BUCCAL DELIVERY OF ATENOLOL FROM POLYMERIC

MUCO ADHESIVE FILM

 

 

R.Venkatalakshmi*1Yajaman Sudhakar2,  C. Madhuchudana Chetty3, C.Sasikala3

 

School of Pharmacy, International Medical University, Bukit Jalil, Malaysia1.

Govt. Polytechnic for Women, Kadapa, Andhrapradesh, India2.

 

Faculty of Pharmacy, Asia Metropolitan University, Cheras, Malaysia3.

.

SUMMARY:

 

Buccal delivery is considered to be an important alternative to the per oral route for the systemic administration of drugs. The aim of the study was to formulate and evaluate mucoadhesive buccal films of atenolol for systemic delivery. This paper explains the fabrication of new bilayered films consisting of a mucoadhesive layer containing drug and a drug free backing layer. The films were fabricated by a solvent casting technique with various polymer combinations and were evaluated for thickness, Surface pH, folding endurance, uniformity of weight, drug content, moisture absorption studies, swelling index, in-vitro release and ex-vivo residence time. The present buccal dosage form could be an ideal system to enhance the bioavailability of the atenolol by eliminating hepatic first-pass metabolism and gastric degradation of the drug. 

Key words: Buccal film, Atenolol, hepatic first-pass metabolism, in- vitro release, ex-vivo residence time

 

INTRODUCTION

From 1980’s there has been improved interest in the use of mucooadhesive compounds to lengthen representative time in the different mucosal despatch of drug administration. Absorption of drug via a biomucosal layer is effective since mucosal surfaces are highly ample in supply of blood, gives fast drug delivery to the systemic absorption and eliminating degradation by intestinal enzymes and first pass metabolism. Following buccal delivery, the agent attains direct release into the systemic absorption by bypassing the liver. The buccal mucosa area is large enough to keep a dosage system to be placed at various times that could be beneficial if the dosage form or other components reversibly damage the mucosal tissue. There is possible handiness to the buccal tissues that cover the buccal cavity which creates administration painless and without discomfort, precise delivery system localization feasible and facilitates ease of withdrawl without significant possible pain and discomfort. Thus, patients can maintain the period of use or avoid delivery in case of urgencies. Better patient compliance can be achieved in buccal route than the vaginal or rectal route.  Bioavailabilty of atenolol in oral doses is up to 50%, it is mainly indicated in the treatment of hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol withdrawal[1-5].

 

MATERIALS AND METHODS:

Atenolol and HPMC E15, SCMC, SA and PVA were received as gift samples from Shasun Pharmaceuticals Ltd., Puducherry, India and Dr. Reddy's Laboratories Ltd Hyderabad, India.  All other chemicals were of analytical grade.

Preparation of bilayered fabricated buccal film:

Secondary layer (backing layer)

For developing a formulation, 7.5 cm diameter glass petri plate was used as a casting surface. Initially, backing membrane of ethyl cellulose was prepared by slowly pouring a solution containing 750 mg of ethyl cellulose and 4 drops propylene glycol in 13 ml dichloromethane and methanol (1:1) to the glass petri plate. Mercury was employed as a substrate and air dried for 9 hrs.

Primary layer (Mucoadhesive layer containing drug)

Initially, HPMC E15 polymer 750 mg was dissolved in 10 ml of distilled water under constant stirring till clear solution was obtained. Then to this solution, 4 drops of propylene glycol was added and kept for 4 hrs for swelling. To this solution atenolol 701 mg required for 14.02 films (2cm diameter of 1 film=50 mg) were dissolved in distilled water and was added by stirring. The resultant solution was then poured on the preformed backing layer and allowed to dry at 50°C for 18 hrs in the oven. The dried bilayered film was cut into 2 cm diameter. Similarly atenolol formulations from 2 to 12 were developed by employing various concentrations of HPMC E15, SCMC, SA and PVA. The films were kept in desiccators until further use [6-11]. The compositions of formulation of buccal films of atenolol were given in table 1.

Thickness

The ten randomly chosen films thickness from each batch was measured by employing a standard screw gauge and the average value was noted and reported in table 2(a).

Uniformity of weight of the films:

Each film from each batch was directly weighed by the help of electrical balance and the mean weight was measured and calculated and reported in table 2(a).

Folding endurance

This test was performed by randomly three  films were chosen from all batches and each film folded at the same place up to 300 times manually or till it broke. The number at which the film could be folded without breaking gave the folding endurance value and the average value was noted and reported in table 2(b).

Surface pH:

The surface pH of the formulated mucoadhesive films was measured to identify the possible irritation effects on the buccal tissue.  The films were left to swell in 1 ml of distilled water (pH 6.8) in small beakers, and the pH was noted after 1 hrs by placing the electrode in contact with the surface of the swollen films allowing it to equilibrate for 1 minute. The mean pH of five measurements was reported in table 2(a).

Percentage moisture absorption (PMA)

              The pepared films physical stability checked at high humid condition. The weight of three 2 cm films were weighed exactly and then kept in desiccators consists of aluminium chloride saturated solution at relative humidity 79.5%. The films were reweighed after three days. The mean % moisture absorption of the films were measured using the formula

The results were reported in table 2(b).

Percentage moisture loss (PML)

              The pepared films physical integrity checked at dry condition. The weight of three 2 cm films were weighed exactly and then kept in desiccators consists of fused anhydrous calcium chloride. The films were reweighed after three days.  The mean % moisture loss of the films was measured using the formula

The results were reported in table 2(b).

Swelling Index (%S)

Swelling Index testes were carried out by, 5% w/v agar hot solution was poured to petri plates and kept to solidify. Then 6 films from each batch were weighed and left over the agar surface and kept at 37ºC for 3 hrs in the incubator and the hydrated films were reweighed[12-13]. The % of moisture absorbed was measured using the formula:

% S = [(Final weight - Initial weight)/Initial weight] × 100

The results were reported in table 2(a).

 

Water vapor transmission rate (Q)

              This test is performed by 1 g of calcium chloride was placed in the transmission cell and the films 2 cm2 area were measured, fixed over the edge with an adhesive. Before transferring the film into closed desiccators consists of saturated solution of potassium chloride, the initial weight was noted. The desiccator’s humidity was maintained in range of 80 – 90% RH. After 18, 36, 54 and 72 hrs the cells were removed out and reweighed. It was measured by employing the formula

Q = WL/S

Where,

Q -Water vapor transmission rate

W -Water vapor transmitted in mg

L – Film thickness in mm

S - Exposed surface area in cm2

The results were reported in table 2(b).

Drug content uniformity

Three randomly chosen films of each formulation were weighed exactly and dissolved in 50 ml of methanol and stirred continuously for 1 h on a magnetic stirrer. The volume was made up to 100 ml with phosphate buffer (pH 6.8) and then 0.1 ml was transferred to 10 ml volumetric flask and the volume was adjusted with phosphate buffer (pH 6.8). The absorbance was measured on a UV/Vis spectrophotometer at 274 nm. The concentrations of atenolol were measured from the standard curve. The results were reported in table 2(a).

In-vitro drug release studies

The in-vitro drug release of buccal films was carried out by USP 28 type II dissolution test apparatus. The phosphate buffer (PH 6.8), 500 ml of was employed as the dissolution medium, at 37.0 ± 0.5ºC, and 50 rpm was used. Backing layer of the buccal film was attached to the paddle with water proof adhesive tape. Samples (5 ml) were withdrawn at 0.5, 1, 1.5, 2, 3, 4 hrs intervals and replaced with same volume of fresh medium to achieve sink condition. The samples were filtered through 0.45-μm Whatman filter paper and analyzed. The drug concentrations were measured spectrophotometrically at the wavelength of 241 nm. The experiments were carried out in triplicate and mean values were noted. The reports were shown in fig 2, 3 and 4 for Zero order, Higuchi model and Korsmeyer-Peppas model respectively.

Ex vivo residence time

The ex-vivo mucoadhesion time was carried out (n = 3) after employment of films on freshly cut porcine buccal mucosa. The inner side of a beaker the fresh porcine buccal mucosa was fixed about 2.5 cm from the bottom with water proof adhesive tape. Mucoadhesive layer containing drug of each film was moistened with 1 drop of phosphate buffer (pH 6.8) and pasted to the porcine buccal mucosa by employing a light force with a fingertip for 30 seconds. 200 ml of phosphate buffer (pH 6.8) was taken in the beaker and was kept at 37ºC ± 1ºC. After 2 minutes, a 50 rpm stirring rate was employed to create the buccal cavity environment and the film adhesiveness was observed for 8 hrs. The time needed for the patch to detach from the porcine buccal mucosa was observed as the mucoadhesion time and the reports were shown in table 2(a) and fig 1.

RESULTS AND DISCUSSION

              The formulated preparations were characterized for its physico-chemical evalutions. In all the formulations, measured folding endurance was observed more than 290 times. This cause the fims were acceptable for buccal cavity usage due to good elasticity. The observed folding endurance of all the formulations was found to be in the range of 297±1.0 to 303±2.0. The formulation atenolol F9 shows high folding endurance because of high percentage of sodium alginate.

The measured surface pH of all the batches was noted between 6.65±1.23 to 7.03±1.32. The reports revealed that there were no remarkable changes of pH in all the batches and the pH range lies between salivary pH i.e. 6.2 to 7.4. hence do not cause any sensitivity reaction and achieve patient compliance. The % moisture absorption of the formulation F6 shows maximum value of moisture absorption 9.21±0.06. This may be due to high percentage of SCMC. The formulation atenolol F12 shows higher value of Moisture loss of 7.84±0.08.

              The swelling capacity of the polymer is very important for its bioadhesive property. Atenolol film F6 shows higher value of swelling percentage of 42.96±1.22 which is due to presence of higher concentration of SCMC.  The atenolol F12 shows higher value of water vapor transmission of 7.4±0.20 which is due to presence of higher concentration of PVA. The formulation atenolol F2 shows lower water vapor transmission of 6.37±0.44 among all the films. This may be due to the presence of low amount of HPMC E15 in the formulation. The obtained reports of uniformity of drug content shown that the drug was uniformly distributed and which was within the limits. Ex-vivo residence time of all the prepared films of atenolol were shows the values between 6.8±1.12 to 7.6±1.09.

An increase in the polymer content was related with decrease in the drug release rates. The in-vitro drug release and Higuchi’s plot have reported that the release of drug showed zero order kinetics that was noted from the correlation value (r). An Increasing the quantity of the polymer in the films produced  an increase in the viscosity of the gel and the water swallon-gel like state that would substantially decrease the permeation of the dissolution medium into the films and so the drug release was declined. This may cause a reduce in the effective diffusion coefficient of the drug and therefore a decrease in the drug release rate however, the variation is insignificant among the formulations. Zero-order release from swellable hydrophilic matrices occurs as a result of consistent diffusional pathlengths. In this investigation similar behavior was predicted and obtained.

The correlation coefficient values (r) revealed that drug release kinetic was zero order. The drug release mechanism by Korsmeyer-Peppas model reveals the non-fickian demonstrated with diffusion exponent values.

Conclusion:

The present study indicates enormous potential of erodible mucoadhesive buccal films containing atenolol for systemic delivery with an added advantage of circumventing the hepatic first pass metabolism and gastric degradation of drugs. It may be concluded that the films containing 50 mg Atenolol shown good swelling, a convenient residence time and promising drug release, thus seems to be a right candidate for the development of buccal film for effective therapeutic use employing various mucoadhesive polymers.

 

REFERENCE:

1. Okamoto H, Taguchi H, Iido K, Danjo K. Development of polymer film dosage forms of lidocaine for buccal administration, I: penetration rate and release rate. J Control Release. 2001; 77:253Y260.

2. Vishnu M. Patel, Bhupendra G. Prajapati and Madhabhai M. Patel. Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design. AAPS PharmSciTech 2007; 8 (2) Article 45.

3. Chandra Sekhar K, Naidu K. V. S, Vamshi Vishnu Y, Ramesh Gannu, Kishan V and Madhusudan Rao Y. Transbuccal delivery of chlorpheniramine Maleate from mucoadhesive buccal patches. Drug Delivery, 2008, 15:185–191.

4. Sanjay Singh, Rajeev Soni, Manoj Kumar Rawat, Achint Jain, Shripad Bheemrao Deshpande, Sanjeev Kumar Singh, and Madaswamy Sona Muthu C. In-vitro and in-vivo evaluation of buccal bioadhesive films containing salbutamol sulphate. Chem. Pharm. Bull. 2010, 58(3) 307—311.

5. Hoogstraate A. J and Wertz P. W. Drug delivery via the buccal mucosa. PSTT. 1998, 17:309–316.

6. Vishnu M. Patel, Bhupendra G. Prajapati and Madhabhai M. Patel. Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design. AAPS PharmSciTech 2007; 8 (2) Article 45.

7. Shojaei, A.H. Buccal Mucosa as a route for systemic drug delivery. J. Pharm. Pharmaceut. Sci., 1998, 1, 15-30.

8. Giunchedi, P, Juliano, C, Gavini, E, Cossu M, Sorrenti M. Formulation and in-vivo evaluation of chlorhexidine buccal tablets prepared using drug loaded chitosan microsphears. Eur. J. Pharm. Biopharm., 2002, 53, 233-9.

9. Khanna R, Agarwal S P, Ahuja A. Preparation and evaluation of muco adhesive buccal films of clotrimazole for oral candida infections. Int. J. Pharm., 1996, 138, 67-73.

10. Nagai, T, Konishi R. Buccal/gingival drug delivery systems. J.Control. Release, 1987, 6, 353-60.

11. Burgalassi S, Panichi L, Saettone M.F Jacobsen J Rassing M.R. Development and in-vitro/in vivo testing of mucoadhesive buccal patch releasing benzydamine and lidocaine. Int. J. Pharm., 1996, 133, 1-7.

12. Reinhold A, Hans P.M. Evaluation of laminated mucoadhesive patches for buccal drug delivery. Int. J. Pharm., 1989, 49, 231-40.

13. Wong C.F, Yuen, K.H, Peh K.K. Formulation and evaluation of controlled release eudragit buccal patches. Int. J. Pharm., 1999,178, 11-22.

 

Table 1: The compositions of atenolol buccal films

Component

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

Primary layer (Mucoadhesive layer)

Atenolol (mg)

701

701

701

701

701

701

701

701

701

701

701

701

HPMC E15 (mg)

750

500

1000

-

-

-

-

-

-

-

-

-

SCMC

-

-

-

750

500

1000

-

-

-

-

-

-

Sodium alginate

-

-

-

-

-

-

750

500

1000

-

-

-

PVA

-

-

-

-

-

-

-

-

-

750

500

1000

Propylene glycol

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

Distilled water (ml)

15

15

15

15

15

15

15

15

15

15

15

15

Secondary layer (Backing layer)

Ethyl cellulose (mg)

750

1000

1000

750

1000

1000

750

1000

1000

750

1000

1000

Propylene glycol

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

4 drops

Dichloromethane: Methanol (ml) 1:1

13

13

13

13

13

13

13

13

13

13

13

13

 

 

 

 

Table 2(a): Physicochemical parameters of the atenolol bucco adhesive films:

F. code

Film weight mg.

±(SD)

Surface pH

±(SD)

(Assay)% Drug Content w/w ±(SD)

Film thickness mm

±(SD)

Swelling index (3h)

±(SD)

Ex-vivo residence time (h)

±(SD)

F1

265.2±2.26

6.73±1.11

99.52±1.36

1.31±1.08

41.47±1.33

7.3±1.20

F2

264.3±1.32

6.65±1.23

100.01±1.11

1.06±1.09

40.13±1.12

7.2±1.12

F3

266.5±1.87

6.83±1.22

99.44±1.21

1.33±1.29

42.91±1.33

7.4±2.11

F4

266.2±1.12

6.94±1.31

99.99±1.31

1.52±1.12

41.29±1.21

7.03±1.33

F5

265.9±2.81

6.93±1.58

99.73±1.22

1.36±2.11

40.22±1.21

6.9±2.21

F6

267.1±1.21

7.02±1.44

100.09±1.33

1.56±1.03

42.96±1.22

6.8±1.12

F7

265.9±1.36

7.02±1.11

99.92±2.36

1.51±1.02

41.57±1.13

7.1±1.10

F8

264.2±1.32

7.01±1.22

99.78±3.11

1.41±1.11

40.11±1.11

7.0±2.18

F9

266.3±1.27

7.03±1.32

101.04±1.33

1.59±1.03

42.12±1.33

7.2±1.02

F10

266.1±1.12

6.94±1.22

100.98±1.31

1.68±1.09

40.29±1.35

7.5±1.33

F11

265.9±1.38

6.93±1.28

99.71±1.32

1.62±1.51

39.81±1.57

7.3±1.21

F12

267.1±1.22

7.01±1.14

101.09±1.13

1.69±1.33

41.56±1.01

7.6±1.09

 

Table 2(b): Physicochemical parameters of atenolol bucco adhesive films

 

F. Code

Folding endurance

±(SD)

PMA±(SD)

PML±(SD)

Q ±(SD)

F1

298 ±1.0

6.21±0.07

4.97±0.12

6.58±0.25

F2

297 ±1.0

5.32±0.04

4.14±0.72

6.37±0.44

F3

300±1.0

7.24±0.09

4.99±0.10

6.75±0.34

F4

299±3.0

8.32±0.11

3.84±0.20

6.49±0.35

F5

298±3.0

7.13±0.09

3.68±0.03

6.48±0.08

F6

301±5.0

9.21±0.06

3.88±0.02

6.69±0.32

F7

302±4.0

7.86±0.27

6.44±0.10

6.87±0.35

F8

301±3.0

6.18±0.13

6.13±0.08

6.48±0.52

F9

303±2.0

8.34±0.12

7.12±0.07

6.98±0.42

F10

298±3.0

3.12±0.13

7.66±0.06

7.3±0.29

F11

297±3.0

2.56±0.25

7.21±0.06

6.9±0.48

F12

301±5.0

3.33±0.23

7.84±0.08

7.4±0.20

 

 

 

Fig: 1. Ex-vivo residence time of atenolol films

Fig: 2. In-vitro drug release of atenolol films-Zero order

 

Fig: 3. In-vitro drug release of atenolol films- Higuchi model

Fig: 4. In-vitro drug release of atenolol films- Korsmeyer-Peppas model


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