91 + 0.23 0.68 7.4 + 0.12 2.61 + 0.049

C 20 101.39 + 4.44 99.90 + 0.41 0.50 7.0 + 0.23 2.60 + 0.051

C 21 100.78 + 3.12 100.01 +0.26 0.31 7.2 + 0.21 2.61 + 0.057

C 22 100.37 + 3.45 100.13 + 0.29 0.52 7.7 + 0.12 2.62 + 0.031

C 23 101.45 + 3.16 102.51 + 0.31 0.56 7.0 + 0.24 2.61 + 0.050

Table No. 5: - In-vitro Mucoadhesive strength study of prepared bioadhesive buccal tablets of carvedilol.

Batch

Code

Bioadhesive strength (gm)

(Mean + S. D.)

Force of adhesion

(N)C1 8.730 + 0.239 0.856

C2 8.270 + 0.147 0.811

C3 9.220 +0.152 0.904

C4 9.750 + 0.249 0.956

C5 7.790 + 0.339 0.764

C6 14.250 + 0.296 1.398

C7 9.130 + 0.975 0.896

C8 8.790 + 0.118 0.862

C9 11.130 + 0.819 1.092

C10 10.450 + 0.798 1.025

C11 9.458 + 0.334 0.928

C12 11.970 + 0.893 1.174

C13 9.170 + 0.117 0.900

C14 8.954 + 0.197 0.878C15 4.950 + 0.153 0.486

C16 3.850 + 0.119 0.378

C17 7.830 + 0.754 0.768

C18 8.420 + 0.791 0.826

C19 9.680 + 0.775 0.950

C20 9.750 + 0.814 0.956

C21 8.540 + 1.239 0.838

C22 8.750 + 0.333 0.858

C23 6.120 + 0.547 0.600


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0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

FORCE

OFADHESION

(N)

BATCH CODE

MUCOADHESIVE STRENGTH

Fig No. 2: In-vitro Mucoadhesive strength study of prepared bioadhesive buccal tablets of carvedilol.

Swelling Study [19]

The swelling rates of the mucoadhesive tablets of carvedilol were evaluated using a 1% w/v agar gel plate. An agar gel

plate was chosen as the simple model of the mucosa can keep an amount of water that resembles the secreting fluid in and

around the buccal mucosa required for bioadhesion and subsequent swelling of the formulation to provide adequate release o

the drug.

Fig No.3: In-vitro swelling study of prepared bioadhesive buccal tablets of carvedilol.


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Method:

Four tablets of every batch were weighed and then kept on the agar gel plate surface in petridishes, which were

placed in an incubator at 370C + 0.10C. Then, these all swollen tablets were weighed at different intervals; the excess water on

the surface of tablets were removed by using filter paper. The average weight was calculated and the swelling index was

calculated by the formula,

Swelling Index (S.I.) = {(Wt-Wo)/Wo} 100

Where, S.I. = swelling index; Wt = average weight of tablet at time t.; Wo = average weight of dry tablet before

placing on the agar Plate; The Swelling Index of tablets given in Table No.6.

Table No.6: In-vitro swelling study of prepared bioadhesive buccal tablets of carvedilol.

Batch

Code

% Swelling Index (Mean + S. D.)

Time (hrs)

1 2 4 6

C 1 30.76 + 0.141 39.23 + 0.0471 49.03 + 0.035 53.14 + 0.035

C 2 25.00 + 0.193 33.42 + 0.723 42.31 + 0.210 44.23 + 0.250C 3 35.96 + 0.259 42.11 + 0.412 54.39 + 0.439 58.33 + 0.451

C 4 27.64 + 0.263 43.49 + 0.115 50.14 + 0.141 52.11 + 0.179

C 5 41.66 + 0.271 50.71 + 0.129 TABLET BREAK ------------

C 6 25.00 + 0.282 44.76 + 0.235 57.14 + 0.179 60.61 + 0.201

C 7 17.74 + 0.259 29.41 + 0.341 36.47 + 0.497 42.35 + 0.593

C 8 17.65 + 0.143 24.41 + 0.044 37.5 + 0.214 44.71 + 0.057

C 9 19.25 + 0.211 30.39 + 0.054 40.31 + 0.098 45.19 + 0.081

C 10 21.67 + 0.089 28.33 + 0.341 37.70 + 0.258 41.80 + 0.129

C 11 22.95 + 0.075 32.79 + 0.300 41.80 + 0.261 41.85 + 0.214

C 12 40.00 + 0.103 51.42 + 0.041 64.21 + 0.113 64.75 + 0.149

C 13 49.04 + 0.091 62.54 + 0.071 81.73 + 0.061 83.31 + 0.125

C 14 43.41 + 0.034 49.71 + 0.039 61.49 + 0.237 63.79 + 0.218

C 15 23.81 + 0.246 34.29 + 0.211 57.43 + 0.124 55.71 + 0.105

C 16 21.75 + 0.143 34.02 + 0.291 49.13 + 0.129 53.79 + 0.092

C 17 29.41 + 0.119 47.06 + 0.034 74.12 + 0.012 80.00 + 0.091

C 18 46.00 + 0.131 62.00 + 0.089 TABLET BREAK ---------------

C 19 40.00 + 0.144 53.00 + 0.091 82.00 + 0.045 93.00 + 0.087

C 20 42.40 + 0.138 53.17 + 0.209 85.14 + 0.046 94.00 + 0.076

C 21 57.61 + 0.146 83.71 + 0.201 TABLET BREAK ---------------C 22 53.06 + 0.310 75.44 + 0.091 TABLET BREAK ---------------

C 23 37.25 + 0.111 59.71 + 0.081 TABLET BREAK ---------------

In Vitro Release Study [20, 21]

The influence of technologically defined condition and difficulty in simulating in vivo condition has led to

development of a number of in vitro release methods for controlled release mucoadhesive formulation; however no standard

in vitro method has been developed.


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Standard USP or IP dissolution apparatus have been used to study in vitro release profile using both rotating paddle

and basket.

In vitro release study of mucoadhesive buccal tablets of carvedilol was carried out using the USP I (basket apparatus)

method at 50 rpm. Medium used for release rate study was 500 ml of phosphate buffer (pH 6.8) solution containing 20%

methanol for maintaining the sink conditions. During the course of study whole assembly was maintained at 37 0C. Five ml o

the sample was withdrawn at time intervals of 0.1, 1, 2, 3 upto 10 hrs and replaced with the same amount of the fresh

medium.

The amount of carvedilol released was determined spectroscopically at 242 nm. The observations for different batches

are shown in succeeding tables the cumulative percentage of carvedilol released with respect to time for each batch are

graphically shown in succeeding figures.

Table No. 7: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P in different concentration.

Batch codeCumulative % release

C1 C2

0.5 2.60 4.32

1 7.51 8.63

2 13.62 23.77

3 26.03 53.81

4 30.45 64.55

5 34.29 77.49

6 38.25 91.40

7 41.23 99.60

8 45.37 100.00

9 50.33 100.00

10 57.48 100.00

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Cumulative%

Release

Time (hrs)

C1

C2

Fig No. 4: In-vitro release profile of C1, C2


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Table No. 8: Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K4M, Methocel K15M

Sodium CMC.

Batch

code

Cumulative % release

C1 C3 C4 C50.5 2.60 4.30 3.64 30.35

1 7.51 12.80 8.93 56.04

2 13.62 28.15 18.41 66.443 26.03 40.00 31.72 73.73

4 30.45 55.62 47.49 82.47

5 34.29 63.27 54.20 92.87

6 38.25 69.28 59.14 95.17

7 41.23 79.13 65.10 99.87

8 45.37 83.30 71.12 100.44

9 50.33 86.81 73.19 100.44

10 57.48 91.54 76.05 100.44

Fig No. 5: In-vitro release profile of C1, C3, C4, C5.

Table No. 9: Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K4M.

Batchcode


C1 C6 C7 C8

0.5 2.60 2.03 2.94 4.28

1 7.51 4.92 5.26 7.70

2 13.62 8.47 9.63 13.43

3 26.03 14.43 14.13 19.48

4 30.45 18.23 22.07 30.095 34.29 27.14 26.09 33.34

6 38.25 30.41 31.00 37.35

7 41.23 34.25 37.74 47.82

8 45.37 40.16 40.39 51.40

9 50.33 43.32 47.72 57.50

10 57.48 49.51 52.49 64.33


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Fig No. 6: In-vitro release profile of C1, C6, C7 ,C8

Table No. 10: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K15M.

Batch

code


C1 C9 C10 C11

0.5 2.60 2.00 1.78 2.31

1 7.51 2.95 3.40 4.97

2 13.62 6.50 7.63 12.41

3 26.03 10.81 11.47 15.61

4 30.45 19.42 18.20 22.44

5 34.29 22.32 21.24 25.50

6 38.25 27.11 28.43 35.34

7 41.23 30.62 31.47 38.40

8 45.37 37.49 35.60 49.99

9 50.33 42.00 43.68 56.03

10 57.48 44.23 47.52 59.70

Fig No. 7: - In-vitro release profile of C1, C9, C10, C11.


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Table No. 11: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Sodium CMC.

Batch

code


C1 C12 C13 C14

0.5 2.60 2.59 3.05 4.17

1 7.51 5.53 9.70 10.75

2 13.62 17.41 16.54 22.41

3 26.03 25.02 27.84 30.744 30.45 36.41 34.48 36.77

5 34.29 42.45 40.63 44.59

6 38.25 47.96 47.10 47.78

7 41.23 51.50 51.58 51.43

8 45.37 54.71 54.23 58.00

9 50.33 59.31 61.94 61.94

10 57.48 61.44 65.47 70.33

Fig No. 8: - In-vitro release profile of C1, C12, C13,, C14.

Table No. 12: - Cumulative % release of carvedilol from tablets comprising of Methocel K4M and Methocel K15M.

Batchcode


C1 C15 C16 C17

0.5 2.60 5.60 7.41 7.60

1 7.51 12.30 15.51 14.73

2 13.62 20.39 19.55 19.74

3 26.03 25.43 26.43 24.794 30.45 35.71 30.37 42.70

5 34.29 39.31 32.64 48.00

6 38.25 41.42 38.25 52.00

7 41.23 54.09 43.98 56.00

8 45.37 58.30 45.53 62.70

9 50.33 69.47 49.37 73.80

10 57.48 79.36 55.02 78.70


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Fig No. 9: - In-vitro release profile of C1, C15, C16,, C17.

Table No. 13: - Cumulative % release of carvedilol from tablets comprising of Methocel K4M and Sodium CMC.

Batchcode

Cumulative % releaseC1 C18 C19 C20

0.5 2.60 20.90 31.10 4.51

1 7.51 42.33 58.28 10.60

2 13.62 56.54 85.54 22.51

3 26.03 71.50 100.54 28.11

4 30.45 75.56 100.54 31.07

5 34.29 79.32 100.54 33.37

6 38.25 89.98 100.54 39.40

7 41.23 100.86 100.54 45.44

8 45.37 100.86 100.54 58.42

9 50.33 100.86 100.54 65.10

10 57.48 100.86 100.54 72.00



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Table No. 14: - Cumulative % release of carvedilol from tablets comprising of Methocel K15M and Sodium CMC.

Batch

code


C1 C21 C22 C23

0.5 2.60 3.77 25.20 12.81

1 7.51 9.62 66.63 20.59

2 13.62 22.90 87.59 20.69

3 26.03 28.93 96.98 30.554 30.45 34.19 100.00 31.12

5 34.29 44.50 100.00 32.81

6 38.25 49.55 100.00 41.63

7 41.23 56.93 100.00 47.19

8 45.37 68.80 100.00 50.91

9 50.33 72.98 100.00 58.66

10 57.48 77.13 100.00 64.90

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Cumulative%Release

Time (hrs)

C1

C2

1C2

2


Data Analysis [22, 23]

To characterize the release mechanism of carvedilol from controlled release bioadhesive buccal tablets, the dissolution

data were evaluated according the relationship proposed by Korsmeyer et al., as in following equation:

Mt/ M = Ktn

Where, Mt / M: is the fractional release of drug, t: - denotes the release time,K: - constant incorporating structural an

geometrical characteristics of the device and n: - diffusional exponent that characterized the type of release mechanism

during the dissolution process.

--------------------------------------------------------------------------------

n Mechanism

----------------------------------------------------------------------------------

n>1 Fickian Diffusion (Higuchi Matrix)

0.5


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The values of n as estimated by linear regression of log (M t/ M) versus log (t) of different formulations were calculated

This model used, when the release mechanism is not known or when more then one type of release phenomenon could b

involved.Different kinetic equations were applied to interpret the release rate of carvedilol from bioadhesive buccal tablet

The coefficient of determination (r2) determined graphically [24], are shown in table no. 15.

Table No 15: - Kinetic assessment of release data (r2) of C3

Kinetic order r2 (C3)

Zero order kinetic 0.9691

First order kinetic 0.9899

Square root t kinetic 0.9979

Stability Protocol

Stability studies were carried out on the formulation C3. Tablets of batch C3 were first wrapped in aluminum foil the

placed in a amber colored bottle. These were stored at 40 oC, 75% + 5% relative humidity for 2 months. Tablet was evaluate

for physical characteristics; mucoadhesive properties, and in vitro drug release and I. R. spectroscopy after two month.

Results obtained were compared with data obtained for zero time at ambient temperature.

Table No. 16: - Cumulative % release of carvedilol from C3 stored at 400C, 75 + 5% relative humidity.

Batch

code


Zero Month After two months

0.5 4.30 4.25

1 12.80 12.79

2 28.15 28.52

3 40.00 39.51

4 55.62 54.13

5 63.27 63.10

6 69.28 68.51

7 79.13 78.02

8 83.30 83.359 86.81 88.76

10 91.54 90.16

Fig No. 12: - Comparative in-vitro release profile of C3 after zero and two month respectively at 400C, 75 + 5% relative

humidity.


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Result: - The in-vitro release profile of C3 after zero and two month respectively at 400C, 75 + 5% relative humidity showed n

significant difference in release pattern. Thus it can be said that formulation C3 was stable at 400C, 75 + 5% relativ

humidity for atleast two months.

Mucoadhesive strength study:

Table No. 17: - Mucoadhesion measurement of C3 stored at 400C, 75 + 5% relative humidity.

Duration Force of adhesion (N)

Zero month 0.904

Two month 0.951

Result: - The bioadhesion measurement profile of C3 after two month C3 stored at 400C, 75 + 5% relative humidity showed n

significant difference in bioadhesion.

DISCUSSION

Physical characterization

The mucoadhesive buccal tablets of carvedilol were prepared by direct compression method were evaluated for weightvariation, drug content, friability, hardness, and thickness for all batches (C 1 to C23).

No significant difference was observed in the weight of individual tablets from the average weight. Tablet weights of all

bathes were found within recommended I.P. limits. Data for drug content indicated that tablets of all batches had drug content

within I.P. limits. Tablets with hardness between 6.7 Kg/cm2 8.6 Kg/cm2 was in acceptable limits, which shows in the

literature. All the formulation showed % friability less then 1% that indicates ability of tablets to withstand shocks, which may

encountered. No significant difference was observed in the thickness of individual tablet from the average weight.

Standard calibration curve of carvedilol were prepared in phosphate buffer pH 6.8 and isotonic phosphate buffer pH 7.4.

The equation of line was found to be y = 0.0874x + 0.0154 (r2 = 0.9996) for calibration curve in phosphate buffer in 6.8 and y =

0.0891x + 0.0120 (r2 = 0.9996) for isotonic phosphate buffer pH 7.4. Correlation coefficient values indicate the linear

correlation between concentration and absorbance.

In-vitro swelling study

Swelling index was calculated with respect to time. Swelling index increased with time as the tablet weight gain by the

tablet was increased proportionally with the rate of hydration. Maximum swelling was obtained in 4 hrs, after which polymer

starting eroding slowly in the medium. The tablets of bathes C5, C18, C21, C22, C23 was breaked after 2 hrs, these al bathes

contain Sodium CMC, and these batches may show this property due to presence of Sodium CMC, as Sodium CMC has viscosity

less as compared to Methocel K4M, Methocel K15M and Carbopl 974P, results in low binding forces between the molecules.

Maximum swelling was seen with the batches C6, C9, C12 containing Carbopol 974P (7.5 %) in combination with 27 % K4M,

K15M and Sodium CMC respectively.

In-vitro bioadhesion study

The mucoadhesive property of mucoadhesive buccal tablets of carvedilol containing varying proportion of polymers

was determined with a view to develop a compact with good adhesiveness without any irritation and other problems. The

bioadhesion characteristics were affected by the type and ratio of the polymers. The highest adhesion force i.e. the highest

strength of mucoadhesive bonds (1.398 N) was proposed by batch C-6 i.e. the formulation containing Carbopol 974P (7.5%)


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and Methocel K4M (27.5 %) and the least force of adhesion was proposed by batch C-16 i.e. the formulation containing

Methocel K4M and Methocel K15M in the ratio 1:2. By observing the results from batches C-6 to C-14, it was concluded that as

the concentration of Carbopol 974P was decreased the mucoadhesive strength decreased in combinations with Methocel K4M,

Methocel K15M, and Sodium CMC respectively. The Methocel K4M, Methocel K15M, Sodium CMC and Carbopol 974P shows

good mucoadhesive strength alone. Batch C-16 had the lowest bioadhesion force, the combination of Methocel K4M and

Methocel K15M in 1:2 ratio, this may be due to the high viscosity of Methocel K15M that resist the penetration of liquid inside

the tablet at faster rate.

In-vitro diffusion study

The in-vitro diffusion study of carvedilol using porcine mucosa shows that more than 90 % drug was permeated through

the mucosa in 2 hrs. These results indicate that in this case the diffusion or absorption was not the rate-limiting step in the

absorption of carvedilol from the controlled released system. The rate-limiting step was the release of drug from the

prolonged release tablets.

In-vitro release study

The release of carvedilol from mucoadhesive buccal tablets of the same varied according to the type and ratio of

polymers used. The release of carvedilol increased with decreased in the concentration of Carbopol 974P. This was shown by

the release pattern of the batches C6, C7, C8, C9, C10, C11, C12, C13, and C14. Methocels are more hydrophilic than carbopol;

this can be shown by the release patterns of the batches mentioned above and C1, C3, C4, C5, because it can swells rapidly but

the Carbopol swells slowly due to their less hydrophobic nature. The maximum cumulative drug release and fast release was

obtained with the formulations that contains the Sodium CMC in the more amount then the other polymer or as alone, this was

due to the high swelling capacity of this polymer. The continuous swelling of the polymer matrix causes the drug to diffuse

from formulation at a faster rate. The Aggarwal, V., et al, also reported it. This type release was also due to the erodible nature

of the Sodium CMC.

The batches C15 to C17 show that increased in the K15M conc. resulted in decrease in the drug release. This may occur

due to the increase in the viscosity and less rate of erosion. As the drug was water insoluble the main mechanism of drug

release was erosion of the matrix tablets.

The increase in the rate of drug release could be explained by the ability of the hydrophilic polymers to absorb wate

rapidly, thereby promoting matrix welling, erosion and finally the drug release of the water insoluble drugs occur. Moreove

the hydrophilic polymers would leach out and, hence the more amount of drug released from the matrix. The presence of th

lactose in the large amount creates more pores and channels for the drug to diffuse out of the tablets. Optimized batch show

near zero order and significant release from the matrix tablets.

Stability Studies

Results of stability studies of formulation C-3 indicates that it is stable at 40 0C, 75% + 5% relative humidity as there was

no significant difference observed for dissolution (p > 0.05) and bioadhesion data (p > 0.05). The I. R spectra of the optimized

batch when compare with the I. R. spectra of the pure drug, there was not significant change in the peaks of drug were

observed. This also proves that the optimized batch was stable with excipients in the study.

CONCLUSION

Observations of all the formulations for physical characterization had shown that, all of them comply with the officia

compendias. Results of in-vitro release profile indicated that formulation C-3 was the most promising formulation as the exten


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of drug release from this formulation was high as compare to other formulations. Stability study conducted on tablets o

formulation C-3 under stress conditions for two months. Tablets were evaluated for physical parameters bioadhesio

measurement and in-vitro release after two months. No significant changes were found in both the parameters during stud

period thus, it could be concluded that formulation was stable. It can be concluded that in concentration of 35% the Methoce

K4M give the promising results with the water insoluble drug carvedilol for sustained release of carvedilol with adequat

swelling and bioadhesion properties.

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design and development of bioadhesive buccal drug delivery system of carvedilol

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