International Journal of Pharmaceutics 429 (2012) 104–112 Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics journa l h omepa g e: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability Sonali V. Kapse a , Rajiv V. Gaikwad b , Abdul Samad b , Padma V. Devarajan a,∗ a Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India b Veterinary Nuclear Medicine Center, Department of Medicine, Bombay Veterinary College, Parel, Mumbai 400 012, India a r t i c l e i n f o Article history: Received 15 December 2011 Received in revised form 23 February 2012 Accepted 26 February 2012 Available online 5 March 2012 Keywords: Self nanoprecipitating preconcentrate Tamoxifen citrate Polymeric nanoparticles In situ nanoprecipitation Bioavailability Scintigraphy a b s t r a c t We disclose a self nanoprecipitating preconcentrate (SNP) of tamoxifen citrate (TMX), which forms TMX loaded polymeric nanoparticles, on dilution with aqueous media. SNP comprised TMX, polymer (Kolli- don SR) and surfactant/s dissolved in a pharmaceutically acceptable vehicle. Binary surfactant mixtures of Aerosol OT (AOT) with Tween 80 revealed synergistic reduction in surface tension to enable both high entrapment efficiency (EE) and low particle size (PS). Synergism of the surfactants was confirmed by molecular interaction parameter(ˇ  ). Combination of AOT and Tween 80 resulted in EE (∼85%) and PS (<250 nm). Formation of TMX-KSR nanoparticles in situ was reproducible under most experimental conditions and exhibited pH independent behavior. Dilution volume (>80 mL) influenced both PS and EE while dilution temperature influenced only PS. Marginal increase in size was evident at the end of 1 h nevertheless was not of concern as TMX SNP exhibited near complete release in 1 h. DSC and XRD studies revealed amorphous nature of TMX in nanoparticles. FTIR imaging confirmed uniform distribution of TMX in nanoparticles. ESEM and TEM revealed spherical nanoparticles. Biodistribution studies of 99m Tc labeled TMX SNP in rats revealed no significant absorption however oral pharmacokinetics revealed enhanced oral bioavailability of TMX (165%) compared to TMX suspension. SNP presents a new in situ approach, for design of drug loaded polymeric nanoparticles. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Polymeric nanoparticles as drug delivery systems (DDS) have been extensively investigated for manifold applications. Bioen- hancement of poorly water soluble drugs using nanotechnology approaches has been recently reviewed (Fasinu et al., 2011). Poly- meric nanoparticles enable controlled release of drugs, protection of labile drugs especially peptides, proteins, nucleic acids and serve as carriers for targeted and intracellular drug delivery (Jain, 2000; Soppimath et al., 2001; Chawla and Amiji, 2002; Panyam and Labhasetwar, 2003; Allen and Cullis, 2004; Couvreur and Vauthier, 2006; Farokhzad et al., 2006). TMX is recommended for long-term prophylactic therapy in high-risk and post-menopausal women and in advanced or metastatic breast cancer treatment (Buckley and Goa, 1989). TMX exhibits low oral bioavailability, large interindividual variations and extensive liver metabolism, often necessitating high dose with resultant side effects (McVie et al., 1986; Tukker et al., 1986). The therapeutic advantage of oral nanoparticles of TMX is recently reported (Jain et al., 2011). ∗ Corresponding author at: Tel.: +91 22 33612201; fax: +91 22 3361 1020. E-mail address: pvdevarajan@gmail.com (P.V. Devarajan). Technological hurdles that hamper scale-up of polymeric nanoparticles present a major constraint in their exploitation for drug delivery. Simple and practical approaches that address the above are therefore imperative. Nevertheless, achieving high entrapment efficiency and nanosize could prove rate limiting. Bodmeier et al. have discussed the generation of microparti- cles in situ for a number of drugs including leuprolide acetate (Dong et al., 2006; Luan and Bodmeier, 2006a, 2006b) lysozyme (Körber and Bodmeier, 2008), vinpocetine (Li et al., 2008), dilti- azem hydrochloride (Kranz and Bodmeier, 2007), buserelin acetate (Kranz et al., 2001; Kranz and Bodmeier, 2007) and bupivacaine hydrochloride (Kranz et al., 2001; Kranz and Bodmeier, 2007). A two-syringe/connector system comprising one syringe (single syringe) containing a solution of drug and polymer (internal phase) and another syringe containing oil/aqueous media (external phase) were mixed using connector system to form an o/o emulsion. This emulsion when injected into the body fluids formed microparticles in situ (Luan and Bodmeier, 2006a). We present in this study a simple method for generation of drug loaded polymeric nanoparticles in situ. The system discussed in the study is a self nanoprecipitating preconcentrate (SNP), a monopha- sic liquid composed of drug, polymer (Kollidon SR) and surfactants which on aqueous dilution could reproducibly provide drug loaded TMX nanoparticles. The objective of the present study was 0378-5173/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2012.02.042