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Oral Bioavailability: Issues and Solutions via Nanoformulations

Clinical Pharmacokinetics volume 54, pages 325–357 (2015)Cite this article

Abstract

The delivery of drugs through the oral route is regarded as most optimal to achieve desired therapeutic effects and patient compliance. However, poor pharmacokinetic profiles of oral drug candidates remains an area of concern, and approaches to enhance their bioavailability are widely cited in the literature. Traditionally, the approaches have been confined to molecular optimization of the drug molecule, which has gradually evolved into development of microsized and nanosized formulations. Nanoformulations, by virtue of their nanosize, are widely acclaimed for circumventing the obstacles of poor pharmacokinetics. In this review, an attempt has been made to discuss existing challenges of bioavailability and approaches to overcome the same, with in-depth compilation of the literature on nanoformulations. The nanoformulations reviewed include nanocrystals, nanoemulsions, polymeric nanoparticles, self-nanoemulsifying drug delivery systems, dendrimers, carbon nanotubes, polymeric micelles and lipid nanocarriers. This review confirms the potential of nanomedicines to improve the pharmacokinetics of drugs via nanoformulations. Chemotherapeutic applications and patent reports are also compiled in the review. Despite the promising benefits, nanomedicines are associated with hazards to human health. Hence, the review also deals with toxicological consequences of nanomedicines, and with in vitro/in vivo screening methods to assess bioavailability as per regulatory considerations. Nanotechnology has been shown to facilitate the clinical translation of drug candidates that were deemed to be bioavailability failures. Conclusively, nanotechnological approaches to particle design and formulation are beginning to expand the market for many drugs with improved bioavailability and therapeutics. However, dedicated efforts are needed to develop advanced nanomedicines with minimal or no adverse effects.

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References

  1. Lavelle EC, Sharif S, Thomas NW, Holand J, Davis SS. The importance of gastrointestinal uptake of particles in the design of oral delivery systems. Adv Drug Deliv Rev. 1995;18:5–22.

    CAS  Google Scholar 

  2. Daugherty AL, Mrsny RJ. Regulation of the intestinal epithelial paracellular barrier. Pharm Sci Technol Today. 1999;2:144–51.

    CAS  Google Scholar 

  3. Thakkar H, Patel B, Thakkar S. A review on techniques for oral bioavailability enhancement of drugs. Int J Pharm Sci Rev Res. 2010;4:203–23.

    CAS  Google Scholar 

  4. US Food and Drug Administration. Code of federal regulation. Title 21, volume 5, chapter 1, subchapter D, part 320. Bioavailability and bioequivalence reagents.

  5. Badawy SIF, Ghorab MM, Adeyeye CM. Characterization and bioavailability of danazolhydroxypropyl-β-cyclodextrin coprecipitates. Int J Pharm. 1996;128:45–54.

    CAS  Google Scholar 

  6. Borin MT, Ayres JW. Single dose bioavailability of acetoaminophen following oral administration. Int J Pharm. 1989;54:199–209.

    CAS  Google Scholar 

  7. Chen H, Khemtong C, Yang X, Chang X, Gao J. Nanonization strategies for poorly water-soluble drugs. Drug Discov Today. 2010;1–7.

  8. Riehemann K, Schneider SW, Luger TA, Godin B, Ferrari M, Fuchs H. Nanomedicine—challenge and perspectives. Angew Chem Int Ed Engl. 2009;48:872–97.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Doherty MM, Pang KS. First-pass effect: significance of the intestine for absorption and metabolism. Drug Chem Toxicol. 1997;20:329–44.

    CAS  PubMed  Google Scholar 

  10. Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Depos. 2010;38:1147–58.

    CAS  Google Scholar 

  11. Arora S, Ali J, Ahuja A, Khar RK, Baboota S. Floating drug delivery systems: a review. AAPS Pharm Sci Tech. 2005;6:E372–90.

    Google Scholar 

  12. Soppimath KS, Kulkarni AR, Kukulkarni AR, Rudzinski WE, Aminabhavi TM. Microspheres as floating drug-delivery systems to increase gastric retention of drugs. Drug Metab Rev. 2001;33:149–60.

    CAS  PubMed  Google Scholar 

  13. Gholap SB, Banariee SK, Gaikwad DD, Jadhav SL, Thorat RM. Hollow microspheres: a review. Int J Pharm Sci Rev Res. 2010;1:74–9.

    CAS  Google Scholar 

  14. Hirtz J. The gastrointestinal absorption of drugs in man: a review of current concepts and methods of investigation. Br J Clin Pharmacol. 1985;19:17S–83S.

    Google Scholar 

  15. Goyel M, Prajapati R, Purohit KK, Mehta SC. Floating drug delivery system. J Curr Pharm Res. 2011;5:7–18.

    Google Scholar 

  16. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Control Release. 2000;63:235–59.

    CAS  PubMed  Google Scholar 

  17. Nayak AK, Maji R, Das B. Gastroretentive drug delivery systems: a review. Asian J Pharm Clin Res. 2010;3:1–10.

    Google Scholar 

  18. Mullertz A. Oral drug absorption, 2nd edn. Ebook;2010.

  19. Melander A. Influence of food on the bioavailability of drugs. Clin Pharmacokinet. 1978;3(5):337–51.

    CAS  PubMed  Google Scholar 

  20. Winstanley PA, Orme LE. The effect of food on drug bioavailability. Br J Clin Pharmacol. 1989;28:621–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Cebrian MJC, Zornoza T, Granero L, Polache A. Intestinal absorption enhancement via paracellular route by fatty acids, chitosans and other: a target for drug delivery. Curr Drug Deliv. 2005;2:9–22.

    Google Scholar 

  22. Stenberg P, Luthaman K, Artursson P. Virtual screening of intestinal drug permeability. J Control Release. 2000;65:231–43.

    CAS  PubMed  Google Scholar 

  23. Simon DB, Lu Y, Choate KA, Velazquez H, Sabban AE, Praga M, et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2 resorption. Science. 1999;285:103–6.

    CAS  PubMed  Google Scholar 

  24. Werle M, Samhaber A, Bernkop-Schnurch A. Degradation of teriparatide by gastro-intestinal proteolytic enzymes. J Drug Target. 2006;14:109–15.

    CAS  PubMed  Google Scholar 

  25. Svenson S, Chauhan AS. Dendrimers for enhanced drug solubilization. Nanomedicine. 2008;3(5):679–702.

    CAS  PubMed  Google Scholar 

  26. Lipinski CA. Drug like properties and the cause of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44:235–49.

    CAS  PubMed  Google Scholar 

  27. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004;58:265–78.

    PubMed  Google Scholar 

  28. Veber DF, Johnson SR, Cheng H, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615–23.

    CAS  PubMed  Google Scholar 

  29. Ungell AL, Nylander S, Bergstrand S, Sjönerg A, Lennernäs H. Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci. 1998;87:360–6.

    CAS  PubMed  Google Scholar 

  30. Vemulapalli V, Khan NM, Jasti B. Physicochemical characteristics that influence the transport of drugs across intestinal barrier. AAPS News Mag. 2007:18–21.

  31. Rasheed A, Kumar CK, Sravanthi VNSS. Cyclodextrins as drug carrier molecule: a review. Sci Pharm. 2008;76:567–98.

    CAS  Google Scholar 

  32. Farh A, Liu X. Drug delivery strategies for poorly water soluble drugs. Expert Opin Drug Deliv. 2007;4:403–16.

    Google Scholar 

  33. Mehramizi A, Monfared AE, Pourfarzib M, Bayati KH, Dorkoosh FA, Rafiee T. Influence of β-cyclodextrin complexation on lovastatin release from osmotic pump tablets (OPT). DARU. 2007;15(2):71–8.

    CAS  Google Scholar 

  34. Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm. 2001;225:15–30.

    CAS  PubMed  Google Scholar 

  35. Ueda H, Ou D, Endo T, Nagase H, Tomono K, Nagai T. Evaluation of a sulfobutyl ether beta-cyclodextrin as a solubilizing/stabilizing agent for several drugs. Drug Dev Ind Pharm. 1998;24:863–7.

    CAS  PubMed  Google Scholar 

  36. Li J, Guo Y, Zografi G. The solid-state stability of amorphous quinapril in the presence of βCD. J Pharm Sci. 2002;91:229–43.

    CAS  PubMed  Google Scholar 

  37. Szejtli J. Cyclodextrins and their inclusion complexes. Starch. 1982. doi:10.1002/star.19820341113.

    Google Scholar 

  38. Uekama K, Otagiri M. Drug carrier system—a review. Crit Rev Ther Drug Care Syst. 1987;3:1–12.

    CAS  Google Scholar 

  39. Mayur CA. Senthikumaran. Cyclodextrin in drug delivery: a review. Res Rev J Pharm Pharm Sci. 2012;1(1):19–29.

    Google Scholar 

  40. Sekiguchi K, Obi N. Studies on absorption of eutectic mixture: I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem Pharm Bull. 1961;9:866–72.

    CAS  Google Scholar 

  41. Goldberg AH, Galbaldi M, Kanig KL. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures III. Experimental evaluation of griseofulvin-succinic acid solution. J Pharm Sci. 1966;55:487–92.

    CAS  Google Scholar 

  42. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88:1058–66.

    CAS  PubMed  Google Scholar 

  43. Sharma A, Jain CP. Solid dispersion: a promising technique to enhance solubility of poorly water soluble drug. Int J Drug Deliv. 2011;3:149–70.

    CAS  Google Scholar 

  44. Khandare JJ, Chandna P, Wang Y, Pozharov VP, Minko T. Novel polymeric prodrug with multivalent component for cancer therapy. J Pharmacol Exp Ther. 2006;317(3):929–37.

    CAS  PubMed  Google Scholar 

  45. Philip AK, Philip B. Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Med J. 2010. doi:10.5001/omj.2010.24.

    PubMed Central  PubMed  Google Scholar 

  46. Tiwari G, Tiwari R, Pranay W, Wal A, Rai AK. Primary and novel approaches for colon targeted drug delivery: a review. Int J Drug Deliv. 2010;2:1–11.

    CAS  Google Scholar 

  47. Junginger HE. Polymeric permeation enhancers. Oral Deliv Macromol Drugs. 2009. doi:10.1007/978-1-4419-0200-9_6.

    Google Scholar 

  48. Singh N, Gupta P, Bhattacharyya A. Enhancement of intestinal absorption of poorly absorbed ceftriaxone sodium by using mixed micelles of polyoxy ethylene (20) cetyl ether & oleic acid as peroral absorption enhancers. Arch Appl Sci Res. 2010;2(3):131–42.

    Google Scholar 

  49. Whitehead K, Karr N, Mitragotri S. Safe and effective permeation enhancers for oral drug delivery. Pharm Res. 2007. doi:10.1007/s11095-007-9488-9.

    PubMed  Google Scholar 

  50. Chauhan NS, Alam S, Mittal A, Bajaj U. A description on study of intestinal barrier, drug permeability and permeation enhancers. Int J Clin Pharmacol Toxicol. 2013;2:501.

  51. Holmes EH, Devalapally H, Li L, Perdue ML, Ostrander GK. Permeability enhancers dramatically increase zanamivir absolute bioavailability in rats: implications for an orally bioavailable influenza treatment. PLoS One. 2013;8:1–7.

    Google Scholar 

  52. Gupta V, Hwang BH, Doshi N, Mitragotri S. A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine. J Control Release. 2013;172(2):541–9.

    CAS  PubMed  Google Scholar 

  53. Bansode SS, Banarjee SK, Gaikwad DD, Jadhav SL, Thorat RM. Microencapsulation: a review. Int J Pharm Sci Rev Res. 2010;1:38–43.

    CAS  Google Scholar 

  54. Singh MN, Hemant KSY, Shivakumar HG. Microencapsulation: a promising technique for controlled drug delivery. Res Pharm Sci. 2010;5(2):65–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Siepmann J, Siepmann F. Microparticles used as drug delivery systems. Prog Coll Pol Sci. 2006;133:15–21.

    CAS  Google Scholar 

  56. Padalkar AN, Sadhana R, Shahi SR. Microparticles: an approach for betterment of drug delivery system. Int J Pharma Res Dev. 2011;3:99–115.

    Google Scholar 

  57. Upadhyay MS, Pathak K. Glyceryl monooleate-coated bioadhesive hollow microspheres of riboflavin for improved gastroretentivity: optimization and pharmacokinetics. Drug Deliv Transl Res. 2013;3:209–23.

    CAS  Google Scholar 

  58. Srivastava R, Kumar D, Pathak K. Colonic luminal surface retentive meloxicam microsponges delivered by erosion based colon targeted matrix tablet. Int J Pharm. 2012;427:156–62.

    Google Scholar 

  59. Arya P, Pathak K. Assessing the viability of microsponges as gastro retentive drug delivery system of curcumin: optimization and pharmacokinetics. Int J Pharm. 2014;460:1–12.

    CAS  PubMed  Google Scholar 

  60. Sigfridsson K, Nordmark A, Theilig S, Lindahl A. A formulation comparison between micro- and nanosuspensions: the importance of particle size for absorption of a model compound, following repeated oral administration to rats during early development. Drug Dev Ind Pharm. 2011;37(2):185–92.

    CAS  PubMed  Google Scholar 

  61. Sahoo SK, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discov Today. 2008;13(3–4):144–51.

    CAS  PubMed  Google Scholar 

  62. Muller RH, Gohla S, Keck CM. State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78:1–9.

    PubMed  Google Scholar 

  63. Nasimi P, Haidari M. Medical use of nanoparticles drug delivery and diagnosis diseases. Int J Green Nanotechnol. 2013. doi:10.1177/1943089213506978.

    Google Scholar 

  64. Junghanns JUAH, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomed. 2008;3:295–309.

    CAS  Google Scholar 

  65. Pawar VK, Yuvraj Singh Y, Meher JG, Gupta S, Chourasia MK. Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery. J Control Release. 2014;183:51–66.

  66. Müller RH, Shegokar R, Gohla S, Keck CM. Nanocrystals: production, cellular drug delivery, current and future products. Fund Biomed Technol. 2011;5:411–32.

    Google Scholar 

  67. Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1–2):129–39.

    CAS  PubMed  Google Scholar 

  68. Song J, Wang Y, Song Y, Chan H, Bi C, Yang X, et al. Development and characterisation of ursolic acid nanocrystals without stabiliser having improved dissolution rate and in vitro anticancer activity. AAPS PharmSciTech. 2014. doi:10.1208/s12249-013-0028-0.

    PubMed Central  Google Scholar 

  69. Moeschwitzer J. Nanotechnology: particle size reduction technologies in the pharmaceutical development process. Am Pharm Rev. 2010;54–59.

  70. Wu L, Zhang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Adv Drug Deliv Rev. 2011;63:456–469. doi:10.1016/j.addr.2011.02.001.

  71. Keck CM, Muller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62:3–16.

    CAS  PubMed  Google Scholar 

  72. Chan HK, Kwok PC. Production methods for nanodrug particles using the bottom-up approach. Adv Drug Deliv Rev. 2011;63(6):406–16.

    CAS  PubMed  Google Scholar 

  73. Li Y, Yue PF, Hu PY, Wu ZF, Yang M, Yuan HL. A novel high-pressure precipitation tandem homogenization technology for drug nanocrystals production—a case study with ursodeoxycholic acid. Pharm Dev Technol. 2014;19(6):662–70.

    CAS  PubMed  Google Scholar 

  74. Zhang H, Hollis CP, Zhang Q, Li T. Preparation and antitumor study of camptothecin nanocrystals. Int J Pharm. 2011;415(1–2):293–300.

    CAS  PubMed  Google Scholar 

  75. Sinha B, Müller RH, Möschwitzer JP. Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals. Int J Pharm. 2013;458(2):315–23.

    CAS  PubMed  Google Scholar 

  76. Sarnes A, Kovalainen M, Häkkinen MR, Laaksonen T, Laru J, Kiesvaara J, et al. Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus Sporanox® is not realized in in vivo drug absorption. J Control Release. 2014;180:109–16.

    CAS  PubMed  Google Scholar 

  77. Mou D, Chen H, Wan J, Xu H, Yang X. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int J Pharm. 2011;413(1–2):237–44.

    CAS  PubMed  Google Scholar 

  78. Patel K, Patil A, Mehta M, Gota V, Vavia P. Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: preparation, characterization and antitumor activity. Int J Pharm. 2014;472(1–2):214–23.

    CAS  PubMed  Google Scholar 

  79. Xia D, Quan P, Piao H, Piao H, Sun S, Yin Y, et al. Preparation of stable nitrendipine nanosuspensions using the precipitation–ultrasonication method for enhancement of dissolution and oral bioavailability. Eur J Pharm Sci. 2010;40:325–34.

    CAS  PubMed  Google Scholar 

  80. Mohanty C, Sahoo SK. The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials. 2010;31:6597–611.

    CAS  PubMed  Google Scholar 

  81. Zhao L, Feng SS. Enhanced oral bioavailability of paclitaxel formulated in vitamin E-TPGS emulsified nanoparticles of biodegradable polymers: in vitro and in vivo studies. J Pharm Sci. 2010;99(8):3552–60.

    CAS  PubMed  Google Scholar 

  82. Onoue S, Takahashi H, Kawabata Y, Seto Y, Hatanaka J, Timmermann B, et al. Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. J Pharm Sci. 2010;99(4):1871–81.

    CAS  PubMed  Google Scholar 

  83. Zhang J, Lv H, Jiang K, Gao Y. Enhanced bioavailability after oral and pulmonary administration of baicalein nanocrystal. Int J Pharm. 2011;420(1):180–8.

    CAS  PubMed  Google Scholar 

  84. Jiang T, Han N, Zhao B, Xie Y, Wang S. Enhanced dissolution rate and oral bioavailability of simvastatin nanocrystal prepared by sonoprecipitation. Drug Dev Ind Pharm. 2012;38(10):1230–9.

    CAS  PubMed  Google Scholar 

  85. Thadkala K, Nanam PK, Aukunuru J. Preparation and characterization of amorphous ezetimibe nanosuspensions intended for enhancement of oral bioavailability. Int.J Pharm Investig. 2014;4(3):131–37.

  86. Shi-Ying J, Jin H, Shi-Xiao J, Qing-Yuan L, Jin-Xia B, Chen HG. Characterization and evaluation in vivo of baicalin-nanocrystals prepared by an ultrasonic-homogenization-fluid bed drying method. Chin J Nat Med. 2014;12(1):71–80.

    PubMed  Google Scholar 

  87. Luo C, Yan L, Sun J, Zhang Y, Chen Q, Liu X, He Z. Felodipine nanosuspension: a faster dissolution rate and higher oral absorption efficiency. J Drug Del Sci Technol. 2014;24(2):173–7.

    CAS  Google Scholar 

  88. Borhade V, Pathak S, Sharma S, Patravale V. Formulation and characterization of atovaquone nanosuspension for improved oral delivery in the treatment of malaria. Nanomed (Lond). 2014;9(5):649–66.

    CAS  Google Scholar 

  89. Fu Q, Sun J, Zhang D, Li M, Wang Y, Ling G. Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies. Colloids Surf B Biointerfaces. 2013;109:161–6.

    CAS  PubMed  Google Scholar 

  90. Ige PP, Baria RK, Gattani SG. Fabrication of fenofibrate nanocrystals by probe sonication method for enhancement of dissolution rate and oral bioavailability. Colloids Surf B Biointerfaces. 2013;108:366–73.

    CAS  PubMed  Google Scholar 

  91. Ravichandran R. Pharmacokinetic study of nanoparticulate curcumin: oral formulation for enhanced bioavailability. J Biomat Nanobiotechnol. 2013;4:291–9.

    CAS  Google Scholar 

  92. Quan P, Xia D, Piao H, Piao H, Shi K, Jia Y, et al. Nitrendipine nanocrystals: its preparation, characterization, and in vitro–in vivo evaluation. AAPS PharmSciTech. 2011;12(4):1136–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Ravichandran R. In vivo pharmacokinetic studies of albendazole nanoparticulate oral formulations for improved bioavailability. Int J Green Nanotech Biomed. 2010. doi:10.1080/1943085x.2010.488200.

    Google Scholar 

  94. Shah M, Chuttani K, Mishra AK, Pathak K. Oral solid Compritol 888 ATO nanosuspension of simvastatin: optimization and biodistribution studies. Drug Dev Ind Pharm. 2011;37(5):526–37.

    CAS  PubMed  Google Scholar 

  95. Pokharkar VB, Malhi T, Mandpe L. Bicalutamide nanocrystal with improved oral bioavailability: in vitro and in vivo evaluation. Pharm Dev Technol. 2013. doi:10.3109/10837450.2012.663391.

    Google Scholar 

  96. Gao F, Zhang Z, Bu H, Huang Y, Gao Z, Shen J. Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: performance and mechanism. J Control Release. 2011;149:68–74.

    Google Scholar 

  97. Landfester K, Willert M, Antonietti M. Preparation of polymer particles in nonaqueous direct and inverse miniemulsions. Macromolecules. 2000;33(7):2370–6.

    CAS  Google Scholar 

  98. Usón N, García MJ, Solans C. Formation of water-in-oil (w/o) nano-emulsions in a water/mixed non-ionic surfactant/oil systems prepared by a low-energy emulsification method. Colloid Surf A Physicochem Eng Asp. 2004;250:415–21.

    Google Scholar 

  99. Morales D, Gutiérrez JM, Garcia-Celma JM, Solans C. A study of the relation between bicontinuous microemulsions and oil/water nanoemulsion formation. Langmuir. 2003;19:7196–200.

    CAS  Google Scholar 

  100. Laouini A, Fessi H, Charcosset C. Membrane emulsification: a promising alternative for vitamin E encapsulation within nano-emulsion. J Membrane Sci. 2012;423–424:85–96.

    Google Scholar 

  101. Gorain B, Choudhury H, Kundu A, Sarkar L, Karmakar S, Jaisankar P, Pal TP. Nanoemulsion strategy for olmesartan medoxomil improves oral absorption and extended antihypertensive activity inhypertensive rats. Colloid Surf B. 2014;115:286–94.

    CAS  Google Scholar 

  102. Singh S, Kamla Pathak K, Bali V. Product development studies on surface-adsorbed nanoemulsion of olmesartan medoxomil as a capsular dosage form. AAPS PharmSciTech. 2012;13:1212–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Devalapally H, Silchenko S, Zhou F, Owen A, Hidalgo IJ. Evaluation of a nanoemulsion formulation strategy for oral bioavailability enhancement of danazol in rats and dogs. J Pharm Sci. 2013;102(10):3808–15.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Chavhan SS, Petkar KC, Sawant KK. Simvastatin nanoemulsion for improved oral delivery: design, characterisation, in vitro and in vivo studies. J Microencapsul. 2013;30(8):771–9.

    CAS  PubMed  Google Scholar 

  105. Belhaj N, Dupuis F, Tehrany EA, Denis FD, Paris C, Lartaud I, et al. Formulation, characterization and pharmacokinetic studies of coenzyme Q10 PUFA’s nanoemulsions. Eur J Pharm Sci. 2012;47:305–12.

    CAS  PubMed  Google Scholar 

  106. Shen Q, Wang Y, Zhang Y. Improvement of colchicine oral bioavailability by incorporating eugenol in the nanoemulsion as an oil excipient and enhancer. Int J Nanomed. 2011;6:1237–43.

    CAS  Google Scholar 

  107. Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm; 460:131–43.

  108. Sessa M, Balestrieri ML, Ferrari G, Servillo L, Castaldo D, Onofrio ND. Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems. Food Chem. 2014;147:42–50.

    CAS  PubMed  Google Scholar 

  109. Jain K, Kumar RS, Sood S, Gowthamarajan K. Enhanced oral bioavailability of atorvastatin via oil-in-water nanoemulsion using aqueous titration method. J Pharm Sci Res. 2013;5(1):18–25.

    CAS  Google Scholar 

  110. Yu H, Huang Q. Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions. J Agric Food Chem. 2012;60:5373–9.

    CAS  PubMed  Google Scholar 

  111. Ma Y, Li HG, Guan SX. Enhancement of the oral bioavailability of breviscapine by nanoemulsions drug delivery system. Drug Dev Ind Pharm. 2014;12:1–6.

    Google Scholar 

  112. Chhabra G, Chuttani K, Mishra AK, Pathak K. Design and development of nanoemulsion drug delivery system of amlodipine besilate for improvement of oral bioavailability. Drug Dev Ind Pharm. 2011;37(8):907–16.

    CAS  PubMed  Google Scholar 

  113. Zhao L, Wei Y, Fu J. Nanoemulsion improves the oral bioavailability of baicalin in rats: in vitro and in vivo evaluation. Int J Nanomed. 2013;8:3769–79.

    Google Scholar 

  114. Sukanya G, Mantry S, Shireen A. Review on nanoemulsion. Int J Innov Pharm Sci Res. 2013;1(2):192–205.

    Google Scholar 

  115. Bruxel F, Cojean S, Bochot A, Teixeira H, Bories C, Loiseau PM, Fattal E. Cationic nanoemulsion as a delivery system for oligonucleotides targeting malarial topoisomerase II. Int J Pharm. 2011;416(2):402–9.

    CAS  PubMed  Google Scholar 

  116. Bruxel F, Bochot A, Diel D, Fattal E, Teixeira HF. Adsorption of antisense oligonucleotides targeting malarial topoi-somerase II on cationic nanoemulsions optimized by a full factorial design. Curr Topics Med Chem. 2014;14(9):1161–71.

    CAS  Google Scholar 

  117. Li X, Xu Y, Chen G, Wei P, Ping Q. PLGA nanoparticles for the oral delivery of 5-fluorouracil using high pressure homogenization—emulsification as the preparation method and in vitro/in vivo studies. Drug Dev Ind Pharm. 2008;34:107–15.

    CAS  PubMed  Google Scholar 

  118. Sarmento B, Ribeiro A, Veiga F, Ferreira D, Neufeld R. Oral bioavailability of insulin contained in polysaccharide nanoparticles. Biomacromolecules. 2007;8:3054–60.

    CAS  PubMed  Google Scholar 

  119. Bharadwaj V, Ravikumar MNV. Polymeric nanoparticles for oral delivery. New York: Taylor and Francis; 2006.

    Google Scholar 

  120. Galindo-Rodriguez SA, Allemann E, Fessi H, Doelker E. Polymeric nanoparticles for oral delivery of drugs and vaccines: a critical evaluation of in vivo studies. Crit Rev Ther Drug Carrier Syst. 2005;22:419–64.

    CAS  PubMed  Google Scholar 

  121. Seju U, Kumar A, Sawant KK. Development and evaluation of olanzapineloaded PLGA nanoparticles for nose-to-brain delivery: in vitro and in vivo studies. Acta Biomater. 2011;7:4169–76.

    CAS  PubMed  Google Scholar 

  122. Hosseinzadeh H, Atyabi F, Dinarvand R, Ostad SN. Chitosan–pluronic nanoparticles as oral delivery of anticancer gemcitabine: preparation and in vitro study. Int J Nanomed. 2012;7:1851–63.

    CAS  Google Scholar 

  123. Joshi G, Kumar A, Sawant K. Enhanced bioavailability and intestinal uptake of gemcitabine HCl loaded PLGA nanoparticles after oral delivery. Eur J Pharm Sci. 2014;60:80–9.

    CAS  PubMed  Google Scholar 

  124. Suwannateep N, Banlunara W, Wanichweeharumgruang SP, Chiablaem K, Lirdprapamongkol K, Svast J. Mucoadhesive curcumin nanospheres: biological activity adhesion to stomach mucosa and release of curcumin into circulation. J Control Release. 2011;151:176–82.

    CAS  PubMed  Google Scholar 

  125. Yang YY, Wang Y, Powell R, Chan P. Polymeric core-shell nanoparticles for therapeutics. Clin Exp Pharmacol Physiol. 2006;33:557–62.

    CAS  PubMed  Google Scholar 

  126. Bolmal UB, Manvi FV, Kotha Rajkumar K, Palla SS, Paladugu A, Reddy KR. Recent advances in nanosponges as drug delivery system. Int J Pharm Sci Nanotechnol. 2013;6.

  127. Sharma R, Pathak K. Nanosponges: emerging drug delivery system. Pharma Stud. 33–35.

  128. Thomas N, Holm R, Mullertz A, Rades T. In vitro and in vivo performance of novel supersaturated selfnanoemulsifying drug delivery systems (super-SNEDDS). J Control Release. 2012;160(1):25–32.

    CAS  PubMed  Google Scholar 

  129. Porter CJH, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2008;60(6):673–91.

    CAS  PubMed  Google Scholar 

  130. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6:231–48.

    CAS  PubMed  Google Scholar 

  131. Nangwade BK, Patel DJ, Udhani RA, Manvi FV. Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs. Sci Pharm. 2011;79(4):705–25.

    Google Scholar 

  132. Date AA, Desai N, Dixit R, et al. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomed. 2010;5(10):1595–616.

    CAS  Google Scholar 

  133. Jing-Ling T, Jin S, Zhong-Gui H. Emulsifying drug delivery systems: strategy for improving oral delivery of poorly soluble drugs. Curr Drug Ther. 2007;2:85–93.

    Google Scholar 

  134. Patel A, Shelat P, Lalwani A. Development and optimization of solid self-nanoemulsifying drug delivery system (S-SNEDDS) using Scheffe’s design for improvement of oral bioavailability of nelfinavir mesylate. Drug Deliv Transl Res. 2014;4:171–86.

    CAS  PubMed  Google Scholar 

  135. Heshmati N, Cheng X, Eisenbrand G, Fricker G. Enhancement of oral bioavailability of e804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats. J Pharm Sci. 2013;102(10):3792–9.

    CAS  PubMed  Google Scholar 

  136. Sakloetsakun D, Dünnhaupt S, Barthelmes J, Perera G, Schnürch AB. Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration. Int J Biol Macromol. 2013;61:363–72.

    CAS  PubMed  Google Scholar 

  137. Quan Q, Kim DW, Marasini N, Kim DH, Kim JK, Kim JO. Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel. J Microencapsul. 2013;30(4):307–14.

    CAS  PubMed  Google Scholar 

  138. Seo YG, Kim DH, Ramasamy T, Kim JH, Marasini N, Oh YK. Development of docetaxel-loaded solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced chemotherapeutic effect. Int J Pharm. 2013;452(1–2):412–20.

    CAS  PubMed  Google Scholar 

  139. Mahmoud DB, Shukr MH, Bendas ER. In vitro and in vivo evaluation of self-nanoemulsifying drug delivery systems of cilostazol for oral and parenteral administration. Int J Pharm. 2014;476(1–2):60–9.

    CAS  PubMed  Google Scholar 

  140. Singh B, Singh R, Bandyopadhyay S, Kapil R, Garg B. Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol. Colloid Surf B. 2013;101:465–74.

    CAS  Google Scholar 

  141. Bajaj A, Rao MRP, Khole I, Munjapara G. Self emulsifying drug delivery system of cefpodoxime proxetil containing tocopherol polyethylene glycol succinate. Drug Dev Ind Pharm. 2013;39(5):635–45.

    CAS  PubMed  Google Scholar 

  142. Janga KY, Jukanti R, Sunkavalli S, Kandadi P, Veerareddy PR. In situ absorption and relative bioavailability studies of zaleplon loaded self-nanoemulsifying powders. J Microencapsul. 2013;30(2):161–72.

    CAS  PubMed  Google Scholar 

  143. Kumar SR, Syamala SU, Revathi P, Raghuveer P, Gowthamarajan K. Self nanoemulsifying drug delivery system of olanzapine for enhanced oral bioavailability: in vitro, in vivo characterisation and in vitro -in vivo correlation. J Bioequiv Availab. 2013. doi:10.4172/jbb.1000159.

    Google Scholar 

  144. Kamel AO, Mahmoud AA. Enhancement of human oral bioavailability and in vitro antitumor activity of rosuvastatin via spray dried self-nanoemulsifying drug delivery system. J Biomed Nanotechnol. 2013;9(1):26–39.

    CAS  PubMed  Google Scholar 

  145. Akhter MH, Ahmad A, Ali J, Mohan G. Formulation and development of CoQ10-loaded s-SNEDDS for enhancement of oral bioavailability. J Pharm Innovat. 2014;9(2):121–31.

    Google Scholar 

  146. Jain AK, Thanki K, Jain S. Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen: part II in vivo pharmacokinetics, antitumor efficacy and hepatotoxicity. Pharm Res. 2014;31(4):946–58.

    CAS  PubMed  Google Scholar 

  147. Singh G, Pai RS. Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization. Expert Opin Drug Deliv. 2014;11(7):1023–32.

    CAS  PubMed  Google Scholar 

  148. Patel J, Dhingani A, Garala K, Raval M, Sheth N. Quality by design approach for oral bioavailability enhancement of irbesartan by self-nanoemulsifying tablets. Drug Deliv. 2014;21(6):412–35.

    CAS  PubMed  Google Scholar 

  149. Zhang Z, Huang J, Jiang S, Liu Z, Gu W, Yu H, Li Y. A high-drug-loading self-assembled nanoemulsion enhances the oral absorption of probucol in rats. J Pharm Sci. 2013;102(4):1301–6.

    CAS  PubMed  Google Scholar 

  150. Zhang J, Peng Q, Shi S, Gong T, Zhang Z. Preparation, characterization, and in vivo evaluation of a self-nanoemulsifying drug delivery system (SNEDDS) loaded with morin–phospholipid complex. Int J Nanomed. 2011;6:3405–14.

    CAS  Google Scholar 

  151. Patel J, Patel A, Raval M, Sheth N. Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan. J Adv Pharm Technol Res. 2011;2(1):9–16.

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Ruan J, Liu J, Zhu D, Hao X, Zhang Z. Preparation and evaluation of self-nanoemulsified drug delivery systems (SNEDDSs) of matrine based on drug–phospholipid complex technique. Int J Pharm. 2010;386(1–2):282–90.

    CAS  PubMed  Google Scholar 

  153. Larsen AT, Ogbonna AG, Polentarutti B, Barker RA, Phillips AR, Rmaileh AR. Oral bioavailability of cinnarizine in dogs: relation to SNEDDS particle size, drug solubility and in vitro precipitation. Eur J Pharm Sci. 2013;48:339–50.

    CAS  PubMed  Google Scholar 

  154. Larsen AT, Ogbonna AB, Rmaileh AR, Østergaard A, Müllertz J. SNEDDS containing poorly water soluble cinnarizine; development and in vitro characterization of dispersion, digestion and solubilization. Pharmaceutics. 2012;4:641–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173–82.

    PubMed  Google Scholar 

  156. Khan AW, Kotta S, Ansari SH. Potentials and challenges in selfnanoemulsifying drug delivery systems. Expert Opin Drug Deliv. 2012;9(10):1305–17.

    CAS  PubMed  Google Scholar 

  157. Zhao Y, Wang C, Chow AHL, Ren K, Gong T, Zhang Z, Zheng Y. Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of zedoary essential oil: formulation and bioavailability studies. Int J Pharm. 2010;383:170–7.

    CAS  PubMed  Google Scholar 

  158. Dabhi MR, Limbani MD, Sheth NR. Preparation and in vivo evaluation of self-nanoemulsifying drug delivery system (SNEDDS) containing ezetimibe. Curr Nanosci. 2011;7(4):616.

    CAS  Google Scholar 

  159. Bandyopadhyay S, Katare OP, Singh B. Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: effect of polymersand efflux transporters. Expert Opin Drug Deliv. 2014;11(4):479–92.

    CAS  PubMed  Google Scholar 

  160. Tran T, Guo Y, Song D, Bruno RS, Lu XI. Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability. J Pharm Sci. 2014;103:840–52.

    CAS  PubMed  Google Scholar 

  161. Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discov Today. 2008;13(13–14):606–12.

    CAS  PubMed  Google Scholar 

  162. Yi T, Wan J, Xu H, Yang X. A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs. Eur J Pharm Biopharm. 2008;70(2):439–44.

    CAS  PubMed  Google Scholar 

  163. Wang Z, Sun J, Wang Y, Liu X, Liu Y, Fu Q, et al. Solid self-emulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation. Int J Pharm. 2010;383(1–2):1–6.

    CAS  PubMed  Google Scholar 

  164. Abbaspour M, Jalayer N, Makhmalzadeh BS. Development and evaluation of a solid self-nanoemulsifying drug delivery system for loratadin by extrusion-spheronization. Adv Pharm Bull. 2014;4(2):113–9.

    PubMed Central  PubMed  Google Scholar 

  165. Beg S, Jena SS, Patra CN, Rizwan M, Swain S, Sruti J, et al. Development of solid self nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential. Colloid Surf B. 2013;101:414–23.

    CAS  Google Scholar 

  166. Piao ZZ, Choe JS, Oh KT, Rhee YS, Lee BJ. Formulation and in vivo human bioavailability of dissolving tablets containing a self-nanoemulsifying itraconazole solid dispersion without precipitation in simulated gastrointestinal fluid. Eur J Pharm Sci. 2014;51:67–74.

    CAS  PubMed  Google Scholar 

  167. Shono Y, Jantratid E, Dressman JB. Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. Eur J Pharm Biopharm. 2011;79:349–56.

    CAS  PubMed  Google Scholar 

  168. Attama AA. SLN, NLC, LDC: state of the art in drug and active delivery. Recent Pat Drug Deliv Formul. 2011;5:178–87.

    CAS  PubMed  Google Scholar 

  169. Muchow M, Maincent P, Müller RH, Keck CM. Production and characterization of testosterone undecanoate-loaded NLC for oral bioavailability enhancement. Drug Dev Ind Pharm. 2011;37(1):8–14.

    CAS  PubMed  Google Scholar 

  170. Varshosaz J, Minayian M, Moazen E. Enhancement of oral bioavailability of pentoxifylline by solid lipid nanoparticles. J Liposome Res. 2010;20(2):115–23.

    CAS  PubMed  Google Scholar 

  171. Hu LD, Xing Q, Meng J, Shang C. Preparation and enhanced oral bioavailability of cryptotanshinone-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2010;11(2):582–7.

    PubMed Central  PubMed  Google Scholar 

  172. Varshosaz J, Tabbakhian M, Mohammadi MY. Formulation and optimization of solid lipid nanoparticles of buspirone HCl for enhancement of its oral bioavailability. J Liposome Res. 2010;20(4):286–96.

    CAS  PubMed  Google Scholar 

  173. Zhuang CY, Li N, Wang M, Zhang XN, Peng JJ, Pan WS. Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability. Int J Pharm; 394:179–85.

  174. Ravi PR, Vats R, Dalal V, Murthy AN. A hybrid design to optimize preparation of lopinavir loaded solid lipid nanoparticles and comparative pharmacokinetic evaluation with marketed lopinavir/ritonavir coformulation. J Pharm Pharmacol. 2014;66(7):912–26.

    CAS  PubMed  Google Scholar 

  175. Zhang Z, Bu H, Gao Z, Huang Y, Gao F, Li Y. The characteristics and mechanism of simvastatin loaded lipid nanoparticles to increase oral bioavailability in rats. Int J Pharm. 2010;394(1–2):147–53.

    CAS  PubMed  Google Scholar 

  176. Beloqui A, Solinís MA, Rieux A, Préat V, Gascón AR. Dextran protamine coated nanostructured lipid carriers as mucus-penetrating nanoparticles for lipophilic drugs. Int J Pharm. 2014;468:105–11.

    CAS  PubMed  Google Scholar 

  177. Thulasi Ram D, Debnath S, Niranjan Babu M, Chakradhar Nath T, Thejeswi B. A review on solid lipid nanoparticles. Res J Pharm. Technol. 2012;5(11):1359–68.

  178. Muchow M, Maincent P, Maincent P. Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for oral drug delivery. Drug Dev Ind Pharm. 2008;34:1394–405.

    CAS  PubMed  Google Scholar 

  179. Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.

    CAS  PubMed  Google Scholar 

  180. Pathak P, Keshri L, Shah M. Lipid nanocarriers: influence of lipids on product development and pharmacokinetics. Crit Rev Ther Drug. 2011;28(4):357–93.

    CAS  Google Scholar 

  181. Tarr BD, Yalkowsky SH. Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size. Pharm Res. 1989;6(1):40–3.

    CAS  PubMed  Google Scholar 

  182. Kreuter J. Peroral administration of nanoparticles. Adv Drug Deliv Rev. 1991;7:71–86.

    CAS  Google Scholar 

  183. Manjunath K, Venkateswarlu V. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration. J Control Release. 2005;107:215–28.

    CAS  PubMed  Google Scholar 

  184. Fricker G, Wendel A, Blume A, Zirkel J, Rebmann H, Setzer C, et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharm Res. 2010;27:1469–86.

    CAS  PubMed  Google Scholar 

  185. Olbrich C, Gebner A, Kayser O, Muller RH. Lipid-drug conjugate (LDC) nanoparticles as a novel carrier system for the hydrophilic antitrypanosomal drug diminazenediaceturate. J Drug Target. 2002;10:387–96.

    CAS  PubMed  Google Scholar 

  186. Muller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev. 2002;54:S131–55.

    CAS  PubMed  Google Scholar 

  187. Xie S, Pan B, Wang M, Zhu L, Wang F, Dong Z, et al. Formulation, characterization and pharmacokinetics of praziquantel-loaded hydrogenated castor oil solid lipid nanoparticles. Nanomed (Lond). 2010;5(5):693–701.

    CAS  Google Scholar 

  188. Luo CF, Yuan M, Chen MS, Liu SM, Zhu L, Huang BY, et al. Pharmacokinetics, tissue distribution and relative bioavailability of puerarin solid lipid nanoparticles following oral administration. Int J Pharm. 2011;410:138–44.

    CAS  PubMed  Google Scholar 

  189. Alex AMR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci. 2011;42(1–2):11–8.

    Google Scholar 

  190. Montenegro L, Campisi A, Sarpietro MG, Carbone C, Acquaviva R, Raciti G, et al. In vitro evaluation of idebenone-loaded solid lipid nanoparticles for drug delivery to the brain. Drug Dev Ind Pharm. 2011;37(6):737–46.

    CAS  PubMed  Google Scholar 

  191. Zhang X, Qiao H, Zhang T, Shi Y, Ni J. Enhancement of gastrointestinal absorption of isoliquiritigenin by nanostructured lipid carrier. Adv Powder Technol. 2014;25(3):1060–8.

    CAS  Google Scholar 

  192. Patil-Gadhe A, Pokharkar V. Montelukast-loaded nanostructured lipid carriers: part I oral bioavailability improvement. Eur J Pharm Biopharm. 2014;88(1):160–8.

    CAS  PubMed  Google Scholar 

  193. Muchow M, Maincent P, Müller RH, Keck CM. Testosterone undecanoate—increase of oral bioavailability by nanostructured lipid carriers (NLC). J Pharm Technol Drug Res. 2010. doi:10.7243/2050-120X-2-4.

    Google Scholar 

  194. Shangguan M, Lu Y, Qi J, Han J, Tian Z, Xie Y, et al. Binary lipids-based nanostructured lipid carriers for improved oral bioavailability of silymarin. J Biomater Appl. 2014;28(6):887–96.

    PubMed  Google Scholar 

  195. Sun M, Wang S, Nie S, Zhang J. Enhanced oral bioavailability of quercetin by nanostructured lipid carriers. FASEB J. 2014;28(1) (supplement 1044.24).

  196. Liu L, Tang Y, Gao C, Li Y, Chen S, Xiong T, et al. Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers. Colloid Surf B. 2014;115:125–31.

    CAS  Google Scholar 

  197. Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: drug-dendrimer interactions and toxicity issues. J Pharm Bioallied Sci. 2014;6(3):139–50.

    PubMed Central  PubMed  Google Scholar 

  198. Cheng Y, Xu Z, Ma M, Xu T. Dendrimers as drug carriers: applications in different routes of drug administration. J Pharm Sci. 2008;97(1):123–43.

    CAS  PubMed  Google Scholar 

  199. Menjoge AR, Rinderknecht AL, Navath RS, Faridnia M, Kim CJ, Romero RJ. Controlled Release. 2011;149:21.

    Google Scholar 

  200. Kaminskas LM, McLeod VM, Kelly BD, Sberna G, Boyd BJ, Williamson M. A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Nanomed Nanotechnol Biol Med. 2012;8:103–11.

    CAS  Google Scholar 

  201. Sadekar S, H. Ghandehari H. Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral. Adv Drug Deliv Rev. 2014;64:571–88.

  202. Patel J, Garala K, Dharamsi A. Solubility of aceclofenac in polyamidoamine dendrimer solutions. Int J Pharm Investig. 2011;1(3):135–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  203. Patel RM, Patel HN, Gajjar DG, Patel PM. Enhanced solubility of non-steroidal anti-inflammatory drugs by hydroxyl terminated S-triazine based dendrimers. Asian J Pharm Clin Res. 2014;7:156–61.

    CAS  Google Scholar 

  204. Teow HM, Zhou Z, Najlah M, Yusof SR, Abbott NJ, D’Emanuele A. Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier. Int J Pharm. 2012. doi:10.1016/j.ijpharm.2012.10.024.

    PubMed  Google Scholar 

  205. Abufazali R. Carbon nanotubes: a promising approach for drug delivery. Iranian J Pharm Res. 2010;9(1):1–3.

    Google Scholar 

  206. Sui L, Yang T, Gao P, Ai M, Pingting Wang PA, Zhenzhen WuZ, et al. Incorporation of cisplatin into PEG-wrapped ultrapurified large-inner- diameter MWCNTs for enhanced loading efficiency and release profile. Int J Pharm. 2014;471:157–65.

    CAS  PubMed  Google Scholar 

  207. Tan JM, Karthivashan G, Arulselvan P, Fakurazi S, Hussein MZ. Characterization and in vitro sustained release of silibinin from pH responsive carbon nanotube-based drug delivery system. J Nanomater. 2014. doi:10.1155/2014/439873.

    Google Scholar 

  208. Hilder TA, Hill JM. Modeling the loading and unloading of drugs into nanotubes. Small. 2009. doi:10.1002/smll.200800321.

    Google Scholar 

  209. Giorgia P. Crucial functionalizations of carbon nanotubes for improved drug delivery: a valuable option. Pharm Res. 2009;26(4):746–69.

    Google Scholar 

  210. Prajapati VK, Awasthi K, Gautam S, et al. Targeted killing of Leishmania donovani in vivo and in vitro with amphotericin B attached to functionalized carbon nanotubes. J Antimicrob Chemother. 2010;66:874–9.

    Google Scholar 

  211. Prajapati VK, Awasthi K, Yadav TP, Srivastava ON, Sundar S. An oral formulation of amphotericin B attached to functionalized carbon nanotubes is an effective treatment for experimental visceral leishmaniasis. J Infect Dis. 2012;205(2):333–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  212. Foldvari M, Bagonluri M. Carbon nanotubes as functional excipients for nanomedicines: I. Pharmaceutical properties. Nanomed Nanotechnol Biol Med. 2008;4:173–82.

    CAS  Google Scholar 

  213. Foldvari M, Bagonluri M. Carbon nanotubes as functional excipients for nanomedicines: II. Drug delivery and biocompatibility issues. Nanomed Nanotechnol Biol Med. 2008;4:13–200.

    Google Scholar 

  214. Ye S, Jiang Y, Zhang H. Modulation of apoptotic pathways of macrophages by surface-functionalized multi-walled carbon nanotubes. PLoS One. 2013;8.

  215. Ito Y, Venkatesan N, Hirako N, Sugioka N, Takada K. Effect of fiber length of carbon nanotubes on the absorption of erythropoietin from rat small intestine. Int J Pharm. 2008;337:357–60.

    Google Scholar 

  216. Lee Y, Geckeler KE. Carbon nanotubes in the biological interphase: the relevance of noncovalence. Adv Mater. 2010;22(36):4076–83.

    CAS  PubMed  Google Scholar 

  217. Fisher C, Rider AE, Han ZJ, Kumar S, Levchenko I, Ostrikov K. Applications and nanotoxicity of carbon nanotubes and graphene in biomedicine. J Nanomater. 2012. doi:10.1155/2012/315185.

    Google Scholar 

  218. Kostarelos K, Bianco A, Lacerda L, et al. Translocation mechanisms of chemically functionalised carbon nanotubes across plasma membranes. Biomaterials. 2012;33(11):3334–43.

    PubMed  Google Scholar 

  219. Zhao F, Zhao Y, Liu Y, Chang X, Chen C, Zhao Y. Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small. 2011;7(10):1322–37.

    CAS  PubMed  Google Scholar 

  220. Jones MC, Leroux JC. Polymeric micelles: a new generation of colloidal drug carriers. Eur J Pharm Biopharm. 1999;48:101–11.

    CAS  PubMed  Google Scholar 

  221. Kwon GS, Okano T. Polymeric micelles as new drug carriers. Adv Drug Deliv Rev. 1996;21:107–16.

    CAS  Google Scholar 

  222. Riess G. Micellization of block copolymers. Prog Polym Sci. 2003;28:1107–70.

    CAS  Google Scholar 

  223. Xu W, Ling P, Zhang T. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv. 2013. doi:10.1155/2013/340315.

    Google Scholar 

  224. Kabanov AV, Batrakova EV, Alakhov EY. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002;82(2–3):189–212.

    CAS  PubMed  Google Scholar 

  225. Bae Y, Kataoka K. Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61(10):768–84.

    CAS  PubMed  Google Scholar 

  226. Meier MAR, Aerts SNH, Staal BBP, Rasa M, Schubert US. PEO-b-PCL block copolymers: synthesis, detailed characterization, and selected micellar drug encapsulation behavior. Macromol Rapid Commun. 2005;26(24):1918–24.

  227. Ruan G, Feng SS. Preparation and characterization of poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) microspheres for controlled release of paclitaxel. Biomaterials. 2003;24(27):5037–44.

    CAS  PubMed  Google Scholar 

  228. Taek GK, Lee H, Jang Y, Tae GP. Controlled release of paclitaxel from heparinized metal stent fabricated by layer-by-layer assembly of polylysine and hyaluronic acid-g-poly(lactic-co-glycolic acid) micelles encapsulating paclitaxel. Biomacromolecules. 2009;10:1532–9.

    Google Scholar 

  229. Lee H, Ahn CH, Park TG. Poly[lactic-co-(glycolic acid)]-grafted hyaluronic acid copolymer micelle nanoparticles for target-specific delivery of doxorubicin. Macromol Biosci. 2009;9:336–42.

    CAS  PubMed  Google Scholar 

  230. Benahmed A, Ranger M, Leroux J. Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-block-poly(d, l lactide). Pharm Res. 2001;18:323–38.

    CAS  PubMed  Google Scholar 

  231. Inoue T, Chen G, Nakamae K, Hoffman AS. An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drags. J Control Release. 1998;51:221–9.

    CAS  PubMed  Google Scholar 

  232. Attia ABE, Ong ZY, Hedrick JL, Phin Peng Lee PP, Pui Lai Rachel EE. Mixed micelles self-assembled from block copolymers for drug delivery. Curr Opin Colloid Interface Sci. 2011;16:182–94.

    Google Scholar 

  233. Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymers for drug delivery. J Pharm Sci. 2003;92:1343–55.

    CAS  PubMed  Google Scholar 

  234. Rieux A, Fievez V, Garinot M, Schneider YM, Préat Y. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release. 2006;116:1–27.

    PubMed  Google Scholar 

  235. Pierri E, Avgoustakis K. Poly(lactide)-poly(ethylene glycol) micelles as a carrier for griseofulvin. J Biomed Mater Res A. 2005;75:639–47.

    CAS  PubMed  Google Scholar 

  236. Kim MS, Lee DS. In vitro degradability and stability of hydrophobically modified pH-sensitive micelles using MPEG-grafted poly(B-amino ester) for efficient encapsulation of paclitaxel. J Appl Polym Sci. doi:10.1002/app.32685.

  237. Lee I, Park M, Kim Y, Hwang O, Khang G, Lee D. Ketal containing amphiphilic block copolymer micelles as pH-sensitive drug carriers. Int J Pharm. 2013;448(1):259–66.

    CAS  PubMed  Google Scholar 

  238. Wang F, Zhang D, Zhang Q, Chen Y, Zheng D, Hao L, et al. Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel–polymer micelles to overcome multi-drug resistance. Biomaterials. 2011;32(35):9444–56.

    CAS  PubMed  Google Scholar 

  239. Heffeter P, Riabtseva A, Senkiv Y, Kowol CR, Körner W, Jungwith U. Nanoformulation improves activity of the (pre)clinical anticancer ruthenium complex KP1019. J Biomed Nanotechnol. 2014;10(5):877–84.

    CAS  PubMed  Google Scholar 

  240. Sulfikkarali N, Krishnakumar N, Manoharan S, Nirmal RM. Chemopreventive efficacy of naringenin-loaded nanoparticles in 7,12-dimethylbenz(a)anthracene induced experimental oral carcinogenesis. Pathol Oncol Res. 2013;19(2):287–96.

    CAS  PubMed  Google Scholar 

  241. Rodríguez GRR, Alonso MK, Torres D. Poly-l-asparagine nanocapsules as anticancer drug delivery vehicles. Eur J Pharm Biopharm. 2013;85(3)part A:481–87.

  242. Kanwar JR, Mahidhara G, Kanwar RK. Novel alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers for oral delivery in colon cancer therapy. Nanomedicine (Lond). 2012;7(10):1521–50.

    CAS  PubMed  Google Scholar 

  243. Yao HJ, Ju RJ, Wang XX, Zhang Y, Li RJ, Yu Y, et al. The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery. Biomaterials. 2011;32(12):3285–302.

    CAS  PubMed  Google Scholar 

  244. Sagnella SM, Gong X, Moghaddam MJ, Conn CE, Kimpton K, Waddington LJ, et al. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents. Nanoscale. 2011;3(3):919–24.

    CAS  PubMed  Google Scholar 

  245. Liu X, Huang H, Wang J, Wang C, Wang M, Zhang B, et al. Dendrimers-delivered short hairpin RNA targeting hTERT inhibits oral cancer cell growth in vitro and in vivo. Biochem Pharmacol. 2011;82(1):17–23.

    CAS  PubMed  Google Scholar 

  246. Jain A, Agarwal A, Majumder S, Lariya N, Khaya A, Agrawal H, et al. Mannosylated solid lipid nanoparticles as vectors for site-specific delivery of an anti-cancer drug. J Control Release. 2010;148(3):359–67.

    CAS  PubMed  Google Scholar 

  247. Yassin AEB, Anwer MK, Mowafy HA, Bagory IME, Bayomi MA, Alsarra IA. Optimization of 5-fluorouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer. Int J Med Sci. 2010;7(6):398–408.

    PubMed Central  CAS  PubMed  Google Scholar 

  248. Mei L, Zhang Z, Zhao L, Huang L, Yang XL, Tang J, Feng SS. Pharmaceutical nanotechnology for oral delivery of anticancer drugs. Adv Drug Deliv Rev. 2013;65:880–90.

    CAS  PubMed  Google Scholar 

  249. Maynard AD, Baron PA, Foley M, Shvedova AA, Kisin ER, Castranova V. Exposure to carbon nanotube material: aerosol release during the handling of unrefined single-walled carbon nanotube material. J Toxicol Environ Health Part A. 2004;67:87–107.

    CAS  PubMed  Google Scholar 

  250. Han SG, Andrews R, Gairola CG. Acute pulmonary response of mice to multi-wall carbon nanotubes. Inhalation Toxicol. 2010;22(4):340–7.

    CAS  Google Scholar 

  251. Porter DW, Hubbs AF, Mercer RR, Wu N, Wolfarth MG, Sriram K, et al. Mouse pulmonary dose- and time course-responses induced by exposure to multi-walled carbon nanotubes. Toxicology. 2010;269(2–3):136–47.

    CAS  PubMed  Google Scholar 

  252. Wolfarth MG, McKinney W, Chen BT, Castranova V, Porter DW. Acute pulmonary responses to MWCNT inhalation. Toxicologist. 2011;120:A53.

    Google Scholar 

  253. Reddy AR, Reddy YN, Krishna DR, Himabindu V. Multiwall carbon nanotubes induce oxidative stress and cytotoxicity in human embryonic kidney (HEK293) cells. Toxicology. 2010;272(1–3):11–6.

    CAS  PubMed  Google Scholar 

  254. Lam CW, James JT, McCluskey R, Hunter RL. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicol Sci. 2004;77:126–34.

    CAS  PubMed  Google Scholar 

  255. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AF, et al. Unusual inflammatoryand fibrogenic pulmonary, response to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005;289:L698–708.

    CAS  PubMed  Google Scholar 

  256. Warheit DB, Laurence BR, Reed KL, Roach DH, Reynolds GA, Webb TR. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci. 2004;77:117–25.

    CAS  PubMed  Google Scholar 

  257. Liao L, Zhang M, Liu H, Gong T, Sun X. Subchronic toxicity and immunotoxicity of MeO-PEG-poly(d, l-lactic-co- glycolic acid)-PEG-OMe triblock copolymer nanoparticles delivered intravenously into rats. Nanotechnology. 2014;25(24):245.

    Google Scholar 

  258. Zhao B, Wang XQ, Wang XY, Wu HN, Zhang Q. Nanotoxicity comparison of four amphiphilic polymeric micelles with similar hydrophilic or hydrophobic structure. Particle Fibre Toxicol. 2013;10(1):47.

    Google Scholar 

  259. Thiagarajan G, Greish K, Ghandehari H. Charge affects the oral toxicity of poly(amido amine) dendrimers. Eur J Pharm Biopharm. 2013;84(2):330–4.

    CAS  PubMed  Google Scholar 

  260. Onoue S, Yamada S, Chan HK. Nanodrugs: pharmacokinetics and safety. Int J Nanomed. 2014;9:1025–37.

    CAS  Google Scholar 

  261. Nagender RP, Pena-Mendez EM, Havel J. Gold and nano-gold in medicine: overview, toxicology and perspectives. J Appl Biomed. 2009;7:75–91.

    Google Scholar 

  262. Parrott N, Lave T. Applications of physiologically based absorption models in drug discovery and development. Mol Pharm. 2008;5(5):760–75.

    CAS  PubMed  Google Scholar 

  263. Gu CH, Rao D, Gandhi RB, Hilden J, Raghavan K. Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility. J Pharm Sci. 2005;94(1):199–208.

    CAS  PubMed  Google Scholar 

  264. Gupta V, Doshi N, Mitragotri S. Permeation of insulin, calcitonin and exenatide across Caco-2 monolayers: measurement using a rapid, 3-day system. PLOS One. 2013;8(2):1–19.

    CAS  Google Scholar 

  265. Wu YF, Liu H, Ni JM. Advances in parallel artificial membrane permeability assay and its applications. Yao Xue Xue Bao. 2011;46(8):890–5.

    PubMed  Google Scholar 

  266. Nielsen PE, Avdeef A. PAMPA—a drug absorption in vitro model 8. Apparent filter porosity and the unstirred water layer. Eur J Pharm Sci. 2004;22:33–41.

    CAS  PubMed  Google Scholar 

  267. Kansy M, Avdeef A, Fischer H. Advances in screening for membrane permeability: high-resolution PAMPA for medicinal chemists. DDT Technol. 2004;1:349–55.

  268. Tavelin S, Taipalensuu J, Hallbook F, Vellonen KS, Moore V, Artursson P. An improved cell culture model based on 2/4/A1 cell monolayers for studies of intestinal drug transport: characterization of transport routes. Pharm Res. 2003;20:373–81.

    CAS  PubMed  Google Scholar 

  269. Tavelin S, Taipalensuu J, Soderberg L, Morrison R, Chong S, Artursson P. Prediction of the oral absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers. Pharm Res. 2003;20:397–405.

    CAS  PubMed  Google Scholar 

  270. Bryan WJ. Enhancement & controlled release as a synergistic tools. Drug Deliv Technol. 2002;2(6).

  271. Beg S, Swain S, Rizwan M. Irfanuddin, Malini DS. Bioavailability enhancement strategies: basics, formulation approaches and regulatory considerations. Curr Drug Deliv. 2011;8(6):1–12.

    Google Scholar 

  272. Lappin G, Garner R. The use of accelerator mass spectrometry to obtain early human ADME/PK data. Expert Opin Drug Metabol. Toxicol. 2005;1(1):23–31.

    CAS  Google Scholar 

  273. Bonnafous D, Cav G, Dembri A, Binay SL, Ponchel G, GPE. Oral formulations of chemotherapeutic agents. 2010;WO 2010015688 A1.

  274. Sung HW, Kiran Sonaje K, Tu H. Pharmaceutical composition of nanoparticles for protein drug delivery. 2012;US20120003306 A1.

  275. Schobel AM, Myers, Garry ML, Joseph KK, Thomas R, Jan M, Justin NW. Nanoparticle film delivery systems. 2011;WO/2011/156711.

  276. Park TG, Kim HR, Kim IK. LDL-like cationic nanoparticles for delivering nucleic acid gene, method for preparing thereof and method for delivering nucleic acid gene using the same. 2010;US 20100297242A1.

  277. Radovic-Moreno AF, Zhang L, Langer RS, Farokhzad OC. Polymer-encapsulated reverse micelles. 2010;US20100196482 A1.

  278. Rios MDL, Oh KL. Self-assembling nanoparticle drug delivery system. 2011;US7964196 B2.

  279. Bronich TK, Kabanov AV. Synthesizing an amphiphilic block polymer micelle having ionically-charged polymeric segments and nonionically-charged polymeric segments; neutralizing under conditions that allow for self-assembly of polymer micelles; crosslinking; removing the moieties of opposite charge; drug delivery; stability. 2013;US 8415400 B2.

  280. Baker JR, Zhang Y. Hydroxyl-terminated dendrimers. 2011;WO 2011053618A2.

  281. Matuschek M, Ernst A, Köpsel C, Jager MB, Kleber A, Krohn M, et al. Use of water-dispersible carotenoid nanoparticles as taste modulators, taste modulators containing water-dispersible carotenoid nanoparticles, and method for test modulation. 2010;US20100028444 A1.

  282. Porter V, Morgan A, Prencipe M. Oral care composition. 2013;US20130017240.

  283. Sahoo SK, Mohanty C. Novel water soluble curcumin loaded nanoparticulate system for cancer therapy. 2011;WO Patent 2011101859 A1.

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  1. Department of Pharmaceutics, Rajiv Academy for Pharmacy, N.H. #2, P.O. Chattikara, Mathura, 281001, Uttar Pradesh, India

    Kamla Pathak & Smita Raghuvanshi

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  1. Kamla Pathak
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Correspondence to Kamla Pathak.

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Pathak, K., Raghuvanshi, S. Oral Bioavailability: Issues and Solutions via Nanoformulations. Clin Pharmacokinet 54, 325–357 (2015). https://doi.org/10.1007/s40262-015-0242-x

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Keywords

  • Curcumin
  • Solid Dispersion
  • Ezetimibe
  • Silymarin
  • Polymeric Micelle