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Research Article

Preparing amorphous hydrophobic drug nanoparticles by nanoporous membrane extrusion

    Peng Guo

    Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA

    Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA

    School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA

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    ,
    Tammy M Hsu

    Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA

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    ,
    Yaping Zhao

    Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA

    School of Chemistry & Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China

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    ,
    Charles R Martin

    Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA

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    &
    Richard N Zare

    * Author for correspondence

    Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. .

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    Email the corresponding author at zare@stanford.edu

    Published Online:11 Mar 2013https://doi.org/10.2217/nnm.12.119

    Abstract

    Aim: The aim of the present study was to develop a simple and straightforward method for formulating hydrophobic drugs into nanoparticulate form in a scalable and inexpensive manner. Materials & methods: The nanoporous membrane extrusion (NME) method was used to prepare hydrophobic drug nanoparticles. NME is based on the induced precipitation of drug-loaded nanoparticles at the exits of nanopores. Three common hydrophobic drug models (silymarin, β-carotene and butylated hydroxytoluene) were tested. The authors carefully investigated the morphology, crystallinity and dissolution profile of the resulting nanoparticles. Results: Using NME, the authors successfully prepared rather uniform drug nanoparticles (∼100 nm in diameter). These nanoparticles were amorphous and show an improved dissolution profile compared with untreated drug powders. Conclusion: These studies suggest that NME could be used as a general method to produce nanoparticles of hydrophobic drugs.

    Original submitted 8 June 2011; Revised submitted 7 May 2012; Published online 3 September 2012

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • 1  Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods44(1),235–249 (2000).▪ Discusses the problems caused by poor drug solubility.
      Medline CASGoogle Scholar
    • 2  Cooper ER. Nanoparticles: a personal experience for formulating poorly water soluble drugs. J. Control. Release141(3),300–302 (2010).▪ Discusses the problems caused by poor drug solubility and the difficulties in overcoming this obstacle.
      Medline CASGoogle Scholar
    • 3  Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J. Nanopart. Res.10(5),845–862 (2008).
      CASGoogle Scholar
    • 4  Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul.41,189–207 (2001).
      Medline CASGoogle Scholar
    • 5  Gradishar WJ. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol.23(31),7794–7803 (2005).▪ Use of nanoparticles for delivering hydrophobic drugs.
      Medline CASGoogle Scholar
    • 6  Baba K, Pudavar HE, Roy I et al. New method for delivering a hydrophobic drug for photodynamic therapy using pure nanocrystal form of the drug. Mol. Pharm.4(2),289–297 (2007).▪ Use of nanoparticles for delivering hydrophobic drugs.
      Medline CASGoogle Scholar
    • 7  Peters K, Leitzke S, Diederichs JE et al. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J. Antimicrob. Chemother.45(1),77–83 (2000).▪ Use of nanoparticles for delivering hydrophobic drugs.
      Medline CASGoogle Scholar
    • 8  Wagner V, Dullaart A, Bock A-K, Zweck A. The emerging nanomedicine landscape. Nat. Biotechnol.24(10),1211–1217 (2006).
      Medline CASGoogle Scholar
    • 9  Legrand P, Lesieur S, Bochot A et al. Influence of polymer behaviour in organic solution on the production of polylactide nanoparticles by nanoprecipitation. Int. J. Pharm.344(1–2),33–43 (2007).
      Medline CASGoogle Scholar
    • 10  Antonietti M. Polyreactions in miniemulsions. Prog. Polym. Sci.27(4),689–757 (2002).
      CASGoogle Scholar
    • 11  Tokumitsu H, Ichikawa H, Fukumori Y. Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture therapy of cancer: preparation by novel emulsion-droplet coalescence technique and characterization. Pharm. Res.16(12),1830–1835 (1999).
      Medline CASGoogle Scholar
    • 12  Jacobson GB, Shinde R, Contag CH, Zare RN. Sustained release of drugs dispersed in polymer nanoparticles. Angew. Chem. Int. Ed.47(41),7880–7882 (2008).
      Medline CASGoogle Scholar
    • 13  Jacobson GB, Gonzalez-Gonzalez E, Spitler R et al. Biodegradable nanoparticles with sustained release of functional siRNA in skin. J. Pharm. Sci.99(10),4261–4266 (2010).
      Medline CASGoogle Scholar
    • 14  Jacobson GB, Shinde R, McCullough RL et al. Nanoparticle formation of organic compounds with retained biological activity. J. Pharm. Sci.99(6),2750–2755 (2010).
      Medline CASGoogle Scholar
    • 15  Guo P, Martin CR, Zhao Y, Ge J, Zare RN. General method for producing organic nanoparticles using nanoporous membranes. Nano Lett.10(6),2202–2206 (2010).▪▪ The first example of nanoporous membrane extrusion for nanoparticle formation.
      Medline CASGoogle Scholar
    • 16  Ge J, Jacobson GB, Lobovkina T, Holmberg K, Zare RN. Sustained release of nucleic acids from polymeric nanoparticles using microemulsion precipitation in supercritical carbon dioxide. Chem. Commun. (Camb.)46(47),9034–9036 (2010).
      Medline CASGoogle Scholar
    • 17  Buyukserin F, Medley CD, Mota MO et al. Antibody-functionalized nano test tubes target breast cancer cells. Nanomedicine (Lond.)3(3),283–292 (2008).
      CASGoogle Scholar
    • 18  Buyukserin F, Kang M, Martin CR. Plasma-etched nanopore polymer films and their use as templates to prepare “nano test tubes.” Small3(1),106–110 (2007).
      Medline CASGoogle Scholar
    • 19  Hillebrenner H, Buyukserin F, Stewart JD, Martin CR. Template synthesized nanotubes for biomedical delivery applications. Nanomedicine1(1),39–50 (2006).
      CASGoogle Scholar
    • 20  Hillebrenner H, Buyukserin F, Kang M, Mota MO, Stewart JD, Martin CR. Corking nano test tubes by chemical self-assembly. J. Am. Chem. Soc.128(13),4236–4237 (2006).
      Medline CASGoogle Scholar
    • 21  Maas M, Guo P, Keeney M et al. Preparation of mineralized nanofibers: collagen fibrils containing calcium phosphate. Nano Lett.11(3),1383–1388 (2011).▪▪ The first example of nanoporous membrane extrusion for nanofiber formation and its biomedical applications.
      Medline CASGoogle Scholar
    • 22  Liversidge G. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm.125(1),91–97 (1995).▪ Study of nanoparticle size on bioavailability for hydrophobic drug delivery.
      CASGoogle Scholar
    • 23  Müller R. Nanosuspensions for the formulation of poorly soluble drugs I. Preparation by a size-reduction technique. Int. J. Pharm.160(2),229–237 (1998).
      CASGoogle Scholar
    • 24  Panyam J. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev.55(3),329–347 (2003).
      Medline CASGoogle Scholar
    • 25  Farokhzad OC. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA103(16),6315–6320 (2006).
      Medline CASGoogle Scholar
    • 26  Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci.86(1),1–12 (1997).
      Medline CASGoogle Scholar
    • 27  Sun N, Zhang X, Lu Y, Wu W. In vitro evaluation and pharmacokinetics in dogs of solid dispersion pellets containing Silybum marianum extract prepared by fluid-bed coating. Planta Med.74(2),126–132 (2008).
      Medline CASGoogle Scholar
    • 28  Wang Y, Zhang D, Liu Z et al.In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery. Nanotechnology21(15),155104 (2010).
      MedlineGoogle Scholar
    • 29  Rabinow BE. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov.3(9),785–796 (2004).
      Medline CASGoogle Scholar
    • 30  You J-O, Almeda D, Ye GJ, Auguste DT. Bioresponsive matrices in drug delivery. J. Biol. Eng.4(1),15 (2010).
      Medline CASGoogle Scholar
    • 31  Ferenci P, Dragosics B, Dittrich H et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J. Hepatol.9(1),105–113 (1989).
      Medline CASGoogle Scholar
    • 32  Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med.334(18),1150–1155 (1996).
      Medline CASGoogle Scholar
    • 33  Burton G, Ingold K. beta-Carotene: an unusual type of lipid antioxidant. Science224(4649),569–573 (1984).
      Medline CASGoogle Scholar
    • 34  Branen AL. Toxicology and biochemistry of butylated hydroxyanisole and butylated hydroxytoluene. J. Am. Oil Chem. Soc.52(2),59–63 (1975).
      Medline CASGoogle Scholar
    • 35  Yinwin K, Feng S. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials26(15),2713–2722 (2005).
      MedlineGoogle Scholar
    • 36  Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett.6(4),662–668 (2006).
      Medline CASGoogle Scholar
    • 37  Müller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv. Drug Deliv. Rev.47(1),3–19 (2001).
      Medline CASGoogle Scholar
    • 38  Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev.53(2),283–318 (2001).
      Medline CASGoogle Scholar
    • 39  Wong J, Brugger A, Khare A et al. Suspensions for intravenous (IV) injection: a review of development, preclinical and clinical aspects. Adv. Drug Deliv. Rev.60(8),939–954 (2008).
      Medline CASGoogle Scholar
    • 40  Gupta AK, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials26(18),3995–4021 (2005).
      Medline CASGoogle Scholar