Oral Liquids

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A SEMINAR ON

Recen t i nnovat i ons i n

ORAL LIQUIDS

Presented by:

Sachin Prajapati

Roll No. : 15M.Pharm Sem-II

PHARMACEUTICS

1NOOTAN PHARMACY COLLEGE,VISNAGAR

GUIDED BY :

DR. MANISH PATEL

MS. VIBHA CHAMPAVAT


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C o n t e n t s

Suspension as oral

Nano suspension

Micro suspension

Emulsion as oral

Micro emulsion

Nano emulsion

Multiple emulsion

Dry emulsion

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liquids D e f i n i t i on

This is a general term used to describe a solution, suspension or emulsion

in which the active ingredient is dissolved or dispersed in a suitableliquid vehicle.

A solution is a liquid-preparation that contains one or more soluble

chemical substances dissolved in a specified solvent.

A d van tage s

Immediately available for absorption.

Administration convenient, particularly for infants, psychotic patients.

Easy to color, flavor & sweeten.

Liquids are easier to swallow than solids and are therefore particularly

acceptable for pediatric patient. A solution is an homogeneous system and therefore the drug will be

uniformly distributed throughout the preparation.

Some drugs like aspirin, KCl can irritate gastric mucosa if used orally as a

solid dosage forms. But this effect can be reduce by solution system.

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Disadvantages

Bulky than tablets or capsule, so difficult to carry transport.

Less stable in aqueous system. Incompatibility is faster insolution than solid dosage form.

Patients have no accurate measuring device.

Accident breakage of container results in complete loss.

Solution often provide suitable media for the growth of

microorganisms.

The taste of a drug, which is often unpleasant, is always

more pronounced when in solution than in a solid form.

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Classif ication of l iquids

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LIQUID

Monophasic

Oraluse

Solution

Draught

Drops

Linctuses

Syrups

Elixirs

External use Parenteral Special use

Used inOral cavity

THROATPAINTS

GLYCERITES

MOUTHWASHES

THROATSPRAYS

Used in otherthan oral cavity

DOUCHES

ENEMAS

EYE DROPS

EYE LOTIONS

NASAL DROPS

INHALANTS

Biphasic

Liquid inliquid

Oral use

EMULSION

Externaluse

Liniments

Solids inliquid

Parenteral Oral

SUSPENSION

External

Lotion


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SUSPENSION AS ORAL

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Nano suspension

Micro suspension


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Suspension

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Mixture of two substances, one of which is finely divided anddispersed in the other. Suspensions:

S-S,L-S (OR S-L),

G-S Colloidal suspension 1 nm to 0.5 m Coarse suspension 1 to 100 m

A suspension of liquid droplets or fine solid particles in a gas is

called an aerosol.

Blood is an example of suspensions Suspensions are useful for administering insoluble or poorly

soluble drugs or in situations when the presence of a finely

divided for the material in the GI tract is required.


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The Difference Between Solution & Suspensions

When the 2 substances totally mix it is called a solution.

E.g. Solute + Solvent = Solution

(sugar) + (water) = Solution

Then, We can say sugar is soluble in water, it has dissolved.

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Contd

Suspensions

Sometimes when we mix substances they stay inclusters. We therefore say it is insoluble in water.

E.g. Chalk + Water = Suspension

Eventually the particles sink to the bottom to formsediment.

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More than 40% of drugs are poorly soluble in water, so they show problems in

formulating them in conventional dosage forms.

For class II drugs (e.g.-Itraconazole & carbamazepine), WHICH ARE

POORELY SOLUBLE IN AQUEOUS AND ORGANIC MEDIA, THE

PROBLEM IS MORE COMPLEX.

Various approaches to resolve problems of low solubility and low

bioavailability

- Micronization, co-solvancy, oily solution, salt formation- SOME OTHER TECHNIQUES ARE LIPOSOMES, EMULSIONS,

MICROEMULSION, SOLID DISPERSION, - CYCLODEXTRIN

INCLUSION COMPLEX etc.

Many of these techniques are not universally applicable to all drugs or are notapplicable to drugs which are not soluble in both aqueous & organic media.

A different but simple approach is needed to tackle the formulation problem

to improve their efficacy and to optimize the therapy with respect to

pharmacokinetics. 11


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A pharmaceutical nanosuspension is defined as very finely

dispersed solid drug particles in an aqueous or organic vehicle

for either oral and topical use or parenteral and pulmonaryadministration.

The particle size distribution of the solid particles in

nanosuspensions is usually less than one micron with an

average particle size ranging between 200 and 600 nm.

Nanosuspensions differ from nanoparticles.

Nanoparticles are commonly polymeric colloidal carriers of

drugs whereas solid lipid nanoparticles are lipidic carriers ofdrugs. In nanosuspension technology, the drug is maintained in

the required crystalline state with reduced particle size, leading

to an increased dissolution rate and therefore improved

bioavailability.12

Nanosuspension


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Nanosuspensionpreparation

Top down

Media Milling(Nanocrystals)

HPH in water

(Dissocubes)

HPH in nonaqueous media

(Nanopure)

Combination ofprecipitation andHPH (Nanoedge)

Bottom up

Precipitation

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Drugdissolved inthe solvent

Added tonon -solvent

Precipitation

Of

Crystals

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Main advantage is the use of simple and low cost equipments.

Basic challenge is that during the precipitation proceduregrowing of the crystals need to be controlled by addition of

surfactant to avoid formation of microparticles.

Limitation of this precipitation technique is that the drug

needs to be soluble in at least one solvent and the solvent

needs to be miscible with non-solvent.

Moreover,

It is not applicable to the drugs, which are poorly soluble in

both aqueous and non-aqueous media.

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The nanosuspensions are prepared by using high shear media

mills. The milling chamber charged with milling media,water,drug & stabilizer is rotated at very high shear rate under

controlled temp. for 2-7 days.

The major concern with this method is the residues of milling

media remaining in the finished product could be problematic foradministration.

Principle

The high energy and shear forces generated as a result of the

impaction of the milling media with the drug provide the energyinput to break the micro particulate drug into nano-sized

particles.

The milling medium is composed of glass, zirconium oxide or

highly cross-linked polystyrene resin. 17


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Coolant Large

drug

crystals

Charged

with

drug, water

and

stabilizer

Re-circulation

chamber

Milling chamber

Screen

retaining

milling media

in chamber

Milling

shaft

Nanocrystals

Milling media

Motor


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ADVANTAGES OF MEDIA MILLING

1. applicable to the drugs that are poorly soluble in both aqueous and

organic media.

2. Very dilute as well as highly concentrated nanosuspensions can be

prepared by handling 1mg/ml to 400mg/ml drug quantity.

DISADVANTAGES OF MEDIA MILLING

1. Nanosuspensions contaminated with materials eroded from balls

may be problematic when it is used for long therapy.2. The media milling technique is time consuming.

3. Some fractions of particles are in the micrometer range.

4. Scale up is not easy due to mill size and weight.

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The instrument can be operated at pressure varying from 100

1500 bars (2800 21300psi) and up to 2000 bars with

volume capacity of 40ml (for laboratory scale).

Have to be started with micronized drug particle size less than25 to prevent blocking of homogenization gap.

So it is essential to prepare a presuspension of the micronized

drug in a surfactant solution using high speed stirrer.

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High pressure homogenizer

-Cavitation, High shear forces and

collision of particles against each other

-The drug suspension, contained in acylinder of diameter about 3 mm, passes

suddenly through a very narrow

homogenization gap of 25 m, which leads

to a high streaming velocity.

-In the homogenization gap, according to

Bernoullis equation, the dynamic pressure

of the fluid increases with the

simultaneous decrease in static pressure

below the boiling point of water at room

temperature.

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- water starts boiling at room temperature, leading to the

formation of gas bubbles, which implode when the

suspension leaves the gap (called Cavitation) andnormal air pressure is reached again.

- The implosion forces are sufficiently high to break

down the drug microparticles into nanoparticles.

- Additionally, the collision of the particles at high speed

helps to achieve the nano-sizing of the drug.

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Ad


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Drugs that are poorly soluble in both aqueous and organic

media can be easily formulated into nanosuspensions.

Ease of scale-up and little batch-to-batch variation. Narrow size distribution of the nanoparticulate drug present in

the final product.

Allows aseptic production of nanosuspensions for parenteral

administration.

Flexibility in handling the drug quantity, ranging from 1 to

400mg/mL, thus enabling formulation of very dilute as well as

highly concentrated nanosuspensions.

Prerequisite of micronized drug particles.

Prerequisite of suspension formation using high-speed mixers

before subjecting it to homogenization.

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Advantages

Disadvantages


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The drugs that are chemically labile can be processed in

such non-aqueous media or water-miscible liquids likepolyethyleneglycol-400 (PEG), PEG1000 etc. The

homogenization can be done at room temperature, 0o C and

below freezing point (-20o C).

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Precipitated

drug particles

(nanosize

desired)

Continues to

grow till

microcrystal

size

So the precipitated particle suspension is subsequentlyhomogenized which preserve the particle size obtained

after the precipitation step.

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Evaluation of Nanosuspensions

In-Vitro Evaluation

-Particle size & Size Distribution-Particle Charge (Zeta potential)

-Crystalline state & Morphology

-Saturation Solubility & Dissolution Velocity

In- Vivo Evaluation-Surface Hydrophobicity-Interaction with Body Protein

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Mean particle

size and size

distribution

Photon correlation

Spectroscopy

Laser

DiffractometryAtomic Force

Microscopy29

P i l Ch ( i l)


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Particle Charge ( zeta potential)

Gives idea about physical stability of the Nanosuspension

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Potential difference between the ions in the tightly bound layer

and the electroneutral region, referred to as zeta potential.


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Crystalline State and Particle Morphology

Differential

Scanning

Calorimetry

Crystalline Structure

X- Ray DiffractionChange in physical state and

extent of amorphous drug.

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SCANNING ELECTRON MICROSCOPY


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Saturation solubility & Dissolution Velocity

Help to anticipate In-vivo performance

blood profiles,

plasma peaks,bioavailability

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Oral applications:

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e.g.:

IMPROVED BIOAVAILABILITY

1) Atovaquone 10-15% bioavailable high dose (750mg, twice a day)

NANOSUSPENSION 2.5 FOLD INCREASE IN BIOAVAILABILITY

2) Danazole poorly soluble gonadotropin inhibitor

Marketed Suspension(Danocrine) 5.2% Bioavailability

NANOSUSPENSION 82.5% BIOAVAILABILITY

QUICK ONSET OF ACTION:

3) NAPROXEN, an NSAID

Nanosuspension

Tmax= 1.69 hr

Naprosyn

(Suspension)

Tmax= 3.33 hr

Anaprox

(Tablet)

Tmax= 3.2 hr

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Patented technologies for Preparation:

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MARKETED NANOSUSPENSIONS:

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Microsuspension is a registered trademark used for Aqueous Solutions

Sold As a Component of Veterinary Pharmaceutical Preparations For Use In

the Treatment of Respiratory Disease In Livestock and owned by G. C.

Hanford Manufacturing Company.

Drug is in micro size range.

No significant advantages over the macrosuspension or Nanosuspension.

Same methods of preparation as the Nanosuspension.

MICROSUSPENSION (?)


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Emulsion as Oral

MICROEMULSIONNANOEMULSION

MULTIPLE EMULSION

DRY EMULSION 39


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EMULSION

An emulsion is a mixture of two or more liquids that arenormally immiscible (nonmixable or unblendable).

In an emulsion, one liquid (the dispersed phase) is dispersed in

the other (the continuous phase).

Examples of emulsions include vinaigrettes, milk, and some

cutting fluids for metal working.

The word "emulsion" comes from the Latin word for "tomilk", as milk is (among other things) an emulsion of milk fat

and water.


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MICROEMULSION

Microemulsions are dispersions of nanometer-

sized droplets of an immiscible liquid within

another liquid. Droplet formation is facilitated bythe addition of surfactants and often also co

surfactants.

Microemulsions can have characteristic properties such

as ultralow interfacial tension, large interfacial area and

capacity to solubilize both aqueous and oil-soluble

compounds.41


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Microemulsions are clear, stable, liquid mixtures of oil,water and surfactant, frequently in combination with a co

surfactant like short chain alcohol or amine.

Diameter of the droplets in a microemulsion is in the range

of 0.1 to 10 m. The two basic types of microemulsions are

(1) o/w (oil dispersed in water) and

(2) w/o (water dispersed in oil).

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Difference between Ordinary emulsion and Microemulsion:

Ordinary emulsion Microemulsion

Size of globule: 0.5-50 m 0.1-10 m

Appearance: Turbid Clear

Thermodynamically: Stable but coalesce

finally.

More stable

Viscosity: - Less compared to other

emulsion.

Preparation: It require high shear

condition

By simple mixing of the

component and do not

require high shear

condition

Surfactant concentration: 2-3 %Waight 6-8 %Waight

Phases: 2 1

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Types of microemulsion systems

According to Winsor, there are four types of microemulsion

phases exists in equilibria , these phases are referred as Winsorphases. They are,

Winsor I: With two phases, the lower (o/w)

Microemulsion phases in equilibrium with the upper excess oil.

Winsor II: With two phases, the upper(w/o)

Microemulsion phase in equilibrium with lower excess water.

Winsor III: With three phases, middle

Microemulsion phase (o/w plus w/o, called bi continous) in equilibriumwith upper excess oil and lower excess water.

Winsor IV: In single phase, with oil, water and

Surfactant homogenously mixed.

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Advantages Of Microemulsion Over Other Dosage Forms

Increase the rate of absorption.

Eliminates variability in absorption.

Helps solublize lipophilic drug.

Provides a aqueous dosage form for water insoluble drugs.

Increases bioavailability.

Various routes like tropical, oral and intravenous can be used to

deliver the product.

Rapid and efficient penetration of the drug moiety.

Helpful in taste masking.

Provides protection from hydrolysis and oxidation as drug in oilphase in O/W microemulsion is not exposed to attack by water and

air.

Liquid dosage form increases patient compliance.

Less amount of energy requirement.


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A large number of oils and surfactant are available but their use in the

microemulsion formulation is restricted due to their toxicity, irritation

potential and unclear mechanism of action.

Oils and surfactant which will be used for the formulation of microemulsion

should be biocompatible, non-toxic, clinically acceptable, and use emulsifiers

in an appropriate concentration range that will result in mild and non-

aggressive microemulsion.

The emphasis is, excipients should be generally regarded as safe.

Component of Microemulsion System


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1. Oil phase

2. Surfactant3. Aqueous Component

If a cosurfactant is used, it may sometimes be represented at a fixed ratio

to surfactant as a single component, and treated as a single "pseudo-component".

The relative amounts of these three components can be represented in a

ternary phase diagram.

Gibbs phase diagrams can be used to show the influence of changes in the

volume fractions of the different phases on the phase behavior of the

system.

Main three components


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In case turbidity appears followed by a phase

separation, the samples shall be considered as

biphasic.

In case monophasic, clear and transparentmixtures are visualized after stirring; the samples

shall be marked as points in the phase diagram.

The area covered by these points is considered as

the microemulsion region of existence.

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contd.


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Oi l Componen t

The oil component influences curvature by its ability to

penetrate and swell the tail group region of the surfactantmonolayer.

Following are the different oil are mainly used for the

formulation of microemulsion:

Saturated fatty acid-lauric acid, myristic acid,capric acid

Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid

Fatty acid ester-ethyl or methyl esters of lauric, myristic and

oleic acid.

The main criterion for the selection of oil is that the drugshould have high solubility in it.

This will minimize the volume of the formulation to deliver

the therapeutic dose of the drug in an encapsulated form.

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Sur f ac t an t s


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Sur f ac t an t s

The role of surfactant in the formulation of microemulsion is to

lower the interfacial tension.

The surfactant should have appropriate lipophilic character to

provide the correct curvature at the interfacial region.

Generally, low HLB surfactants are suitable for w/o microemulsion,

whereas high HLB (>12) are suitable for o/w microemulsion.

Following are the different surfactants are mainly used for

microemulsion-

Polysorbate (Tween 80 and Tween 20), Lecithins, Decyl

polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate

(Plurol Oleique), Dioctyl sodium sulfosuccinate (Aersol OT),

PEG-8 caprylic /capril glyceride (Labrasol).

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Co su r f actan t s


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Co su r f actan t s

Cosurfactants are mainly used in microemulsion formulation for

following reasons:

They allow the interfacial film sufficient flexible to take up differentcurvatures required to form microemulsion over a wide range of

composition.

1. Short to medium chain length alcohols (C3-C8) reduce the

interfacial tension and increase the fluidity of the interface.

2. Surfactant having HLB greater than 20 often require the presence

of cosurfactant to reduce their effective HLB to a value within the

range required for microemulsion formulation.

Following are the different co surfactant mainly used for

microemulsion:

sorbitan monoleate, sorbitan monosterate, propylene glycol,

propylene glycol monocaprylate (Capryol 90), 2-(2-

ethoxyethoxy)ethanol (Transcutol) and ethanol.

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Pr epar at i on of M i cr oemu l si on

Following are the different methods are used

for the preparation of microemulsion:

1. Phase titration method

2. Phase inversion method

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Contd


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Microemulsions are thermodynamically stable, so they

can prepared simply by blending oil, water, surfactant

and cosurfactant with mild agitation or mild heat.

Titrating the mixer of surfactant ,cosurfactant,and oil

against the water till the clear solution is obtained.

If solution is still slight turbid then add some more

amount of cosurfactant to get the clear solution.

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Co d


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Phase inversion method


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Phase inversion method

Phase inversion of microemulsion is carried out upon addition of

excess of the dispersed phase or in response to temperature.

During phase inversion drastic physical changes occur including

changes in particle size that can ultimately affect drug release

both in vitro and in vivo.

For non-ionic surfactants, this canbe achieved by changing the

temperature of the system,

forcing a transition from an o/w microemulsion at low

temperature to a w/o microemulsion at higher temperatures

(transitional phase inversion).

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Contd


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During cooling, the system crosses a point zero spontaneous

curvature and minimal surface tension, promoting the formationof finely dispersed oil droplets.

Apart from temperature, salt concentration or pH value may

also be considered.

A transition in the radius of curvature can be obtained bychanging the water volume fraction.

Initially water droplets are formed in a continuous oil phase by

successively adding water into oil. Increasing the water volume

fraction changes the spontaneous curvature of the surfactantfrom initially stabilizing a w/o microemulsion to an o/w

microemulsion at the inversion.

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Many examples of microemulsion based formulations

are now on the market ;

Among them, the performances of microemulsionsare well demonstrated in the reformulation of

Cyclosporin A by Novartis into a microemulsion

based formulation marketed under the trade mark

Neoral

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Contd..

Ch t i ti Of Mi l i


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Characterization Of Microemulsion

1. The droplet size,

2. viscosity,

3. density,

4. turbidity,

5. refractive index,

6. phase separation and

7. pH measurements shall be performed tocharacterize the microemulsion.

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Th d l t i


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The droplet size

The droplet size distribution of microemulsion vesicles can be

determined by either light scattering technique or electron

microscopy.

This technique has been advocated as the best method for

predicting microemulsion stability.

Dynamic light-scattering measurements.

The DLS measurements are taken at 90 in a dynamiclight-scattering spectrophotometer which uses a neon

laser of wavelength 632 nm. The data processing is done

in the built-in computer with the instrument.

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Phase analysis and viscosity measurement


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Phase analysis and viscosity measurement

Polydispersity

Studied using Abbe refractometer.

Viscosity measurement

The viscosity of microemulsions of several compositions can be

measured at different shear rates at different temperatures using

Brookfield type rotary viscometer.The sample room of the instrument must be maintained at 37

0.2C by a thermobath, and the samples for the measurement are

to be immersed in it before testing.

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Ph l i


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Bulb glows with O/W

Bulb doesnt glow with W/O

Emulsion Emulsion

Phase analysisTo determine the type of microemulsion that has formed, the

phase system (o/w or w/o) of the microemulsions is determined by

measuring the electrical conductivity using a conductometer.

St bilit St di


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Stability Studies

The physical stability of the microemulsion must be determinedunder different storage conditions (4C, 25C and 40 C) during12 months.

Depending on different regulatory agency requirement itll vary

according to them.

Fresh preparations as well as those that have been kept undervarious stress conditions for extended period of time is subjected

to droplet size distribution analysis.

Effect of surfactant and their concentration on size of droplet isalso be studied.

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Application of microemulsion in delivery of drug


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Application of microemulsion in delivery of drug

Oral delivery

Microemulsions have the potential to enhance the solubilizationofpoorly soluble drugs (particularly BCS class II or class IV)

and overcome the dissolution related bioavailability

problems.

These systems have been protecting the incorporated drugsagainst oxidation, enzymatic degradation and enhance

membrane permeability.

Presently, Sandimmune Neoral(R) (Cyclosporine A),

Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are thecommercially available microemulsion formulations.

Microemulsion formulation can be potentially useful to improve

the oral bioavailability of poorly water soluble drugs by

enhancing their solubility in gastrointestinal fluid. 65

Topical delivery


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p y

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 drug and related toxicity effects.

Another is the direct delivery and target ability of the drug to affected

areas of the skin or eyes.

Now a day, there have been a number of studies in the area of drug

penetration into the skin.

They are able to incorporate both hydrophilic (5-flurouracil,apomorphine hydrochloride, diphenhydramine hydrochloride,

tetracaine hydrochloride, methotrexate) and lipophilic drugs

(estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide)

and enhance their permeation.

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Evaluation of Microemulsion


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Evaluation of Microemulsion1)Percentage Transmittance:

Transparency of microemulsion formulation was determined by

measuring percentage transmittance through U.V. Spectrophotometer.

2)Droplet Size Analysis:

By microscopic method

3)Zeta-Potential Determination:

4)Viscosity

5)Stability Studies:

The optimized ME was stored at three different temperature ranges

for 6 months i.e., refrigerating condition (20C 80C), room

temperature and elevated temperature (50 20C) and shelf life of thestored microemulsion system was evaluated by visual inspection

(phase separation), % transmittance, Particle size and % Assay.

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Research Work carried out on Microemulsions


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Drug Name Route Purpose/Result

Flurbiprofen Parenteral Increased the solubility

Apormorphine HCl Transdermal Increased the permeability

Ketoprofen Transdermal Enhancement of permeability

Prilocainne-HCL Transdermal Increased the solubility

Estradiol Transdermal Improvement in solubilization

Aceclofenac Dermatological Increased the solubility

Piroxicam Oral Increased the solubility

Diclofenac Transdermal Permeability enhancement

Dexamethasone Topical Ocular Enhanced the BioavailabilityChloramphenicol Ocular Increased the solubility

Ibuprofen Parenteral Increased the solubility

Sumatriptan Intranasal Enhanced the Bioavailability

Ibuprofen Topical Increasing the solubility

NANOEMULS ION


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NANOEMULS ION

Nanoscale emulsion having size less than 100nm.

Due to their small droplet size, nano-emulsions may appear

transparent, and Brownian motion prevents sedimentation or

creaming, hence offering increased stability.

In contrast to microemulsions, nanoemulsions aremetastable and can be diluted with water without changing

the droplet size distribution.

Nanoemulsion are thermodynamically stable system in

which the two immisible liquid (water and oil)are mix to

form a single phase by means of appropriate surfactant .

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h d f


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Method of preparation

1)High pressure homoginization: By high pressure homoginizer or piston homoginizer which

produce NEs of exrtemly low particle size upto 1 nm.

2)Microfluidization:

This make use of microfluidizer.

This device use high pressure positive displacement

pump(500-20000 psi) which force the product through the

interaction chamber which consist of small micro channel.

Product flow throgh the micro channel on to the impigmentresulting in the formation of nano size droplet.

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CHARACTERIZATION OF NANOPARTICALS


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Nano-emulsions are not thermodynamically stable, and because of

that, their characteristics will depend on preparation method. Here

some parameters are discussed which should be analysed at the

time of preparation of nanoemulsion.

Phase Behavior Study

This study is necessary in characterization and optimization of

ingredients. This is used in case of NE formulation prepared byphase inversion temperature method and self-emulsification

method.

Particle Size Analysis

Generally Dynamic Light Scattering(DLS) method are used.

Surface Charge Measurement

Surface zeta potential of NE droplets should be measured with the

help of mini electrode to predict the surface properties of NEs..72

Contd


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Transmission Electron Microscopy

TEM is used to observe the morphology in Nano-emulsion. Viscosity

Viscosity should be measured to ensure the better delivery of

the formulation.

Morphology & structure

Morphology and structure of nanoemulsion can be studied

using TEM. The study of globule shape and surface can be

observed by TEM. To perform TEM observations, a drop of

the nanoemulsion is deposited on the holey film grid andobserved after drying.

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Contd


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Advantages of nanoemulsion

Reduction of globules: Increase surface area,

Enhance solubility, Increase bioavailability

They do not show the problems of flocculation,

coalescence and sedimentation.

They are non-toxic ,non-irritant

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Limitations Of Nanoemulsions


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The manufacturing of nanoemulsion formulation is an expensive

process because size reduction of droplets is very difficult as it

required a special kind of instruments and process methods.

For example, homogenizer (instruments required for the

nanoemulsion formulation) arrangements is an expensive process.

Again microfluidization and ultrasonication (manufacturing

process) required high amount of financial support.

Stability of nanoemulsion is quite unacceptable and creates a big

problem during the storage of formulation for longer time of

period. Ostwald ripening is the main factor associated with

unacceptability of nanoemulsion formulations. This is due to highrate of curvature of small droplets show greater solubility as

compared to large drop with a low radius of curvature.

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APPLICATIONS OF NANO-EMULSIONS


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The compositional flexibility of nanoemulsions offers a wide range of

applications.

The incorporation offluorescent dyes and other molecules into nanoemulsions

makes the interesting probes for exploring properties of living cells and for

drug delivery.

Nanoemulsion vaccine could inactivate and kill the virus and thensubsequently induce immunity to the virus that includes cellular immunity,

antibody immunity and mucosal immunity.

The deformable and liquid nature of the droplets may lead to discoveries of

new pathways for cellular uptake and dispersal. Both oil-soluble and water-

soluble drug molecules can be incorporated into the nanodroplets of direct and

inverse nanoemulsions forpotential pharmaceutical uses.

In the printing and data storage industries, one may imagine the resolution of

droplets.

Contd


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In the personal care and food industries, nanoemulsions may

provide interesting alternatives as pleasantly transparent and soft

solids that possess plastic-like rheologicalproperties. While beingappealing from an optical and rheological point of view,

nanoemulsion also can deliver moisturizers to the skin quite

efficiently and also block ultraviolet light without leaving a white

residue. The small size of the nano droplets will likely increase transport

efficiency of any active drugs or other molecules inside the

droplets across biological membranes, including the skin. Thus,

nanoemulsions may have significant applications in medical

patches.

High-throughput production methodologies make nanoemulsions a

realistic commercial-scale alternative for diverse areas, including

lotions and pharmaceuticals.77

Marketed products:


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Marketed products:

Drug Brand Manufacturer Indication

Propofol Diprivan Astra zeneca Anesthatic

Dexamethazone Limethasonn Mitsubishipharmaceutical,

Japan

Steroids

Palmitate

alprostadil

Liple Mitsubishi

pharmaceutical,

Japan

Vasodilator

Flubriprofen axetil Ropion Kaken

pharmaceutical,

Japan

NSAIDS

Vitamines A,D,E,K Vitalipid Fresenius

kabi,Europe

Parenteral

nutrition

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Multiple emulsion

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Introduction


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Introduction Multiple emulsion systems are novel developments in the field of

emulsion technology and are more complex type of dispersedsystem.

These are the emulsion systems in which the dispersed phasecontain smaller droplets that have the same compositon as theexternal phase.

These made possible by the double emulsification hence thesystems are also called as doubleemulsion.

Diameter of the droplets in a Multiple emulsion is in the range of0.5 to 3m.

Multiple emulsions are defined as emulsions in which bothtypes of emulsions, i.e. water-in-oil (w/o) and oil-in-water(o/w) exist simultaneously.

They combine the properties of both w/o and o/w emulsions

These two liquids forming a system are characterized by theirlow thermodynamic stability .

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Like simple emulsion multiple emulsion are

classified into two type.1)O/W/O type

2)W/O/W type

The immiscible phase ,which separates the two

miscible phase is known as liquidmembrane and

act as a diffusion barrier and semipermeable

membrane for drugs or moities entrapped in theinternal aqueous phase.

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Preparation


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p

Multiple emulsions, either W/O/W or O/W/O emulsions, aregenerally prepared using a 2-step procedure.

For W/O/W emulsions, the primary emulsion (W/O) is first

prepared using water and a low-HLB surfactant solution in oil.

In the second step, the primary emulsion (W/O) is re-emulsified

in an aqueous solution of a high-HLB surfactant to produce a

W/O/W multiple emulsion.

The first step is usually carried out in a high-shear device to

produce very fine droplets. The second emulsification step is

carried out in a low-shear device to avoid rupturing the multiple

droplets.

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Multiple emulsion (w/o/w or o/w/o), Prepared by two step procedure


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First step (o/w)

Primary emulsion

Second step (o/w/o)

Secondary emulsificationphase

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Oil + Aqueous phase Low HLB surfactant + Oil

Blend and heat up to

70-80 C

Formation of very fine droplets

Heat and blend with

low shear

Oil

Multiple emulsion

Blend with low shear

EVALUATION OF MULTIPLE EMULSION


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84

Viscosity

surface tension

conductivity

pH

Globule size

Test for sterility

Microscopic method

Particle size distribution


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85

Multiple

Emulsion

Application :


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Controlled and sustained drug delivery.

Vaccine adjuvant.

Cosmetic application.

As a preparative tool for microencapsulation

technology.

Miscellaneous.Protection action.

Taste masking.

Absorption enhancement through GIT.

Dry emulsion


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A novel oral dosage formulation of insulin consisting of a surfactant, a

vegetable oil, and a pH-responsive polymer has been developed. First, a

solid-in-oil (S/O) suspension containing a surfactantinsulin complex wasprepared.

Solid-in-oil-in-water (S/O/W) emulsions were obtained by homogenizing the

S/O suspension and the aqueous solution of hydroxy propyl methyl cellulose

phthalate (HPMCP). A micro-particulate solid emulsion formulation was successfully prepared

from the S/O/W emulsions by extruding them to an acidic aqueous solution,

followed by lyophilization.

The insulin release from the resultant dry emulsion responded to the changein external environment simulated by gastrointestinal conditions, suggesting

that the new enteric coated dry emulsion formulation is potentially applicable

for the oral delivery of peptide and protein drugs.

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Homogenization and membrane emulsification

Dropwise extrusion through a syringe

Recovery and lyophilization.

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89

Jiraporn CHINGUNPITUK,

Nanosuspension Technology for Drug Delivery,

Walailak J Sci & Tech 2007; 4(2): 139-153.

V. B. Patravale, Abhijit A. Date and R. M. Kulkarni,

Nanosuspensions: a promising drug delivery strategy

JPP 2004, 56: 827840

Rong LiuWater-Insoluble Drug Formulation

Second Edition, page no. 122-123

Nanoparticle Technology for Drug Delivery,

edited by Ram B. Gupta and Uday B. Kompella


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Advances in controlled and novel drug delivery.

By N.K.Jain.Targeted and controlled drug delivery

By S.P.Vyas and R.K.Khar

Nano emulsion: A pharmaceuticle review.

http:/www.sysrevpharm.orgReview Article :Microemulsions: a novel drug carrier

system.International Journal of Drug Delivery Technology

2009; 1(2): 39-41 www.ijddt.com

TOPICAL REVIEW: nanoemulsions:

Formation, structure, and physical properties. Journal of

physics: condensed matter 18 (2006) r635r666

Stacks.Iop.Org/jphyscm/18/R633
http://www.ijddt.com/http://www.ijddt.com/http://www.ijddt.com/http://www.ijddt.com/http://www.ijddt.com/http://www.ijddt.com/


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Thank you

Oral Liquids

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