A SEMINAR ON

Recent Innovations in

ORAL LIQUIDS

Presented by: Sachin Prajapati

Roll No. : 15

M.Pharm Sem-II

PHARMACEUTICS

1NO O TAN PH ARM ACY CO LLEG E,VISNAG AR

2

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

3

liquidsDef 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 suitable liquid vehicle.

“A solution is a liquid-preparation that contains one or more soluble chemical substances dissolved in a specified solvent.”

Advant age sImmediately 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.

4

DisadvantagesBulky 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.

5

Classifi cation of l iquids

LIQUID

Monophasic

Oral use

Solution

Draught

Drops

Linctuses

Syrups

Elixirs

External use

Parenteral

Special use

Used in Oral cavity

THROAT PAINTSGLYCERITESMOUTH WASHESTHROATSPRAYS

Used in other than oral cavity

DOUCHESENEMAS

EYE DROPSEYE LOTIONS

NASAL DROPSINHALANTS

Biphasic

Liquid in liquid

Oral use

EMULSION

External use

Liniment

s

Solids in liquid

Parenteral

Oral

SUSPENSION

External

Lotion

6

SUSPENSION AS ORAL

Nano suspension

Micro suspension

7

NANOSUSPENSION

INTRODUCTION

PREPARATION

EVALUATION

APPLICATIONS

8

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 µm Coarse suspension 1 to 100 µm

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.

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.

9

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.   

10

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, ß- 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.11

NANOSUSPENSION

12

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.

Nanosuspension

13

Nanosuspension preparation

Top down

Media Milling

(Nanocrystals)

HPH in water

(Dissocubes)

HPH in non aqueous

media(Nanopure)

Combination of precipitation

and HPH (Nanoedge)

Bottom up

Precipitation

14

Bottom Up technology

Drug dissolved in the solvent

Added to non -solvent

PrecipitationOfCrystals

15

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.

16

Top Down Approaches

17

Media MillingThe 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.

18

19

Coolant Largedrugcrystals

Chargedwithdrug, waterandstabilizer

Re-circulationchamber

Milling chamber

Screenretainingmilling mediain chamber

Millingshaft

Nanocrystals

Milling media

Motor

20

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.

21

HIGH PRESSURE HOMOGENISATION IN WATER(DISSOCUBES)

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 25μ 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.

22

High pressure homogenizer

-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 μm, which leads to a high streaming velocity.

-In the homogenization gap, according to Bernoulli’s equation, the dynamic pressure of the fluid increases with the simultaneous decrease in static pressure below the boiling point of water at room temperature.

23

- 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.

24

• 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.

Advantages

Disadvantages

25

Homogenisation In Nonaqueous Media (Nanopure)

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).

26

Combined Precipitation And Homogenization (Nanoedege)

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.

28

Evaluation of NanosuspensionsIn-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

29

Mean particle size and size

distribution

Photon correlation Spectrosco

py

Laser Diffractom

etry

Atomic Force

Microscopy

3 nm to 3 μm

0.05

–200

0

μm

30

Particle Charge ( zeta potential)

Gives idea about physical stability of the Nanosuspension

Electrostatically stabilized

nanosuspension>+30 eV

Electrostatic & Steric stabilization >+20eV

“Potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential.”

31

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

32

Saturation solubility & Dissolution Velocity

Help to anticipate In-vivo performance blood profiles, plasma peaks, bioavailability

33

APPLICATIONS

Oral applications:

↑ Bioavailability(↓drug dose, ↑cost-effectiveness,No undue drug dumping in the body.)

↑concentration gradient between the GI lumen and blood,↑dissolution velocity.

adhesiveness of the drug NS,increased surface area

34

e.g.:IMPROVED BIOAVAILABILITY1) Atovaquone 10-15% bioavailable high dose (750mg, twice a day)NANOSUSPENSION 2.5 FOLD INCREASE IN BIOAVAILABILITY

2) Danazole poorly soluble gonadotropin inhibitorMarketed Suspension(Danocrine) 5.2% BioavailabilityNANOSUSPENSION 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

35

Patented technologies for Preparation:

36

MARKETED NANOSUSPENSIONS:

37

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 (?)

38

39

Emulsion as Oral

MICROEMULSION

NANOEMULSION

MULTIPLE EMULSION

DRY EMULSION

40

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.

41

MICROEMULSION

“Microemulsions are dispersions of nanometer-sized 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.

42

• 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 µm.

• The two basic types of microemulsions are

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

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

43

Difference between Ordinary emulsion and Microemulsion:

Ordinary emulsion Microemulsion

Size of globule: 0.5-50 µm 0.1-10 µm

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

44

45

Types of microemulsion systemsAccording 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.

46

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.

47

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

48

1.Oil phase2.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

49

50

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.

contd….

51

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.

52

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).

53

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-(2-

ethoxyethoxy)ethanol (Transcutol) and ethanol.

54

Preparation of Microemulsion

Following are the different methods are used for the preparation of microemulsion:

1. Phase titration method

2. Phase inversion method

55

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.

Contd…

56

57

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).

58

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.

Contd…

59

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®

Contd..

60

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 to characterize the microemulsion.

61

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.

62

Phase analysis and viscosity measurement Polydispersity

Studied using Abbe refractometer.

Viscosity measurementThe 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 ± 0.2°C by a thermobath, and the samples for the measurement are to be immersed in it before testing.

63

Bulb glows with O/W Bulb doesn’t 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.

64

Stability Studies

The physical stability of the microemulsion must be determined under different storage conditions (4°C, 25°C and 40 °C) during 12 months.

Depending on different regulatory agency requirement it’ll 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.

65

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.

66

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.

67

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 the

stored microemulsion system was evaluated by visual inspection

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

68

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 Bioavailability

Chloramphenicol Ocular Increased the solubility

Ibuprofen Parenteral Increased the solubility

Sumatriptan Intranasal Enhanced the Bioavailability

Ibuprofen Topical Increasing the solubility

Research Work carried out on Microemulsions

69

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 .

70

Method of preparation1)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.

71

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

73

• 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.

Contd…

74

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

75

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.

76

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 water-

soluble 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.

77

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.

Contd…

78

Marketed products:

Drug Brand Manufacturer Indication

Propofol Diprivan Astra zeneca Anesthatic

Dexamethazone Limethasonn Mitsubishi pharmaceutical, 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

79

Multiple emulsion

80

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

3µm. 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 .

81

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.

82

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.

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

83

Oil + Aqueous phase Low HLB surfactant + Oil

Blend and heat up to 70-80º C

Formation of very fine droplets

Heat and blend with low shear

Oil

Multiple emulsion

Blend with low shear

84

Viscosity

surface tension

conductivity

pH

Globule size

Test for sterility

Microscopic method

Particle size distribution

EVALUATION OF MULTIPLE EMULSION

85

Multiple Emulsion

86

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.

87

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 surfactant–insulin 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.

88

Homogenization and membrane emulsification

Dropwise extrusion through a syringe

Recovery and lyophilization.

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: 827–840

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

REFERENCES

90

Advances in controlled and novel drug delivery.By N.K.Jain.Targeted and controlled drug delivery

By S.P.Vyas and R.K.KharNano 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.comTOPICAL REVIEW: nanoemulsions:

Formation, structure, and physical properties. Journal of physics: condensed matter 18 (2006) r635–r666

Stacks.Iop.Org/jphyscm/18/R633

91

92

Thank you