1 / 12

BTM Nanocapsules for Formulation of Drugs and Vaccines and Imaging Agents

BTM Nanocapsules for Formulation of Drugs and Vaccines and Imaging Agents. Russell J. Mumper, Ph.D. Center for Nanotechnology in Drug Delivery Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina.

abba
Télécharger la présentation

BTM Nanocapsules for Formulation of Drugs and Vaccines and Imaging Agents

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BTM Nanocapsules for Formulation of Drugs and Vaccines and Imaging Agents Russell J. Mumper, Ph.D. Center for Nanotechnology in Drug Delivery Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina Carolina Seeds of Innovation November 4, 2010

  2. Nanotemplate Engineering Focus Areas • Materials (Handbook of Pharmaceutical Excipients) • Engineering & Characterization • Cell Interaction / Uptake • Biofate & Biometabolism • Bio- and Hemocompatibility (toxicological aspects of NPs) • Cell and Tissue Targeting (therapeutics) • Therapeutic (and Imaging) Areas • Addressing resistance in human cancer using nanotechnology  • Subunit (protein) vaccines for HIV 

  3. = surfactant oil droplet nanotemplate + _ HO oil droplets Rx Rx Rx Rx Rx Ni Y PEG Rx Rx Rx Rx Rx Ligand RXN PEG -SH -NH2 -COOH OH Nanotemplate Engineering • Enables manufacturing of stable NPs <200 nm using a reproducible and scalable process • Manufacturing process is as few as 3-steps and is completed in one vessel • Overcomes the limitations of commonly used methods to make sub-micron sized particles Oil Add, Heat & Mix at 50-65oC Clear, Stable Oil-in-Water Microemulsion “Nanotemplate” at 50-65oC Surfactant(s) Water Cool to 25oC Oil Drug (Rx) Surfactant(s) + Water Step 2 Step 3 Step 1 Nanoparticles or Nanocapsules

  4. E78 Nanoparticles vs. BTM Nanocapsules Solid Lipid E78 Nanoparticles Oil-Filled BTM Nanocapsules Cetyl Alcohol (m.p. 49oC) Miglyol® 812 Caprylic/Capric Triglyceride C8 (50-65%); C10 (30-45%) Oil Phase CH3 (CH2)14CH2OH E78 NPs BTM NPs + Vitamin E TPGS (d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate) Surfactants Brij 78 (Polyoxyethylene 20 stearyl ether) CH3 (CH2)17 (OCH2CH2)20OH

  5. A New Nanocapsule Formulation - “BTM NPs” 15 s after rehydration • First Generation BTM NPs identified by Sequential Simplex Optimization • Composition: liquid tri-glyceride core with two surfactants • Scalable, one vessel manufacturing process • Lipid/drug ~ 20-30:1 w/w; [drug] up to 1.5 mg/ml • Sustained-release of drug • Can be pegylated to make ‘pegBTM NPs’ • Easily sterile filtered • Can be lyophilized with no cryoprotectant • Very stable in suspension or lyophilized • ‘Plug & Play’ platform based on oil properties • Very well tolerated, repeated i.v. injection up to 750 mg/kg Lyophilized BTM NPs Dong et al. Eur. J. Pharm. Biopharm. (2009)

  6. In-Vivo Efficacy Study in Nude Mice Bearing P-gp+ Resistant Human Ovarian Tumors Saline Empty BTM NPs (4.5 mg/kg) Taxol (4.5 mg/kg) 1200 Taxol (20 mg/kg) Empty BTM NPs + Taxol (4.5 mg/kg) 1000 PX BTM NPs (4.5 mg/kg) 800 Tumor size (mm3) # 600 400 * 200 * * * * * * 0 0 5 10 15 20 25 30 Day Mice (n=6/group) were dosed i.v. with PX (4.5 mg/kg) on day 0, 7, 14, and 21

  7. Retreatment of Mice Day 31 of Study #2 Taxol-failed mice can be salvaged with PX BTM NP treatment Previously PX BTM NP treated mice respond to new course of PX BTM NP treatment 1000 1000 900 800 800 700 600 542 600 559 500 519 509 * Tumor size (mm3) * * 400 400 * 420 * * 383 364 300 340 303 200 200 100 0 0 0 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 15 18 21 24 27 30 Day Day 49 of Study #2 Day PX BTM dose 4.5 mg/kg 7.5 mg/kg

  8. Enhancement of Tumor MRI Image with BTM-DTPA-Gd NPs Control BTM-DTPA-Gd NPs 5 hr after i.v. injection in A549 s.c. xenograft tumors ~50-70 mm3 Compliments of Dr. Michael Jay in collaboration with SAICF at UNC-BRIC using 9.4T Micro-MRI

  9. Nano-based Subunit HIV Vaccines NIH-NIAID R01 AI058842 A DC-targeted nanoparticle with conserved proteins Tat (1-72) and Gag p24 to generate protective Th1, CTL, and neutralizing antibody responses that may be further enhanced by co-delivery of Adjuvants (PRLs) DiOC18 NPs in DC NP benefits: Increased DC uptake/processing/ presentation Dose sparing Enhance MHC1 processing Enhance Th1-type responses Enhance (neutralizing) antibodies Co-delivery of antigen/adjuvant Dendritic Cell Toll-like Receptor (TLR-9) Tat (1-72) Receptor MHC I PEG Adjuvant (PRL) MHC II DC targeting Ligand J. Biomed. Nanotech. (2007) Pharmaceutical Research (2007) Vaccine (2004, 2006) HIV/AIDS (2009) Gag p24 Tat & Gag antigens: conserved; critical; CTLs detected in LTNPs

  10. p41 Immunization; BTM-Ni vs. E78-Ni NPs 4.0 * 3.5 1,000 2,000 3.0 5,000 2.5 10,000 * P41 specific IgG O.D. at 450 nm 2.0 1.5 * * 1.0 # # 0.5 # 0.0 E78-Ni (1 µg) BTM-Ni (0.1 µg) BTM-Ni (0.5 µg) BTM-Ni (1 µg) Alum (1 µg) Naive BALB/c mice (n=8/group) were dosed by s.c. injection on day 0 and 14; ELISA day 28 Doses: 0.1, 0.5, or 1 mg p41 His-tag p41 provided by Dr. Robert Seder, NIH-NIAID Vaccine Research Center

  11. Concluding Remarks • “Nanoparticle Compositions Comprising Liquid Oil Cores” • (PCT /US2009/060593 ) • “Translational Nanotechnology” – all required elements • Nanotemplate Engineering • simple, one-vessel process, reproducible, scalable, cost-effective • keys: 1) physical chemistry/pharmacy 2) excipient selection • Some ‘GRAS’ or USP/NF excipients may be ‘biological modifiers’ • Nano-based Drug Delivery Systems • Improve drug solubility / bioavailability • Address MDR in cancer to improve outcomes • Can be used for imaging • Co-delivery of antigens / adjuvants for improved vaccines

  12. Russell J. Mumper, Ph.D. Center for Nanotechnology in Drug Delivery Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina E-mail: mumper@email.unc.edu

More Related