Formulation and Evaluation of Self-emulsifying Drug Delivery System of Aceclofenac use:Improve Aceclofenac delivery to body

1. WELCOME
TO MY
PRESENTATION
Department of Pharmacy
Noakhali Science and Technology University
Sonapur,Noakhali 3814,Bangladesh
1

2. Formulation and Evaluation of Self-
emulsifying drug delivey system of
Aceclofenac
Department of Pharmacy
Noakhali Science and Technology University
Sonapur,Noakhali 3814,Bangladesh
Presented by
ASIFUL ALAM
Roll-ASH0903017M
Session: 2008-2009
2

3. CONTENT
AIM AND OBJECTIVE
RESEARCH DESIGN
INTRODUCTION
ADVANTAGES AND DRAWBACKS OF SEDDS
COMPOSITION OF SEDDS
MECHANISM OF SEDDS
MATERIALS OF SEDDS
FORMULATION AND PREPARATION SEDDS
In-VITRO EVALUATION OF SEDDS
CONCLUSION
3

4. AIM AND OBJECTIVE
Most of the new drug candidates in
development today are sparingly soluble and
associated with poor bioavailability
The main purpose is to prepare SMEDDS for
oral bioavailability enhancement of a poorly water
soluble drug
4

5. Research design
5

6. Bio-pharmaceutical classification system
6

7. INTRODUCTION
SEDDS or self-emulsifying oil formulations (SEOF) are defined as Isotropic
mixtures of natural or synthetic oils, solid or liquid surfactants or, alternatively, one
or more hydrophilic solvents and co-solvents/ surfactants.
SEDDS typically produce 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 concept of SEDDS for pharmaceutical purpose was initially developed by
the Group of Groves (Dunkan QM et al., 2000, Fernando- Warnkulasuriya GLP
et al., 1981). 7

8. Protection of sensitive drug substances
More consistent drug absorption,
Selective targeting of drugs toward specific absorption window in GIT
Protection of drug(s) from the gut environment.
Control of delivery profile
Reduced variability including food effects
Enhanced oral bioavailability enabling reduction in dose
High drug loading efficiency.
ADVANTAGES OF SEDDS
8

9. For both liquid and solid dosage forms.
These dosage forms reduce the gastric irritation produced by drugs.
Emulsion are sensitive and metastable dispersed forms while S(M)EDDS are
physically stable formulation that are easy to manufacture.
As compared with oily solutions, they provide a large interfacial area for partitioning of
the drug between oil and water.
DRAWBACK OF SEDDS:
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.
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10. COMPOSITION OF SEDDS
10

11. OILS:
Oils are the most important excipient because oils can solubilize the lipophilic
drug in a specific amount.
Both long-chain triglyceride and medium-chain triglyceride oils with
different degrees of saturation have been used for the formulation of SEDDSs.
Unmodified edible oils have poor ability to dissolve large amount of hydrophilic
drugs.
Modified or hydrolyzed vegetable or edible oils have contributed widely to the
success of SEDDSs owing to their formulation and physiological advantages.
Corn oil, Olive oil, Oleic acid, Peppermint oil, Hydrogenated soya bean oil,
Hydrogenated vegetable oils,Soyabean oil, Peanut oil, Beeswax
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12. Surfactant
• 1: Anionic Surfactants, where the hydrophilic group carries a negative charge such
as carboxyl (RCOO-), sulphonate (RSO3 -) or sulphate (ROSO3 -).
Examples: Potassium laurate, SLS
• 2: Cationic surfactants, where the hydrophilic group carries a positive charge.
Example: quaternary ammonium halide.
• 3: Ampholytic surfactants (also called zwitterionic surfactants)
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), Polysorbate (Tween).
o Nonionic surfactants with high Hydrophilic Lipophilic Balance (HLB) values
are used in formulation of SEDDS (e.g., Tween, Labrasol, Labrafac CM 10,
Cremophore, etc.).
o The usual surfactant strength ranges between 30–60% w/w of the
formulation in order to form a stable SEDDS.
12

13. 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
Drug release is increased with increasing concentration of cosurfactant in
formulation.
Examples of cosolvents:
Ethanol
Propylene glycol
Polyethylene glycol
Cremphore EL
13

14. Mechanism
• The process by which self-emulsification takes place is not yet well
understood.
• But ,According to ‘Reiss’ self emulsification occurs when the
entropy change that favors dispersion is greater than the energy
required to increase the surface area of the dispersion.
• The free energy of the conventional emulsion is a direct function of
the energy required to create a new surface between the oil and
water phases and can be described by the equation:
ΔG = Σ N π r2
σ
• Where,
• ΔG is the free energy associated with the process (ignoring the free
energy of mixing), N is the number of droplets of radius r and σ
represents the interfacial energy.
• In the case of self-emulsifying systems, the free energy required to
form the emulsion is either very low and positive or negative (then,
the emulsification process occurs spontaneously).
• Lesser interfacial tension→lesser free energy →stable emulsion
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15. METERIALS
Aceclofenac
Peppermint oil
Capmul PG8
Tween 80
Cremphore EL
Microcrystalline Cellulose (MCC PH101)
Capsule shell
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16. FORMULATION OF SEDDS
Ingredient Amount(mg) Amount (mg) Amount (mg) Amount (mg)
F1 F2 F3 F4
Aceclofenac 100 100 100 100
Peppermint oil 50 50 50
Capmul PG8 50
Tween 80 150 50 50 100
Cremphore EL 100 100 50
Microcrystalline
Cellulose
300 300 300 300
Total 600 600 600 600
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17. PREPARATION OF SEDDS
Accurately weighed amount of drug was placed in a glass vial, and oil,
surfactant and cosurfactant were added.
Then the components were mixed by gentle stirring and vortex mixing for 30
min.
This mixture were heated at 40ºC on a magnetic stirrer, until drug was perfectly
dissolved.
The mixture was stored at room temperature until further use.
Finally filled using a Hand operated capsule machine having A bed with 200-
300 holes, a capsule loading tray, a powder tray ..
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18. IN VITRO EVALUATION OF SEDDS
Appearence
Weight Uniformity
Drug Content
Micromeritic Properties
Thermodynamic stability Studies
Dispersibility test
Ph Determination
In-vitro Release studies(zero order, first order, higuichi model, hixson-crowel
plot, Krosmeyer-peppas kinetics )
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19. 1. Apperance:
The filled capsules showed no signs of leakage, discoloration,
pinholes and shell distortion. Aceclofenac loaded SEDDS appeared
as clear homogenous at room temperature. No traces of particulate
matter nor drug precipitation were observed.
2. Weight Unifomity:
None of the capsules were found to deviate from the average
capsule by more than 7.5 % and were found to comply with
I.P’96 standards for uniformity of weight for capsules
3. Drug Content:
The drug content of various self-microemulsifying formulations
was found to be within the range of 99-101% which was in
agreement with pharmacopoeial specifications.
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Capsule Weight
Variation
(%)
F-1 1.50±0.02
F-2 2.26±0.01
F-3 2.18±0.03
F-4 1.68±0.04
Capsul
e
Drug Content
(%)
F-1 99.28±0.07
F-2 99.34±0.09
F-3 98.17±0.06
F-4 97.19±0.07

20. 4.Micromeritic Properties
• The self emulsifying powders were evaluated for bulk density (BD), tapped
density (TD), compressibility (Carr’s) index and angle of repose. The bulk
density of different formulations Batch 1, 2, 3 and 4 were found to be in the
range of 0.21 to 0.57 and tapped density from 0.37 to 0.71 respectively. The
compressibility index (29.99%) indicated poor flowability of aceclofenac. Angle
of repose was determined for the measurement of flowability. The
formulations 1, 2 and 4 showed improved flowability in the form of powder.
This was further supported by the value of Hausner’s ratio (<1.25).The
improved flowability of self emulsifying powders may be due to good
sphericity and small size of granules.
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21. 5.Thermodynamic stability studies:
 The poor physical stability of the formulation can lead to phase separation of
the excipient, which affects not only formulation performance, as well as visual
appearance of formulation.
 Incompatibilities between the formulation and the gelatin capsules shell can
lead to brittleness or deformation, delayed disintegration, or incomplete release
of drug.
 For thermodynamic stability studies we have performed three main steps, they
are-
Heating cooling cycle
Centrifugation
Freez thaw cycle
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22. • All the formulations were found to remain stable after centrifugation and
freeze-thaw cycle process and no phase separation or drug precipitation was
observed. Particle size and polydispersity remained unaffected after freeze-
thaw process, thus confirming the stability of developed microemulsions..
self-microemulsification efficiency:
Formulations were found to release the contents immediately upon rupturing
and self-emulsify within a minute.
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23. 6.Dispersibility test :
The efficiency of self-emulsification of oral nano or micro emulsion is assessed by using a
standard USP XXII dissolution apparatus 2 for dispersibility test. One millilitre of each
formulation was added in 500 mL of water at 37 ± 1 0
C at 50 rpm. It passes the test
 If it is rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance.
Or
 If it is rapidly forming, slightly less clear emulsion, having a bluish white appearance. Or
 If it is fine milky emulsion that formed within 2 min.
7.Ph DETERMINATION
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ACF incorporation into SEDDS lowered the pH of the systems towards acidic
side; this change may be attributed to the acidic nature of the drug. After the
dilutions of the preconcentrates with distilled water, the pH values were found
to increase. This may be probably due to encapsulation of major quantity of
drug into microemulsion and so decrease in acidic nature of the systems

24. In-Vitro Drug Release Studies
Dissolution Study Procedure
a) The in vitro dissolution studies were performed using USP type-IΙ dissolution
apparatus (Rotating Peddle method) at 100 rpm.
b) The dissolution medium consisted of potassium di-hydrogen phosphatebuffer of pH 7.4 up
to 900 mL, maintained at 37°C ± 0.5°C.
c) An aliquot (5 mL) was withdrawn at specific time intervals which replaced by equivalent
amount of buffer solution.
d) The drug content was determined by UV-visible spectrophotometer (SHIMADZU UV-
1800 spectrophotometer) at 276 nm.
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25. In-Vitro Drug Release Studies
25
To know the mechanism of drug release from these formulations, the data were treated
according to:
1. Zero order (cumulative amount of drug released vs time),
2. First-order (log cumulative percentage of drug remaining vs time),
3. Higuchi’s (cumulative percentage of drug released vs square root of time),
4. Korsmeyer et al.’s (log cumulative percentage of drug released vs log time) and
5. Hixson-Crowell (cubic root of percent drug release vs time) pattern for kinetics of drug
release during dissolution process.

26. 26

27. Code Zero order
regression coefficient
(r2
)
First order
regression coefficient
(r2
)
Higuchi equation
regression coefficient
(r2
)
Korsmeyer’
s
regression coefficient
(r2
)
Hixon-Crowell
regression coefficient
(r2
)
F-1 0.919 0.922 0.919 0.861 0.884
F-2 0.902 0.905 0.902 0.882 0.889
F-3 0.902 0.967 0.902 0.825 0.861
F-4 0.917 0.930 0.917 0.922 0.910
Release kinetics parameters of designed Self-emulsifying Aceclofenac Capsule:
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28. The dissolution data (from the values of 0 to 2 hours to know which drug
release) of all formulations were fitted into various mathematical models (zero-
order, first-order, Higuchi, , Hixon-Crowell plot, Korysmeyer-Pappas model) to
know which mathematical model will best fit for the drug release profile.
From release kinetics parameters we can say that the highest regression
coefficient value (r2
) the best-fit model for all formulations was Higuchi model. It
is clearly indicated that, the formulations did not follow a zero-order release
pattern because the regression value for all formulations did not show high
linearity.
When the data were plotted according to the first-order equation, the tablets
showed a first order release, with regression value of (F1 to F4) 0.912, 0.905,
0.967, 0.930.
The formulations showed to be best expressed by Higuchi’s equation, as the
plots showed high linearity with regression value of (F1 to F4) 0.919, 0.902,
0.902, 0.917 , indicating that the release of drug follows the Higuchi release
kinetics and diffusion is the dominating mechanism for drug release.
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29. 29
RECENT APPROACHES IN SEDDS

30. 30
Drug Name Compound Dosage form Company Indication
Neoral® Cyclosporine A/I Soft gelatin capsule Novartis Immune suppressant
Norvir® Ritonavir Sof tgelatin capsule
Abbott
Laboratories HIV antiviral
Fortovase® Saquinavir Soft gelatin capsule
Hoffmann-La
Roche inc. HIV antiviral
Agenerase® Amprenavir Soft gelatin capsule Glaxo Smithkline HIV antiviral
Convulex® Valproic acid Soft gelatin capsule Pharmacia Antiepileptic
Lipirex® Fenofibrate Hard gelatin capsule Genus
Antihyper-
lipoproteinemic
Sandimmune® Cyclosporine A/II Soft gelatin capsule Novartis Immuno suppressant
Targretin® Bexarotene Soft gelatin capsule Ligand Antineoplastic
Rocaltrol® Calcitriol Soft gelatin capsule Roche Calcium regulator
Gengraf® Cyclosporine A/III Hard gelatin capsule Abbott Laboratories Immuno suppr
MARKETED PRODUCTS OF SEEDS

31. CONCLUSIONCONCLUSION
• SEDDSs are a promising approach for the formulation of liphophilic drugs and to
improve the oral bioavailability of drugs with poor aqueous solubility.
• The current study demonstrated a successful and simple method to prepare self
emulsifying aceclofenac Capsule, where Capsule produced emulsion with uniform
drug content to enhance its aqueous solubility and dissolution rate. The prepared SE
Capsule showed a significant improvement in in-vitro and in comparison with pure
drug. The developed SEDDS were found to exhibit good release activity . This
potential technique has ability to develop stable dosage forms which can be scaled up
• It appears that more drug products will be formulated as SEDDS in the very near
future and these aspects are the major areas for future research into S-SEDDS.

32. Thanking
you
Have a good
day………………. 32