SELF-EMULSIFYING DRUG DELIVERY SYSTEM(SEDDS)

Presented by:Varun M Girme

(Pharmaceutics semII)

Sinhgad Technical Education Society,

SINHGAD INSTITUTE OF PHARMACY, NARHE, PUNE.

4/15/2015 1SEDDS

NEED FOR NEW APPROACH

WHAT IS SEDDS?

ADVANTAGES OF SEDDS

DISADVANTAGES OF SEDDS

COMPOSITION OF SEDDS

MECHANISM OF SELF EMULSIFICATION

PREPARATION OF SEEDDS

DOSAGE FORMS

4/15/2015 2SEDDS

EVALUATION

APPLICATIONS

KEY REFERENCES

4/15/2015 3SEDDS

NEED FOR NEW APPROACH:-

Oral route is the easiest and most convenient route for non

invasive administration.

Approximately 40% of new chemical drug moieties have poor

aqueous solubility and it is a major challenge to modern drug

delivery system.

To overcome these problems, various formulations strategies

are exploited including the use of surfactant, lipid permeation

enhancers, micronisation, salt formation, cyclodextrins,

nanoparticles and solid dispersions.

4/15/2015 4SEDDS

Combination SURFACTANT

CO-

SURFACTANT

DRUG

OILS

Defined as isotropic mixtures of natural or synthetic oils, solid

or liquid surfactants and co-solvents/surfactants.

SEDDSs emulsify spontaneously to produce fine oil in- water

emulsions when introduced into an aqueous phase under gentle

agitation and spread readily in the gastro intestinal tract.

4/15/2015 5SEDDS

xxxxx

SEDDSs typically produce emulsions with a droplet size

between 100–300 nm while self-micro-emulsifying drug

delivery systems (SMEDDSs) form transparent micro

emulsions with a droplet size of less than 50 nm

40% of New Drug Candidates show poor aqueous solubility

and thus poor bioavailability.

4/15/2015 6SEDDS

ADVANTAGES:-

Quick Onset of Action.

Reduction in the Drug Dose.

Ease of Manufacture & Scale-up.

Improvement in oral bioavailability.

Inter-subject and Intra-subject variability and food effects.

No influence of lipid digestion process.

Increased drug loading capacity.

4/15/2015 7SEDDS

DISADVANTAGES:-

Lack of good in vitro models for assessment of the

formulations for SEDDS.

The traditional dissolution methods does not work, because

these formulations potentially are dependent on digestion prior

to release of the drug.

4/15/2015 8SEDDS

COMPOSITION OF SEDDS:-

1.DRUG

The drugs with poor aqueous solubility and high permeability

are classified as class II drug by Biopharmaceutical classification

system (BCS). These drugs are use to formulate SEDDS.

Class IV

Low Solubility

Low

Permeability

Class I

High Solubility

High

Permeability

Class III

High Solubility

Low

Permeability

Class II

Low Solubility

High

Permeability

P

e

r

m

e

a

b

i

l

i

t

y Solubility4/15/2015 9SEDDS

2. OIL

Oils are the most important excipient.

Help in solubilizing the lipophilic drug in a high amount.

Facilitate self-emulsification and increase the fraction of

lipophilic drug transported.

Increase absorption from the GI tract.

Both long-chain triglyceride and medium-chain triglyceride oils

with different degrees of saturation have been used for the

formulation of SEDDSs.

4/15/2015 10SEDDS

Excipient name

(commercial name)

Examples of commercial products

in which it has been used

Corn oil Sandimmune soft gelatin capsule,

Depakene capsule

Olive oil Sandimmune oral solution

Oleic acid Ritonavir soft gelatin capsule,

Norvir soft gelatin capsule

Sesame oil Marinol soft gelatin capsule

Hydrogenated soybean

oil

Accutane soft gelatin capsule,

Vesanoid soft gelatin capsule

DL-α-Tocopherol Neoral oral solution, Fortovase soft

gelatin capsule

Beeswax Vesanoid soft gelatin capsule

Peanut oil Prometrium soft gelatin capsule4/15/2015 11SEDDS

3. SURFACTANTS:-

Natural surfactants have limited ability to emulsify.

Non ionic surfactants are less toxic when compared to ionic

surfactants.

The usual surfactant strength ranges between 30–60% w/w of

the formulation in order to form a stable SEDDS.

Non-ionic surfactants with high hydrophilic–lipophilic balance

(HLB) values are used in formulation of SEDDS.

Surfactants are amphiphilic in nature and they can dissolve or

solubilize relatively high amounts of hydrophobic drug

compounds

4/15/2015 12SEDDS

Excipient name

( commercial name)

Examples of commercial

products in which it has been

used

Polysorbate 20 (Tween 20) Targretin soft gelatin capsule

Polysorbate 80 (Tween 80) Gengraf hard gelatin capsule

Sorbitan monooleate (Span

80)

Gengraf hard gelatin capsule

Polyoxyl-35-castor oil

(Cremophor EL)

Gengraf hard gelatin capsule,

Ritonavir soft gelatin capsule

Polyoxyethylated glycerides

(Labrafil M 2125Cs)

Sandimmune soft gelatin

capsules

D-α-Tocopheryl polyethylene

glycol 1000 succinate (TPGS)

Agenerase soft gelatin capsule,

Agenerase

oral solution

4/15/2015 13SEDDS

4. COSOLVENTS/ COSURFACTANTS-

Cosolvents may help to dissolve large amounts of hydrophilic

surfactants or the hydrophobic drug in the lipid base.

These solvents sometimes play the role as co-surfactant in the

microemulsion systems.

Alcohol is not included in SEDDS/SMEDDS due to it’s

migration.

Drug release is increased with increasing concentration of

cosurfactant in formulation.

4/15/2015 14SEDDS

Excipient name

( commercial name)

Examples of commercial

products in which it has been

used

Ethanol Neoral soft gelatin capsule, Neoral

oral solution, Gengraf hard gelatin

capsule, Sandimmune soft gelatin

capsule.

Glycerin Neoral soft gelatin capsule,

Sandimmune soft gelatin capsule

Propylene glycol Neoral soft gelatin capsule, Neoral

oral solution, Lamprene soft

gelatin capsule.

Polyethylene glycol Targretin soft gelatin capsule,

Gengraf hard gelatin capsule,

Agenerase soft gelatin capsule.

4/15/2015 15SEDDS

TERNARY PHASE DIAGRAM

Pseudo ternary phase diagram is used to map the for three

key excipients according to the resulting droplet size

following self emulsification, stability upon dilution and

viscosity.

A Titration method is employed to construct phase diagram.

Mixture of oil with surfactant is prepared at different ratios

(e.g. 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0:10) into

different vials.

A small amount of water in 5 % (w /w) increments is added

into the vials.

Following each water addition the mixture in vials is

centrifuged for 2 to 3 minute and is incubated at 25 C or 48

hrs with gentle shaking.

4/15/2015 16SEDDS

CONSTRUCTION OF PHASE DIAGRAM

•The resulting mixture is evaluated by visual and microscopy

observation. For phase diagram the micro emulsion is the

region of clear and isotropic solution.

•Coarse emulsion is the region of cloudy dispersion.

4/15/2015 17SEDDS

MECHANISM OF SELF EMULSIFICATION-

Self-emulsification takes place when the entropy change

favouring dispersion is greater than the energy required to

increase the surface area of the dispersion.

The free energy of a conventional emulsion formulation is a

direct function of the energy required to create a new surface

between the oil and water phases.

The two phases of the emulsion tend to separate with time to

reduce the interfacial area and thus the free energy of the

systems.

Free energy in the micro-emulsion formation is directly

proportional to the energy required to create new surface

between the two phases, and is given by the equation-

4/15/201518

SEDDS

Where,

ΔG=Free energy associated with the process.

N=No. of droplets of radius r.

σ=Represents interfacial energy.

4/15/2015 19SEDDS

PREPARATION OF SEDDS:-

A) SOLIDIFICATION TECHNIQUES FOR TRANSFORMING

LIQUID/SEMISOLID:

Capsule filling with liquid and semisolid self-

emulsifying formulations:

Capsule filling is the simplest and the most common technology

for the encapsulation of liquid or semisolid SE formulations for

the oral route.

four-step process:

A)Heating of the semisolid excipient to at least 20˚C above its

melting point.

B) Incorporation of the active substances (with stirring). 4/15/2015

20SEDDS

C) Capsule filling with the molt cooling to room temperature.

For liquid formulations, it involves a two-step process.

D) Filling of the formulation into the capsules followed by

sealing of the body and cap of the capsule, either by banding or

by micro spray sealing.

B) SPRAY DRYING: -

Technique involves the preparation of a formulation by mixing

lipids, surfactants, drug, solid carriers, and solubilization of the

mixture before spray drying.

The solubilized liquid formulation is then atomized into a spray

of droplets.

4/15/2015 21SEDDS

The droplets are introduced into a drying chamber, where the

volatile phase (e.g. the water contained in an emulsion)

evaporates, forming dry particles under controlled temperature

and airflow conditions.

4/15/2015 22SEDDS

C) MELT GRANULATION

Melt granulation is a process in which powder agglomeration

is obtained through the addition of a binder that melts or

softens at relatively low temperatures.

D) MELT EXTRUSION SPHERONIZATION

Melt extrusion is a solvent-free process that allows high drug

loading (60%), as well as content uniformity.

Extrusion is a procedure of product of uniform shape and

density, by forcing it through a die under controlled

temperature, product flow, and pressure conditions.

4/15/2015 23SEDDS

(1)ORAL DELIVERY

(A) SELF EMULSIFYING CAPSULE

Poor water soluble drugs can be dissolved in SEDDS and

encapsulated in hard or soft gelatin capsules to produce

convenient single unit dosage forms.

Administration of capsules containing conventional liquid SE

formulations, micro emulsion droplets form and subsequently

disperse in the GI tract to reach sites of absorption.

If irreversible phase separation of microemulsion occurs an

improvement of drugs absorption can’t be expected.

For handling this problem, sodium dodecyl sulfate was added

into the SE formulation.

DOSAGE FORMS OF SEDDS:-

4/15/201524SEDDS

(B) SELF--EMULSIFYING SUSTAINED /

CONTROLLED RELEASE: Combination of lipids and surfactant has presented great

potential preparing SE tablets.

SE tablets are of great utility in obviating adverse effect.

Inclusion of indomethacin (or other hydrophobic NSAID)

for example, into SE tablets may increase its penetration

efficacy through GI mucosal membrane, potentially reducing

GI bleeding

(C) SELF EMULSIFYING SUSTAINED /

CONTROLLED RELEASE PELLETS:

Pellets, as a multiple unit dosage form, possess many advantages

over conventional solid dosage form, such as 4/15/2015 25SEDDS

Flexibility of manufacture, reducing intra subject and inter

subject variability of plasma profile and minimizing GI

irritation without lowering drug bioavailability.

(D) SELF EMULSIFYING SOLID DISPERSIONS:

Solid dispersions could increase the dissolution rate and

bioavailability of poorly water soluble drugs but still some

manufacturing difficulties and stability problems existed.

(2) TOPICAL DELIVERY:

Topical administration of drugs can have advantages over other

methods for several reasons, one of which is the avoidance of

hepatic first pass metabolism of the drugs and related toxicity

effects. 4/15/2015

26SEDDS

(3) OCULARS AND PULMONARY DELIVERY:

For the treatment of eye disease, drugs are essentially delivered

topically o/w microemulsion have been investigated for ocular

administration, to dissolve poorly soluble drugs, to increase

absorption and to attain prolong release profile.

(4) PARENTERAL DELIVERY:

Parenteral administration of drugs with limited solubility is a

major problem in industry because of the extremely low

amount of drug actually delivered as target site.

4/15/2015 27SEDDS

EVALUATION OF SEEDS:-

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 studies4/15/2015 28SEDDS

THERMODYNAMIC STABILITY STUDIES

Heating cooling cycle

•Six cycles between refrigerator temperature 4⁰C and 45⁰Cwith storage at each temperature of not less than 48 h is

studied.

•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 30 min.

•Those formulations that does not show any phase separation are

taken for the freeze thaw stress test.4/15/2015 29SEDDS

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.

4/15/2015 30SEDDS

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.4/15/2015 31

SEDDS

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 2 min).

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 SEDDS formulation.

4/15/2015 32SEDDS

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.

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)

4/15/2015 33SEDDS

VISCOSITY DETERMINATION:-

oThe SEDDS 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.

oThe rheological properties of the micro emulsion are evaluated

by Brookfield viscometer.

oThe viscosities determination conform whether the system is

w/o or o/w.

oIf 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

4/15/2015 34SEDDS

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.

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).4/15/2015

35SEDDS

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.

ELECTRO CONDUCTIVITY STUDY:-

The SEDD system contains ionic or non-ionic surfactant, oil,

and water.

This test is performed for measurement of the electro

conductive nature of system.

4/15/2015 36SEDDS

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.

IN VITRO DIFFUSION STUDY:-

In vitro diffusion studies are carried out to study the drug release

behavior of formulation from liquid crystalline phase around the

droplet using dialysis technique.

DRUG CONTENT:-

Drug from pre-weighed SEDDS 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.4/15/2015

37SEDDS

APPLICATION

Improvement in Solubility and bioavailability:

Protection against Biodegradation:

Controlling the release of

drug:

4/15/2015 38SEDDS

KEY REFERENCES

Nigade P.M., Patil S. I., Tiwari S.S. (2012). “Self

Emulsifying Drug Delivery System (SEDDS)”: A Review.

IJPBS. 2(2), 42-52.

Sarpal K., Pawar Y. B., and . Bansal A.K .(2010)”Self

Emulsifying Drug Delivery System (SEDDS) A Strategy To

Improve Oral Bioavailability”, (CRIPS). 11(3), 42-49.

Mistry R .B., Sheth N .S.,(2011) A review: “Self Emulsifying

Drug Delivery System”. IJPPS. 3(2), 23-28

4/15/2015 39SEDDS

Mahapatra A K., Murthy P N., Swadeep B, Swain R P.(2014).

”Self-Emulsifying Drug Delivery Systems (SEDDS): An

Update from Formulation Development to Therapeutic

Strategies”. IJPTR 6(2), 546-568

Taksande J. B., Trivedi R., Mahore J. G., Wadher K J.(2011)

“Self-Emulsifying Drug Delivery System: Hitherto and Resent

advances”. IJRAP 2011, 2(4) 1087-1095

4/15/2015 40SEDDS

4/15/2015 SEDDS 41

4/15/2015 42SEDDS