LYOPHILIZATION OF SOLID LIPID NANOPARTICLES FOR BRAIN TARGETING Original Article WASSIM ABDELWAHED Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Aleppo University Email: wassimabed@yahoo.fr Received: 15 Jul 2015 Revised and Accepted: 02 Sep 2015 ABSTRACT Objective: The aim of this work is to investigate formulation and process parameters that could impact freeze drying of loperamide-loaded Solid Lipid Nanoparticles (Loperamide loaded SLN). Methods: Loperamide loaded SLN was prepared by high shear homogenization method and freeze dried in vials without and with different types and concentrations of cryoprotectants (lactose, glucose, mannitol and povidon) using pilot freeze dryer. Results: The best result has been obtained by using 5 % of monosaccharide glucose solution, although Nanoparticles size has been increased 6 folds. However, the total concentration of loperamide hydrochloride (Loperamide HCl) remained unchanged after freeze drying. It has been found that the type and ratio of surfactants adsorbed at the surface of SLN have impact on the success of the drying process. Conclusion: Results revealed that polymeric nanoparticles could withstand freeze drying stress more than SLN because polymers have higher mechanical resistance in comparison with waxes and lipids. Keywords: Solid lipid Nanoparticles, Lyophilization, Stability, Brain targeting. INTRODUCTION In recent years, it has become evident that the development of new active ingredients is not sufficient to ensure progress in drug therapy. Promising experimental data obtained in vitro are very often followed by unsuccessful results in vivo. Main reasons for this failure include: - Insufficient drug concentration due to poor absorption, rapid metabolism and elimination. - Drug distribution to other tissues combined with high drug toxicity. - Poor drug solubility, which excludes intravenous injection of aqueous drug solution. - High fluctuation of plasma levels due to unpredictable bioavailability after per oral administration [1]. During last decades, new drug delivery systems have been developed to overcome the previous problems. These delivery systems offer a possibility to provide targeted delivery of drugs, improved bioavailability, or controlled drug release in target tissue In the middle of the 1990s, new type of nanoparticles made from solid lipids (SLN or lipospheres) appeared. The SLNs combine the advantages of other innovative carry systems such as; physical stability, protection of incorporated labile drugs from degradation, controlled release, excellent tolerability, avoidance of organic solvents and the possibility of large scale production and sterilization [2]. Solid lipid nanoparticles can be defined as submicron colloidal solid systems made from lipids such as waxes. The main disadvantages of SLN are the lack of physical (agglomeration and fusion of particles) and chemical (Oxidation of lipids) stability during long-term storage. To improve the physical and chemical stability of SLN, water should be removed from the colloidal suspension. Freeze drying is the most common technique applied for making SLN system to allow extended periods of shelf-lives. Lyophilization or freeze drying can transform colloidal suspensions into stable solid cakes for long term storage. Freeze drying is an industrial process which involves water removal from frozen samples by sublimation under vacuum. However, it is a complex process that generates stress sources itself, which can destabilize the nanoparticles formulation in the process such as freezing and drying stresses. Cryoprotectants have been used to decrease SLN aggregations due to the stress during the process of freeze-drying. For this reasons, both formula and process should be carefully studied to select the suitable excipients and optimal freeze drying conditions [3]. Successful nanoparticles lyophilizate should have: - Elegant aspect. - Short reconstitution time in water. - Physical and chemical stability (ex: particle size, encapsulation efficiency) - Low residual water [4]. Loperamide hydrochloride is a common-used anti diarrhea drug, an opioid agonist that is unable to cross the blood-brain barrier (BBB). In this work, Loperamide was loaded on nanoparticles to improve its crossing to BBB and to have a strong central analgesic effect [5]. So far, there have been few studies into achieving freeze-dried SLNs using different cryoprotectants. The aim of this research was to study the freeze drying of solid lipid nanoparticles loaded with loperamide and to find the suitable excipients and conditions for successful lyophilization process. To the best of our knowledge, this is the first study of freeze drying of loperamide loaded SLN. MATERIALS AND METHODS Materials Loperamide hydrochloride was supplied by sigma-Aldrich (Italy). Beeswax, carnauba wax, and egg lecithin was all obtained from Carl Roth (Germany). The surfactant Tween 80 was purchased from Sigma-Aldrich (France). Triton x was supplied by Rasayan Laboratories and finally, HPLC grade acetonitrile was provided from Scharlau (spain). Preparation of solid lipid nanoparticles Loperamide loaded SLN was prepared by High shear homogenization method. Briefly, a mixture of beeswax (0.48 g), carnauba wax (0.12 g), egg lecithin (0.12 g) and Loperamide hydrochloride (50 mg) was melted in a water bath at 65ºC. Then 0.18 mg of tween 80 was mixed International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 7, Issue 10, 2015 Innovare Academic Sciences