Characterization of pharmaceutical nanotechnology delivery systems

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Characterization of pharmaceutical nanosystems

• Ali Badiee (Pharm. D., Ph.D.)
• School of Pharmacy,
• Mashhad University of Medical Sciences,
• Iran
• Badieea_at_mums.ac.ir

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Why is nanotechnology important?
nanotechnology will be a strategic branch of
science and engineering for the 21st century, one
that will fundamentally restructure the
technologies currently used for manufacturing,
medicine, defence, energy production,
environmental management, transportation,
communication, computation and education.

Projected world-wide market for n-t enabled
products will be lt3 trillion by 2015
It is estimated that Nanotechnology is presently
at a level of development similar to that of
computer/information technology in the 1950s
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Application of nanoparticles to drug discovery
and biology

• Fluorescent biological markers
• Detection of proteins
• Probing of DNA structures
• Separation and purification of biological
  molecules and cells
• MRI contrast enhancement
• Tumor destruction via heating
• Tissue engineering
• Drug and gene delivery

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Possible opportunities for nanotechnology in drug
delivery

• Enhanced drug properties such as
• Solubility
• Rate of dissolution
• Oral bioavailability
• Targeting ability
• Enhanced dosing requirements
• Lower dosed administered
• Better side effect profile
• More convenient dosage forms

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FDA-regulated products expected to be impacted by
nanotechnology

• Drugs (novel NMEs or delivery systems)
• Medical devices
• Biotechnology products
• Tissue engineering products
• Vaccines
• Cosmetics
• Combination products

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What are combination products?

• Are made of multiple constituents drug-device,
  drug-biologic, device-biologic or
  drug-device-biologic that are physically or
  chemically combined, co-packaged in a kit or
  separate cross-labeled products
• All components work as a system and are critical
  to achieve desired therapeutic effect

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Who regulates combination products?

• www.FDA.gov/oc/combination

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Nanoparticles for Drug Delivery

• Metal or Carbon-based nanoparticles (fullerenes,
  quantum dots, nanoshells, nanotube, )
• Lipid-based nanoparticles
• Polymer-based nanoparticles
• Biological nanoparticles

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Targeting Ligands
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Currently approved nano-scale therapeutics

• Gadolinium chelate for MRI imaging (Gd-DTPA
  Dimeglumine)
• Iron oxide particles for MRI imaging (Feridex)
• Products using NanoCrystal technology (Rapamune,
  Emend)
• Liposomes (Doxil, DaunoXome)
• Microemulsions (Cyclosporine)
• Albumin-bound nanoparticles (Abraxane)

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Currently approved nano-scale devices

• Silver nanoparticles (anti-bacterial wound
  dressing)
• Engineered Calcium Phospahate (NanOss TM)
• Nanoparticle dental restorative (3M ESPE Filtek)

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Currently approved nanoparticle-containing
products

• Cosmetics (containing lipid nanoparticles or
  nanosomes used as delivery systems, for
  controlled release of active ingredients
  LOreal, Estee Lauder)
• Sunscreens (containing titanium dioxide and zinc
  oxide nanoparticles which make the product appear
  transparent)

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Reasons for special consideration of
nanotechnolgy products

• Rapidly growing area of science
• Private sector, academic centers and federal
  agencies are developing substantial programs in
  nanotechnology
• Significant research dollars being invested in
  nanotechnology
• Particle size reductions of drugs has the
  potential to

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Nanosizing of Drugs

• Increase surface area
• Enhance solubility
• Increase rate of dissolution
• Increase oral bioavailability
• More rapid onset of therapeutic action
• Decrease the dose needed
• Decrease fed/fasted variability
• Decrease patient to patient variability

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General considerations for nano- products

• Characterization
• Safety
• Environmental impact

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Characterization Considerations

• What are the forms in which particles are
  presented to host, cells and organelles?
• Soluble vs. insoluble particles
• Organic vs. inorganic molecules
• Nanoemulsions, nanocrystal colloid dispersions,
  Liposomes,

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Characterization Considerations

• What are the standard tools used for
  characterization of nanoparticle properties?
• What are validated assays to detect and quantify
  nanoparticles in drug product and in tissues?
• How do we determine long and short-term stability
  of nanomaterials (in various environments)?

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Characterization Considerations

• What are the critical physical and chemical
  properties, including residual solvents,
  processing variables, impurities and excipients?
• How do physical characteristics impact product
  quality and performance?
• What are the critical steps in the scale-up and
  manufacturing process for nanotechnology
  products?

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Characterization

• Critical attributes of nanotech. products might
  include
• Drug Loading release
• Particle size and size distribution
• Surface area, surface chemistry, porosity
• Hydrophilicity, surface charge density
• Purity, sterility
• Stability (aggregation, protein interactions, )
• Does in vitro behavior reflect in vivo behavior
• Drug release parameters and bioequivalence
  testing considerations

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Properties of particles in dispersions
Properties of Dispersant (s) Aqueous or
organic? (or mix?) Bulk composition Additives
(what?, how much?) Ionic or non-charged
Small molecules Bio and macro molecules pH,
conductivity Viscosity Refractive index Density
Properties of Particles Average size
(diameter) Size distribution Shape Bulk chemical
composition Crystalline/amorphous Pore
size/roughness Surface composition
covalently linked molecules adsorbed
species Compliance/modulus, etc Refractive
index Density Surface charge
Properties of Particles in dispersion or
cellular milieu Average size (diameter) Size
distribution Shape Bulk chemical
composition Surface composition covalently
linked molecules adsorbed species
surface charge (zeta potential) Compliance/modulus
, etc Pore size/roughness Crystalline/amorphous Re
fractive index Density
tissue, cells or sub-cellular system under study
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Introduction/Context Properties of particles in
dispersions/emulsions
Properties of Particles in dispersion or
cellular milieu Average size (diameter) Size
distribution Shape Bulk chemical
composition Surface composition covalently
linked molecules adsorbed species
surface charge (zeta potential) Compliance/modulus
, etc Pore size/roughness Crystalline/amorphous Re
fractive index Density
Properties of Particles Average size
(diameter) Size distribution Shape Bulk chemical
composition Crystalline/amorphous Pore
size/roughness Surface composition
covalently linked molecules adsorbed
species Compliance/modulus, etc Refractive
index Density
Properties of Dispersant (s) Aqueous or
organic? (or mix?) Bulk composition Additives
(what?, how much?) Ionic or non-charged
Small molecules Bio and macro molecules pH,
conductivity Viscosity Refractive index Density
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Dynamic Light Scattering (DLS) aka Photon
Correlation Spectroscopy (PCS) aka Quasielastic
Light Scattering (QELS)
Step 1 Make the optical measurement Temporal
fluctuations in intensity of scattered light
(wavelength and angle are set by instrument RI
is input or assumed)
speckle pattern
Figures from http//www.science.uva.nl/sprik/mas
terlaser/dlsexp/dls.html
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Example Sizing of Nanoparticles with Dynamic
Light Scattering
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• Fractionation Methods for loading
• Size Exclusion and other chromatography
• Capillary Hydrodynamic Flow
• Capillary Electophoresis
• Sedimentation/Centrifugation

The details are not important, but note that
fractionation is much more time and labor
intensive than the ensemble methods. User must
establish calibration curve
Now, lets take a closer look
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Fractionation Methods Measurement Principles
Adsorption, partition, size exclusion Affinity,
polarity,size
Chromatography
Electrophoretic mobility Ionic size, charge
Electrophoresis
Laminar flow profile (velocity gradient) Size
(big first)
Hydrodynamic flow
Laminar flow profile Particle mass Size (small
first)
Field-flow fractionation
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Structural characterization

• shape, size, surface morphology, structural
  arrangement spatial distribution, density,
  geometric feature
• Scanning electron microscopy (SEM)
• Transmission electron microscopy (TEM)
• Scanning force microscopy or atomic force
  microscopy(AFM)

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Au_at_SiO2 nanoparticles. Core size 16 nm
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Polystyrene spheres coated with carbon nanotubes
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Crystalline Status

• to assess any possible changes brought about in
  the physical form of the drug during processing
• Differential scanning calorimetry (DSC)
• X ray diffraction
• other analytical methods

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Equipments for Nanoparticles

• Homogenizer
• Ultra Sonicator
• Mills
• Spray Milling
• Supercritical Fluid Technology
• Electrospray
• Ultracentrifugation
• Nanofiltration

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Safety Considerations

• As particle size gets smaller, there may be
  size-specific effects on activity, such as
• Will nanoparticles gain access to tissues and
  cells that normally would be bypassed by larger
  particles?
• Once nanoparticles enter tissues, how long do
  they remain there?
• How are they cleared from tissues and blood?
• If nanoparticles enter cells, what effects do
  they have on cellular and tissue functions
  (transient and/or permanent)?
• Might there be different effects in different
  cells types?

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Safety Considerations (Contd)

• Route-specific issues
• Inhalation
• Local respiratory toxicity
• Distribution in respiratory tissues
• Systemic bioavailability
• Sub-cutaneous
• Sensitization
• Ocular
• Intravitreal retention
• Oral
• Increased bioavailability

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Safety Considerations (Contd)

• Route-specific issues (contd)
• Dermal
• Increased dermal and systemic bioavailability
• Increased follicule retention
• Distribution to local lymph nodes
• Phototoxicity
• IV
• Hemocompatibility
• Sterility
• Different tissue distribution and half-life of
  API (with targeted delivery and liposomes)

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Safety Considerations (Contd)

• ADME
• What are the differences in the ADME profile, for
  nanoparticles versus larger particles of the same
  drug?
• Are current methods used for measuring drug
  levels in blood and tissues adequate for
  assessing levels of nanoparticles
  (appropriateness of method, limits of detection)?
• How accurate are mass balance studies, especially
  if levels of drug administered are very low i.e.
  can 100 of the amount of drug administered be
  accounted for?

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Safety Considerations (Contd)

• ADME (Contd)
• How is clearance of targeted nanoparticles
  accurately assessed? If nanoparticles concentrate
  in a particular tissue, how will clearance be
  assessed accurately?
• Can nanoparticles be successfully labeled for
  ADME studies?

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Environmental Considerations

• Can nanoparticles be released into the
  environment following human and animal use?
• What methodologies would identify the nature, and
  quantify the extent, of nanoparticle release in
  the environment?
• What might be the environmental impact on other
  species (animals, fish, plants, microorganisms)?

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Current Preclinical Tests for Safety Evaluation

• Pharmacology
• Safety pharmacology
• Toxicology (including clinical pathology and
  histopathologic analysis)
• ADME
• Genotoxicity
• Developmental toxicity
• Immunotoxicity
• Carcinogenicity
• Other

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Preclinical Safety Assessment

• Our current system is expected to identify
  possible hazard resulting from drug exposure, due
  to the extensive pre-clinical evaluation of new
  drugs.
• For nanotechnology drugs
• Are current required studies adequate? YES
• Are new testing models needed? MAYBE

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Adequacy of Current Preclinical System?

• Existing battery of preclinical tests is
  currently believed to be adequate.
• Why?
• High dose multiples used
• At least 2 animal species used
• Extensive histopathology on most organs
• Functional tests (cardiac, neurologic,
  respiratory, reproductive, immune system, etc/)
• Extended treatment periods (up to 2 years for
  carcinogenicity studies)

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Are There Special Testing Requirements for
Nanotechnology Products?

• Currently there are no testing requirements that
  are specific to nanotechnology products.
• CDER/FDAs current requirements for safety
  testing of products is very rigorous. However if
  research identifies toxicological risks that are
  unique to nanomaterials, additional testing
  requirements may become necessary.

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Challenges

• New technology unknown risks
• Limited scientific data available to address
  public health concerns
• Timely and accurate reporting of all relevant
  scientific findings.
• Working in multidisciplinary teams.
• Terminology and Nomenclature

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CDER Nanotechnology Working Group in FDA

• Goals and Objectives
• Definition and terminology
• Identify and propose development of regulatory
  guidance documents
• Identify training and research needs
• Coordination (between Centers/Agencies) and
  collaboration

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Current nanotechnology standards

• Only National standards to date
• China 12 National standards published and
  adopted
• Terminology
• GB/T19619-2004 Terminology for nanomaterials
• Sizing
• GB/T13221-2004 Nanometer powder - Determination
  of particle size distribution - Small angle X-ray
  scattering method (ISO/TS13762)
• GB/T19587-2004 Determination of the specific
  surface area of solids by gas absorption using
  the BET method (ISO 92771999)
• GB/T19627-2005 Particle size analysis - Photon
  correlation spectroscopy (ISO 133211996)
• GB/T 15445.2-2006 Representation of results of
  particle size analysisPart 2Calculation of
  average particle sizes/diameters and moments from
  particle size distributions(ISO 9276-22001,IDT)
• GB/T 15445.4-2006 Representation of results of
  particle size analysisPart 2Characterization of
  a classification process(ISO 9276-42001,IDT)
• GB/T 20307-2006 General rules for nanometer-scale
  length measurement by SEM
• GB/T 20099-2006 Sample preparation dispersing
  procedures for powders in liquids
• Nano-material specificiations
• GB/T19588-2004 Nano-nickel power
• GB/T19589-2004 Nano-zinc oxide
• GB/T19590-2004 Nano-calcium carbonate
• GB/T19591-2004 Nano-titanium dioxide
• UK PAS 71 2005 Vocabulary Nanoparticles
• Several standards (International, regional and
  national) that also apply to the nanoscale

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ISO/TC 229 JWG1 Strategic Roadmap
Nanomaterials classification
Base Definitions
Nanoscale
Nano films
Nano dispersions
Terminology carbon nanostructures
Terminology nano-bio interface
Nanoscale attribute
Terminology - nanoparticles
Nano-processes
Nanoscale objects
Nanostructured materials
Nanotechnologies
Nanomaterials
Terminology - nanomaterials
Nano-production
Framework and core terms
Complex assemblies
Terminology - nanostructures
Terminology - nanofabrication
Nomenclature model
Nanomedical devices
Nanosensors
Nanomeasurement
Devices and applications
Terminology medical and consumer
Nanometrology
Nanomeasurement tools
Nanoelectronic devices
Nanophotonic devices
Terminology nanoscale measurement
(IEC) Vocabulary - electrotechnical
(IEC) Terminology nano-optics
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There are 567 ISO standards and other documents
applying to road vehicles plus ISO 3779 covering
the vehicle identification number (VIN)
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Thanks for your attention