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Bicellar Systems As New Delivery Strategy for Topical Application of flufenamic Acid

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Bicellar Systems As New Delivery Strategy for Topical Application of flufenamic Acid G Model IJP 13084 1–10 ARTICLE IN PRESS International Journal of Pharmaceutics xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics jo urnal homepage: www.elsevier.com/locate/ijpharm 1 Pharmaceutical nanotechnology 2 Bicellar systems as new delivery strategy for topical application of flufenamic acid a,∗ a a a b a 3 Q1 L. Rubio ,C.Alonso , G. Rodríguez , M. Cócera , C. López-Iglesias , L. Coderch , a a a 4 A. De la Maza , J.L. Parra , O. López a 5 Department of Chemical and Surfactants Technology (IQAC-CSIC), C/Jordi Girona 18-26, 08034 Barcelona, Spain b 6 Scientific and Technological Centers-University of Barcelona (CCiT-UB), Barcelona Science Park, C/Baldiri Reixac, 10, 08028 Barcelona, Spain 7 8 a r t i c l e i n f o a b s t r a c t 9 10 Article history: In this work, bicellar systems, bilayered disc-shaped nanoaggregates formed in water by phospholipids, 11 Received 10 October 2012 are proposed as a novel strategy for delivery of the anti-inflammatory flufenamic acid (FFA) to the skin. A 12 Received in revised form 14 January 2013 comparative percutaneous penetration study of this drug in bicellar systems and other vehicles was 13 Accepted 17 January 2013 conducted. The effects induced on the skin by the application of FFA in the different vehicles were Available online xxx analyzed by attenuated total reflectance-fourier transform infrared (ATR-FTIR). Additionally, using the 14 microscopic technique freeze-substitution transmission electron microscopy (FSTEM) and X-ray scat- 15 Keywords: tering technique using synchrotron radiation (SAXS-SR), we studied the possible microstructural and 16 Bicellar systems organizational changes that were induced in the stratum corneum (SC) lipids and the collagen of the 17 Flufenamic acid 18 DSC skin by the application of FFA bicellar systems. Bicellar systems exhibited a retarder effect on the per- 19 ATR-FTIR cutaneous absorption of FFA with respect to the other vehicles without promoting disruption in the SC 20 SAXS-SR barrier function of the skin. Given that skin disruption is one of the main effects caused by inflammation, 21 FS-TEM prevention of disruption and repair of the skin microstructure should be prioritized in anti-inflammatory 22 In vitro percutaneous absorption formulations. 23 Drug delivery © 2013 Published by Elsevier B.V. 24 1. Introduction (avoiding conventional surfactants) and nanodimensions of bicel- 36 lar systems, their use as delivery systems for topical applications 37 25 Bicellar systems are mixtures of two types of phospholipids has emerged as an interesting strategy. The use of bicellar systems 38 26 in aqueous medium, one with long alkyl hydrophobic chains and has been explored by our group for the transdermal delivery of the 39 27 another with short alkyl hydrophobic chains. These phospholipids amphiphilic drug diclofenac (Rubio et al., 2010). Additionally, we 40 28 are able to self-assemble, forming different nanoaggregates. The have demonstrated that these systems are able to work for skin 41 29 most common nanostructures formed are discoidal bicelles, which applications in two ways: as permeabilizing agents of the skin or 42 30 are intermediate forms between lipid vesicles and classical mixed as reinforcing agents of the lipid structures of the stratum corneum 43 31 micelles (Sanders and Prosser, 1998; Seddon et al., 2004). Long- (SC) (Barbosa-Barros et al., 2008b,c). The skin represents the largest 44 32 chain phospholipids constitute the bilayer structure in the central and most easily accessible organ of the body, and it is readily avail- 45 33 part of the bicelle, and the short-chain phospholipids complete able for drug application. Transdermal drug delivery offers many 46 34 the margins of the disc (Sanders and Schwonek, 1992; Vold and advantages compared to the conventional routes of application, 47 35 Prosser, 1996). Considering the structure, chemical composition including avoidance of the first-pass effect, stable blood levels, easy 48 application and higher compliance of the patient (Prausnitz et al., 49 2004; Thomas and Finnin, 2004) (Bal et al., 2010). To evaluate the 50 passage of substances through the skin and their distribution over 51 Abbreviations: SC, stratum corneum; FFA, flufenamic acid; DSC, differential scan- the different cutaneous compartments (Elias and Feingold, 2006; 52 ning calorimetry; ATR-FTIR, attenuated total reflectance-fourier transform infrared OECD, 2004; Schaefer and Redermeier, 1996), in vitro percutaneous 53 spectroscopy; SAXS-SR, small angle X-ray scattering using synchrotron radiation; absorption studies have been performed to determine the effec- 54 FSTEM, freeze-substitution transmission electron microscopy; DPPC, dipalmitoyl tiveness of some vehicles as permeability enhancers of different 55 phosphatidylcholine; DHPC, dihexanoyl phosphatidylcholine; BSA, bovine serum 56 albumin; PBS, phosphate buffer saline; TEWL, transepidermal water loss; E, epider- compounds (Gwak and Chun, 2002). mis; D, dermis; RF, receptor fluid; Perc. Abs., total percutanous absorption; HEX, Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug 57 hexagonal; OR, orthorhombic; C, corneocytes; L, lipids; CD, corneodesmosomes; of the anthranilic acid group with potent anti-inflammatory and 58 DPPC, dimyristoyl phosphatidylcholine; Tm, gel-liquid phase transition tempera- analgesic effects (Wagner et al., 2004). This drug, which is com- 59 ture; SPP, short periodicity phase. ∗ monly included in products for topical application, is insoluble 60 Corresponding author. Tel.: +34 93400 61 00; fax: +34 93204 59 04. 61 E-mail addresses: [email protected], [email protected] (L. Rubio). in water, and organic solvents that solubilize this drug could 0378-5173/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.01.034 Please cite this article in press as: Rubio, L., et al., Bicellar systems as new delivery strategy for topical application of flufenamic acid. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.01.034 G Model IJP 13084 1–10 ARTICLE IN PRESS 2 L. Rubio et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 62 impair the skin. Given that skin disruption is one of the major molar ratio 2:1. 10 mg of FFA was weighed and mixed with the 122 63 proinflammatory stimulators (Rahman et al., 2011), prevention of DPPC/DHPC chloroformic solution. The chloroform was removed by 123 64 disruption and reparation of the skin microstructure should be rota-evaporation, and the lipid film was dissolved in 1 ml of water 124 65 of primary importance in anti-inflammatory topical formulations. to reach a 20% (w/v) total lipid concentration and sonicated until a 125 66 Thus, in these formulations, not only should the drug be effec- transparent solution was obtained. pH measurements of FFA bicel- 126 67 tive, but the vehicle must also work in the same way to potentiate lar systems were performed with a Model 720 pH meter and a ROSS 127 68 the drug effect. Additionally, the deleterious effects of some anti- Model 8103 SC pH electrode (both from Orion Research, Cambridge, 128 69 inflammatory molecules themselves on skin structure (Schacke MA, USA). 129 70 et al., 2002) should be considered and avoided by using appropri- 71 ate skin-repairing vehicles. In this context, we think that the use 2.2.2. HPLC analysis 130 72 of bicellar systems as carriers of FFA may be a good alternative for FFA was quantified by high-performance liquid chromatogra- 131 73 dermal applications. phy (HPLC) using a Hitachi LaChrom Elite (Darmstadt, Germany). 132 74 Bicellar systems including FFA have been characterized (Rubio The equipment consisted of an L-2130 pump, L-2200 autosam- 133 75 et al., 2011) using a combination of different techniques, such as pler and L-400 UV detector. The system was operated using the 134 76 dynamic light scattering (DLS), freeze-fracture electron microscopy Merck EZChrom Elite v3.1.3 software. The chromatographic sep- 135 77 (FFEM), cryo-transmission electron microscopy (Cryo-TEM), X-ray aration was performed at room temperature using a Lichrocart 136 78 scattering and differential scanning calorimetry (DSC). The present 250-4/Lichrosorb RP-18 (5 ␮m) column (Merck) with a flow rate 137 79 study investigates the percutaneous penetration of FFA in differ- of 1.0 ml/min. 20 ␮l of sample or calibration standard was injected 138 80 ent vehicles, as well as the effects induced on the skin by the into the column and eluted with a mobile phase of methanol and 139 81 application of FFA bicellar systems. Attenuated total reflectance- phosphate buffer (pH 2.5) (79:21, v/v). Detection was performed 140 82 fourier transform infrared (ATR-FTIR) spectroscopy, small-angle by monitoring the absorbance signals at 284 nm. The calibration 141 83 X-ray scattering (SAXS) using synchrotron radiation (SR) and elec- curve exhibited linear behavior (>0.99%) over the concentration 142 84 tron microscopy were used. ATR-FTIR is a suitable technique to range of 0.078–97 ␮g/ml. The intraday and interday variations of 143 85 determine the vibrational characteristic frequencies of the alkyl the method were less than 2%. 144 86 chain lipids related to differently ordered phases (Boncheva et al., 87 2008; Obata et al., 2010; Rodríguez et al., 2009). SAXS is an excellent 145 88 tool to study the structural organization of the collagen in the skin 2.2.3. In vitro percutaneous absorption studies 146 89 and the lipid lamellar organization of the SC (Cócera et al., 2011). The in vitro permeation experiments through porcine skin were 90 Freeze-substitution transmission electron microscopy (FSTEM) has performed using Franz-type diffusion cells with an exposure area 147 2 91 been commonly used to visualize the microstructure of the skin of 1.86 cm (Lara-Spiral, Courtenon, France).
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