International Journal of Pharmaceutics 443 (2013) 26–38 Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics jo ur n al homep age: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Enhanced transdermal delivery of an anti-hypertensive agent via nanoethosomes: Statistical optimization, characterization and pharmacokinetic assessment Abdul Ahad a,b , Mohd. Aqil a,∗ , Kanchan Kohli a , Yasmin Sultana a , Mohd. Mujeeb a a Faculty of Pharmacy, Jamia Hamdard (Hamdard University), M. B. Road, New Delhi 110062, India b Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia a r t i c l e i n f o Article history: Received 22 October 2012 Received in revised form 4 January 2013 Accepted 5 January 2013 Available online 10 January 2013 Keywords: Transdermal Ethosomes Pharmacokinetics Valsartan Hypertension a b s t r a c t The aim of the current investigation is to develop and statistically optimize nanoethosomes for transdermal valsartan delivery. Box-Behnken experimental design was applied for optimization of nanoethosomes. The Independent variables were phospholipids 90G (X 1 ), ethanol (X 2 ), valsartan (X 3 ) and sonication time (X 4 ) while entrapment efﬁciency (Y 1 ), vesicle size (Y 2 ) and ﬂux (Y 3 ) were the dependent variables. The optimized formulation obtained was then tested in rats for an in vivo pharma- cokinetic study. Results indicate that the nanoethosomes of valsartan provides better ﬂux, reasonable entrapment efﬁciency, more effectiveness for transdermal delivery as compared to rigid liposomes. Optimized nanoethosomal formulation with mean particle size is 103 ± 5.0 nm showed 89.34 ± 2.54% entrapment efﬁciency and achieved mean transdermal ﬂux 801.36 ± 21.45 g/cm 2 /h. Nanoethosomes proved signiﬁcantly superior in terms of, amount of drug permeated in the skin, with an enhancement ratio of 43.38 ± 1.37 when compared to rigid liposomes. Confocal laser scanning microscopy revealed an enhanced permeation of Rhodamine-Red loaded nanoethosomes to the deeper layers of the skin as compared to conventional liposomes. In vivo pharmacokinetic study of nanoethosomal transdermal therapeutic system showed a signiﬁcant increase in bioavailability (3.03 times) compared with oral sus- pension of valsartan. Our results suggest that nanoethosomes are an efﬁcient carrier for transdermal delivery of valsartan. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Hypertension, or high blood pressure, is one of the primary risk factors for cardiovascular diseases. There is a direct relationship between the level of blood pressure and the risk for developing cardiovascular diseases such as coronary artery disease and stroke (Lewington et al., 2002; Campbell et al., 2012). Management of hypertension has been indicated as an international health priority (Kearney et al., 2005; Ralston et al., 2012). The World Health Report 2002 identiﬁed hypertension as the third-ranked factor for disability adjusted life years. Based on a pooled analysis of available national and regional data, it was predicted that the burden of hypertension would increase by 60% to approximately 1.56 billion in the year 2025 (Kearney ∗ Corresponding author at: Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), M. B. Road, New Delhi 110062, India. Tel.: +91 9811798725. E-mail addresses: abdul aahad@yahoo.com (A. Ahad), aqilmalik@yahoo.com, aqilmalik@gmail.com (Mohd. Aqil). et al., 2004; Chockalingam et al., 2006). Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration (Aqil et al., 2004). The need of transdermal drug delivery is felt on the shortcomings of other exist- ing drug delivery systems. Transcutaneous drug delivery is a nonin- vasive technique and can be exploited to circumvent the variables, which could inﬂuence the oral absorption of drugs such as pH, food intake and gastrointestinal motility (Barry, 2002; Langer, 2004). The greatest challenge with transdermal drug delivery is the barrier nature of the stratum corneum (SC) the upper most layer of the skin that restricts the entry of most of the drugs (Lim et al., 2006; Aqil et al., 2007; Ahad et al., 2009). Many overtures have been tried to overcome the barrier of SC to achieve higher transdermal permeability. Among them, lipid based systems offer excellent can- didature for transdermal delivery due to their biocompatibility and ease of mixing with the skin lipids (Chourasia et al., 2011). Liposomal carriers for topical drug delivery have been studied since the 1980s and have evoked a considerable interest. However, the conventional liposomes do not deeply penetrate into the skin and remain conﬁned to the outer layer of SC (Jain et al., 2007; Gillet 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.01.011