A SEMINAR ON

Recent innovations in
ORAL LIQUIDS
GUIDED BY :
DR. MANISH PATEL MS. VIBHA CHAMPAVAT

Presented by:
Sachin Prajapati
Roll No. : 15 M.Pharm Sem-II PHARMACEUTICS

N O O TA N P H A R M A C Y C O L L E G E , V I S N A G A R

Contents
Suspension as oral
Nano suspension Micro suspension

Emulsion as oral
Micro emulsion Nano emulsion Multiple emulsion Dry emulsion

liquids
Definition
This is a general term used to describe a solution, suspension or emulsion in which the active ingredient is dissolved or dispersed in a suitable liquid vehicle. A solution is a liquid-preparation that contains one or more soluble chemical substances dissolved in a specified solvent.

Advantages
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 in solution 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.

Classification of liquids
LIQUID
Monophasic
Oral use

Biphasic

External use

Parenteral

Special use

Liquid in liquid

Solids in liquid

Solution Draught Drops Linctuses Syrups Elixirs

Used in Oral cavity

Oral use

Used in other than oral cavity

EMULSION

External use Parenteral Oral External

THROAT PAINTS GLYCERITES MOUTH WASHES THROATSPRAY S

Liniments
DOUCHES ENEMAS EYE DROPS EYE LOTIONS NASAL DROPS INHALANTS

Lotion

SUSPENSION

SUSPENSION AS ORAL
Nano suspension

Micro suspension

Suspension
Mixture of two substances, one of which is finely divided and dispersed 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.

Contd
Suspensions Sometimes when we mix substances they stay in clusters. We therefore say it is insoluble in water. E.g. Chalk + Water = Suspension

Eventually the particles sink to the bottom to form sediment.

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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 not applicable 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.
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Nanosuspension
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 pulmonary administration.
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 of drugs. 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.
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Nanosuspension preparation

Top down

Bottom up

Media Milling (Nanocrystals)

HPH in water (Dissocubes)

HPH in non aqueous media (Nanopure)

Combination of precipitation and HPH (Nanoedge)

Precipitation

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Added to non -solvent Drug dissolved in the 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 procedure growing 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 for administration.

Principle
The high energy and shear forces generated as a result of the impaction of the milling media with the drug provide the energy input 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.
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18

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 than 25 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.

21

-Cavitation, High shear forces and collision of particles against each other

-The drug suspension, contained in a cylinder of diameter about 3 mm, passes suddenly through a very narrow homogenization gap of 25 m, which leads to a high streaming velocity.

High pressure homogenizer

-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.

22

- water starts boiling at room temperature, leading to the formation of gas bubbles, which implode when the suspension leaves the gap (called Cavitation) and normal 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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Advantages

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.

Disadvantages
Prerequisite of micronized drug particles. Prerequisite of suspension formation using high-speed mixers before subjecting it to homogenization.
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The drugs that are chemically labile can be processed in such non-aqueous media or water-miscible liquids like polyethyleneglycol-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 subsequently homogenized 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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Photon correlation Spectroscopy

Mean particle size and size distribution

Atomic Force Microscopy
Laser Diffractometry
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Particle Charge ( zeta potential)

Potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential. Gives idea about physical stability of the Nanosuspension

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Crystalline State and Particle Morphology

Differential Scanning Calorimetry

Crystalline Structure

X- Ray Diffraction

Change in physical state and extent of amorphous drug.

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

Naprosyn Nanosuspension (Suspension)

Anaprox (Tablet)

Tmax= 1.69 hr

Tmax= 3.33 hr

Tmax= 3.2 hr
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 Patented technologies for Preparation:

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MARKETED NANOSUSPENSIONS:

36

MICROSUSPENSION (?)

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.
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38

Emulsion as Oral

MICROEMULSION NANOEMULSION MULTIPLE EMULSION DRY EMULSION

39

EMULSION
An emulsion is a mixture of two or more liquids that are normally 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 "to milk", as milk is (among other things) an emulsion of milk fat and water.
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MICROEMULSION

Microemulsions are dispersions of nanometersized droplets of an immiscible liquid within another liquid. Droplet formation is facilitated by the 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.

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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 Size of globule: Appearance: 0.5-50 m Turbid Microemulsion 0.1-10 m Clear

Thermodynamically:
Viscosity:

Stable but coalesce finally.

-

More stable
Less compared to other emulsion. By simple mixing of the component and do not require high shear condition 6-8 %Waight 1
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Preparation:

It require high shear condition

Surfactant concentration: Phases:

2-3 %Waight 2

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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 Winsor phases. 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 equilibrium with 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 oil phase 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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Component of Microemulsion System

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 nonaggressive microemulsion. The emphasis is, excipients should be generally regarded as safe.
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Main three components

1. Oil phase 2. Surfactant 3. 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 "pseudocomponent". 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.
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49

contd.
In case turbidity appears followed by a phase separation, the samples shall be considered as biphasic. In case monophasic, clear and transparent mixtures 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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Oil Component
The oil component influences curvature by its ability to penetrate and swell the tail group region of the surfactant monolayer. 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 drug should 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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Surfactants
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 surfactants
Cosurfactants are mainly used in microemulsion formulation for following reasons: They allow the interfacial film sufficient flexible to take up different curvatures 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-(2ethoxyethoxy)ethanol (Transcutol) and ethanol.
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Preparation of Microemulsion
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
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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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 can be 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
During cooling, the system crosses a point zero spontaneous curvature and minimal surface tension, promoting the formation of 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 by changing 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 surfactant from initially stabilizing a w/o microemulsion to an o/w microemulsion at the inversion.
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Contd..
Many examples of microemulsion based formulations are now on the market ; Among them, the performances of microemulsions are 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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Characterization Of Microemulsion

1. 2. 3. 4. 5. 6. 7.

The droplet size, viscosity, density, turbidity, refractive index, phase separation and pH measurements shall be performed to characterize the microemulsion.
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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 dynamic light-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

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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Phase analysis
To 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.

Emulsion Bulb glows with O/W

Emulsion Bulb doesnt glow with W/O

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Stability Studies
The physical stability of the microemulsion must be determined under different storage conditions (4C, 25C and 40 C) during 12 months. Depending on different regulatory agency requirement itll vary according to them. Fresh preparations as well as those that have been kept under various stress conditions for extended period of time is subjected to droplet size distribution analysis. Effect of surfactant and their concentration on size of droplet is also be studied.
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Application of microemulsion in delivery of drug Oral delivery

Microemulsions have the potential to enhance the solubilization of poorly soluble drugs (particularly BCS class II or class IV) and overcome the dissolution related bioavailability problems. These systems have been protecting the incorporated drugs against oxidation, enzymatic degradation and enhance membrane permeability. Presently, Sandimmune Neoral(R) (Cyclosporine A), Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are the commercially 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
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
1)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 the stored microemulsion system was evaluated by visual inspection (phase separation), % transmittance, Particle size and % Assay.
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Research Work carried out on Microemulsions

Drug Name Flurbiprofen Apormorphine HCl Ketoprofen Prilocainne-HCL Estradiol Aceclofenac Piroxicam Diclofenac Dexamethasone Chloramphenicol Route Parenteral Transdermal Transdermal Transdermal Transdermal Dermatological Oral Transdermal Topical Ocular Ocular Purpose/Result Increased the solubility Increased the permeability Enhancement of permeability Increased the solubility Improvement in solubilization Increased the solubility Increased the solubility Permeability enhancement Enhanced the Bioavailability Increased the solubility

Ibuprofen Sumatriptan
Ibuprofen

Parenteral Intranasal
Topical

Increased the solubility Enhanced the Bioavailability

Increasing the solubility
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NANOEMULSION
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 are metastable 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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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 impigment resulting in the formation of nano size droplet.

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CHARACTERIZATION OF NANOPARTICALS
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 by phase 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
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 and observed after drying.

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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 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 high rate 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
The compositional flexibility of nanoemulsions offers a wide range of applications. The incorporation of fluorescent 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 then subsequently 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 watersoluble drug molecules can be incorporated into the nanodroplets of direct and inverse nanoemulsions for potential pharmaceutical uses. In the printing and data storage industries, one may imagine the resolution of droplets.
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Contd
In the personal care and food industries, nanoemulsions may provide interesting alternatives as pleasantly transparent and soft solids that possess plastic-like rheological properties. While being appealing 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.
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Marketed products:
Drug Propofol Dexamethazone Brand Diprivan Limethasonn Manufacturer Astra zeneca Mitsubishi pharmaceutical, Japan Indication Anesthatic Steroids

Palmitate alprostadil
Flubriprofen axetil

Liple

Mitsubishi pharmaceutical, Japan

Kaken pharmaceutical, Japan Fresenius kabi,Europe

Vasodilator

Ropion

NSAIDS

Vitamines A,D,E,K

Vitalipid

Parenteral nutrition
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Multiple emulsion

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Introduction
Multiple emulsion systems are novel developments in the field of emulsion technology and are more complex type of dispersed system. These are the emulsion systems in which the dispersed phase contain smaller droplets that have the same compositon as the external phase. These made possible by the double emulsification hence the systems are also called as double emulsion. Diameter of the droplets in a Multiple emulsion is in the range of 0.5 to 3m.

Multiple emulsions are defined as emulsions in which both types 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 their low 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 liquid membrane and act as a diffusion barrier and semipermeable membrane for drugs or moities entrapped in the internal aqueous phase.

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Preparation
Multiple emulsions, either W/O/W or O/W/O emulsions, are generally 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

First step (o/w) Primary emulsion

Second step (o/w/o) Secondary emulsification phase

Oil + Aqueous phase

Low HLB surfactant + Oil

Blend and heat up to 70-80 C

Heat and blend with low shear

Oil

Formation of very fine droplets

Blend with low shear Multiple emulsion 83

EVALUATION OF MULTIPLE EMULSION

Viscosity surface tension

conductivity
pH

Globule size
Test for sterility Microscopic method Particle size distribution
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Multiple Emulsion

85

Application :
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.

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Dry emulsion
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 was prepared. 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 change in 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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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 Liu Water-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.org Review 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
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