Paridhi et al., ARPB, 2012; Vol 2 (IV) ISSN

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1 FORMULATION AND IN-VITRO CHARACTERIZATION OF SELF EMULSIFYING DRUG DELIVERY SYSTEM OF CISAPRIDE *P. Porwal 1, S. Bhargava 1, R.S. Bhaduria 1, S.S. Shukla 2 and S.J. Daharwal 3 1Shrinathji Institute of Pharmacy, Nathdwara (Raj) 2Columbia Institute of Pharmacy,, Tekari, Raipur (C.G.) 3Institute of Pharmacy, Pt. R. S. University Raipur (C.G.) Received on 20/11/2012 Revised on 29/11/2012 Accepted on 02/12/2012 ABSTRACT: In the present work, an attempt has been made to develop a self emulsifying formulation of cisapride to increase its solubility and bioavailability. Cisapride is practically insoluble in water, sparingly soluble in methanol, and soluble in acetone and it is highly lipophilic drug. SEDDS or self-emulsifying oil formulations (SEOF) are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or alternatively, one or more hydrophilic solvents and cosolvents/ surfactants. In this study we prepared 7 different formulations of cisapride with varying concentration of oil, surfactant and cosurfactant and evaluated all the formulations for various parameter. From the study it was concluded that Formulation no. 4 has good emulsification property with uniform globule size and satisfactory in- vitro drug release profile. Keywords: Cisapride, Solubility, Bioavailability, Lipophilic. *Corresponding Author: Mrs. Paridhi Porwal Shrinathji Institute of Pharmacy Nathdwara, Rajasthan India paridhimph@gmail.com INTRODUCTION SEDDS or self-emulsifying oil formulations (SEOF) are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or alternatively, one or more hydrophilic solvents and co-solvents/ surfactants. 1-5 Self-emulsifying drug delivery systems (SEDDSs) have gained exposure for their ability to increase solubility and bioavailability of poorly soluble drugs. 6 SEDDS systems act as carriers for drugs by forming fine emulsions, or micro-emulsions, under gentle stirring when diluted in water or physiological media with physiological motion. Drug molecules are either dissolved or suspended in the self system, which maintains the drug in very fine dispersion droplets inside the intestinal lumen, providing optimal conditions for absorption. 7 Cisapride is a parasympathomimetic agent which acts as a serotonin 5-HT 4 agonist. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. This results in increased tone and amplitude of gastric (especially antral) contractions. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride is practically insoluble in water, sparingly soluble in methanol, and soluble in acetone. It is highly lipophilic drug. Cisapride is rapidly absorbed with an absolute bioavailability of 35-40%.Cisapride is extensively metabolized and its elimination half life is about 8-10 hours. Cisapride is poorly water soluble with solubility 1.20 mg/ml hence it is used as a model drug. Self emulsifying formulation of cisapride was formulated employing oleic acid, tween 80, propylene glycol in varying proportions and evaluated for emulsification property and drug release profile. Thus, for cisapride with poor solubility and absorption, these systems may offer an improvement in the rate and 324 P a g e w w w. a r p b. i n f o

2 extent of absorption and more reproducible plasma appearance from turbid to transparent or from concentration profiles. 5 transparent to turbid. All the ratios in this study are reported as weight-to-weight ratios (W/W).the phase diagram was constructed by using Sigma Plot 10 software. Fig 1: 1 Cisapride MATERIALS AND METHOD Materials: Cisapride was procured as a gift sample from Vasudha Pharma Chem Limited, Jeedimetla, Hyderabad. Oleic acid, tween 80, tween 20, propylene glycol, castor oil, olive oil, span 80 were supplied by Loba Chemie Pvt. Ltd. Mumbai., and were used as received. Methods: Fig. No. 2 Ternary Phase Diagram of Mixture Consisting Solubility Determination : For the preparation of self of Oleic Acid, Propylene Glycol and Tween 80 emulsifying system mainly lipophilic drugs are used. Preparation of self emulsifying formulation and For this study poorly water soluble cisapride was solubility determination of drug: Various formulations chosen for the preparation of SEDDS. The solubility of were prepared with a constant amount of cisapride cisapride was studied in various solvents to select the (20mg) and varying ratios of oil, surfactant to solvent exhibit maximum solubility for drug. cosurfactant. In brief, cisapride was dissolved in stated Table No.1 Solubility study of Cisapride in various volume of oleic acid (used as oil phase) in stoppered solvents glass vials. Required amounts of tween 80 and Solvent Solubility (mg/ml) propylene glycol were added to the mixture and mixed Water Insoluble 1.20 well. These systems were warmed to 40 C using a water Oleic acid bath for 30 min with intermittent shaking to ensure Castor oil 3.19 complete mixing. The prepared formulations were then Olive oil 2.16 stored until further use. The formula for optimized Tween SEDDS is shown in table no. 2. Span 80 Insoluble Table No. 2 Optimized Formula for SEDDS Propylene glycol 8.90 S. No. Ingredients % used Construction of Pseudo-Ternary Phase Diagrams : 1 Oleic aicd 60 To obtain an optimum formula of the cisapride SEDDS, 2 Tween which can form a microemulsion upon dilution with 3 Propylene glycol 10 water, pseudo-ternary phase diagrams were 4 Cisapride 20 mg constructed using the water titration method at Table No. 3 Determination of solubility of cisapride in ambient temperature. Based on preliminary different formulations. experiments, Oleic acid was used as the oil phase, tween Temperature: 25 o c±2 o c 80 was used as the surfactant, and propylene glycol was Formulations Cisapride mg/ml used as the cosurfactant. The oil content used was 90, Formulation , 70, and 60%. The surfactant/cosurfactant ratio used Formulation was 10/0, 10/10, 20/10, and 30/10. Cisapride was Formulation added to the mixture of oil, surfactant and cosurfactant, Formulation water was added drop by drop to this mixture. During Formulation the titration, the samples were agitated gently in order Formulation to reach equilibrium quickly. The phase boundary was Formulation determined by observing the changes in the sample 325 P a g e w w w. a r p b. i n f o

3 EVALUATION Pharmacopeia XXIV dissolution apparatus 2. The Viscosity Determination : Viscosity measurements paddles were rotated at 100 rpm. The SEDDS were performed at 25.0 o C ± 2 o C using a Brookfield formulations were put into hard gelatin capsules (1 digital viscometer-dv I (Spindle: SC4-63) at 100 rpm. size) and used for drug release studies; results were The observations are shown in table no.4 and figure compared with those of plain cisapride. During the no.3 release studies, a 5-ml sample of medium was taken out Table No. 4 Viscosity determination. and subjected to drug analysis using UV. The removed Formulation no. Viscosity in centipoises volume was replaced each time with 5 ml of fresh Time of Emulsification 15 : Different formulations containing oleic acid, tween 80 and propylene glycol in different ratios (preconcentrated) were evaluated for time of emulsification. Time of emulsification was measured by observing the one ml of each formulation was added dropwise to 200 ml of 0.1 N HCl at 37 C. Gentle agitation was provided by a standard stainless steel dissolution paddle rotating at 60 rpm. The time when turbidity observed visually was considered as time of emulsification. The observations are shown in table no. 5 and figure no. 4. Table No. 5 Determination of time of Emulsification Temperature: 25 o c±2 o c Formulation No. Time of emulsification Min: Sec 1 12:20 2 8:13 3 5: : : : :11 Transmission Electron Microscopy: Samples for transmission electron microscopy were prepared by adding distilled water to prepared SEDDS and shaking the mixture manually for 5 minutes. A drop of the resultant microemulsion was placed onto a carbon coated copper grid, forming a thin liquid film. The films on the grid were negatively stained by adding immediately a drop of 2% (w/w) ammonium molybdate in 2% (w/v) ammonium acetate buffer (ph 6.8), removing the excess staining solution with a filter paper, and followed by a thorough air-drying. The stained films were then viewed on a transmission electron microscopy (TEM, FEI-Philips Tecnai 12) and photomicrograph was taken (Fig. 5) In-Vitro Study Dissolution study: The quantitative in-vitro release test was performed in 900 ml of buffer ph 7.4 using US medium. (Fig. 6) Filling of Self Emulsifying Formulation in Hard Gelatin Capsule: All the prepared formulations were filled in hard gelatin capsules (size 1) by hand filling method. RESULTS AND DISCUSSION Viscosity determination: It was found that viscosity decreases with decrease in oil content. The results are shown in table no. 4, figure no.3 Fig. no. 3: Plot of Viscosity for various formulations. Time of Emulsification: It was found from the time of emulsification study that with the increase in surfactant concentration the time of emulsification decreases. The results are shown in table no. 5, figure no. 4. Fig. No. 4: Plot of time of emulsification for various formulations TEM Study: Globule size determination was done by transmission electron microscopy. The result of transmission electron microscopy (TEM) shown in Fig. 5 In-vitro dissolution studies: The in-vitro dissolution studies reveals that formulation No.4 (oleic acid 60%, 30% tween 80 & 10% propylene glycol) showed maximum in-vitro percentage drug release. The formulation was also found to contain maximum 326 P a g e w w w. a r p b. i n f o

4 amount of drug in 1ml i.e.19.23mg/ml. The optimized hard gelatin capsules (Size 1) by hand filling method. formulation was found to form emulsion within 50 There was no change observed in capsule shell. seconds at mild agitation. The comparative in-vitro drug release is shown in fig. no. 6. CONCLUSION Self-emulsifying drug delivery system is a novel approach for the formulation of drug compounds with poor aqueous solubility. SEDDS represent a good alternative for the formulation of poorly water soluble drugs. By this approach it is possible to prolong the release of drug via incorporation of polymer in composition. SEDDS appears to be unique and industrially feasible approach. Since it is made up of nonionic surfactant it dissolves the lipids of the biological membrane and reaches inside. In the present study an attempt was made to prepare self emulsifying Fig. No. 5: Transmission electron microscopy (TEM) of drug delivery system and evaluate its performance. microemulsion (f-4) On the basis of emulsification study, as the concentration of surfactant increases, time of emulsification decreases. Likewise droplet size also decreases with respect to increase in surfactant concentration. As the droplet size decreases, surface area increases allow more rapid dissolution. Formulations 4 found to possess less time of emulsification. Drug release was found to be high with formulation 4. At the end we can conclude by saying that SEDDS formed from oleic acid, tween 80 and propylene glycol in the ratio 60:30:10 (in mmol) is a Fig. No. 6: Comparative in-vitro release study of promising approach to improve the solubility, cisapride dissolution rate and bioavailability of Cisapride in Filling of Hard Gelatin Capsule: The liquid self period of time. Finally we conclude that SEDDS of emulsifying formulation was conveniently filled in to Cisapride gives better drug release as compare to plain drug. Table No. 6 Comparative in-vitro release study of Cisapride S.N Time % Drug Release o (min) Formulation No Market preparation ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.1 61± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.015 REFERENCE 1. R. N. Gursoy, and S. Benita. Self-emulsifying drug lipophilic drugs, Eur J Pharm Biopharm, 50: delivery systems (SEDDS) for improved oral (2000). delivery of lipophilic drugs, Biomed Pharmacother, 3. N. H. Shah, M. T. Carvajal, C. I. Patel, M. H. Infeld, and 58: (2004). A. W. Malick. Self-emulsifying drug delivery systems 2. T. Gershanik, S. Benita. Self-dispersing lipid (SEDDS) with polyglycolized glycerides for formulations for improving oral absorption of 327 P a g e w w w. a r p b. i n f o

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