title: Formulation, Pharmacokinetic, and Efficacy Studies of Mannosylated Self-Emulsifying Solid Dispersions of Noscapine.
abstract: OBJECTIVE
  To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability.
  
  
  METHODS
  Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg.
  
  
  RESULTS
  The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 μm with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96±4.66 and 32.05±3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94±0.18 × 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin.
  
  
  CONCLUSIONS
  Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences University, 19 Foster Street, Worcester, MA, United States of America.
authors.forename: Terrick
authors.initials: T
authors.lastname: Andey
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 South Martin Luther King Jr. Blvd., Tallahassee, FL, United States of America.
authors.forename: Apurva
authors.initials: A
authors.lastname: Patel
authors.affiliation: Institute for Stem cell biology and Regenerative Medicine (inStem), National Centre for Biological Sciences (NCBS), Bangalore, India.
authors.forename: Srujan
authors.initials: S
authors.lastname: Marepally
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. St., Hilo, HI 96720, United States of America.
authors.forename: Mahavir
authors.initials: M
authors.lastname: Chougule
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 South Martin Luther King Jr. Blvd., Tallahassee, FL, United States of America.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Spencer
authors.affiliation: Department of Oncology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 South Martin Luther King Jr. Blvd., Tallahassee, FL, United States of America.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D004337:Drug Carriers; D065546:Drug Liberation; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D004357:Drug Synergism; D004655:Emulsions; D006801:Humans; D008358:Mannose / Q000737:chemistry; D051379:Mice; D023421:Models, Animal; D053758:Nanoparticles / Q000737:chemistry; D009665:Noscapine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D013997:Time Factors; D057900:Transcytosis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D004655:Emulsions; D009665:Noscapine; D008358:Mannose; D002945:Cisplatin