Cubic Phase Nanoparticles
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Cubic Phase Nanoparticles Presentation Transcript

  • 1. Formulation and Characterization of Cubosomes using Lipids and Block Copolymers Ashish L. Sarode Master of Science Biomedical and Pharmaceutical Sciences University of Rhode Island
  • 2. Outline
    • Introduction
    • Materials
    • Methods
    • Results and Discussion
    • Conclusions
  • 3. Dextromethorphan (DXM)
    • Chemistry
    • Pharmacodynamics
    • Pharmacokinetics
    • Controlled Release
  • 4. Dextromethorphan (DXM)
    • Equivalence and Dose
      • 50 mg DXM Tannate = 30 mg DXM HBr
      • DXM Tannate Suspensions – 25 mg/5ml – 10 ml every 6 hours
      • Delsym – DXM Polistirex = 30 mg DXM HBr
      • Delsym – 10 ml every 12 hours
      • Controlled Release DXM Tannate Suspension – 50 mg/5ml – 10 ml every 12 hours
  • 5. Cubic Phase
    • Geometry
      • Water channel diameter – 5 nm
      • Interfacial area – 400 m 2 /g
      • Thermodynamic stability – curvature energy of each monolayer vs. stretching energy of amphiphile chains
      • Characterization – X-ray / neutron diffraction, TEM, FT-IR, ESR, NMR, DSC, and hot stage microscopy
      • Crystal lattices – double diamond (D-surface/Pn3m), body centered (P-surface/Im3m), gyroid (G-surface/Ia3d)
    References: Shah et al., 2001; Wyatt and Dorschel, 1992 Reference: Spicer, 2001 Reference: Spicer, 2005
  • 6. Cubic Phase
    • Lipids
      • Examples – monoolein or glyceryl monooleate (GMO), monoelaidin, phospholipids, PEGylated phospholipids, and phosphatidylethanolamine
      • GMO phases – reversed micellar (L 2 ), lamellar (L α ), reversed hexagonal (H π ), and cubic (C)
      • Low water solubility (10 -6 M) of GMO – cubic phase co-exist in equilibrium with water (oral controlled release)
    References: Shah et al., 2001; Larsson, 1989; Nielsen et al., 1998)
  • 7. Cubic Phase
    • Block Copolymers
      • Tri-block copolymers
        • (-PEO-PPO-PEO-)
      • Various phases depending on temperature and concentration
      • Pluronic F127 – lower critical solution temperature below 37 °C (20% solution)
      • Thermoreversible property – parenteral controlled release
      • Cubic phase can’t co-exist in equilibrium with excess water (no oral controlled release)
    Reference: Hamley, 2004
  • 8. Cubosomes
    • Geometry
      • Dispersed particles of cubic phase
      • Mathematical characterization by nodal surface approximations
      • Identification – Cryo-TEM analysis
    Reference: Spicer, 2004
  • 9. Cubosomes
    • Manufacture
      • Bottom-up technique
        • Formation and crystallization of cubosomes from precursors on molecular scale
      • Top-down technique
        • Dispersion of cubic phases into cubosomes by high energy input
        • Energy sources – high pressure homogenization, and sonication
        • Formation of complex dispersions – vesicles and cubosomes
        • Aqueous solutions of block copolymers – low energy input, prevent recoalescence
  • 10. Objective
    • Recent discoveries in biotechnology and genetics – proteins, peptides, plasmid DNA, and oligonucleotides
    • Demand targeted delivery to specific cells – need of drug delivery vehicles
    • Lipidic cubic phase formulations is an option
    • To acquire knowledge and experience of working with lipids and polymers that are used to make cubic phase formulations
    • To investigate potential of cubosome delivery in oral controlled release
  • 11. Materials
    • Instrumentation
      • High shear mixer and homogenizer
      • USP Dissolution apparatus # 2
      • Phenomenex partisil column (10 SCX, 4.6x250 mm, P/N00G-0127-E0)
      • HPLC-UV analytical system
      • Cryo-TEM
  • 12. Materials
    • Chemicals and Reagents
      • Glyceryl Monooleate (Myverol 18-92K, and 18-99K) – Kerry Biosciences
      • Block Copolymers (Pluronic F-127, & L-64) – BASF
      • Oleic Acid – Fisher Scientific
      • Dextromethorphan Tannate, Dextromethorphan HBr, formulation excipients, and analytical reagents – Hi-Tech Pharmacal. Co., Inc.
  • 13. Methods – Formulation Ingredient Formulation F1 F2 F3 F4 F5 F6 F7 1. GMO 10 g 10 g 10 g 10 g 10 g 10 g 11 g 2. Oleic Acid 0 g 1 g 1 g 1 g 2 g 2 g 2 g 3. Dextromethorphan Tannate 0.5 g 0.5 g 0.5 g 1 g 1 g 1 g 1 g 4. Pluronic F-127 1 g 1 g 1 g 1 g 1 g 1 g 1.2 g 5. Purified Water 40 ml 40 ml 40 ml 40 ml 40 ml 40 ml 40 ml 6. Sucrose Syrup 40 ml 40 ml 40 ml 40 ml 40 ml 40 ml 40 ml 7. Propylene Glycol 2 g 2 g 2 g 2 g 2 g 2 g 2 g 8. Methylparaben 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g 9. Propylparaben 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 10. Sucralose 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 0.02 g 11. Citric Acid 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 12. Sodium Citrate 1 g 1 g 1 g 1 g 1 g 1 g 1 g 13. Xanthan Gum 1 g 1 g 1 g 1 g 1 g 0.3 g 0.5 g 14. Sodium Alginate 0 g 0 g 0 g 0 g 0 g 0.15 g 0.1 g 15. Flavor qs qs qs qs qs qs qs 16. Color qs qs qs qs qs qs qs 17. Purified Water qs 100 ml qs 100 ml qs 100 ml qs 100 ml qs 100 ml qs 100 ml qs 100 ml Note1: GMO for F3 is Myverol 18-99K, for all other formulations GMO is Myverol 18-92K Note2: Actual formulations were prepared in 1000 ml Note3: Concentration of the drug was then increased gradually in formulation F7 in the order 0.25% w/v, 0.5% w/v, 0.75% w/v, and 1% w/v
  • 14. Methods – Formulation
  • 15. Methods
    • In-vitro Analysis
      • Number of vessels – 6
      • Medium – 0.1N HCl or 2%SDS
      • Volume – 900 ml
      • Temperature – 37 °C
      • Speed – 50 RPM and 250 RPM for infinity
  • 16. Methods
    • Quantitative Analysis
      • Buffer – 0.087 M potassium phosphate monobasic aqueous solution
      • Mobile phase – methanol : buffer :: 4:6
      • Standard – dissolved in dissolution medium
      • Injection volume – 10 µl
      • Flow Rate – 1.5 ml/min
      • Run Time – 20 minutes
      • Wavelength – 205 nm
  • 17. Methods
    • Cryo-TEM Analysis
      • Final formulation (F7)
      • Samples
        • Overnight equilibration
        • Two weeks’ storage
      • Chamber humidity – 95%
      • Carbon grid – 100nm to 2 µm pore diameter
      • Film thickness – 50 to 100 nm
      • Equilibrated for 3 seconds – plunged in liquid ethane – stored in liquid nitrogen
      • TEM images were taken at -170°C
  • 18. Results and Discussion
    • In-vitro Analysis
  • 19. Results and Discussion
    • In-vitro Analysis
  • 20. Results and Discussion
    • In-vitro Analysis
  • 21. Results and Discussion
    • In-vitro Analysis
  • 22. Results and Discussion
    • In-vitro Analysis
  • 23. Results and Discussion
    • In-vitro Analysis
  • 24. Results and Discussion
    • Cryo-TEM Analysis (overnight equilibration)
  • 25. Results and Discussion
    • Cryo-TEM Analysis (two weeks’ storage)
  • 26. Conclusions
    • Release of hydrophobic salts of some drugs can be controlled by oral cubosome delivery
    • Balance of cubosome structure, charge, and viscosity is important to achieve controlled release
    • Equivalent to suspensions of resin complexed drugs
  • 27. Acknowledgements
    • Dr. Hossein Zia
    • Dr. Polireddy Dondeti
    • Dr. Arijit Bose
  • 28. References
    • Hamley, I. W. (2004). Introduction to Block Copolymers. In I. W. Hamley (Ed.), Developments in Block Copolymer Science and Technology: John Wiley & Sons, Ltd: Chichester.
    • Larsson, K., 1989. Cubic lipid-water phases: structures and biomembrane aspects. J. Phys. Chem. 93, 7301–7314.
    • Nielsen, S.L., Schubert, L., Hansen, J., 1998. Bioadhesive drug delivery systems. I. Characterization of mucoadhesive properties of system based on glyceryl mono-oleate and glyceryl mono-linoleate. Eur. J. Pharm. Sci. 6, 231–239.
    • Shah, J.C., Sadhale, Y., Chilukuri, D.M., 2001. Cubic phase gels as drug delivery system. Adv. Drug Deliv. Rev. 47, 229–250.
    • Spicer, P. T., Hayden, K. L., Lynch, M. L., Ofori-Boateng, A., Burns, J. L. (2001). Novel Process for Producing Cubic Liquid Crystalline Nanoparticles (Cubosomes). Langmuir, 17, 5748-5756.
    • Spicer, P. T. (2004). Cubosomes: Bicontinuous Cubic Liquid Crystalline Nanostructured Particles, Dekker Encyclopedia of Nanoscience and Nanotechnology (Vol. 1, pp. 881-892): Marcel Dekker.
    • Spicer, P. T. (2005). Progress in liquid crystalline dispersions: Cobosomes. Current Opinion in Colloid & Interface Science, 10, 274-279.
    • Wyatt, D., Dorschel, D., 1992. A cubic-phase delivery system composed of glyceryl monooleate and water for sustained release of water-soluble drugs. Pharm. Technol. 16, 116–130.