KELOMPOK II

MUHAMMAD RAIS
CAHYANI PURNASARI
RAHMITA BURHAMZAH
MEGAWATI SYAFRIN
DIANAYU LESTARI
SOENDARIA INTAN
• The term “nanoemulsion” refers to a thermodinamically stable
isotropically clear dispersion of two immiscible liquids, such as
water and oil, stabilized by an interfacial film of surfactant
molecul.
• The disperse phase typically comprises small particles or
droplets, with a size range of 5-200 nm, and has very low
oil/water interfacial tension.
 The Skin

The skin has a wide variety of functions:

Protect the organism from water loss and
mechanical, chemical, microbial, and physical
influences.
 Structure of the Skin
The skin is the largest human organ and is composed of:
 A film of emulsified material present upon the surface of
the skin composed of a complex mixture of sebum, sweat.

 Blood capillaries and

nerve fibers.
 Sweat glands.
 Hair follicles.
 Three functional layers:
 Epidermis,
 Dermis (true skin)
 Hypodermis
(Subcutaneous fat layer).
The epidermis is the outermost layer of the skin

 0.02 to 5 mm thickness
 It has five layers,
o Horny layer (stratum
corneum).
 The uppermost layer
 Composed of dead epidermal
cells forms the permeability
barrier

o Barrier layer (stratum germinativum).

 Beneath the hornylayer
 Composed of living epidermal cells.
The stratum corneum consists of:
Horny skin cells (corneocytes) which are connected via protein-
rich attachments of the cell membrane.

The corneocytes are embedded in a lipid matrix in “Brick and

mortar” structure.
The corneocytes of hydrated keratin comprise the bricks and the
epidermal lipids fill the space between the dead cells like mortar.
 Routes of skin Penetration
There are two diffusional routes to penetrate intact skin:

The Transappendageal route: 1 2

Include transport via:

1- Hair follicles and sebaceous
glands
2- Sweat glands

 These routes avoid penetration through the stratum corneum

and therefore known as shunt routes.
 Although these routes offer high permeability, they are of
minor importance because of their relatively small area,
0.1% of the total skin area.

The transappendageal route

seems to be most important for
ions and large polar molecules
which hardly permeate through the 1 2
stratum corneum.
Transepidermal transport means
that molecules cross the intact
horny layer.
Two potential micro-routes are exist
The transcellular (or intracellular) route.
The intercellular pathways.

The principal pathway taken by drugs is decided by its partition

coefficient.

Hydrophilic drugs partition into

the intracellular pathways,
whereas lipophilic drugs
traverse the stratum corneum
via the intercellular route.
 Age
Individual Absorption
Site
Occlusion
Temperature
Race
Disease
A. In-Vitro method
• In Vitro Percutaneous Absorption Method
• In-vitro short term skin exposure
B. In-Vivo method
• Skin Stripping: short term exposure
• Skin flaps
• Systemic bioavaiability (blood and excreta)
• Microdialysis
• Surface disappearance
• Suction blister
• Biological response (pharmacodynamics)
• Raman spectroscopy
a. USP apparatus 5 provides a watch glass-patch-Teflon mesh
assembly with the paddle method and an appropriate
dissolution medium is suggested for TDS products.
b. A simple static VDC system with a synthetic membrane and an
appropriate receptor medium has been proposed for topically
applied drug products.
• ADVENTAGE
 Nanoemulsion have higher surface area and free energy that make them an
effective transport system
 They don’t show the problems of inherent creaming, flocculation, coalesence and
sedimentation.
 It can be formulated in variety of formulation such as foams, creams, liquids, and
spray
 They are non toxic, non-irritant hence can easily applied to skin and mucous
membrane
 It can be administrated orally if the formulation contains surfactans which are
biocompatible.
 It don’t damage healthy human and animal cell hence are suitable for human and
veterinary therapeutic purpose
 It may be applied as a substitute for liposome and vesiclea and it’s possible to build
lamellar liquid crystalline phases around the nanoemulsion droplets.
 Due to their small size, nanoemulsion can penetrate through the “rough” skin surface
and this enhances penetration of actives
 Nanoemulsion have been reported to make the plasma concentration profiles and
bioavailability of drugs more reproducible.
• Disadvantage
a. Large concentration of surfactants/cosurfactants is required
for stabilization
b. Its stability affected by temperature and pH
c. Instability can be caused due to Oswald ripening effect.
d. The formulation of nanoemulsion is an expensive process due
to size reduction of droplets is very difficult as it required a
special kind of instrument and process method.
• Bioavailability is the rate and amount (in percent) of unchanged
active substances that becomes available (reaches the target
organ/site of action or systemic circulation) to an organism’s
body for bioactivity after administration of a given dosage
form.
Comparing the bioavailability of two different dosage forms
having same active ingredients is called comparative
bioavailability:
• Absolute bioavailability compares the bioavailability (estimated
as the AUC) of the active drug (with the same given dose) in
systemic circulation following non-intravenous administration (i.e.,
after oral, rectal, transdermal, subcutaneous, or sublingual
administration), with the bioavailability of the same drug
following intravenous administration.
• Relative bioavailability measures the bioavailability (estimated
as the AUC of a formulation (A) of a certain drug when
compared with another formulation (B) of the same drug (with a
same given dose), usually an established standard or innovator
drug. Relative bioavailability is one of the measures used to
assess bioequivalence between two drug products.
• Bioequivalence is a similarity (not differ
significantly) of the bioavailability between two
drugs (one of the drug is the innovator or
branded drug) with different formulations (with
the same route of administration, either in the
same or different dosage form) of the same
active substance (with the same chemical form
or different chemical form but still have the
same action) in a same given dose.
• Pharmacodynamic refers to the relationship between drug
concentrations at the site of action (receptor) and
pharmacologic response. The concentrations of drug at the site
of action (receptor) is affected by the pharmacokinetic of that
drug. Pharmacokinetic is the fate of substances administered
externally to a living organism start from the moment that it is
administered up to the point at which it is completely eliminated
from the body. Thus, pharmacokinetic studies is used to develop
dosing regimens for achieving therapeutic drug concentrations
for optimal safety and efficacy.
1. Materials
Nonionic surfactant, Polysorbat 80 (Tween 80) was purchased
from SAFC, U.S.A. The polymeric surfactant, Pluronic F-68 was
procured from SIGMA, U.S.A. for simplicity, 10% (w/w) solution of
Pluronic F-68 was prepared for the course of this research. The
Palm Oil Esters (POEs) were synthesized in our laboratory.
The active ingredient, DL-a-Tocopherol Acetate (Vitamin E), is an
antioxidant was purchased from FLUKA, Switzerland. Water was
deionised by Milli-Q filtration.
Palm oil esters (POEs) with a surfactant mixture (mixture of Tween 80
and Pluronic F68 in the ratio of 40:1) were weighed into 10 mL
screw-capped glass tube at various weights. Several combinations of
ratio of oil and surfactant mixture were made for the study to
delineate the boundaries of phases precisely in the phase diagrams.
Deionised water was added using the aqueous titration method. The
amount of deionised water added was varied to produce the
percentage of water in the range of 0% to 100% of total volume at
around 5% intervals. The samples were vortexed (Vortex mixer VTX-
3000L, LMS, Japan) and then centrifuged at 4000 rpm (1864 g) for
15 mins using a centrifuge (Hermle Z200A, Germany). The samples
were then examined visually through cross-polarized light. All the
studies were carried out at room temperature, 25°C and 1
atmospheric pressure unless otherwise specified.
Stable emulsion was selected from the homogenous region (1 phase)
for the incorporation of DL-a-Tocopherol Acetate. Vitamin E was
incorporated into the oil phase by substituting part of Palm Oil Esters.
The amount of vitamin E and Palm Oil Esters used were manipulated
to ensure that the percentage of oil phase in the emulsion remains
constant. This is to ensure that the relative proportions of the water
and oil phase were kept constant.
Stable emulsions formed after incorporating of vitamin E was
selected for the preparation of 50 g samples. The surfactant
mixture was first dissolved into a mixture of POEs and vitamin E
via stirring (IKA® - WERKE RW16 basic, Germany) at 150 rpm.
Deionised water was added dropwise while stirring at 150 rpm.
The system was then homogenized at 250 - 350 rpm for 4 hours.
At the end of 4 hours the system was homogenized at 10 000 rpm
for 5 mins using high shear homogenizer (PT3100 High Shear
Homogenizer, POLYTRON, Kinematica AG, Switzerland).
The diameter of the droplets for all the formulations was
measured using the Particle Size Analyzer (Nanophox, SYMPATEC
GmbH, Germany). The size was determined a day after the
formulations were formulated. This ensures that the system has
achieved equilibrium before the measurement was made.
The effect of DL-a-Tocopherol Acetate and Pluronic F- 68 on the nanoemulsions
formulations were investigated by manipulating their percentage in the formulations.
The effect of these components on the formulations prepared was investigated by
carrying out stability test. The stability tests employed in this research are as follows:

6. a. Ostwald ripening
According to Tadros (2005), Ostwald ripening can be quantitatively assessed from
the plot of cubic radius of droplet size, r3 versus time, t. Therefore the droplet sizes
of all the formulations were measured as a function of time and the slope of the
graph plots is the rate of Ostwald ripening. The samples were kept sealed at room
temperature.

6. b. Temperature storage
Each formulation was poured into three individual test tubes until three quarters full.
Each test tube was kept at a different temperature, i.e. 45°C (placed in an
incubator (Shaking Incubator DK-S1020, DAIKI Sciences Co. Ltd, Korea), 25°C (room
temperature) and 5°C (refrigerator). The occurrence of phase separations of the
system was observed after 24 hours and during weekly observations.
1. Phase Diagram
2. Incorporating DL-a-Tocopherol Acetate (Vitamin E)
3. Nanoemulsions formulation
4. Effect of DL-a-Tocopherol Acetate (Vitamin E)
5. Effect of Pluronic F-68
6. Droplet size measurements
7. Temperature storage
 Conclusions
Stable nanoemulsions containing an appropriate amount of
active ingredients were successfully formulated. The best
formulation was found to be formulation FP-5 consisting of
10% (w/w) Palm Oil Esters (POEs), 10% (w/w) vitamin E,
24% (w/w) Tween 80, 2.4% (w/w) Pluronic F-68 and 53.6%
(w/w) deionised water. It proved to be the most stable in
terms of emulsions stability while still containing sufficient
amount of active ingredient. Formulation FP-5 is considered
to be the most suitable formulation for use as a
nanocosmeceutical product because of its particle size of 94
nm and low occurrence of Ostwald ripening. It was found to
be stable at temperatures ranging from 5°C to 45°C during
the fourweek storage stability test. Both vitamin E and
Pluronic F-68 were found to co-emulsify and stabilized the
formulations.