2. Surfactants
Lipids
Polymers
Amphiphiles
In polar solvents the
hydrophobic effect
drives them to
spontaneously self-
assemble into a rich
array of
thermodynamically
stable lyotropic
liquid crystalline
phases with
characteristic
lengths on the
nanometer scale.
3.
4.
5. Bicontinuous cubic phases consist of two separate, continuous but
nonintersecting hydrophilic regions divided by a lipid bilayer The
bicontinuous nature of such cubic phases distinguishes them from
the so-called micellar or discontinuous cubic phases containing
micelles packed in cubic symmetry.
6. • A property of the cubic phases formed by certain classes of
amphiphiles is their ability to be dispersed into particles, termed
cubosomes.
• Cubosomes are liquid crystalline nanostructured particles with
the same unique properties of the bulk cubic phase, however
cubosome dispersions have much lower viscosity.
7. Cubic phase –forming polar lipids:
• Monoglycerides are polar lipids with
poor water solubility that exhibit
aqueous phase behavior, reflecting
their structural similarity to nonionic
surfactants.
• Of particular interest is the large
region of cubic phase exhibited by
each of the aqueous monoglyceride
systems, with the largest being that of
monoolein, the unsaturated C18
monoglyceride
8. Monoolein has a slightly larger cross-sectional area of its
hydrophobic tail region, leading to a ratio of the hydrophobic tail
group area to the hydrophilic head group area slightly larger
than one (1.03). As a result, the cubic phases are often referred
to as reversed or inverse cubic phases, indicating the curvature
of the constituent bilayers toward the polar medium
9. The formation of cubosomes is possible in binary an ternary
systems
Cubosomes form in the two-
phase region of equilibrium
between the cubic phase and
water or solvent
Cubosomes form in the two-
phase region of equilibrium
between the cubic phase and
water or solvent
Cubosomes, vesicles,
and/or sponge phase
particles may form in the
multiphase regions between
the cubic phase, sponge
phase, lamellar phase, and
water.
10. Vesicles
over the course
of several weeks fusion
Membrane
Cubosomes
Such metastability is characteristic
of cubosome systems
11. Top down
technique
Suppose that this’s
the cubosome
To manufacture this either
break something large
Or build from something
smaller
Bottom up
technique
12. Top down technique (widely
used in research area)
Bulk cubic phase
(Clear rigid gel- like)
Sonication /
high-pressure
homogenization
Vesicles
Cubosomes
13. Bottom up technique
In this cubosomes are allowed to form or crystallize from precursors
1. Liquid Cubosome Precursors :
“The hydrotrope dilution process”
Particles are formed by nucleation and growth,
as employed in crystallization and
precipitation processes
Monoolein + Ethanol
(hydrotrope)
Poloxamer 407 +
Water
Dilute with
Cubosomes
14. Hydrophobic
compounds
Hydrotrope
Hydrotropes do not have a critical concentration above which
self-aggregation 'suddenly' starts to occur (as found for micelle-
and vesicle-forming surfactants, which have a critical micelle
concentration or CMC and a critical vesicle concentration or
CVC, respectively). Instead, some hydrotropes aggregate in a
step-wise self-aggregation process, gradually increasing
aggregation size)
Hydrophilic part
Hydrophobic part is
generally too small to
cause spontaneous self-
aggregation c.f. SAA
15. 2. Powdered Cubosome Precursors :
Powdered cubosome precursors are powders composed of
dehydrated surfactant coated with polymer (which are
better than liquid hydrotropic cubosome precursors).
Hydration of the precursor powders forms cubosomes with
a mean particle size of 600 nm.
The lipids used to make cubosomes (monoolein)
are waxy, sticky solids, rendering them unable to
form small discrete particles.
Coat with a water-soluble non-cohesive starch
coating on the waxy lipid to prevent
agglomeration and allow control of particle size.
16. 1. Via High shear treatment to form
a coarse cubosome dispersion that
is then pumped through a nozzle
and dried.
Monoolein in
aqueous starch
solution
Spray Drying
17. 2. From a hydrotropic solution of
monoolein emulsified in water
A small change in the formula is required to accommodate
the ethanol (hydrotropic solution) A new polymer e.g.
dextran, is needed for encapsulation of the monoolein, as
the insolubility of starch in ethanol prevents its use.
Preparation of the quaternary
system (water, dextran, ethanol, and
monoolein):
Dextran + Water Monoolein + Ethanol
Emulsion of two
distinct phases
One phase is optically
isotropic
And the other is
optically birefringent.
*Both phases has low
viscosity and is easily
spray dried.
18. The volatile content remains constant
for several months, indicating good
encapsulation of both the ethanol and
the monoolein by the dextran.
19.
20.
21.
22. A key requirement for optimal application of these
formulations is a detailed understanding of how the liquid
crystalline particles interact with a model cellular
membrane whilst varying two parameters :
23. All cells have –ve
charges
But Cancer cells
have more –ve
charges due to a
different
composition of fatty
molecules on their
surface.
The sensitivity of the
interaction to small changes
in charge suggests that
simple adjustments to the
proportion of charged lipids
and macromolecules could
optimize this process. In the
future this can be used in
targeting cancer cells by
encouraging the molecules
to penetrate through & bind
to the surface, forming an
attached reservoir.
24. The analysis showed that the aggregates interacted
preferentially with membranes only when they were
located above the sample.
One of the professors who conducted this research
says,“Of course it’s not new that particles in formulations
can sink or float, but such dramatically different specific
interactions of these nanocarriers with model
membranes of different orientations took us completely
by surprise” .
“Very small sample volumes are often used in biomedical
investigations so the effects of phase separation cannot
be seen. The findings suggest that laboratory researchers
may need to re-evaluate the way in which they examine
the effectiveness of newly developed formulations to
account for strong gravitational effects.”
25.
26. Cubosomes:Bicontinuous Cubic Liquid Crystalline Nanostructured Particles
Author: Patrick T. Spicer
The Procter & Gamble Company, West Chester, Ohio, U.S.A.
*Online link : www.nonequilibrium.com/SpicerENN.pdf
OVERVIEW OF CUBOSOMES: A NANO PARTICLE
Authors: Madhurilatha Thadanki*, Paruchuri Srivalli Kumari and K.
Suria Prabha
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND
CHEMISTRY
*Available online at : www.ijrpc.com/files/00039.pdf
Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen
with low irritancy and high Bioavailability
Authors: Shun HAN1, #, Jin-qiu SHEN2, #, Yong GAN1, Hai-ming
GENG3, Xin-xin ZHANG1, Chun-liu ZHU1, Li GAN1, *
*Online link: www.nature.com › Journal home › Archive › Original Articles
The interesting properties of the cubic phase formed by this monoglyceride, temperature stability, high internal surface area and the low-cost raw material, which makes them desirable to be used as consumer products and in the pharmaceutical industry applications