Development of Oral Mucoadhesive Tablets of Terbutaline Sulphate Using Some Natural Materials Extracted from Albelmoschus esculeatus and Tamarindus indica

 

Ranabir Chanda1*, S. K. Mahapatro1, Tutun Mitra1, Amit Roy2 and Sanjib Bahadur2

 

1Himalayan Pharmacy Institute, Majhitar, Rangpo, E. Sikkim-737136, India.

2GRY Institute of Pharmacy, Vidya Vihar, Borawan, Khargone- 451228 M.P

*Corresponding Author E-mail: ranabirchanda@yahoo.com

 

ABSTRACT

Mucoadhesive polymers that bind to the gastric mucin or epithelial cell surface are useful in drug delivery for the purpose of increasing the intimacy and duration of contact of drug with the absorbing membrane. Several synthetic polymers are in use for this purpose.  Since the biodegradability of the synthetic polymers are questionable, in this investigation an oral mucoadhesive controlled delivery system has been developed for terbutaline sulphate using natural mucoadhesive materials extracted from edible fruits like Albelmoschus esculeatus and Tamarindus indica that have better mucoadhesive property than synthetic polymer carbopol 934. The in-vitro  adhesive and mucoadhesive strength and swelling property of mucoadhesive materials extracted from edible fruits of Albelmoschus esculeatus and Tamarindus indica were evaluated and compared with Carbopol 934 by Share Stress and Park and Robinson methods. Different formulations of oral mucoadhesive coated terbutaline sulphate tablets were prepared using these natural materials and carbopol 934 and hardness, thickness, friability, weight variation and assay of tablets were tested. The in-vitro release of terbutaline sulphate was studied in buffer pH 7.2 at 370C± 0.50C. The blood plasma concentration of terbutaline sulphate in rabbits was determined using HPLC. It was found that mucoadhesive materials extracted from edible fruits of Albelmoschus esculeatus and Tamarindus indica exhibited better adhesiveness and mucoadhesiveness as compared with the synthetic mucoadhesive agent Carbopol 934 by different methods. The in-vitro and in-vivo drug release study of terbutaline sulphate exhibited extended drug release profile for tablets prepared with natural materials than synthetic polymers. After in-vitro and in-vivo correlation study it was seen that both in-vitro and in-vivo drug release study showed the same release profile. The present study shows that natural mucoadhesive materials extracted from edible fruits of Albelmoschus esculeatus and Tamarindus indica have greater mucoadhesive property than synthetic polymer i.e. Carbopol 934 where both are used in the same amount..

KEY WORDS       Mucoadhesive, Terbutaline sulphate, Tablets.

 


INTRODUCTION:

 

Mucoadhesion, or the attachment of a natural or synthetic polymer to a biological substrate, is a practical method of drug immobilization or localization and an important new aspect of controlled drug delivery1. While the subject of mucoadhesion is not new, there has been increased interest in recent years in using mucoadhesive polymers for drug delivery2-3. Substantial effort has recently been focused on placing a drug or a formulation in a particular region of the body for extended periods of time. This is needed not only for targeting of drugs but also to better control of systemic drug delivery4. Drugs that are absorbed through the mucosal lining of tissues can enter directly into the blood stream and not be inactivated by enzymatic degradation in the gastrointestinal tract5. Several polymeric bioadhesive drug delivery systems have been fabricated and studied in the past. Different types of bioadhesive synthetic polymers such as acrylic-based hygrogels6 i.e. synthetic polymers such as carbopol 934, carbopol 937 and hydroxypropylmethylcellulose are also used to prepare oral mucoadhesive tablets7

 

However, the adhesiveness and drug delivery capabilities of these devices can continue to be improved as presently known bioadhesive materials are modified and more bioadhesive materials are discovered8-19. Some natural mucoadhesive materials extracted from edible fruits and vegetables having good mucoadhesive properties are also used for this purpose20.

 

Terbutaline Sulphate is widely used as an effective bronco dilator in the management of asthma21. This is used as prophylactic drug as well as to prevent acute exacerbations of asthma. During acute attack of asthma it becomes difficult for a patient to take oral medications repeatedly. Hence, it is rational to administer terbutaline sulphate in a sustained release dosage form, which will minimize repeated administration of drug.

MATERIAL AND METHODS:

Terbutaline sulphate and Carbopol 934 were collected as gift samples from M/S Union Drugs Ltd, Kolkata. Acetone GR, talc IP and magnesium stearate IP were procured from M/S Loba Chemicals, Mumbai. Dihydrogen potassium phosphate LR, sodium hydroxide LR, concentrated hydrochloric acid LR and dibasic calcium phosphate (commercial grade) were purchased from Process Chemical Ltd, Kolkata. Monobasic potassium phosphate LR and Pancreatin were procured from E. Marck (India) ltd, Mumbai. Terbutaline sulphate RS was collected from Central Drug Laboratory, Kolkata.  The fruits of Albelmoschus esculeatus and Tamarindus indica were purchased from local market.

 

Figure1: Results of adhesiveness  of materials extracted from Ladys’ Finger, Tamarindus indica and Carbopol 934* by Shear Stress Method. *Weight required was average of three determinations (±SD). 0.75% w/v solution of synthetic polymer and mucoadhesive materials in  purified water I.P. was used.* Ladys’ Finger= Albelmoschus esculentus

 

Extraction of natural mucoadhesive materials:

The mucilage from above materials was extracted following method of Rao et al22 with little modifications. In this method, 250gm edible fruits of Albelmoschus esculeatus and Tamarindus indica  were soaked in double distilled water and boiled for 5 hrs in a water bath until slurry was formed. The slurry was cooled and kept in refrigerator overnight so that most of the undissolved portion was settled out. The upper clear solution was decanted off and centrifuged at 500 rpm 20min. The supernatant was concentrated at 600C on a water bath until the volume reduced to one third of its original volume. Solution was cooled down to the room temperature and was poured into thrice the volume of acetone by continuous starring. The precipitate was washed repeatedly with acetone and dried at 500C under vacuum. The dried material was powdered and kept in a desiccator.

 

Study of swelling property of natural mucoadhesive materials and Carbopol 934:

Each 250mg of natural bioadhesive materials and carbopol 934 was allowed to hydrate in 25ml of distilled water at 250C in a 25ml graduated cylinder. The volume of the natural bioadhesive materials and Carbopol 934 measured at 5min intervals until there was no further hydration observed. Swelling property of different mucoadhesive polymer and materials were checked in different pH23.

 

Shear Stress Method:

Two smooth, polished plexi glass blocks were selected; one block was fixed with adhesive ‘Araldide’ on a glass plate, which fixed on leveled table. To the upper block a thread was tied and the thread was passed down through a pulley. At the end of the thread a beaker was fixed. The

 

Figure 2: Results of adhesiveness of materials extracted from Ladys’ Finger, Tamarindus indica and Carbopol 934 * by Park and Robinson Method. *Weight required was average of three determinations (±SD). 0.75% w/v solution of synthetic polymer and mucoadhesive materials in purified water I.P. was used. * Ladys’ Finger= Albelmoschus esculentus.

 

length of the thread from pulley to beaker was 7cms. The weight of the beaker was counteracted24. 0.75% w/v solution of natural mucoadhesive materials extracted from the fruits of Albelmoschus esculeatus and Tamarindus indica and synthetic polymer, Carbopol 934 was prepared using purified water I.P. as solvent. A fixed volume (0.5ml) of 0.75% w/v solution of Carbopol 934 and natural bioadhesive material solutions of Albelmoschus esculeatus and Tamarindus indica were kept on the centre of the fixed block with a pipette, and then second block was placed on the first block and pressed by applying 100 gm of weight, so that the drop of synthetic polymer and natural bioadhesive material solutions spreads as a uniform film in between the two blocks. After keeping it for a fixed time intervals of 5, 10, 15, and 20min, purified water was added into the beaker gradually, the weight of purified water just sufficient to pull the upper block or to make it slide down from the base block was recorded. This weight was considered as the adhesion strength, i.e. shear stress required to measure the adhesion. Before every experimentation care was taken so that no air bubble form in between the two blocks, which may give erratic results, and the distance from pulley to glass block was always same in all observations.

 

Park and Robinson Method:

In this method, the force required to separate bio-adhesive sample from freshly excised rabbit stomach was determined using a modified tensiometer. A section of the tissue, having the mucus side exposed, was secured on a weighted glass vial placed in a beaker containing USP simulated intestinal fluid. Another section of the same tissue was placed over a rubber stopper, again with the mucus side exposed, and secured with a vial cap. Then a small quantity of synthetic polymer or natural mucoadhesive agent was placed between the two mucosal tissues. The force used to detach the polymers or nature mucoadhesive agents from the tissue was then recorded. Experimentations were performed at room temperature4.

 

Calculation of Initial and Maintenance Doses of Terbutaline Sulphate:

The amount of terbutaline sulphate to be taken as loading and maintenance doses were calculated from the pharmacokinetic data.   Knowing its biological half –life (2.76 or 3h) and sustaining its desired blood level for 12h the loading and maintenance doses were calculated to be 1.5mg (first hour) and 6mg respectively by applying the following equations:

Dt = DI (corrected) + Dm                      ……1

Where,     Dt = Total dose.

DI (corrected) = corrected form of non-sustained loading dose required to achieve initial blood level.

Dm = maintenance dose.

Again,

DI (corrected) = DI – K1. Wo. Tp         .……2

and          Dm = K1. Wo.h                                      ….…3

DI= non-sustained loading dose which is equal to 2 mg in case of terbutaline sulphate.

K1 = elimination rate constant which is equal to 0.693/ t ½, where t ½ is the biological half-life of the drug. Wo = initial dose required to produce desired biological activity. tp = time required for the onset of action which is equal to one hour in case of terbutaline sulphate, and h= duration (hours) for which sustained action is desired25.

 

Figure 3: Release Profiles of Mucoadhesive Tablets of Terbutaline Sulphate*. *Average of the three dimensions (±SD). Only batches F1 and F2 release drug up to 12h. In case of other batches total amount of drug was released before 12h.

 

Preparation of mucoadhesive tablets:

Mucoadhesive coated tablets each containing 7.5mg of terbutaline sulphate were prepared by conventional wet granulation method employing part of the mucoadhesive materials as filler and part of the natural mucoadhesive materials and Carbopol 934 as binding agent as per the formulae given in Table 2. A blend of all ingredients was granulated with water. The wet masses were passed through 12-mesh sieve and the resulting granules were dried at 600C for 24h. The dried granules were passed through 18-mesh sieve. After blending with talc and magnesium stearate in a laboratory cube blender for 10 min, they were compressed into 100 mg tablets to a harness of 4-5kg/cm2 on a single punch tablet machine. All the prepared tablets were coated with 1% w/v aqueous solution of natural mucoadhesive materials and Carbopol 934 and then evaluated for hardness, friability, average weight and disintegration time.

Identification and Estimation of terbutaline sulphate:

The spectrophotometric method based on the measurement of absorbance at 276nm in phosphate buffer of pH 7.4 was used for the identification of terbutaline sulphate. Terbutaline sulphate was assayed by HPLC method26 using an 276UV detector and a 4.6mm X 25cm column that contains 5μm packing LI. The flow rate was about 1ml per min. The mobile phase was used as a mixture of ion-pair solution and methanol (77:23). Terbutaline sulphate USP RS was used as standard.

 

Figure 4: Mean serum concentration of Terbutaline Sulphate (mcg/ml) of different     batches*. *Average of the six dimensions (±SD).

 

In-vitro Drug release study:

Release of terbutaline sulphate from the mucoadhesive coated tablets was studied in phosphate buffer of pH 7.2 (900ml) as prescribed in the dissolution rate test of terbutaline sulphate tablets in USP XXIV (Method A) using USP Apparatus ll by the rotation of the paddle at 100 rpm. Samples were withdrawn through a filter (0.45µm) at different time intervals, suitably diluted and assayed for terbutaline sulphate at 276nm. Drug release experiments were conducted in triplicate27.

 

In-vivo drug absorption study:

Six health male albino rabbits weighing between 2.5-3.0kg were fasted overnight. The oral terbutaline sulphate tablets (7.5mg) were administered to rabbits. At determination time intervals, 1 ml blood samples were withdrawn from the marginal ear vein. The serum was subsequently separated, and in order to limit degradation, serum samples were stored at 00C. The samples were analysis through HPLC and drug plasma concentration was computed using Kinetica 2000 Verson 3.0 (InnaPhase Corporation, USA).

The Institutional Ethics Committee has approved and given the permission to conduct the in-vivo study using healthy rabbits.

 

Terbutaline sulphate was separated from serum samples through liquid-liquid extraction, by buffering with phosphate buffer pH 7.2, obtained with chloroform. The chloroform layer was separated and mixed with 0.5M hydrochloride chloride acid. The aqueous layer was then separated by centrifuge and analysed. The amount of terbutaline sulphate was determined using HPLC containing hypersil ODS column (4.6 X 150mm) with UV detector (Waters 2487 dual 1 absorbance detector)28.

 

In-vitro and In-vivo correlation study:

In-vitro and  in-vivo correlation was evaluated using Level A Correlation29. This level of correlation is the highest category of correlation and represents a point-to-point relationship between in-vitro dissolution rate and in-vivo input rate of the drug from the dosage form30.

 

Figure 5: Relationship between percent Terbutaline Sulphate released in-vitro and absorbed in-vivo for batch F1.

 

 

RESULTS:

Studies of Swelling Property of Natural Mucoadhesive Materials and Carbopol 934:

The swelling property of natural mucoadhesive materials extracted from the fruits of Albelmoschus esculeatus and Tamarindus indica and synthetic polymer Carbopol 934 was studied in buffer of pH 5.5, 6.5 and 7.5 and swelling capacity was determined at different time intervals (Tab 1).

 

In-vitro adhesiveness and mucoadhesiveness study:

The results obtained from Shear Stress, and Park and Robinson method for natural mucoadhesive materials and synthetic polymer carbopol 934 with different contact time were presented in Figure 1-2. The experiments were performed thrice and the average values are reported. Mucoadhesive materials extracted from fruits of Albelmoschus esculeatus exhibited better adhesiveness (18g) after 20min from initial in shear shress method followed by natural materials extracted  from the fruits of Tamarindus indica (17.6g) and Carbopol 934 (9.6g). In Park and Robinson method materials extracted from the  fruits of Albelmoschus esculeatus exhibited 25.6g after 20 min using USP simulated intestinal fluid followed by materials from the fruits of Tamarindus indica (25.3g) and Carbopol 934 (16.3g).

 

Evaluation of oral mucoadhesive coated terbutaline sulphate tablet:

The disintegration test of tablets prepared and coated with mucoadhesive materials was performed in purified water I.P, in 0.1(N) HCl and in buffer of pH 7.2. Hardness of the tablets was found in the range 4-5 kg/cm2 . Percentage weight loss in the friability test was found less than 0.1% in the all batches. The tablets in all batches contained terbutaline sulphate within 100±2% of the labeled content. Overall the prepared tablets were of good quality with regard to hardness, friability, and drug content.

 

In-vitro drug release study:

The results of in-vitro drug release studies of different batches are depicted in Figure3.The formulation with natural mucoadhesive material extracted from the fruits of Albelmoschus esculeatus in 1:1 drug-mucoadhesive material ratio (Formula F1) exhibited the extended cumulative percentage of drug release value (95.5%) after 12h followed by Tamarindus indica (95.85%). Other formulation did not show the results of drug release upto that extend.

 

In-vivo drug absorption study:

Serum terbutaline concentrations and standard deviations achieved are shown graphically in Figure 4. The blood sample was withdrawn at 30 minutes intervals.  Batch A and Batch B showed the greater Cmax values as compare to other batches. Mucoadhesive materials do not interfere the release and absorption of terbutaline sulphate and at the same time promote the retention of order units in the G.I tract.

 

In-vitro and In-vivo correlation study:

A good correlation between the dissolution profiles bioavailability was observed. The relationship between percent drug released and percent drug absorbed is illustrated in Figure 5 and Figure 6.

 

Figure 6: Relationship between percent Terbutaline Sulphate released in-vitro and absorbed in-vivo for batch F2.

 

DISCUSSION:

Table 1 represented the swelling property of Carbopol 934 and mucoadhesive materials obtained from Albelmoschus esculeatus and Tamarindus indica. From this results it was confirmed that swelling property of Carbopol 934 is maximum followed by the material extracted from the edible fruits of Tamarindus indica and it was minimum for the materials extracted from the edible fruits of  Albelmoschus esculeatus. The results obtained from Shear Stress (Fig.1) and Park and Robinson method (Fig.2). it is confirmed that the mucoadhesive materials extracted  from the fruits of Albelmoschus esculeatus and Tamarindus indica showed better adhesive and mucoadhesive property than the synthetic polymer carbopol 934. The adhesive and mucoadhesive strength of this synthetic polymer and

 

Table1: Determination of swelling property of natural mucoadhesive materials and Carbopol 934. *250 mg natural mucoadhesive materials and Carbopol 934 were passed through sieve no.60 and 25 ml measuring cylinder was used for this experiment

Polymer/Mucoadhesive Materials

Contact Time (min.)

Volume Changes in pH 5.5 (ml.)

Volume Changes in pH 6.5 (ml.)

Volume Changes in pH 7.5 (ml.)

Albelmoschus esculeatus

00

05

10

15

20

25

30

35

0.9

1.0

1.1

1.2

1.3

1.4

1.4

1.4

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.5

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6

Tamarindus indica

 

00

05

10

15

20

25

30

35

1.2

1.3

1.4

1.5

1.6

1.6

1.6

1.6

1.2

1.3

1.4

1.5

1.6

1.7

1.7

1.7

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.8

Carbopol 934

00

05

10

15

20

25

30

35

1.2

1.3

1.4

1.5

1.6

1.7

1.7

1.7

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.8

1.2

1.3

1.4

1.5

1.6

1.7

1.9

1.9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

natural mucoadhesive materials was increased with time and it was maximum in case of material extracted from fruits of Albelmoschus esculeatus and minimum in case of  carbopol 934. The desired sustained release rate for all the batches followed zero order kinetic after a lag time of 1.0h and up to 95.5% was released and gave slow release over a period of 12h. for the tablets of terbutaline sulphate  prepared by natural mucoadhesive materials obtained from the fruits of Albelmoschus esculeatus and Tamarindus indica in 1:1 drug-polymer ratio (batch F1 and F2) (Fig.3). This extension of release time is greater than the tablets prepared by Carbopol 934 in the same drug-polymer ratio (batch F3). Tablets prepared by the natural mucoadhesive materials in 1:2 drug:mucoadhesive materials ratio (batch F4 and F5) showed extended release  over a period of 11 h. Total about 95% drug was released at that period and this extension of release time is also greater than the tablets prepared by carbopol 934 (10h) in the same drug-polymer ratio (batch F6). This might be due to slow and continuous supply of terbutaline sulphate at a desirable rate. The drug release rate was suggested by Wagner31.Based on this release rate an oral control release of terbutaline sulphate should extend up to 12h containing total dose of 7.5 mg.

 

The blood serum concentration obtained from batch F1 and batch F2 (Fig. 4) which were prepared from natural mucoadhesive materials were sustained and exhibited a smooth and extended absorption phase as observed with other batches. Batch F1 and Batch F2 showed the Cmax at 12 hours followed by other batches. The data generated in the present investigation indicated that the absorption of terbutalilne sulphate from gastrointestinal tract may depend mostly on the release rate. A direct correlation between the dissolution profiles of batch F1 and batch F2 (Fig.5 and Fig.6) with the relative bioavailability of the formulations could be observed. These two batches have a much slower but continuous absorption as compared to other batches.

 

Table2: Formulations of coated Tablets of Terbutaline Sulphate prepared by mucoadhesive materials extracted from Albelmoschus esculeatus and Tamarindus indica and Carbopol 934.

Ingredient (mg/tablet)

Formulation

F1

F2

F3

F4

F5

F6

Terbutaline Sulphate I.P.

7.5

7.5

7.5

7.5

7.5

7.5

Dibasic Calcium Phosphate

83

83

83

75.5

75.5

75.5

Extract of material from fruits of Albelmoschus esculeatus

7.5

-

-

15

-

-

Carbopol 934

-

-

7.5

-

-

15

Extract of material from fruits of Tamarindus indica

-

 

7.5

-

-

15

-

Magnesium Stearate

1

1

1

1

1

1

Talc

1

1

1

1

1

1

 

 

Short-term stability studies (at 400C for 6 months) of the formulations F1 and F2 was carried on as per ICH guidelines32 and it was confirmed  that the tablets were stable with respect to drug content. IR spectroscopic studies indicated that there was no drug-excipient interaction.

 

In conclusion, the results of the present study indicated that the formulation F1 which was prepared from the mucoadhesive materials extracted from the edible fruits of Albelmoschus esculeatus and used in 1:1 drug: material ratio and the formulation F2 which was prepared from the  mucoadhesive materials extracted from the edible  fruits of Tamarindus indica and used in 1:1 drug: material ratio have shown promising results (release about 95.5% drug in 12h) with reasonably good mucoadhesive properties of natural materials.

ACKNOWLEDGEMENTS:

The authors are thankful to Mr. Ratan Biswas and Mr. Sandip Ghosh of Himalayan Pharmacy Institute, Sikkim for necessary computer assistance.

 

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Received on 27.03.2008          Modified on 04.04.2008

Accepted on 12.04.2008          © RJPT All right reserved

Research J. Pharm. and Tech. 1(1): Jan.-Mar. 2008; Page 46-51