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Department of Pharmacy Noakhali Science and Technology University Sonapur,Noakhali 3814,Bangladesh

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Formulation and Evaluation of Self-emulsifying drug delivey system of Aceclofenac

Department of Pharmacy Noakhali Science and Technology University Sonapur,Noakhali 3814,Bangladesh

Presented byASIFUL ALAM

Roll-ASH0903017MSession: 2008-2009

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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

CONCLUSION3

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

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Research design

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Bio-pharmaceutical classification system

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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

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

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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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COMPOSITION OF SEDDS

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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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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.

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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 EL13

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 tensionlesser free energystable emulsion

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METERIALS

Aceclofenac

Peppermint oil

Capmul PG8

Tween 80

Cremphore EL

Microcrystalline Cellulose (MCC PH101)

Capsule shell

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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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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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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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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.19

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

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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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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• 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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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 0C 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

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 phosphate buffer 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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In-Vitro Drug Release Studies

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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.

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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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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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RECENT APPROACHES IN SEDDS

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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

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.

Thanking you

Have a good day……………….

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