Smedds, self micro emulsifying drug delivery system

self micro emulsifying drug delivery system, seminar on self micro emulsifying drug delivery system, smedds , modren pharmaceutics,smedds;types, application,advantage, disadvantage , composition,method of preparation, evaluations

1. SELF MICRO EMULSIFYING DRUG DELIVERY SYSTEM(SMEDDS)
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Definition-
“SMEDDS are defined as isotropic mixtures of natural or synthetic oils, solid and
liquid surfactants”.
or
alternatively, one or more hydrophilic solvents and co-solvents/surfactants that
have a unique ability of forming fine oil-in-water (o/w) micro emulsions upon
mild agitation followed by dilution in aqueous media, such as GI fluids.
The basic difference between self emulsifying drug delivery systems (SEDDS)
also called as self emulsifying oil formulation (SEOF) and
SMEDDS is SEDDS typically produce opaque emulsions with a droplet size
between 100 and 300 nm while ,
SMEDDS form transparent micro emulsions with a droplet size of less than 50
nm the concentration of oil in SMEDDS is less than 20 % as compared to 40-80%
in SEDDS.
TYPES
1.O/W Micro emulsion
2.W/O Micro emulsion
ADVANTAGES
1. Improvement in oral bioavailability
2 Ease of manufacture and scale-up
3. Reduction in inter-subject and intra-subject variability and food effects
4. Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT
Advantages of SMEDDS over emulsion
1.SMEDDS not only offer the same advantages of emulsions of facilitating the
solubility of hydrophobic drugs, but also overcomes the drawback of the
layering of emulsions after sitting for a long time. SMEDDS can be easily
stored since it belongs to a thermodynamics stable system.
2. Microemulsions formed by the SMEDDS exhibit good thermodynamics
stability and optical transparency. The major difference between the above
microemulsions and common emulsions lies in the particle size of droplets. The
size of the droplets of common emulsion ranges between 0.2 and 10 μm, and
that of the droplets of microemulsionformed by the SMEDDS generally ranges
between 2 and 100 nm (such droplets are called droplets of nano
particles).Since the particle size is small, the total surface area for absorption
and dispersion is significantly largerthan that of solid dosage form and it can
easily penetrate the gastrointestinal tract and be absorbed. The bioavailability of
the drug is therefore improved.
3.SMEDDS offer numerous delivery options like filled hard gelatin capsules or
soft gelatin capsules or can be formulated in to tablets whereas emulsions can
only be given as an oral solutions.

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DISADVANTAGES
1.One of the obstacles for the development of SMEDDS and other lipid-based
formulations is the lack of good predicative in vitro models for assessment of
the formulations.
2. Traditional dissolution methods do not work, because these formulations
potentially are dependent on digestion prior to release of the drug.
3. This in vitro model needs further development and validation before its
strength can be evaluated.
4. Further development will be based on in vitro - in vivo correlations and
therefore different prototype lipid based formulations needs to be developed and
tested in vivo in a suitable animal model.
4. The drawbacks of this system include chemical instabilities of drugs and high
surfactant concentrations in formulations (approximately 30-60%) which irritate
GIT.
6. Moreover, volatile co solvents in the conventional self-micro emulsifying
formulations are known to migrate into the shells of soft or hard gelatin
capsules, resulting in the precipitation of the lipophilic drugs.
7. The precipitation tendency of the drug on dilution may be higher due to the
dilution effect of the hydrophilic solvent.
8. Formulations containing several components become more challenging to
validate.
COMPOSITION
1.OILS
2.SURFSCTANTS
3.CO-SOLVENTS
4.CO-SURFACTANT
1.OIL PHASE
In order to make SMEDDS systems pharmaceutically acceptable, it is necessary
to prepare such systems by using nontoxic and safe components. Oil from
natural sources and their derivatives, e.g. triglycerides and fatty acid methyl
esters are easily degraded by microorganism and considered to be harmless to
the environment. The formation of bicontinuous micro emulsions with mineral
oils has been intensively investigated in model experiments and for application
inNindustrial products. An acceptable lipophilic phase for pharmaceutical
useswould be vegetable oils. The extension of a microemulsion region
generallydependson nature of oil. This is due to differences in oil penetration
into thesurfactant layer.
Example:
Castor oil, Sunflower oil, Olive oil,Seseam oil, Hydrogenated specialty oils

2. SURFACTANT

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A surfactant molecule is formed by two parts with different affinities for the
solvents. One of them has affinity for water (polar solvents) and the other has
for oil (non-polar solvents). A little quantity of surfactant molecules rests upon
the water-air interface and decreases the water surface tension value (the
force per unit area needed to make available surface). That is why the
surfactant name: “surface active agent”.
Classification –
Surfactant molecules may be classified based on the nature of the hydrophilic
group within the molecule. The four main groups of surfactants are
defined as follows,
1. Anionic surfactants
2. Cationic surfactants
3. Ampholytic surfactants
4. Nonionic surfactants
1. Anionic Surfactants, where the hydrophilic group carries a negative charge
such as carboxyl (RCOO-),sulphonate (RSO3-) or sulphate (ROSO3-).
Examples: Potassium laurate, sodium lauryl sulphate.
2: Cationic surfactants, where the hydrophilic group carries a positive charge.
Example: quaternary ammonium halide.
3: Ampholytic surfactants (also called zwitterionic surfactants) contain both a
negative and a positive charge.
Example: sulfobetaines.
4. Nonionic surfactants, where the hydrophilic group carries no charge but
derives its water solubility from highly polar groups such as hydroxyl or
polyoxyethylene (OCH2CH2O).
Examples: Sorbitan esters (Spans), polysorbates (Tweens).
3.CO-SOLVENTS
Organic solvents such as ethanol, propylene glycol (PG) and polyethylene
glycol (PEG) are suitable for oral delivery and they enable the dissolution of
large quantities of either the hydrophilic surfactant or the drug in the lipid base.
solvents can even act as co surfactants in microemulsion systems. Alternately
alcohols and other volatile cosolvents have the disadvantage of evaporating into
the shells of the soft gelatin or hard sealed gelatin capsules in conventional
SMEDDS leading to drug precipitation.

4.CO-SURFACTANT
For the production of an optimum SMEDDS, high concentration of surfactant is
required in order to reduce interfacial tension sufficiently, which can be
harmful, so co-surfactantsare used to reduce the concentration of surfactants.
Co-surfactants together with the surfactants provide the sufficient flexibility to
interfacial film to take up different curvatures required to form micro-emulsion
over a wide range of composition. Selection of proper surfactant and co-

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surfactant is necessary for the efficient design of SMEDDS and for the
solubilization of drug in the SMEDDS.
FORMULATION
Drug has to dissolve in to oil phase(lipophilic part) of microemulsion.
Water phase is combined with the surfactant and then cosurfactant is
added slowly with constant stirring until the system is become transparent.
The amount of surfactant and co-surfactant to be added and the parent
oil phase that can be incorporated is determined with the help of pseudo
ternary phase diagram.
Ultrasonicator can finally used to achieve the desired range for the
dispersed phase.
It is then allow to equilibrate.
Gel may be prepared by the addition of the gelling agent to above
microemulsion.
METHOD OF PREPARATION
1. Phase Titration Method
2. Phase inversion Method
1. Phase Titration Method
dilution of an oil-surfactant mixture with water.(w/o)
dilution of a water-surfactant mixture with oil.(o/w)
mixing all components at once. In some systems, the order of ingredient
addition may determine wheather a microemulsion forms.
2.Phase inversion method
Phase Inversion Temperature (PIT), i.e., the temperature range in
which an o/w microemulsion inverts to a w/o type or vice versa.
EVALUATION TEST
1. Thermodynamic Stability Studies
2. Dispersibility test
3. Turbidimetric Evaluation
4. Viscosity Determination
5. Droplet Size Analysis and Particle Size Measurements
6. Refractive Index and Percent Transmittance
7. Electro Conductivity Study
8. In vitro Diffusion Study
9. Drug Content
10. In vivo permeability studies

1. THERMODYNAMIC STABILITY STUDIES
Heating cooling cycle
•Six cycles between refrigerator temperature 4⁰C and 45⁰C with storage at each
temperature of not less than 48 h is studied.

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•Those formulations, which are stable at these temperatures, are subjected to
centrifugation test.
Centrifugation
•Passed formulations are centrifuged at room temperature at 3500 rpm for
30min.
•Those formulations that does not show any phase separation are taken for the
freeze thaw stress test.
Freeze thaw cycle:-
Freeze was employed to evaluate the stability of formulation.
Thermodynamic stability was evaluated at difference temp. To check the
effect of temp. the formulation was subjected to freeze thaw cycle(-20ºC) for 2-
3 days.
Those formulations passed this test showed good stability with no phase
separation, creaming, or cracking.
2. DISPERSIBILITY TEST:-
The efficiency of self-emulsification of oral nano or micro emulsion is
evaluated by using a standard USP
XXII dissolution apparatus for dispersibility test.
Solution Tested: 1ml
Medium: 500 ml water
Temperature: 37 ± 1 ⁰C.
Paddle speed : 50 rpm
Grade A: Rapidly forming (within 1 min) nano-emulsion, having a clear or
bluish appearance.
Grade B : Rapidly forming slightly less clear emulsion having a bluish white
appearance.
Grade C: Fine milky emulsion that formed within 2 min.
Grade D: Dull, grayish white emulsion having slightly oily appearance that is
slow to emulsify (longer than 2MIN]
Grade E: Formulation, exhibiting either poor or minimal emulsification with
large oil globules present on the surface.
Grade A and Grade B formulation will remain as nanoemulsion when
dispersed in GIT. While formulation falling in Grade C could be recommended
for SMEDDS formulation.
3.TURBIDIMETRIC EVALUATION: -
Nepheloturbidimetric evaluation is done to monitor the growth of
emulsification.
Fixed quantity of Self emulsifying system is added to fixed quantity of
suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on
magnetic hot plate at appropriate temperature, and the increase in turbidity is
measured, by using a turbidimeter.

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However, since the time required for complete emulsification is too short,
it is not possible to monitor the rate of change of turbidity (rate of
emulsification)

4.VISCOSITY DETERMINATION: -
 The SMEDDS system is generally administered in soft gelatin or hard
gelatin capsules. So, it should be easily pourable into capsules and such
systems should not be too thick.

 The rheological properties of the micro emulsion are evaluated by
Brookfield viscometer.
 The viscosities determination conform whether the system is w/o or
o/w.
If the system has low viscosity then it is o/w type of the system
If the system has high viscosity then it is w/o type of the system
5.DROPLET SIZE ANALYSIS:-
The droplet size of the emulsions is determined by photon correlation
spectroscopy (which analyses the fluctuations in light scattering due to
Brownian motion of the particles) using a Zetasizer able to measure sizes
between 10 and 5000 nm.

6. REFRACTIVE INDEX AND PERCENT TRANSMITTANCE :-
Refractive index and percent transmittance prove the transparency of
formulation. The refractive index of the system is measured by refractometer by
putting a drop of solution on slide and comparing it with water (1.333).
The percent transmittance of the system is measured at particular wavelength
using UV spectrophotometer by using distilled water as blank.
If refractive index of system is similar to the refractive index of water (1.333)
and formulation have percent transmittance > 99 percent, then formulation have
transparent nature.

7.ELECTRO CONDUCTIVITY STUDY :-
The SMEDD system contains ionic or non-ionic surfactant, oil, and water.
This test is performed for measurement of the electro conductive nature of
system.
The electro conductivity of resultant system is measured by electro
conductometer.
In conventional SEDDSs, the charge on an oil droplet is negative due to
presence of free fatty acids.


8. IN VITRO DIFFUSION STUDY:-
In vitro diffusion studies are carried out to study the drug release behavior of

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formulation from liquid crystalline phase around the droplet using dialysis
technique.

9.DRUG CONTENT:-
Drug from pre-weighed SMEDDS is extracted by dissolving in suitable solvent.
Drug content in the solvent extract was analyzed by suitable analytical method
against the standard solvent solution of drug.
APPLICATION
SUPERSATURABLE SMEDDS (S -SMEDDS):
The high surfactant level typically present in SMEDDS formulation can lead to
GI side effects and a new class of supersaturable formulations including
supersaturable SMEDDS. (S-SMEDDS) formulations have been designed and
developed to reduce the surfactant side effects and achieve rapid absorption of
poorly soluble drugs
SOLID SMEDDS: SMEDDS are normally prepared as liquid dosage forms that
can be administrated in soft gelatincapsules, which have some disadvantages
especially in the manufacturing process. An alternative method is the
incorporation of liquid self emulsifying ingredients into a powder in order to
create a solid dosage form (tablets,capsules). A pellet formulation of
progesterone in SMEDDS has been prepared by the process of extrusion /
spheronization to provide a good in vitro drug release (100% within 30 min,
T50% at 13 min). The same dose of progesterone (16 mg) in pellets and in the
SEDDS liquid formulation resulted in similar AUC, C max and T max values2


PREPARED BY
SAYED SHAKIL AHMED
M.PHARM (1
ST
SEMESTER)
P.G DEPT. OF PHARMACEUTICS
S C S COLLEGE OF PHARMACY
UNDER THE GUIDANCE
Dr. SHANKRAYYA M
M.Pharm, Ph.D