Transcript Development of Nanotechnology-Based Drugs and its

Development of
Nanotechnology -Based
Drugs and its Guidance
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D
Department of Pharmaceutics
KLE University College of Pharmacy
BELGAUM-590010
E-mail: [email protected]
Cell No: 00919742431000
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CONTENTS
 Nanotechnology
 Nanoparticle
 Dendrimer
 Liposomes
 Micelles
 Nanoemulsions
 Nanocrystals
 Primary Particle
 Metal Colloids
 Guidance for Industry Nontechnology Based Products
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Definitions
 Nanomaterial/Nanoscale Material:
Any material with at least one dimension smaller than
100 nm.
 Nanomedicine:
The use of nanoscale
applications
 Characterization:
Physicochemical
properties
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materials
evaluation
of
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for
relevant
medical
drug
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Nanotechnology Commercialization
1. Consumer product applications, including cosmetics
and sunscreens
2. Food applications, including dietary supplements
3. Medical applications, including drugs and drug
delivery devices.
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Medical Applications
Product
Developed
Applications
Rapamune®
Elan’s
An immunosuppressant
Emend®
Elan’s
Anti-nausea
Estrasorb®
Elan’s
Topical estrogen therapy
Megace® ES
Elan’s
Stimulate appetite
TriCor®
Elan’s
Cholesterol-lowering
Abraxane®
APP
Breast cancer
Doxil®
Alza
Anti-cancer
Acticoat®
Smith & Nephew
Antimicrobial
SilvaGard
AcryMed, Inc.,
Antimicrobial
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Nanotechnology
• The understanding and control of matter at
dimensions between approximately 1 to
100
nanometers,
where
unique
phenomena enable novel applications.
• (Source:
National
Nanotechnology
Initiative Definition)
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Types of pharmaceutical nanosystems
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Nanoparticle
• Nano-object with all three external dimensions at the
nanoscale that is the size range from approximately 1
nm to 100 nm.
• Polymeric nanoparticle platforms are characterized by
their physicochemical structures including solid
nanoparticles, nanoshell, dendrimer, polymeric
micelle, and polymer-drug conjugates.
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Nanoparticle
TEM (a, b, and c) images of prepared mesoporous silica nanoparticles with mean outer
diameter: (a) 20nm, (b) 45nm, and (c) 80nm. SEM (d) image corresponding to (b). The insets are
a high magnification of mesoporous silica particle
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Dendrimer
A polymer in which the atoms are
arranged in many branches and
subbranches along a central backbone of
carbon atoms.
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Dendrimer
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Liposomes
Vesicles composed of one or more
bilayers of amphiphatic lipid molecules
enclosing
one
or
more
aqueous
compartments.
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Liposomes
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Micelles
Self-assembling
nanosized
colloidal
particles with a hydrophobic core and
hydrophilic shell currently used for the
solubilization of various poorly soluble
pharmaceuticals.
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Micelles
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Nanoemulsions
• Emulsions with droplet size in the nanometer scale.
• Emulsion is a thermodynamically unstable system
consisting of at least two immiscible liquid phases,
one of which is dispersed as globules (the dispersed
phase), in the other liquid phase (the continued
phase), stabilized by the presence of an emulsifying
agent.
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Nanoemulsions
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Nanocrystals
Nanoscale solid formed with a periodic lattice
of atoms, ions, or molecules.
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Nanocrystals
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Primary Particle
Smallest identifiable
particulate system.
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subdivision
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a
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Primary Particle
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Metal Colloids
• Metal nanoparticles in colloidal systems where the term
colloidal refers to a state of subdivision.
• This implies that the molecules or polymolecular particles
are dispersed in a medium and have at least in one
direction a dimension roughly between 1 nm and 1μm or,
in a system, have discontinuities at distances of that order.
• For example, silver, gold, titanium dioxide, zinc oxide,
and iron oxide.
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Metal Colloids
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Polymer Colloids
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Guidance for Nano-Industry
I.
Chemistry Manufacturing and Control
II. Human Pharmacokinetics and Bioavailability
III. Labeling
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I. Chemistry Manufacturing and Control
A.
B.
C.
D.
Description and Composition
Physicochemical Properties
Description of Manufacturing Process and Process Control
Control of Excipients: Lipid Components
1.
2.
3.
4.
Description and Characterization
Manufacture
Specifications
Stability
E. Control of Drug Product: Specifications
F. Stability
G. Changes in Manufacturing
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Description and Composition
• The components of liposome drug products are the drug
substance, the lipids, and other inactive ingredients.
• The pharmacological and toxicological properties and the
quality of these drug products can vary significantly with
changes in the formulation, including the lipid composition.
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Physicochemical Properties
• Morphology of the liposome, including lamellarity
determination, if applicable
• Volume of entrapment in liposomal vesicles
• Particle size (mean and distribution profile)
• Phase transition temperature
• Spectroscopic data, as applicable
• In vitro release of the drug substance from the liposome drug
product
• osmotic properties
• light scattering index
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Description of Manufacturing Process and Process Control
• Liposome drug products are sensitive to changes in the
manufacturing conditions, including changes in scale.
• If there are changes in critical manufacturing parameters,
complete characterization of the liposome drug product is
recommended and in vivo studies may be warranted.
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Control of Excipients: Lipid Components
1. Description and Characterization
2. Manufacture
3. Specifications
4. Stability
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Control of Drug Product: Specifications
• Physicochemical parameters of the liposome determined to be
critical to product quality for each batch.
• Assay for encapsulated and unencapsulated (i.e., free) drug
substance.
• Degradation products related to the lipids.
• Assay of lipid components.
• In vitro test for release of drug substance from the liposome.
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Stability
• The physical stability of liposome drug products is a function
of the integrity and the size distribution of the lipid vesicles.
• Liposomes are susceptible to fusion, aggregation, and leakage
of the encapsulated drug substance during storage.
• Liposome drug products should be evaluated for stability of
the encapsulated drug substance as well as stability of the
lipids that compose the liposomal bilayer.
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Changes in Manufacturing
• Liposome drug products are a relatively new dosage form, it is
not possible to provide recommendations on the type of
information that should be generated to demonstrate that the
change has not adversely affected the quality of the drug
product.
• The extent of the information and documentation to be
developed and submitted to support a change should depend
on the types of manufacturing changes and the stage of
manufacturing at which the changes occur.
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II. Human Pharmacokinetics and Bioavailability
A.
B.
C.
D.
E.
Bioanalytical Methods
In Vivo Integrity (Stability) Considerations
Protein Binding
In Vitro Stability
Pharmacokinetics and Bioavailability
1.
2.
3.
Mass Balance Study
Pharmacokinetic Studies
Additional Pharmacokinetic Studies
a.
b.
c.
Food-Effect Studies
Drug Interactions and /or Special Populations
Exposure-response Studies
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Bioanalytical Methods
• Validated bioanalytical methods should be used when
evaluating the pharmacokinetics and bioavailablity of a drug
substance.
• For liposome drug products the bioanalytical method should
also be capable of measuring encapsulated and unencapsulated
drug substance.
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In Vivo Integrity (Stability) Considerations
• In addition to the general stability considerations of the drug
substance in a biological fluid, the stability of the liposome in
vivo should be considered.
• A single-dose study is recommended to assess the in vivo
stability of the liposome.
• The concentration-time profile should be evaluated at multiple
time points over an adequate period of time.
• The concentration of encapsulated and unencapsulated drug
substance should be determined at each sampling time point.
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Protein Binding
• The stability of liposomes in vivo can be affected by
interactions with lipoproteins and other proteins in the blood.
• Interactions of liposomes with serum proteins and lipoproteins
can be dependent on the type of lipids used in formulating the
liposomes.
• The protein (including lipoprotein) binding of the drug
substance and liposome drug product should be determined
over the expected therapeutic concentration range.
• The major binding proteins should be identified.
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In Vitro Stability
• An in vitro test that measures the release of the drug substance
from the liposome can be important for assessing the
(1) Quality of a liposome drug product,
(2) Adequacy of the process controls,
(3) Release characteristics of the product over time, and
(4) The effect of CMC changes
e.g., minor manufacturing process changes or change in site of
manufacture.
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Pharmacokinetics and Bioavailability
1. Mass Balance
2. Pharmacokinetic Studies
3. Additional Pharmacokinetic Studies
a. Food-Effect Studies
b. Drug Interaction and /or special Populations
c. Exposure-Response Studies
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III. Labeling
A. Product Name
B. Cautionary Notes and Warning
C. Dosage and Administration
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Product Name
• The product name should include the established name, dosage
form, terminology to describe that it is a liposome drug
product, and, if desired, a proprietary (i.e., brand) name.
• The descriptive terminology should include the term liposome
and, when appropriate, such terms as Type A, Type B, and
Type C, to distinguish one liposome product from other
liposomal formulations of the same drug substance that are not
therapeutically equivalent.
• For example:
BrandX (Acetaminophen) Liposome-Type A For Injection
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Cautionary Notes and Warning
• A cautionary note should be included in the
description section of the labeling regarding the fact
that liposome drug products may behave differently
from nonliposome drug products.
• A warning should be included in the labeling that the
liposome drug product is not equivalent to or cannot
be substituted for other drug products containing the
same drug substance.
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Dosage and Administration
• This information should be provided for both unloaded
lyophilized liposomes that are reconstituted with a drug
substance-containing solution at the time of use, as well as
products in which the drug substance is loaded into the
liposome by the manufacturer and then lyophilized.
• Other issues that should be addressed, as warranted, include
storage conditions for the reconstituted drug, robustness of the
liposome drug product under varied reconstitution conditions
(e.g., degree of shaking), and appropriateness of using in-line
filters.
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Nanotechnology Product Evaluating
Questions
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Nanotechnology Product Evaluating
Questions
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Template for CDER Nanotechnology
Drug Product Database Entry
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Nanotechnology Product Review Flow Chart
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Nanotechnology Product Review Flow Chart
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Common Techniques for Characterization
• Morphology
• Surface
• Chemical
• Others
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Morphology
Properties
Common Techniques
Size (primary particle)
TEM, SEM, AFM, XRD
Size (primary/aggregate/agglomerate)
TEM, SEM, AFM, DLS, FFF, AUC,
CHDF, XDC, HPLC, DMA(1)
Size distribution
EM, SEM, AFM, DLS, AUC, FFF,
HPLC, SMA
Molecular weight
SLS, AUC, GPC
Structure/Shape
TEM, SEM, AFM, NMR
Stability (3D structure)
DLS, AUC, FFF, SEM, TEM
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Surface
P roperties
Common Techniques
Surface area
BET
Surface charge
SPM, GE, Titration methods
Zeta potential
LDE, ESA, PALS
Surface coating composition
SPM, XPS, MS, RS, FTIR, NMR
Surface coating coverage
AFM, AUC, TGA
Surface reactivity
Varies with nanomaterial
Surface-core interaction
SPM, RS, ITC, AUC, GE
Topology
SEM, SPM, MS
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Chemical
Properties
Common Techniques
Chemical composition (core, surface)
XPS, MS, AAS, ICP-MS, RS, FTIR,
NMR
Purity
ICP-MS, AAS, AUC, HPLC, DSC
Stability (chemical)
MS, HPLC, RS, FTIR
Solubility (chemical)
Varies with nanomaterial
Structure (chemical)
NMR, XRD
Crystallinity
XRD, DSC
Catalytic activity
Varies with nanomaterial
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Other
Properties
Common Techniques
Drug loading
MS, HPLC, UV-Vis, varies with
nanomaterial
Drug potency/functionality
Varies with nanomaterial
In vitro release (detection)
UV-Vis, MS, HPLC, varies with
nanomaterial
Deformability
AFM, DMA(2)
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Abbreviations
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THANK YOU
E-mail: [email protected]
Cell No: 0091-9742431000
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