title: Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by d-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate.
abstract: Andrographolide (ADG) is a diterpenoid isolated fromAndrographis paniculatawith a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box-Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability (Papp) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (P<0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure with significant enhancements inCmaxand area under the curve of plasma concentration versus time from zero to the last sampling time (AUC0-t) (P<0.01). An evaluation of the anti-inflammatory effect on Carr-induced paw edema demonstrated that the ADG-NS were more effective in reducing the rate of paw swelling, producing a greater increase in the serum levels of nitric oxide (NO), Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) (P<0.01) and an increase in superoxide dismutase activity (P<0.05) compared to the ADG coarse powder. This study indicated that nanosuspensions could act as an effective delivery device for ADG to enhance its oral bioavailability and biological efficacy.
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Rui
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Tingming
authors.initials: T
authors.lastname: Fu
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Junsong
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Di
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D018938:Caco-2 Cells; D004224:Diterpenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D036103:Nanotechnology / Q000379:methods*; D009569:Nitric Oxide / Q000097:blood; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D012995:Solubility; D013482:Superoxide Dismutase / Q000097:blood; D013535:Suspensions; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014810:Vitamin E / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D007375:Interleukin-1; D013535:Suspensions; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D009569:Nitric Oxide; D012967:Sodium Dodecyl Sulfate; C030419:andrographolide; D013482:Superoxide Dismutase; C014225:tocophersolan
keywords: BoxBehnken design; andrographolide; d-α-tocopheryl polyethylene glycol 1000 succinate; dissolution rate; nanosuspensions; oral bioavailability