Amol Harsulkar et al.

, IJSID, 2012, 2 (6), 580-597

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries

Research Article
1Research

An International peer Review Journal for Science

Available online through www.ijsidonline.info

Amol Harsulkar1* and S.A. Sreenivas2

DESIGN AND DEVELOPMENT OF BIOADHESIVE BUCCAL DRUG DELIVERY SYSTEM OF CARVEDILOL scholar, Pharmaceutical Sciences Department, J.J.T. University, Jhunjhunu, Rajasthan, India; 2Grurunanak Institute of Pharmacy, Ibrahimpatnam. Dist. RR, Hydrabad, AP, India ABSTRACT Received: 02-12-2012 Accepted: 04-01-2013
*Corresponding Author

offers several advantages over both injectable and enteral methods. Because the oral mucosa is highly vascularized, drugs that are absorbed through the oral mucosa directly

enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. Hence, the present study is focus on the development and blocking agent with 1-blocking activity and bioadhesive polymers for the controlled release of the drug from tablet in the buccal cavity, to increase the bioavailability of carvedilol. Bioadhesive buccal tablets of carvedilol were prepared by direct compression methylcellulose and Carbopol. The different concentrations of carbopol and other The tablets were evaluated for different parameters like weight variation, thickness, evaluation of bio adhesive buccal tablet using Carvedilol a nonselective -adrenergic method using different polymers such as Methocel K4M, Methocel K15M, Sodium-carboxy polymers were used; also combinations of these were prepared in different proportions. INTRODUCTION release study and stability studies on selected formulation. From the results it can be concluded that the formulation C3 containing concentration of 35% the Methocel K4M give optimized formulation shown good stability up to two months. friability, content uniformity, hardness, swelling index, mucoadhesive strength, in-vitro

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

Address: Name: Amol Harsulkar Place: Rajasthan, India E-mail: amol3harsulkar @rediffmail.com

INTRODUCTION promising results for sustained release of carvedilol, as release profile indicated the most
Keywords: Carvedilol, Bio-adhesive, in-vitro, bioavailability, swelling index.

promising formulation as the extent of drug release was high as compare to other formulations with adequate swelling and bioadhesion properties also stability data for this

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Amol Harsulkar et al., IJSID, 2012, 2 (6), 580-597 drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit 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 both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral stratum cornium and with less immune activity than the epidermis. Bioadhesive Drug Delivery System:
[1],

oral administration of certain classes of drugs especially peptides and proteins. The oral cavity, on the other hand, is highly allergens[2].Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over 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 water-soluble polymers, which become adhesive on hydration and hence can be used for targeting a drug to a particular delivery system ii) Oral drug delivery system iii) Rectal drug delivery system drug delivery system vi) Nasal drug delivery system. iv)Vaginal drug delivery system. and the virtual lack of Langerhans cells makes the oral mucosa tolerant to potential

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

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

region of the body for extended period of time. The bioadhesive delivery system includes the following [3,4] i) Buccal drug for commercial application as an alternative to conventional drug therapy. The oral mucosa is composed of an outermost layer superficial layers, where cells are shed from the surface of the epithelium [5, 6, 7, 8]. The present study was carried out about the bioadhesive buccal drug delivery system, which offers a great potential

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

v) Occular

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

-adrenergic blocking agent with 1-blocking activity

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

As the carvedilol has high first pass effect, low aqueous solubility, but high lipid solubility. Carvedilol is a nonselective
[9, 10, 11,].

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

The main route of carvedilol absorption seemed to be

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orthostatic hypotension due to rapid achievement of drug serum concentration. Therefore all the properties mentioned here metabolism of carvedilol, thereby increasing the bioavailibity of the carvedilol. Therefore mucoadhesive buccal route is the route of choice for formulation development of carvedilol. in the buccal cavity, to increase the bioavailability of carvedilol and reducing the chances of orthostatic hypotension. MATERIALS AND METHODS Drug: Materials: Diluents: Methods: Polymers: - Carbopol 974P, Methocel K4M, Methocel K15M, Sodium CMC. Lubricants: - Magnesium Stearate, Talc. Ingredients Carvedilol (mg) Carbopol 974P(mg) Methocel K4M (mg) Sodium CMC (mg) Lactose (mg) Lactose Table No. 1: - Composition of carvedilol bioadhesive buccal tablets. C1 6.25 10 ---------81 C2 6.25 7.5 ---------78.5 C3 6.25 ---35 ------56 C4 6.25 ------35 56 ---C5 6.25 ---------35 56 C6 6.25 7.5 27.5 ------56 C7 6.25 5 30.0 ------56 ------56 Carvedilol (6.25 mg)

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

makes the carvedilol a good candidate for mucoadhesive controlled release buccal drug delivery system to avoid first pass of Bioadhesive buccal tablet using different bioadhesive polymers for the controlled release of the drug carvedilol from tablet So, the current work is focus on the development and evaluation of bioadhesive buccal drug delivery system in the form

Methocel K15M (mg)

C8 6.25 2.5 32.5

C9 6.25 7.5 ---27.5 ---56 0.75 2 6.25 ------17.5 17.5 56 0.75 C21 2

C10 6.25 5 ---30.0 ---56 0.75 2 6.25 ------11.7 23.3 56 0.75 C22 2

C11 6.25 2.5 ---32.5 ---56 0.75 2 6.25 ------23.3 11.7 56 0.75 C23 2

Carvedilol (mg) 6.25 6.25 6.25 6.25 Carbopol 974P (mg) 7.5 5 2.5 ---Methocel K4M (mg) ---------17.5 Methocel K15M (mg) ---------17.5 Sodium CMC (mg) 27.5 30.0 32.5 ---Lactose (mg) 56 56 56 56 Magnesium Stearate 0.75 0.75 0.75 0.75 (%) Talc (%) 2 2 2 2 Preparation of Bioadhesive Buccal Tablets of Carvedilol: Ingredients C12 C13 C14 C15

Magnesium Stearate (%) 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 Table No. 2: - Composition of carvedilol bioadhesive buccal tablets. 6.25 ---11.7 23.3 ---56 0.75 C16 2 6.25 ---23.3 11.7 ---56 0.75 C17 2 6.25 ---17.5 ---17.5 56 0.75 C18 2 6.25 ---11.7 ---23.3 56 0.75 C19 2 C20

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

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

6.25 ---23.3 ---11.7 56 0.75 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. 1. Hardness EVALUATION OF BIOADHESIVE BUCCAL TABLET: All the prepared bioadhesive buccal tablets were evaluated for following official and unofficial parameters.

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

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] formula,

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 Result: The results of measured % friability were shown in Table no. 4. Where, % F = friability in percentage; Wo = Initial weight of tablet; W = weight of tablets after revolution % F = {1-(Wo/W)} 100

Method: Twenty tablets were randomly selected form each batch and individually weighed. The average weight and standard 3. Weight variation [13] 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 of % deviation allowed under weight variation test. Average weight of tablet (X mg) Percentage deviation X < 80 mg 10 80 < X < 250 mg 7.5 X > 250 mg 5 Result: - The average weight and standard deviation of the tablets of each batch given in Table 4. Result: Thickness values are shown in Table no 4. 5. Content uniformity [14] Table 3: - Limits of percentage deviation allowed under weight variation test.

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

Method: Three tablets were selected randomly from each batch and thicknesses were measured by using screw gauge. 4. Thickness Uniformity

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

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

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

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average bioadhesive strength was determined. From the mucoadhesive strength, force of adhesion was calculated. Force of adhesion (N) = (Bioadhesive strength/100) x 9.81. Results are summarized in Table No 5. Batch Code
C1 C2 C3 C4 C5 C6 C7 C8 C9 C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23

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

Table No 4: - Evaluation of physical parameter of prepared bioadhesive buccal tablets of carvedilol. Uniformity of Wt. (gm) (Mean + S.D.)
101.0 + 5.13 101.38 + 5.00 101.44 + 4.82 101.21 +1.56 101.01 +0.71 101.81 + 0.11 101.62 + 0.52 100.34 + 3.85 101.12 + 4.89 100.17 + 1.62 100.48 + 1.71 100.88 + 1.59 100.85 + 1.24 100.92 + 1.95 99.54 + 2.14 101.85 + 2.16 100.89 + 1.99 100.83 + 2.33 100.15 + 1.63 101.39 + 4.44 100.78 + 3.12 100.37 + 3.45 101.45 + 3.16

Evaluation parameter Friability (%)

0.19 0.21 0.41 0.31 0.75 0.15 0.32 0.33 0.48 0.50 0.41 0.42 0.39 0.27 0.42 0.39 0.27 0.36 0.68 0.50 0.31 0.52 0.56

Drug content (%) (Mean + S.D.)

99.48 + 0.40 99.46 + 0.35 100.05 + 0.32 100.12 + 0.41 98.92 + 0.32 98.97 + 0.19 99.98 + 0.31 100.42 + 0.32 102.45 + 0.51 100.69 + 0.05 98.35 + 0.31 99.43 + 0.23 103.23 + 0.21 98.99 + 0.22 99.63 + 0.26 101.10 + 0.50 103.91 + 0.03 99.56 + 0.00 98.91 + 0.23 99.90 + 0.41 100.01 +0.26 100.13 + 0.29 102.51 + 0.31

Hardness (kg/cm2) (Mean + S.D.)

6.7 + 0.49 6.8 + 0.14 8.2 + 0.19 8.6 + 0.10 7.4 + 0.46 7.2 + 0.12 7.1 + 0.12 6.9 + 0.34 7.3 + 0.42 7.5 + 0.29 8.1 + 0.42 7.8 + 0.32 7.6 + 0.19 7.3 + 0.21 7.4 + 0.10 7.5 + 0.10 7.5 + 0.11 7.1 + 0.12 7.4 + 0.12 7.0 + 0.23 7.2 + 0.21 7.7 + 0.12 7.0 + 0.24

Thickness (mm) (Mean + S.D.)

2.61 + 0.059 2.60 + 0.057 2.58 + 0.054 2.58 + 0.051 2.64 + 0.091 2.61 + 0.057 2.62 + 0.051 2.57 + 0.052 2.60 + 0.057 2.61 + 0.010 2.60 + 0.057 2.60 + 0.010 2.60 + 0.000 2.59 + 0.015 2.58 + 0.051 2.62 + 0.050 2.61 + 0.048 2.60 + 0.057 2.61 + 0.049 2.60 + 0.051 2.61 + 0.057 2.62 + 0.031 2.61 + 0.050

Table No. 5: - In-vitro Mucoadhesive strength study of prepared bioadhesive buccal tablets of carvedilol. Batch Code
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23

Bioadhesive strength (gm) (Mean + S. D.)

8.730 + 0.239 8.270 + 0.147 9.220 +0.152 9.750 + 0.249 7.790 + 0.339 14.250 + 0.296 9.130 + 0.975 8.790 + 0.118 11.130 + 0.819 10.450 + 0.798 9.458 + 0.334 11.970 + 0.893 9.170 + 0.117 8.954 + 0.197 4.950 + 0.153 3.850 + 0.119 7.830 + 0.754 8.420 + 0.791 9.680 + 0.775 9.750 + 0.814 8.540 + 1.239 8.750 + 0.333 6.120 + 0.547

Force of adhesion (N)

0.856 0.811 0.904 0.956 0.764 1.398 0.896 0.862 1.092 1.025 0.928 1.174 0.900 0.878 0.486 0.378 0.768 0.826 0.950 0.956 0.838 0.858 0.600

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

MUCOADHESIVE STRENGTH

1.6 1.4
FORCE OF ADHESION (N)

1.2 1.0 0.8 0.6 0.4 0.2 0.0

BATCH CODE

Swelling Study [19]

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

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

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

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

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

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Amol Harsulkar et al., IJSID, 2012, 2 (6), 580-597 Method: 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, placing on the agar Plate; The Swelling Index of tablets given in Table No.6. Batch Code C1 C2 C3 C4 C5 C6 C7 C8 C9 C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 In Vitro Release Study [20, 21] Time (hrs) 30.76 + 0.141 1 25.00 + 0.193 35.96 + 0.259 27.64 + 0.263 41.66 + 0.271 25.00 + 0.282 17.74 + 0.259 17.65 + 0.143 19.25 + 0.211 21.67 + 0.089 22.95 + 0.075 40.00 + 0.103 49.04 + 0.091 43.41 + 0.034 23.81 + 0.246 21.75 + 0.143 29.41 + 0.119 46.00 + 0.131 40.00 + 0.144 42.40 + 0.138 57.61 + 0.146 53.06 + 0.310 37.25 + 0.111 39.23 + 0.0471 2 33.42 + 0.723 42.11 + 0.412 43.49 + 0.115 50.71 + 0.129 44.76 + 0.235 29.41 + 0.341 24.41 + 0.044 30.39 + 0.054 28.33 + 0.341 32.79 + 0.300 51.42 + 0.041 62.54 + 0.071 49.71 + 0.039 34.29 + 0.211 34.02 + 0.291 47.06 + 0.034 62.00 + 0.089 53.00 + 0.091 53.17 + 0.209 83.71 + 0.201 75.44 + 0.091 59.71 + 0.081 49.03 + 0.035 4 TABLET BREAK 57.14 + 0.179 36.47 + 0.497 40.31 + 0.098 37.70 + 0.258 41.80 + 0.261 64.21 + 0.113 81.73 + 0.061 61.49 + 0.237 TABLET BREAK TABLET BREAK TABLET BREAK TABLET BREAK 82.00 + 0.045 85.14 + 0.046 57.43 + 0.124 49.13 + 0.129 74.12 + 0.012 37.5 + 0.214 42.31 + 0.210 54.39 + 0.439 50.14 + 0.141 53.14 + 0.035 6 44.23 + 0.250 58.33 + 0.451 52.11 + 0.179 60.61 + 0.201 42.35 + 0.593 44.71 + 0.057 45.19 + 0.081 41.80 + 0.129 41.85 + 0.214 64.75 + 0.149 83.31 + 0.125 63.79 + 0.218 55.71 + 0.105 53.79 + 0.092 80.00 + 0.091 93.00 + 0.087 94.00 + 0.076 -------------------------------------------------------------------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 Table No.6: In-vitro swelling study of prepared bioadhesive buccal tablets of carvedilol. % Swelling Index (Mean + S. D.) Four tablets of every batch were weighed and then kept on the agar gel plate surface in petridishes, which were

development of a number of in vitro release methods for controlled release mucoadhesive formulation; however no standard in vitro method has been developed. International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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

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and basket.

method at 50 rpm. Medium used for release rate study was 500 ml of phosphate buffer (pH 6.8) solution containing 20% medium. The amount of carvedilol released was determined spectroscopically at 242 nm. The observations for different batches

methanol for maintaining the sink conditions. During the course of study whole assembly was maintained at 37 0C. Five ml of 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 are shown in succeeding tables the cumulative percentage of carvedilol released with respect to time for each batch are graphically shown in succeeding figures. 0.5 1 2 3 4 5 6 7 8 9 10 Table No. 7: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P in different concentration. Batch code Cumulative % release C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 C2 4.32 8.63 23.77 53.81 64.55 77.49 91.40 99.60 100.00 100.00 100.00

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

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

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

100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10

Cumulative % Release

C1 C2

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

Time (hrs)

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Table No. 8: Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K4M, Methocel K15M, Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Sodium CMC. Cumulative % release C3 C4 4.30 3.64 12.80 8.93 28.15 18.41 40.00 31.72 55.62 47.49 63.27 54.20 69.28 59.14 79.13 65.10 83.30 71.12 86.81 73.19 91.54 76.05 C5 30.35 56.04 66.44 73.73 82.47 92.87 95.17 99.87 100.44 100.44 100.44

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

Table No. 9: Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K4M. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Cumulative % release C6 C7 2.03 2.94 4.92 5.26 8.47 9.63 14.43 14.13 18.23 22.07 27.14 26.09 30.41 31.00 34.25 37.74 40.16 40.39 43.32 47.72 49.51 52.49 C8 4.28 7.70 13.43 19.48 30.09 33.34 37.35 47.82 51.40 57.50 64.33

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

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Table No. 10: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Methocel K15M. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Cumulative % release C9 C10 2.00 1.78 2.95 3.40 6.50 7.63 10.81 11.47 19.42 18.20 22.32 21.24 27.11 28.43 30.62 31.47 37.49 35.60 42.00 43.68 44.23 47.52 C11 2.31 4.97 12.41 15.61 22.44 25.50 35.34 38.40 49.99 56.03 59.70

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

Fig No. 7: - In-vitro release profile of C1, C9, C10, C11. International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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Table No. 11: - Cumulative % release of carvedilol from tablets comprising of Carbopol 974P and Sodium CMC. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Cumulative % release C12 C13 2.59 3.05 5.53 9.70 17.41 16.54 25.02 27.84 36.41 34.48 42.45 40.63 47.96 47.10 51.50 51.58 54.71 54.23 59.31 61.94 61.44 65.47 C14 4.17 10.75 22.41 30.74 36.77 44.59 47.78 51.43 58.00 61.94 70.33

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

Table No. 12: - Cumulative % release of carvedilol from tablets comprising of Methocel K4M and Methocel K15M. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Cumulative % release C15 C16 5.60 7.41 12.30 15.51 20.39 19.55 25.43 26.43 35.71 30.37 39.31 32.64 41.42 38.25 54.09 43.98 58.30 45.53 69.47 49.37 79.36 55.02 C17 7.60 14.73 19.74 24.79 42.70 48.00 52.00 56.00 62.70 73.80 78.70

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

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

Table No. 13: - Cumulative % release of carvedilol from tablets comprising of Methocel K4M and Sodium CMC. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 Cumulative % release C1 C18 C19 C20 2.60 20.90 31.10 4.51 7.51 42.33 58.28 10.60 13.62 56.54 85.54 22.51 26.03 71.50 100.54 28.11 30.45 75.56 100.54 31.07 34.29 79.32 100.54 33.37 38.25 89.98 100.54 39.40 41.23 100.86 100.54 45.44 45.37 100.86 100.54 58.42 50.33 100.86 100.54 65.10 57.48 100.86 100.54 72.00

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

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

Fig No. 10: - In-vitro release profile of C1, C18, C19, C20.

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Table No. 14: - Cumulative % release of carvedilol from tablets comprising of Methocel K15M and Sodium CMC. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 C1 2.60 7.51 13.62 26.03 30.45 34.29 38.25 41.23 45.37 50.33 57.48 Cumulative % release C21 C22 3.77 25.20 9.62 66.63 22.90 87.59 28.93 96.98 34.19 100.00 44.50 100.00 49.55 100.00 56.93 100.00 68.80 100.00 72.98 100.00 77.13 100.00 C23 12.81 20.59 20.69 30.55 31.12 32.81 41.63 47.19 50.91 58.66 64.90

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

Cumulative % Release

100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 Time (hrs)

C1 C2 1 C2 2

Data

Analysis [22, 23]

data were evaluated according the relationship proposed by Korsmeyer et al., as in following equation: during the dissolution process. Mt / M = Kt n

Where, Mt / M: is the fractional release of drug, t: - denotes the release time,K: - constant incorporating structural and -------------------------------------------------------------------------------n 0.5<n<1 n>1 1 Mechanism Fickian Diffusion (Higuchi Matrix) Super Case-II transport Anomalous Transport

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

Fig No. 11: - In-vitro release profile of C1, C21, C22, C23.

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

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

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n>1

Case-II Transport (Zero Order Release)

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This model used, when the release mechanism is not known or when more then one type of release phenomenon could be The coefficient of determination (r2) determined graphically [24], are shown in table no. 15. Kinetic order Zero order kinetic First order kinetic Square root t kinetic r2 (C3) 0.9691 0.9899 0.9979 Table No 15: - Kinetic assessment of release data (r2) of C3

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

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

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Stability Protocol

placed in a amber colored bottle. These were stored at 40 oC, 75% + 5% relative humidity for 2 months. Tablet was evaluated 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. Batch code 0.5 1 2 3 4 5 6 7 8 9 10 Cumulative % release Zero Month After two months 4.30 4.25 12.80 12.79 28.15 28.52 40.00 39.51 55.62 54.13 63.27 63.10 69.28 68.51 79.13 78.02 83.30 83.35 86.81 88.76 91.54 90.16 Table No. 16: - Cumulative % release of carvedilol from C3 stored at 400C, 75 + 5% relative humidity.

Stability studies were carried out on the formulation C 3. Tablets of batch C3 were first wrapped in aluminum foil then

Fig No. 12: - Comparative in-vitro release profile of C3 after zero and two month respectively at 400C, 75 + 5% relative humidity. International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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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 no significant difference in release pattern. Thus it can be said that formulation C 3 was stable at 400C, 75 + 5% relative humidity for atleast two months. Table No. 17: - Mucoadhesion measurement of C3 stored at 400C, 75 + 5% relative humidity. Zero month Two month Duration Force of adhesion (N) 0.904 0.951 Mucoadhesive strength study:

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Result: - The bioadhesion measurement profile of C3 after two month C3 stored at 400C, 75 + 5% relative humidity showed no significant difference in bioadhesion. Physical characterization DISCUSSION The mucoadhesive buccal tablets of carvedilol were prepared by direct compression method were evaluated for weight

variation, drug content, friability, hardness, and thickness for all batches (C 1 to C23).

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/cm 2 8.6 Kg/cm2 was in acceptable limits, which shows in the encountered. No significant difference was observed in the thickness of individual tablet from the average weight. correlation between concentration and absorbance. In-vitro swelling study 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 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 K15M and Sodium CMC respectively. In-vitro bioadhesion study less as compared to Methocel K4M, Methocel K15M and Carbopl 974P, results in low binding forces between the molecules. The mucoadhesive property of mucoadhesive buccal tablets of carvedilol containing varying proportion of polymers Maximum swelling was seen with the batches C6, C9, C12 containing Carbopol 974P (7.5 %) in combination with 27 % K4M, was determined with a view to develop a compact with good adhesiveness without any irritation and other problems. The Swelling index was calculated with respect to time. Swelling index increased with time as the tablet weight gain by the Standard calibration curve of carvedilol were prepared in phosphate buffer pH 6.8 and isotonic phosphate buffer pH 7.4.

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

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

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

bioadhesion characteristics were affected by the type and ratio of the polymers. The highest adhesion force i.e. the highest International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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

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

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 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 the tablet at faster rate. In-vitro diffusion study 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 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

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

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

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; due to the high swelling capacity of this polymer. The continuous swelling of the polymer matrix causes the drug to diffuse of the Sodium CMC. 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 Carbopol swells slowly due to their less hydrophobic nature. The maximum cumulative drug release and fast release was

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

obtained with the formulations that contains the Sodium CMC in the more amount then the other polymer or as alone, this was from formulation at a faster rate. The Aggarwal, V., et al, also reported it. This type release was also due to the erodible nature The batches C15 to C17 show that increased in the K15M conc. resulted in decrease in the drug release. This may occur

rapidly, thereby promoting matrix welling, erosion and finally the drug release of the water insoluble drugs occur. Moreover, the hydrophilic polymers would leach out and, hence the more amount of drug released from the matrix. The presence of the near zero order and significant release from the matrix tablets. Results of stability studies of formulation C-3 indicates that it is stable at 400C, 75% + 5% relative humidity as there was

lactose in the large amount creates more pores and channels for the drug to diffuse out of the tablets. Optimized batch shows Stability Studies no significant difference observed for dissolution (p > 0.05) and bioadhesion data (p > 0.05). The I. R spectra of the optimized observed. This also proves that the optimized batch was stable with excipients in the study. CONCLUSION

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

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

compendias. Results of in-vitro release profile indicated that formulation C-3 was the most promising formulation as the extent International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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

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of drug release from this formulation was high as compare to other formulations. Stability study conducted on tablets of formulation C-3 under stress conditions for two months. Tablets were evaluated for physical parameters bioadhesion measurement and in-vitro release after two months. No significant changes were found in both the parameters during study swelling and bioadhesion properties. 1. 2. 3. 4. 5. 6. 7. 8. 9. period thus, it could be concluded that formulation was stable. It can be concluded that in concentration of 35% the Methocel K4M give the promising results with the water insoluble drug carvedilol for sustained release of carvedilol with adequate Rathbone, M.J. and Hadgraft, J., Absorption of drugs from the human oral cavity, Int. J. Pharm., 74, 9-24, (1991). REFERENCES adhesiveness relationships, J. Control. Rel., 13, 225-231, (1990). (1990). Bodde, H.E., De Vries, M.E., and Junginger, H.E., Mucoadhesive polymers for the buccal delivery of peptides, structureMerkle, H.P., Anders, R., and Wermerskirchin, A., Bioadhesive Drug Delivery Systems, CRC Press, Boca Raton, Florida, 105, Jain, N. K., Controlled and Novel Drug Delivery, CBS Publication and Distributors, 1st edition, New Delhi, 353-380, (2002). sciences, J. Pharm. Pharmaceut. Sci., 1(1), 15-30, (1998). (1992). David H. and Robinson J., R., Drug delivery via the mucus 72, 133 -140, (2001). (2002.

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10. Clarke E.C.G., Isolation and Identification Of Drugs, The Pharmaceutical Press, London, 238, (1969). 12. United States Pharmacopoeia, XXIV NF 19, United State Pharmacopoeia Convention, 2148, (2000). 13. Indian Pharmacopoeia, Controller of Publication, Delhi, Vol. II, 735-739, (1996). vitro assembly, Indian Drugs, 30(4), 152-155, (1992). characterization. Int.J.Pharm., 283, 93-103, (2002). 442, (2002). Industrial Pharmacy, (3rd edition), Vargeshe publishing house, Bombay, 300, (1992).

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11. Tripathi K.P., Essentials of Medical Pharmacology, (4 thed.). Jaypee Brothers Medical publishers Pvt. Ltd., India., 381-387, 14. Bankar, G. S. and Anderson, N.R., Tablets in: Lachman, L., Lieberman, H. A. and Kanig, J. L. (eds), The Theory And Practice Of 16. Ali, J., Khar, R., K. and Ahuja, A., Effect of polymer loading on drug release and bioadhesion of buccoadhesive carriers for local drug delivery of triaminocolone acetonitride, The Eastern Pharmacist, 46 (503), 115-119, (1999).

15. Garg, S., Gupta, A., and Khar, R. K., Measurement of bioadhesive strength of mucoadhesive Buccal tablets: Design of an in17. Ali J., Khar, R., Ahuja, A. and Karla, R, Buccoadhesive erodible disk for treat-ment of orodental infections design and 18. Singh B. and Ahuja, N, Development of controlled release buccoadhesive hydro-philic matrices of diltiazem

hydrochloride: Optimization of Bioadhesion, dissolution, and diffusion parameters. Drug Dev. Ind. Pharm. 28 (4), 431International Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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19. Aggarwal, V. and Mishra B., Design, development and biopharmaceutical pro-perties of buccoadhesive compacts of 20. Devarajan, P. V., and Gandhi, A. S., In-vitro and in-vivo models for oral trans mucosal drug delivery, In Jain N. K. (Ed), 21. United States Pharmacopoeia, XXIV NF 19, United State Pharmacopoeia Convention, 1913, (2000). pentazocine, Drug Dev. Ind. Pharm., 25(6), 701-709, (1999). 442, (2002). Advances In Controlled And Novel Drug Delivery, CBS Publishers and Distributors, New Delhi, 71-73, (2001). pentazocine, Drug Dev. Ind. Pharm., 25(6), 701-709, (1999).

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22. Aggarwal, V. and Mishra B., Design, development and biopharmaceutical pro-perties of buccoadhesive compacts of 23. Singh B. and Ahuja, N, Development of controlled release buccoadhesive hydro-philic matrices of diltiazem 24. Dortunc, B., Ozer, L., Uyanik, N., Development and in-vitro evaluation of a buccoadhesive pindolol tablet formulation, Drug Dev. Ind. Pharm., 24(3), 281-288, (1998). hydrochloride: Optimization of Bioadhesion, dissolution, and diffusion parameters. Drug Dev. Ind. Pharm. 28 (4), 431-

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