Nanoemulsion

Nanotechnology
Comprises technological developments on the nanometer scale,
usually 0.1 to 1000 nm.

1. 1
NANOEMULSION
Department of Pharmacy (Pharmaceutics) | Sagar savale
Mr. Sagar Kishor savale
Department of Pharmaceutics
[email protected]
2015-2016

2. Content
Introduction
Classification
Defination and synonyms
Structure of Nanoemulsion
Physical properties of a Nanoemulsion
Methods of preparation
Components of Nanoemulsion
Evaluation of Nanoemulsion
Application
Conclusion
References
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3. Nanotechnology
Comprises technological developments on the nanometer scale,
usually 0.1 to 1000 nm.
The pharmaceuticalsdeveloped on the
basis of nanotechnology are termed as
‘NANOPHARMACEUTICALS ’.
Introduction

4. Emulsion:
“They are thermodynamically unstable
system consisting of atleast two immissible liquid
phase, one of which is dispersed as a globules in
the other liquid phase which is continuous phase.”
4

5. CLASSIFICATION :
It is based upon the nature of Dispersion Phase,
1.Oil-in-water Emulsion(o/w) (0.1-100 µm)
2.Water-in-oil Emulsion (w/o) (0.1-100 µm)
3.Micro Emulsion (0.01 µm)
4.Nano Emulsion (0.1-0.5 µm)
5

6. The various nanopharmaceuticals
currently being used :
Nanoemulsion
Nanosuspension
Nanospheres
Nanoshells
Nanocapsules
Lipid Nanoparticle
Dendrimers
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7. Nanoemulsion
•“Nanoemulsion can be defined as a oil in water(o/w)
emulsion with mean droplet daimeters ranging from
50 to 1000nm.Usually the average droplet size is
between 100-500nm.”
7
Synonyms
Sub micron size emulsion
Mini emulsion
Ultrafine Emulsion

8. •transparent or translucent O/W or W/O emulsion
•droplet diameters ranging from 50-1000 nm.
[avgdroplet size is between 100-500 nm]
•kinetically stable unlike microemulsionswhich are
thermodynamically stable
•Nanoparticlescan exist core of particle
w/o form water
o/w form oil
•Ostwald ripening is the primary instability process :
Can be reduced by the addition of a second less soluble oil phase
and/or
addition of a strongly adsorbed and water insoluble polymeric surfactant.

9. Single nanoparticle
Nanoemulsion: Lipid
monolayer enclosing a liquid
lipid core.
Liposome: Lipid bilayer
enclosing an aqueous core.

10. Structure of Nanoemulsion
10
Fig-1 Fig-2
Fig-3

11. 11
Types of Nanoemulsion

12. 12

13. Physical Properties of Nanoemulsion
The relative transparency of nanoemulsion.
Their response to mechanical shear or ‘rheology’.
The enhanced shelf stability of
nanoemulsionagainst gravitationally driven
creaming.
13

14. A nanoemulsion(a) and A macroemulsion
(b) with droplet diameters of less than 100
nm and more than 1000 nm, respectively.
Nanoemulsion and Macroemulsion
14

15. Difference between Emulsion and
Nanoemulsion
Themodynamically unstable.
Millky appearance.
Droplet upto few micrometer.
Thermodynamically stable.
Transluscent,isotropic.
Droplet 0.1-0.5 µm.
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Emulsion
Nanoemulsion

16. 16
SMEDDS SNEDDS
ItisSelf-Microemulsifyingdrugdelivery
system
ItisSelfNanoemulsifyingdrugdelivery
system
Itisturbidinnature Itistransparentinnature
Largeamountofenergyisrequiredfor
preparationascomparetonanoemulsion
Lessenergyrequiredforpreparation
Dropletsizeis100-300nm Dropletsizeislessthan100nm
Itisthermodynamicallystable Itisthermodynamicallyandkinetically
stable
ItisoptimizedbyternaryphasediagramItisoptimizedbyPsedoternaryphase
diagram
Difference between SMEDDS And SNEDDS

17. Advantages Of Nanoemulsions
1.Reductionof globules as the potential to:
Increase surface area
Enhance solubility
Increase oral bioavailability
More rapid onset of therapeutic action
Decrease the dose needed
2. They do not show the problems of inherent creaming,
flocculation, coalescence and sedimentation.
3.Theyare non-toxic, non-irritanthence can be easily
applied to skin and mucous membranes.
4. They can be taken by enteric routebecozthey are
formulated with surfactants, which are approved for
human consumption (GRAS),

18. Limitations of Nanoemulsion
The manufacturing of Nanoemulsion is an
expensive process.
Stability of Nanoemulsion is a unacceptable and
creates a big problem during the storage of
formulation for the longer period time.
Lessavailabilityofsurfactantandcosurfactant
requiredforthemanufacturingofnanoemulsion.
18

19. Preparation of Nanoemulsion
Drug
poorly water soluble drug
eg: CBZ, Diclofenac, Ramipril
Oil phase
eg: dimethicone oil , castor oil , Soyabean oil
Aqueous phase
Surfactant
Cremphore, lecithin
Cosurfactant : Propylene glycol, polysorbate 80,
cetylphosphate, hydrogenated caster oil

20. Representative pseudoternary phase diagram of
surfactant and cosurfactant (Smix) mixture
showing oil/water nanoemulsion area (shaded
area)

21. Thermodynamic Studies
Prepare number of formulations
Formulations centrifuged for specific period.
select stable formulation
kept under heating and cooling cycle.
select stable formulation
subjected to a freeze-thaw cycle test
select stable formulation for further mfg

22. Methods Of Preparation Of Nanoemulsions:
High-Energy
•1.Highpressurehomogenization
•2Microfludization
•3Ultrasoundenergy
Undesirableforlabile
drugsandmacromolecules
(proteinsandnucleicacids)
(forlab&industrialpreparation)
Low-Energy
1.Spontaneous
2.Solvent-diffusion
3.Phaseinversiontemperature(PIT)
a.RapidcoolingofselectedMEstate
b.Dilutionwithwater
(forlabpreparation)

23. 1.High-Pressure Homogenization
Inahigh-pressurehomogenizer,the
dispersionoftwoliquids(oily
phaseandaqueousphase)is
achievedbyforcingtheirmixture
throughasmallinletorificeatvery
highpressure(500to5000psi),
whichsubjectstheproductto
intenseturbulenceandhydraulic
shearresultinginextremelyfine
particlesofemulsion.

24. Dia: High-Pressure Homogenization
Advantage: produce nanoemulsions of extremely low particle size
(up to 1nm).
Disadvantage: high energy consumption and increase in temperature
of emulsion during processing.

25. 2.Microfluidization
patentedmixingtechnology,
useofadevicecalledmicrofluidizer.
Thisdeviceusesahigh-pressure
positivedisplacementpump(500to
20000psi),whichforcestheproduct
throughtheinteractionchamber,
whichconsistsofsmallchannels
called‘microchannels’.
Theproductflowsthroughthe
microchannelson toan
impingementarearesultinginvery
fineparticlesofsub-micronrange.

26. Coarse emulsion
The two solutions
(aqueous phase and
oily phase) are
combined together
Interaction
chamber Microfluidizer
Filtrations
desired particle size
Stable & uniform nanoemulsion.

28. Lab scale preparation:
High shearing Energy

29. Solvent evaporation method
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30. Phase inversion method
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31. Stability of Nanoemulsion
•Brownianmovement
•Lowrateofsedimentation–duetothesmall
particlesizelowgravitationalforce
•Asparticlesbecomesmaller,theattractiveforce
ofvanderwaalswillbesmaller.
•HighZetapotential-moreelectrostaticrepulsive
forces;resultedinreducingthecoalescenceor
coagulationofemulsiondroplets
•OptimumThermodynamicallystability;buthigh
kineticstability

32. Evaluation Of Nanoemulsion

33. Evaluation parameters of
Nanoemulsion
A) Average Globule Size And Size Distribution:-
Method used are-a)Transmission electon
Mcroscopy.
b)Droplet size analysis.
c)Light scattering.
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B) Rheological Evaluation :-
2 major parameters : -Viscosity.
-Refractive Index.

34. C) Zeta Potential :-It is used to determine surface
charge by the help of mobility & electrophoretic
velocity of dispersed globules.
34
D)Area Of Interfaces :It can be determined by
following formula.
S = 6/d
where, S = Total area of Interface
(sq.cm)
d = Diameter of Globules (cm)
E Analytical test (UV,HPLC)
F Biological studies
G In vitro drug release

35. Transmission Electron Microscopy
•Morphology and structure of the nanoemulsion were
studied using transmission electron microscopy (TEM)
•To perform the TEM observations, a drop of the
nanoemulsion was directly deposited on the holey film grid
and observed after drying

36. e.g.: TEM positive image of
Aceclofenac nanoemulsion showing
the size of some oil droplets.
. Scanning Electron Microscopy
picture of nanoemulsion.

37. Droplet size Analysis
Determined by photon correlation spectroscopy that analyzes the fluctuations in
light scattering due to Brownian motion of the particles, using a Zetasizer 1000 HS
(Malvern Instruments)
Viscosity determination
Brookfield viscometer
Refractive Index
Abbe-type Refractometer
Zeta potential measurement
The zeta potential was measured by electrophoretic mobility using Malvern
Nanosizer/Zetasizer
®
nano-ZS ZEN 3600 (Malvern Instruments, USA).
Biological studies
Skin Irritation Test
Plasma-time profile

38. Applications of Nanoemulsion
Use of Nanoemulsion in cosmetics.
Antimicrobial Nanoemulsion.
Nanoemulsion as Non-toxic disinfectant cleaner.
Nanoemulsion in cell culture technology.
NE as a vehicle for Transdermal drug delivery.
NE in cancer therapy and targeted drug delivery.
Nanoemulsion in the treatment of various other disease condition
Nanoemulsion as a mucosal vaccines.
Nanoemulsion as a vehicle for a ocular delivery
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39. 1.Use Of Nanoemulsions In Cosmetics
Due to their lipophilic interior,
nanoemulsions are more
suitable for the transport of
lipophilic compounds
High skin penetration due to
small size
Body Moisturizer Nanoemulsion
Face Lotion with Vitamin Nanoemulsion
Face Cream for Night Use with Vitamin Nanoemulsion

40. 2.Antimicrobial Nanoemulsions
Antimicrobial nanoemulsions are oil-in-water droplets that range from 200-600
nm.
The nanoemulsion has a broad spectrum activity against
o-bacteria (e.g., E. coli, Salmonella, S. aureus),
o-enveloped viruses (e.g., HIV, Herpes simplex),
o-fungi (e.g., Candida, Dermatophytes),
o-spores (e.g., anthrax).
nanoemulsion particles
are fuse with lipid-
containing organisms.
Due to electrostatic attraction between the
cationic charge of the emulsion and the anionic
charge on the pathogen
active ingredient
and the energy
releases destabilize
the pathogen lipid
membrane
cell lysis and
death

42. In the case of spores

43. Auniqueaspectofthenanoemulsionsistheirselective
toxicitytomicrobesatconcentrationsthatarenon-irritating
toskinormucousmembrane.
Thesafetymarginofthenanoemulsionisduetothelow
levelofdetergent&havesufficientenergyineachdroplet
todestabilizethetargetedmicrobeswithoutdamaging
healthycells.
Asaresult,thenanoemulsioncanachievealeveloftopical
antimicrobialactivitythathasonlybeenpreviouslyachieved
bysystemicantibiotics.

44. Nanoemulsions as a prophylactic medication
Ahumanprotectivetreatment,toprotect
peopleexposedtobio-attackpathogenssuchas
Anthrax,HepatitisandEbola.
Thetechnologyhasbeentestedongangrene
andclostridiumbotulismsporesandevenusedon
contaminatedwoundstosalvagelimbs

45. 3.Nanoemulsions As Mucosal Vaccines
(Under Trial)
Nanoemulsionsarebeingusedtodelivereither
recombinantproteinsorinactivatedorganismstoa
mucosalsurfacetoproduceanimmuneresponse.
nanoemulsion
causes proteins
applied to the
mucosal surface
facilitates
uptake by
antigen
presenting
cells
systemic and mucosal
immune response that
involves the production of
specific IgGand IgA
antibody as well as
cellular immunity
Thefirstapplications,aninfluenza
vaccineandanHIVvaccine,canproceed
toclinicaltrials.

46. 4.Nanoemulsions In Cell Culture Technology
Cell cultures are used for in vitro assays or to produce biological
compounds, such as antibodies or recombinant proteins
it has been very difficult to supplement the media with oil-soluble
substances , only small amounts of these oil-soluble substances
(lipophiliccompounds ) could be absorbed by the cells.
Nanoemulsionsareanewmethodforthedeliveryofoil-soluble
substancestomammaliancellcultures.
Thesenanoemulsionsaretransparentandcanbepassedthrough0.1
µmfiltersforsterilization.
Nanoemulsiondropletsareeasilytakenupbythecells.
Theadvantagesofusingnanoemulsionsincellculturetechnologyare
· Betteruptakeofoil-solublesupplementsincellcultures.
· Improvegrowthandvitalityofculturedcells.
· Allowstoxicitystudiesofoil-solubledrugsincellcultures

47. Nanoemulsion in cancer Therapy

48. “Anti-oxidant Synergy Formulation”(ASF) suppresses
malignancy: Nanoemulsions improve its effectiveness in culture
•ASF forces differentiation of neuroblastoma (most common solid
tumor in children)...Like neurons, if they begin to differentiate, they
no longer multiply

49. The neuroblastoma in the nude mice
Tumor
No Tumor
Control
(no treatment)
ASF
Nano-emulsion

50. Nanoemulsion delivery of
Tamoxifen
to breast cancer cell lines

51. The Effect of Tamoxifen (T) and
Nanoemulsion Preparation of Tamoxifen (NT) on Cell
Proliferation0
20
40
60
80
100
120
140
160

Cell Proliferation
B Control
C Tamoxifen
D Nano-Tamoxifen
Control (no treatment)
Tamoxifen (T)
Nanoemulsion
Preparation of
Tamoxifen
Days of Culture

52. Nanoemulsion delivery of anti-
inflammatory agent Aspirin in mice

53. 0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
The Anti-inflammatory properties of Nanoemulsion
Containing Aspirin in CD-1 Mice
-61%
-25%
Aspirin
+
Nano-emulsion
Alone
Aspirin
Control

millimeters

54. Parenteral nanoemulsions
Carbamazepine IV injection (Under trial)
widely used anticonvulsant drug, is a poorly soluble
drug with no parenteral treatment available for patients.
Solubility of drug increases by decreasing the particle
size uptonanometer
treatment available for patients i.e. CBZ nanoemulsion
given by IV route

55. Oral lipid nanoemulsion of Primaquine
Primaquine is one of the most widely used antimalarial and
is the only available drug till date to combat relapsing form of
malaria especially in case of Plasmodium vivaxand
Plasmodium ovale.
application of PQ in higher doses is limited by severe tissue
toxicity including hematological and GI related side effects
which are needed to be minimized.
when incorporated into oral lipid nanoemulsion having
particle size in the range of 10–200nm showed effective
antimalarial activity against Plasmodium infection in swiss
albino mice at a 25% lower dose level as compared to
conventional oral dose.

56. PATENTEDNANOEMULSIONS
Someimportantpatentsrelatedtonanoemulsions:
1.Patentname:MethodofPreventingandTreatingMicrobial
Infections.Assignee:NanoBioCorporation(US) USPatent
number:6,506,803
2.Patentname:Non-toxicAntimicrobialCompositionsandMethods
ofUse.Assignee:NanoBioCorporation(US) USPatentnumber:
6,559,189and6,635,676,
3.Patentname:Nanoemulsionbasedonphosphoricacidfattyacid
estersanditsusesinthecosmetics,dermatological,
pharmaceutical,and/orophthalmologicalfields.Assignee:L'Oreal
(Paris,FR)USPatentnumber:6,274,150
4.Patentname:Nanoemulsionbasedonoxyethylenatedornon-
oxyethylenatedsorbitanfattyesters,anditsusesinthecosmetics,
dermatologicaland/orophthalmologicalfields.Assignee:L'Oreal
(Paris,FR)USPatentnumber:6,335,022

57. 5.Patentname:Nanoemulsionbasedonethyleneoxideand
propyleneoxideblockcopolymersanditsusesinthecosmetics,
dermatologicaland/orophthalmologicalfields.Assignee:L'Oreal
(Paris,FR)USPatentnumber:6,464,990
6.Patentname:Nanoemulsionbasedonglycerolfattyesters,and
itsusesinthecosmetics,dermatologicaland/orophthalmological
fields.Assignee:L'Oreal(Paris,FR) USPatentnumber:
6,541,018
7.Patentname:Nanoemulsionbasedonsugarfattyestersoron
sugarfattyethersanditsusesinthecosmetics,dermatological
and/orophthalmologicalfields.Assignee:L'Oreal(Paris,FR)US
Patentnumber:6,689,371
8.Patentname:Transparentnanoemulsionlessthan100NM
basedonfluidnon-ionicamphiphiliclipidsanduseincosmeticor
indermopharmaceuticals.Assignee:L'Oreal(Paris,FR)USPatent
number:5,753,241

58. References
•Vyas S.,Khar R., 2002, Targeted And Controlled Drug Delivery
System, 1
st
Edition, CBS Publication, 303-329.
•Jain N.K, 2001, Controlled And Novel Drug Delivery, 1
st
Edition,
CBS Publication,381-399.
•R.S.R. Murthy,Vesicular and Particulate Drug Delivery Systems,
1
st
Edition,Career Publication,105-140.
•Leon Lachman,HerbertA.Liberman,JosephL.Kanig,Thetheory
and practice of industrial pharmacy,Varghesepublishing
house,Thirdedition,502-545.
•MonzerFanun,Colloidsin the drug delivery,CRSpress
group,221-244.
Website :
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Thank you