3. Introduction
Lipid nanoparticles
Second generation lipid nanoparticles
Produced from blends of solid lipids and liquid lipids
The blends obtained are also solid at room
temperature and body temperature
Solid lipids are mixed with liquid lipids preferably in the
ratio of 70:30 up to a ratio of 99.9:0.1
Has lipid matrix with a special nanostructure which
improve drug loading and firmly incorporate the drug
during storage
Can be administered via oral, ocular, topical and
intravenous route
4. Limitations of SLN
Poor drug loading capacity
Drug expulsion after polymeric transition during storage
Relatively high water content of the dispersions (70-
99.9%)
The low capacity to load water soluble drugs due to
partitioning effects during the production process
NLC overcome these limitations
5. Types
Type 1: Imperfect type NLC
• Solid and liquid lipids are blended
• Small amount of liquid lipid
• The difference in the structures of the lipids and special
requirements in the crystallization process lead to a
highly disordered, imperfect lipid matrix structure offering
space for drug molecules and clusters of drugs
Drug
6. Type 2: Multiple type NLC
• The multiple oil/fat/water, drug can be accomodated in
the solid, but at increased solubility in the oily parts of
the lipid matrix
• At high oil concentrations a miscibility gap of two lipids
occurs during the cooling phase, leading to phase
separation, that means precipitation of tiny oily
nanocompartments
Drug
7. Type 3: Amorphous type NLC
• Lipids are mixed in a way that prevents them from
crystallizing
• The lipid matrix is solid but, in a amorphous state
Drug
10. Method of Preparation
Method of
Preparation
Homogenization
Solvent
evaporation
Solvent
emulsification
diffusion
Membrane
contractor
Film ultrasound
dispersion
High speed
homogenization
Microemulsion
based
Supercritical fluid
Double emulsion
Spray drying
11. Homogenization techniques
High pressure
homogenizer
Above the melting
point of lipids
Aqueous emulsifier
phase and pre-
emulsion of drug
loaded lipid melt at
same temperature
Hot homogenization
Drug dispersed in
lipid melt
Then rapid
refrigeration
Presuspension +
aq. surfactant
dispersion
Cold homogenization
12. Factors Affecting Particle size
High temperature, low viscosity of lipid melt, lower
particle size, can lead to degradation of drug and carrier
High homogenization, high kinetic energy of particles,
particle coalescence, higher particle size
Good product obtained through HPH by several passes,
typically 3-5 passes
Factors
Temperature Homogenization speed
13. Solvent Evaporation Technique
Drug Lipid
_-_-_-_-
_-_-_-_-
_-_-_
H2O immiscible
organic solvent
-_-_-_-
_-_-_-
_-_-_-_
Emulsification
with HPH
Microfluidizer
Evaporation of organic
solvent (at room
temperature and reduced
pressure)
14. Concentration of lipid in organic solvent dictates particle
size
Low lipid load, small particle size
Avoidance of thermal stress
Incorporation of thermolabile drugs
Disadvantages: use of organic solvent, may interact with
drug, limited solubility of lipid in organic solvent
Example: Paclitaxel loaded NLC
Emami, et al., 2012. J Nanomat. 1-11.
15. Solvent Emulsification Diffusion technique
-_-
_-_-
_
Saturated water and
organic solvent
Drug + lipid
Emulsification with water saturated
solvent containing stabilizer using
mechanical stirrer
Addition of water (ratio 1:5 to 3:5)
to allow solvent diffusion in
continuous phase
Vacuum distillation or
lyophilization
17. Spray Drying
Colloidal dispersion of NLC is spray dried
Cheaper than lyophilization
Disadvantages:
• Particle aggregation due to high temperature
• Shear forces
• Partial melting of particles
18. Melting Dispersion Technique
Melting of drug and lipids in organic solvent(oil phase)
Simultaneous heating of water at same temperature
Addition of oil phase in small volume of water with
stirring at higher rpm for few hours
Cooling down to room temperature
19. Double Emulsion Technique
Drug dissolved in aqueous phase
Then emulsification in melted lipids: Primary emulsion
Add stabilizer: stabilized primary emulsion
Dispersion in aq. phase containing hydrophilic emusifier
This double emulsion is stirred and filtered
20. High Speed Homogenization
High speed homogenization followed by ultrasonication
Supercritical fluid technique
• Solventless processing
Solvent injection technique
Membrane contactor technique
21. Effect on Stability
Oil concentration increases, crystallization and melting
temperature decrease, polymorphic transformation rate
increases, particles become more spherical, stability
increases
Increase in amount of oil decreases need of surfactant
Ionic surfactant, low emulsification efficiency, increased
zeta potential, high physical stability
Nonionic surfactant, give additional steric stabilization,
avoid aggregation
Yang, et al.,2014. J Coll Interface Sci. 418;261-272. : Li, et al. 2008. Coll Surf Physicochem Eng aspects. 318;210-216
22. Factors Affecting Drug Release
Biphasic release: Burst release then prolonged release
Highest burst release when produced in highest
temperature and HPH and absent in CH
Extent of release also depends on surfactant
High concentration, high burst release
Redistribution effect
23. Heating of lipid/water phase leads to partitioning of drug
from melted lipid to aq. phase
After homogenization, oil in water emulsion is cooled and
lipid core starts crystallising (drug still in higher amount
in water phase)
Cooling leads to supersaturation and drug tries to
partition back into lipid phase
Solid lipid already started forming leaving only liquid
outer shell for accumulation by drug
24.
25. Characterization
Particle Size: Photon Correlation Spectroscopy
Zeta potential: PCS
Electron microscopy: SEM, TEM, AFM
Surface tension: Wilhemy plate method, Contact angle
DSC: Crystallinity
X-Ray Diffraction: Crystallinity
NMR: Mobility of materials in inner core of NLC
Raman spectroscopy: Conformational order of
hydrocarbon chains
26. Fluorometric spectroscopy: Nile red, Molecular
environment
Drug entrapment efficiency: Ultrafiltration,
ultracentrifugation, filtration by sephadex and dialysis
Drug release: Franz cell
27. Advantages
•High drug loading
•Chemical and
physical stability
•Controlled release
•In vivo skin
hydration
•UV protection
NLC
Disadvantages
•Stability of lipids
•Nanotoxicity
Doktorova, et al., 2014. Eur J PharmBiopharm. xxx:xxx-xxx.
32. Patents
Publication number Title Inventor
US20080020058 A1 Lipid nanoparticles based
compositions and methods
for the delivery of
biologically active molecules
Chen, et al.
2008
EP2229936 A1 Nanonized testosterone
formulations for improved
bioavailability
Keck C and Muchow
M
2009
US20090238878 A1 Solid nanoparticle
formulation of water
insoluble
pharmaceutical substances
with reduced Ostwald
ripening
Singh CU
2009
US20110097392 A1 Antibody bound synthetic
vesicle containing
molecules for deliver to
central and peripheral
nervous system cells
Wang KK et al.
2011
WO2011116963 A2 Lipid nanoparticle capsules Viladot Petit V et al.
33. Marketed Products
Products Producer
Cutanova Dr. Rimpler
SuperVital cream IOPE
Surmer Isabella Lancray
NanoLipid Restore CLR Chemisches Laboratorium Dr. Kurt Richter
GmbH
NanoLipid Q 10 CLR Chemisches Laboratorium Dr. Kurt
Richter GmbH
NanoRepair Q 10 Dr. Rimpler
NanoVital Dr. Rimpler
