Formulation Development of Oral Mucoadhesive Coated Terbutaline Sulphate Tablets Using Some Natural Materials Extracted from Edible Fruits Available in India

1. 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 delivery [1]. While the subject of mucoadhesion is not new, there has been increased interest in recent years in using mucoadhesive polymers for drug delivery [2, 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 delivery [4]. 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 tract [5]. Several polymeric bioadhesive drug delivery systems have been fabricated and studied in the past. Different types of bioadhesive synthetic polymers such as acrylic-based hygrogels [6] i.e. synthetic polymers such as carbopol 934,carbopol 937 and hydroxypropylmethylcellu-lose (HPMC) are also used to prepare oral mucoadhesive tablets [7]. 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 discovered [8-12].

      Since the biodegradability of the synthetic polymers is questionable, some natural mucoadhesive materials extracted from edible fruits and vegetables having good mucoadhesive properties are used for this purpose [13].

      Terbutaline sulphate is widely used as an effective bronco dilator in the management of asthma [14]. 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.

2. Materials and methods

2.1. Materials

      Terbutaline sulphate and hydroxypropyl-methylcellulose K4M (HPMCK4M) were 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 Zizyphus mauritiana Lam. and Aegle marmelos (Linn.) Cor. were purchased from local market.

2.2. Extraction of natural mucoadhesive materials

      The mucilage from above materials was extracted following method of Rao et al. [15] with little modifications. In this method, 250 g edible fruits of Z. mauritiana and A. marmelos were soaked in double distilled water and boiled for 5 h 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 20 min. The supernatant was concentrated at 60 C 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 50 C under vacuum. The dried material was powdered and kept in a desiccator.

2.3. Study of swelling property of mucoadhesive materials

      Natural mucoadhesive material obtained from the fruits of A. marmelos [16-18] and Z. mauritiana [19, 20] are nontoxic. Each 250 mg of natural bioadhesive materials and HPMCK4M was allowed to hydrate in 25 ml of distilled water at 25 C in a 25 ml graduated cylinder. The volume of the natural bioadhesive materials and HPMCK4M measured at 5 min. intervals until there was no further hydration observed. Swelling property of different mucoadhesive polymer and materials were checked in different pH [6].

Figure 2.  Results of mucoadhesiveness extracted from Zizyphus mauritiana (ZM), Aegle marmelos (AM) and HPMCK4M by Wilhelmy plate method. Weight required was average of three determinations (±SD). A 0.75% w/v solution of synthetic polymer and mucoadhesive materials in purified water was used. 

2.4. 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 length of the thread from pulley to beaker was 7 cm. The weight of the beaker was counteracted. A 0.75% w/v solution of natural mucoadhesive materials extracted from the fruits of Z. mauritiana and A. marmelos and HPMCK4M was prepared using purified water i.p. as solvent. A fixed volume (0.5 ml) of 0.75% w/v solution of HPMCK4M and natural bioadhesive material solutions of Z. mauritiana and A. marmelos 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 g 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 20 min., 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 experiment, 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.

2.5. Determination of mucoadhesiveness by Wilhelmy plate method

      In this method small glass plates were coated uniform by synthetic polymer and natural bioadhesive material solution to be tested and dried at 60 C. The prepared coated plates were immersed in goat intestinal mucus solution (pH=5.5), or USP simulated intestinal fluid (pH=6.0), or USP simulated gastric fluid (pH=1.2), for 5, 10, 15, and 20 min., at room temperature. The force required to pull the plate out of the solution was determined under constant experimental conditions [21].

Figure 3. Release profiles of mucoadhesive tablets of terbutaline sulphate. Average of the three dimensions (±SD). Only batches F1 and F2 released drug up to 12 h. In case of other batches total amount of drug was released before 12 h.

Natural mucoadhesive materials (250 mg) and HPMCK4M (250 mg) were passed through sieve no. 60 and 25 ml measuring cylinder was used for this experiment.

2.6. 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 3 h) and sustaining its desired blood level for 12 h, the loading and maintenance doses were calculated to be 1.5 mg (first hour) and 6 mg, respectively,  by  applying  the  following equations:

      where, Dt is total dose (non-sustained loading dose which is equal to 2 mg in case of terbutaline sulphate); DI (corrected) is the corrected form of non-sustained loading dose required to achieve initial blood level, and Dm is the maintenance dose; K1 is elimination rate constant which is equal to 0.693/ t_½, where t_½ is the biological half-life of the drug; Wo is the initial dose required to produce desired biological activit; tp is time required for the onset of action which is equal to one hour in case of terbutaline sulphate; and h is duration (hours) for which sustained action is desired [22].

2.7. Preparation of mucoadhesive tablets

       Mucoadhesive coated tablets, each containing 7.5 mg 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 HPMCK4M 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 60 C for 24 h. 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 hardness of 4-5 kg/cm² on a single punch tablet machine. All the prepared tablets were coated with 1% w/v aqueous solution of natural mucoadhesive materials and HPMCK4M and then evaluated for hardness, friability, average weight and disintegration time.

2.8. Identification and estimation of terbutaline sulphate

       The spectrophotometric method based on the measurement of absorbance at 276 nm in phosphate buffer of pH=7.4 was used for the identification of terbutaline sulphate. Terbutaline sulphate was assayed by HPLC method [24] using a 276 UV detector and a 4.6 mm×25 cm column that contains 5 mm packing LI. The flow rate was about 1 ml/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.