Send Orders for Reprints to reprints@benthamscience.net Drug Delivery Letters, 2014, 4, 000-000 1 2210-3031/14 $58.00+.00 © 2014 Bentham Science Publishers Optimization and Formulation of Cinnarizine-Loaded Chitosan Micro- spheres in Liquid Dosage Form for Pediatric Therapy Reham Aman * , Mahasen Meshali and Galal Abdelghani Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt Abstract: Cinnarizine pediatric preparation is extemporaneously prepared from adult tablets or capsules that are unstable in liquid dosage form. The aim of this work is to develop cinnarizine oral pediatric formulation with improved stability and organoleptic properties as well as to achieve ease of administration. For this purpose, cinnarizine-loaded microspheres of chitosan cross-linked with tripolyphosphate anion were prepared. A full 2 3 factorial design of experiment approach was employed to evaluate the individual and the combined effect of the independent variables namely, concentration of each of chitosan (X A ), tripolyphosphate (X B ), and that of cinnarizine (X C ) on the different responses namely drug entrapment efficiency, drug content, percentage yield and drug release rate for the prepared microspheres. Statistical analysis through response-surface methodology as well as contour plots was assessed. The optimized microspheres (formula 4) showed 93.6±3.3 % percentage yield, 74.3±0.8 mg drug loading, 74.3±0.8 % encapsulation efficiency and 0.19 µm particle size. Hence, it was subjected to stability study of cinnarizine in the dry microspheres immediately thereafter preparation through transmission electron microscope, x-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. The microspheres were further dispensed in the prepared syrup and the suspension was subjected to accelerated stability study, as mentioned in the International Conference on Harmonization (ICH) guidelines. Subse- quently, oral bioavailability study of (formula 4) microspheres was conducted on rats and compared with aqueous suspen- sion of the plain drug. Formula 4 complied successfully with ICH guidelines and experienced enhanced extent of bioavailability with long mean residence time (MRT). Keywords: Bioavailability, chitosan, cinnarizine, factorial design, microspheres, pediatric therapy. INTRODUCTION Cinnarizine (CIN) (1-benzhydryl 1-4-cinnamyl piperazine) is a piperazine derivative that was firstly synthesized by Dr. Paul A.J. Janssen in 1955 [1]. It is slightly soluble and permeable and can be classified as class II (Biopharmaceuti- cal Classification System) BCS [2]. Moreover, it is used in vertigo, Meniere's disease, loss of memory and motion sick- ness pharmacotherapy. The drug improves blood flow to the labyrinth and brain stem and thus it is useful in cerebrovas- cular and peripheral disorders [1]. The current commercially marketable dosage forms for CIN are tablets and capsules for adults. Both of these dosage forms exhibit low and erratic oral bioavailability. Several intravenous dosage forms were investigated to overcome these problems [3, 4]. However, the lack of commercially available oral liquid dosage form for CIN makes it difficult for using with children and infants as well. Hence, a pharma- cist is often challenged to provide an extemporaneous oral liquid formulation from a commercially available adult oral solid dosage form by simply opening a capsule and the sub- sequent addition of water or juice to overcome this problem [5]. *Address correspondence to this author at the Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, 35516 Egypt; Tel: +050 2247496; E-mail: reham.aman@yahoo.com Nevertheless, the dose adjustment to children's body weight raised significant concern. In addition, organoleptic drawbacks (e.g. bitterness) have an impact on patient com- pliance and adherence [6]. The latest World Health Assem- bly (WHA) stressed the importance of recognizing children's right to access safe, effective, and proven medicines [7, 8]. Since no liquid formulation of CIN is available, an oral pedi- atric dosage form is highly desirable. Consequently, the aim of this work was to develop pedi- atric oral liquid formulation of CIN enabling convenient dose adjustment, ease of administration and improved or- ganoleptic properties. A method of choice was to load the drug in microspheres prepared from natural polymer and subsequently suspend them in the prepared syrup. Micro- spheres have shown advantages as drug carriers [9]. Recent concepts of microspheres formulations for pediatric use were applied [10, 11]. The polymer of choice should be insoluble in the pre- pared syrup but dissolved in the gastro-intestinal tract. A natural polymer suitable for this purpose is chitosan, (CS) [9]. It is stable, biocompatible and bioadhesive [12, 13]. CS microspheres were used to improve the bioavailability as well as to enhance the uptake of hydrophilic substances across epithelial membrane [14]. Optimized CIN-loaded CS microspheres (CIN–CS) were prepared by adopting factorial design 2 3 with three different independent variables at two levels. Sodium tripolyphosphate (TPP) was the cross-linking