emulsion-solvent evaporation for terbutaline (Cuña et al., 2000), in-situ gelation for theophylline (Miyazaki et al., 2000), emulsion-solvent diffusion for ibuprofen (Kawashima et al., 1991) and spray drying for paclitaxel (Mu et al., 2005). Choosing a suitable microencapsulation method is highly dependent on the drug characteristics, type of polymer used and economic considerations. Emulsion-solvent evaporation technique is one of early methods of microencapsulation which has been widely studied for preparation of polymeric microcapsules. In this technique, a polymer solution which drug substance is dissolved or dispersed in is emulsified in the external phase. By evaporation of the solvent, polymeric capsules are formed around the drug particles. The size and state of the particle in the internal phase play an important role in the final status of the microparticles. The choice of the internal and the external phase of the emulsion, type of emulsifier and method of homogenizing two phases will effectively determine the characteristics of the final microparticles (Matsumoto et al., 2008). Therefore, the method is very flexible for different types of polymers and hydrophilic and lipophilic drugs, and by selecting suitable solvent and emulsifier; various combinations of drug substances and polymers could be applied. We selected ethyl cellulose (EC) as the sustaining polymer since it is a water-insoluble polymer with good film forming ability, durability and low cost and extended drug release properties (Shi et al., 2008; 2009). EC is a nonbiodegradable and biocompatible and gastro-resistant polymer which has been extensively used as drug release retardant which easily forms microcapsules with a one-step encapsulation method (Das and Rao, 2006; Sudhamani et al., 2010). Taking all these into consideration, we aimed at preparing sustained release microcapsules of theophylline by emulsion-solvent evaporation technique using EC. Although theophylline encapsulation in EC microspheres for sustained delivery have been reported in several studies (Pachuau et al., 2008; Thakare et al., 2011), incorporating the microcapsules into the suspension base was not reported elsewhere. The novelty of our work was to provide a microparticle containing oral liquid sustained release dosage form for easy use in pediatric and geriatric patients. MATERIALS AND METHODS The following materials were obtained from commercial sources: EC (ethoxy content 46%, Aldrich, USA), acetone, dichloromethane, liquid paraffin, acacia, ammonium hydroxide 25%, methyl paraben, propyl paraben, sodium lauryl sulfate (SLS), theophylline and sucrose (Merck, Germany), sorbitol syrup 70% and tragacanth (Modarres, Iran). All other chemicals and solvents were of analytical grade. Preparation of microcapsules Microcapsules were prepared by emulsion-solvent evaporation technique with two strategies. First strategy was based on an oil-in- water (o/w) emulsion which prepared after examining large number of variables. For preparing the oil phase, required amount of EC (in three ratios to drug; 1, 2 and 3) was completely dissolved in dichloromethane and 800 mg theophylline was thoroughly dispersed in the mixture by stirring. The oil phase was emulsified into the aqueous phase (1.5% SLS solution in water) under stirring at 300 rpm. The resulting emulsion was stirred for 45 min at room temperature to remove dichloromethane completely. The formed microcapsules were filtered, washed and dried at room temperature. Second strategy was based on emulsifying the drug-containing EC solution in an oil phase. The optimum condition was selected after performing a set of experiments and evaluating the size and drug loading percentage of the particles. The internal phase of the emulsion contained required amount of theophylline dispersed in the EC solution in acetone. The internal phase was then incorporated into the external phase contained 1.3% Tween 80 in 100 ml liquid paraffin. The mixture was stirred at room temperature for 5h to remove acetone and the resulting microcapsules were then filtered and washed with n-hexane and dried at room temperature. Eight formulations (f1 to f8) were prepared by this strategy in the drug to polymer ratios of 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 and 1:2. Morphological studies of microcapsules In order to demonstrate the formation of microcapsules and preliminary studies of their shape, resulting microcapsules were studied using a simple optical microscope (HM-LUX3, Leitz, Germany). Samples of microcapsules were selected randomly. Size of microcapsules was also determined using hemocytometer. Determination of drug loading of microcapsules The drug content of microcapsules was determined according to USP 30 method for testing content uniformity of sustained-release capsules of theophylline (USP, 2007). Briefly, a sample of microcapsules containing 100 mg of drug was triturated with 20 ml of water, transferred to a 100 ml volumetric flask, 25 ml of 6 N ammonium hydroxide added, sonicated for about 45 min, and cooled to room temperature. The mixture was diluted to volume and mixed. The mixture was then filtered and diluted with water and the absorbance of this solution and a standard solution of theophylline, similarly prepared was read at 270 nm with ultraviolet (UV)-visible spectrophotometer (550SE, Perkin-Elmer, USA). The concentration of drug in the sample was then determined according to the standard solution of theophylline. Preparation of suspensions Microcapsules with the optimum range of dissolution (dissolution test will be discussed in following sections) and shape were selected to be formulated in suspensions. Two suspension formulations were prepared as the medium of suspensions (Table 1), either contains 100 mg theophylline / 5 ml (Kawashima et al., 1991). Characterization of suspensions Rheology The rheology of the suspensions was determined using a Brookfield rotational viscometer (Metler RM180) with measuring bob No.2 and
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