Self micro-emulsifying drug delivery system (SMEDDS)

SELF-MICROEMULSIFYING
DRUG DELIVERY SYSTEM
(SMEDDS)
Presented by: Guided by:
Himal Barakoti Ananta Choudhury
M. Pharm, 1st Sem Associate Professor
Department of Pharmacy Department of Pharmacy
Assam Down Town University Assam Down Town University

Contents
 Background
 Introduction
 Mechanism of action
 Improvement of oral absorption by SMEEDS
 Formulations
 Stability testing
 Advantages/ Disadvantages
 Applications
 References
Department of Pharmacy, Assam Down Town University

Background
 Concept introduced by Hoar and Schulman in 1940’s who generated a clear
single phase solution by titrating a milky emulsion with hexanol.
 Alternative names for these systems are often used, such as transparent
emulsion, swollen micelle, micellar solution, and solubilized oil.
 Schulman and co-worker in 1959 subsequently coined the term microemulsion.

Comparison between Emulsion & microemulsion
Emulsion Microemulsion
1. Emulsion consists of roughly spherical
droplets of one phase dispersed to other.
1. They constantly evolve between
various structures ranging from droplet
to bi-continuous structure.
2. They are non transparent as the
particle/droplet size varies from 1-20mm.
2. They are transparent as the
particle/droplet size is only 10-100nm.
3. Formulation requires shaking. 3. It’s a constant formulation.
4. They are thermodynamically unstable. 4. They are thermodynamically stable.
5. They are viscous formulation. 5. They can accommodate 20-40%
without increase in viscosity.
6. They are lyophobic. 6.They are on the borderline between
lyophobic and lyophilic colloids.

Comparison between SEDDS and SMEDDS
SEDDS SMEDDS
1. It is the mixture of oil, surfactant and
drug.
1. It is a mixture of oil, surfactant, co-
surfactant and drug.
2. Droplet size is 100-300 nm. 2. Droplet size is less than 100 nm.
3. It is turbid in nature. 3. It is transparent in nature.
4. It is thermodynamically not stable. 4. It is thermodynamically stable.
5. Ternary phase diagram are used in
optimization.
5. Pseudo Ternary Phase diagram are
used for optimization.

Introduction
 Microemulsions are an isotropic mixture of natural or synthetic oils, solid or liquid
surfactants, co-surfactant and drugs.
 Upon mild agitation followed by dilution in aqueous media, such as gastrointestinal
(GI) fluids, the system can form fine oil in water (O/W) microemulsions which
usually have droplet size less than 100 nm.
 Micro emulsion have been successively used to improve the solubility, chemical
stability and oral bioavailability of poorly water soluble drugs. ( class II & IV as per
BCS classification)

Schematic composition of SMEDDS

Mechanism of action:
 Self-emulsification takes place when the entropy change favoring the dispersion is
greater than the energy required to increase the surface area of the dispersion.
 The interface between the oil and aqueous phases is formed upon addition of a
binary mixture. This is followed by the solubilization of water within the oil phases
as a result of aqueous penetration through the interface.
 Following gentle agitation of the self-emulsifying system, water will rapidly
penetrate into the aqueous cores and lead to interface disruptions and droplet
formation.

Improvement of oral absorption by
SMEDDS
 The release of drug compound takes place upon its partitioning into the intestinal
fluids during droplet transport and disintegration along GI tract.
 Two main factors; small particle size and polarity of the resulting oil droplets
determine the efficient release of the drug compound from SMEDDS.
 Many studies carried out in animals for assessment of oral bioavailability of
hydrophobic drugs formulated in o/w emulsions indicated better absorption
profiles.

Studies
 A study carried out in non-fasting dogs for the assessment of the oral
bioavailability of a lipophilic naphthalene derivative formulated in SMEDDS
demonstrated 3-fold higher values in Cmax and AUC as compared to other
dosage form.
 In another study done on rats, the oral bioavailability of the anti-inflammatory
drug ontazolast was substantially improved when the lipophilic drug was
administered in a lipid based formulation SMEDDS in comparison to the
suspension formulation.
 A multiple dosage study was conducted on human diagnosed with HIV infection
who were given orally an HIV protease inhibitor either as a SMEDDS or as an
elixir. Greater AUC values in addition to higher Cmax and Cmin values were
reported for patients given the SMEDDS as compared to the one given elixir.

Formulations:
This isotropic systems are usually easier to formulate than ordinary
emulsion. The type of associated structure formed from these components at
particular temperature depends not only on the chemical nature of each component
but also on their relative concentration. SMEDDS formulation contains following 4
components:
1. Oil phase: Oils from natural sources and their derivatives. The extension of a
microemulsion region generally depends on the nature of oil. This is due to the
differences in oil penetration onto the surfactant layer.
Examples: castor oil, sunflower oil, seseam oil, hydrogenated specialty
oils

2. Surfactant: Compounds that lower the surface tension (or interfacial tension)
between two liquids or between a liquid and a solid. Surfactants used to stabilize
microemulsion system may be: non-oinic, zwitterionic, cationic and anionic
surfactants. Ionic and non-ionic are effective at increasing the extent of
microemulsion region.
Fig: Surfactant classification according to the composition of their head:
nonionic, anionic, cationic, amphoteric.

Microemulsion formulations can be administered as a form of water-in-oil
microemulsion of surfactant-oil mixture, and are expected to convert to oil-in-
water microemulsion in small intestine.
Examples: Polyoxethylene (20) sorbitan monooleate (Tween 80)
Polyoxyethylene glyceryl trioleate (Tagat TO)
Propylene glycol monocaprylate (Capryol 90)
3. Co-surfactant: Under certain condition, a combination of oil, water and
surfactant will result in a phase where there are orderly planes of oil and water
separated by monolayer of surfactant. Co-surfactants are added to further lower
the interfacial tension between the oil and water phase, to fluidize the
hydrocarbon region of interfacial-film, and to influence the film curvature.
Examples: short chained alcohol (ethanol, propanol, butanol)
Glycols (propylene glycols)

4. Co-solvents: The production of an optimum SMEDDS require relatively high
concentrations (generally more then 30% w/w) of surfactants. Organic solvents
like ethanol, propylene glycol (PG), polyethylene glycol (PEG) are suitable for oral
delivery.
They enable dissolution of large quantities of either the hydrophilic
surfactant or the drug in lipid base.
Alcohol-free formulations have been designed but their lipophilic
drug dissolution ability is limited.

Stability testing
 Temperature stability: SMEEDS is diluted with purified distilled water and to check
the temperature stability, they were kept at 3 different temperature range (4ºC,
25ºC,40ºC) and evidence of any phase separation, flocculation or precipitation is
observed.
 Centrifugation: SMEDDS formulation was diluted with purified distilled water and
was centrifuged at 1000 rpm for 15 min at 0ºC and observed for any change in
homogeneity.
 In vitro release: SMEDDS was placed in dialysis bag during release period to
compare the release pattern with conventional tablet. 10ml of sample solution was
withdrawn at predetermined time intervals, filtered through 0.45 micrometer
membrane filter, dilute suitably and analyzed spectrophotometrically.
Percentage drug dissolved at different time intervals was calculated using
Beer Lambert’s equation.

Advantages
 Enhanced oral bioavailability and AUC enabling reduction in dose
 More consistent temporal profile of drug absorption
 Selective drug targeting towards specific absorption window in GIT
 Protection of sensitive drug from hostile environment in gut
 Fine oil droplets empty rapidly from the stomach and promote wide distribution
of drug throughout the intestinal tract at short time period
 Ease of manufacture and scale up
 Potential to deliver peptides that are processed to enzymatic hydrolysis in GIT.
 Useful for both solid and liquid dosage form

Disadvantages
 Lack of good predicative in vitro models for assessment of the formulation
is the most important problem in the development of SMEEDS.
To mimic this, in-vitro model simulating the digestive processes of the
duodenum has been developed. This in-vitro model needs further development
and validation before the strength can be evaluated.
Further development will be based on in vitro, in vivo correlations and
therefore different prototype lipid based formulations need to be developed and
tested in vivo in a suitable animal model.

Marketed preparation:
BRANDS DRUG DOSAGE FORM DOSE (mg) INDICATION
Neoral® Cyclosporine Soft gelatin Capsules 25, 100 Immunosuppressant
Norvir® Ritonavir Soft gelatin Capsules 100 HIV antiviral
Lipire® Fenofibrate Hard gelatin Capsules 200 Lowering of TG level
Convule® Valproic acid Soft gelatin Capsules 100, 200 Antiepileptic

References
 Maulik J. Patel, Sanjay S. Patel, Natvarlal M. Patel, Mashabhai M. Patel, “A Self-
microemulsifying Drug Delivery System (SMEDDS).” International Journal of
Pharmaceutical Sciences Review and Research: 2010; 005; 29-35
 Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Handicap SR and Bhosale AV.
“Self Emulsifying Drug Delivery System: A Review” Research J. Pharm. And Tech.
2008; 1(4): 313-323
 https://www.slideshare.net/sagarsavale1/microemulsion-56481194
 http://www.chm.bris.ac.uk/eastoe/Surf_Chem/3%20Microemulsions.pdf

Thank you

Self micro-emulsifying drug delivery system (SMEDDS)

Self micro-emulsifying drug delivery system (SMEDDS)

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