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MULTIPLE EMULSIONS: 

MULTIPLE EMULSIONS PRESENTED BY MIS. SWATI T. THOSARE M.PHARM 2 nd SEM ANURADHA COLLEGE OF PHARMACY,CHIKHLI . 1 1 RECENT ADVANCES OF EMULSION

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What is emulsion? Emulsion is a thermodynamically unstable system consists of at least two immiscible phases, one of which is dispersed as a globules (dispersed phase) in another(dispersed medium) and stable by addition of surface active agent or surfactant. 2

RECENT ADVANCES OF EMULSION: 

RECENT ADVANCES OF EMULSION MULTIPLE EMULSION. NANOEMULSION. 3

MULTIPLE EMULSION. : 

4 MULTIPLE EMULSION.

CONTENT: 

5 5 CONTENT Introduction Preparation Aspects Methods Of Preparation Characterization Stability Drug Release Mechanisms And Models In Vivo Study Of Multiple Emulsion Applications References

Introduction : 

6 6 Introduction “Emulsion of emulsion”, “double or triple emulsion” Dispersed phase contain smaller droplets that have the same composition as the external phase. Liquid film which separate the liquid phases acts as a thin semipermeable film through which solute must diffuse in order to travel from one phase to another – “Liquid Membrane System” Two types: - Oil-in-water-in-oil (O/W/O) emulsion system. Water-in-oil-in-water (W/O/W) emulsion system. O/W/O is a system in which water droplets may be surrounded in an oil phase, which in turn encloses one or more oil droplets. Internal oil droplet External oil medium Intermediate water phase

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7 7 W/O/W is a system in which an oil droplet may be surrounded by an aqueous phase, which in turn encloses one or several water droplets. In most cases, two aqueous phase are identical therefore a W1/O/W1 emulsion is a two component system. In some cases a W1/O/W2 is a three component system.

Method of Preparation: 

8 8 Method of Preparation Either by the re-emulsification of a primary emulsion or they can be produced when an emulsion inverts from one type to another. Two Step Emulsification (Double Emulsification) Micro channel emulsification process Phase Inversion Technique (One Step Technique) Membrane Emulsification Technique

Two Step Emulsification: - (Double Emulsification): 

9 9 Two Step Emulsification: - (Double Emulsification)

Modified Double Emulsion Technique: 

10 10 Modified Double Emulsion Technique Stable 1:4:5

Phase Inversion Technique : - (One Step Technique) : 

11 11 Phase Inversion Technique : - (One Step Technique)

Membrane Emulsification Technique: 

12 12 Membrane Emulsification Technique

Characterization : 

13 13 Characterization Average globule size & size distribution: Area of interfaces: Number of globules: Rheological evaluation: Zeta potential: Calculated using the Zeta-potentiometer. ζ = 4 πη µ X 10 3 ε E Percent drug entrapment:

Stability : 

14 14 Stability Depending upon equilibrium between water, oil and surfactant. Unfortunately multiple emulsion are thermodynamically unstable. Possible indication of instability include: Leakage of the contents from the inner aqueous phases Rupture of oil layer on the surface of the internal droplet i. e. expulsion of internal droplet in external phase. Shrinkage and swelling of the internal drops due to osmotic gradient across the oil membrane Phase separation Coalescence of the internal droplets and multiple emulsion drops Methods to stabilize multiple emulsion: Liquid crystal stabilized multiple emulsion Stabilization in the presence of electrolytes Stabilization by forming polymeric gel Steric stabilization

Drug Release Mechanisms And Models : 

15 15 Drug Release Mechanisms And Models 1) Diffusion mechanism: This is most obvious transport mechanism where unionized hydrophobic drug diffuses through the oil layer (Semi permeable liquid membrane) in the stable multiple emulsions. (2) Micellar transport : Inverse micelles play key role in this transport mechanism. Inverse micelles consisting of nonpolar part of surfactant lying outside and polar part inside encapsulate hydrophilic drug in core and permeate through the oil membrane because of the outer lipophilic nature. Inverse micelle can encapsulate both ionized and unionized drug. (3) Thinning of the oil membrane: Transport of water through thin oil membrane region. In this area, it is easier for the water or drug to permeate because of small oily region. Thinning of the oil membrane takes place primarily due to osmotic pressure difference between two aqueous phases.

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16 16 (4) Rupture of oil phase: According to this mechanism rupturing of oil membrane can unite both aqueous phases and thus drug could be released easily. (5) Facilitated diffusion (Carrier-mediated transport): This mechanism involves a special molecule (carrier) for the transfer of hydrophilic, ionic molecule from internal to external aqueous phase. This carrier molecule combines with the drug and makes it compatible to permeate through the oil membrane (lipophilic, nonionic). This type of mechanism behaves like ‘pumping system’ where the carrier molecule act as pump and transfer drugs from internal to external aqueous phase. (6) Release by Breakup after Swelling: The swelling/breakdown process occurs only if there is a concentration gradient between the internal and the external aqueous phases.

In-Vivo Study Of Multiple Emulsion: 

17 17 In-Vivo Study Of Multiple Emulsion Blood, Lymph, Cerebrospinal fluid and Urine are all basically aqueous media and sustained drug delivery to these organs can be claimed if the rate of partitioning from oil into an aqueous media is slow and controllable. W/O/W emulsion could breakdown rapidly in vivo due to an osmotic effect. The use of isotonic system and/or the creation of thick interfacial layer or gelled system that can withstand the osmotic stress provides system that may have controlled drug release characteristics in vivo .

Applications : 

18 18 Applications Controlled and Sustained Drug Delivery Drug Targeting Vaccine Adjuvant Cosmetics preparation Taste masking of the drug

NANOEMULSION: 

NANOEMULSION

Contents:: 

Contents: Introduction of Nanotechnology Introduction of Nanoemulsion Stability Method of Preparation Evalution parameter Advances

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Nanotechnology comprises technological developments on the nanometer scale, usually 0.1 to 1000 nm . The pharmaceuticals  developed on the basis of nanotechnology are termed as ‘ NANOPHARMACEUTICALS ’.

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Current Nanopharmaceuticals used or under  the process of development are: Nanoemulsions (sub-micron sized emulsions) Nanosuspensions (sub-micron sized suspensions) Nanospheres (drug Nanoparticles in polymer matrix) Nanotubes (sequence of nanoscale C 6 0 atoms arranged in a long thin cylindrical  structure) Nanoshells (concentric sphere nanoparticles consisting of a dielectric core and a metal   shell ) Nanocapsules (encapsulated  drug nanoparticles) Lipid nanoparticles (lipid monolayer enclosing a solid lipid core) Dendrimers (nanoscale three-dimensional macromolecules of polymer)

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NANOEMULSION

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Nanoemulsions or mini-emulsion or sub-micron emulsion(SME) defined as transparent or translucent O/W or W/O emulsion droplet diameters ranging from 50-1000 nm. [ avg droplet size is between 100-500 nm ] kinetically stable unlike microemulsions which are thermodynamically stable Nanoparticles can exist core of particle w/o form water o/w form oil Ostwald ripening is the primary instability process : Can be reduced by the addition of a second less soluble oil phase and/or addition of a strongly adsorbed and water insoluble polymeric surfactant.

Single nanoparticle: 

The inner core consisting of any oil Drug or nutrient molecules within the core The emulsifier layer surrounding the nano-particle . Single nanoparticle Nanoemulsion : Lipid monolayer enclosing a liquid lipid core. Liposome : Lipid bilayer enclosing an aqueous core.

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Advantages Of Nanoemulsions 1 . R eduction of globules as the potential to: Increase surface area Enhance solubility Increase oral bioavailability More rapid onset of therapeutic action Decrease the dose needed 2 .do not show the problems of inherent creaming, flocculation, coalescence and sedimentation . 3. are non-toxic, non-irritant hence can be easily applied to skin and  mucous membranes. 5 . they can be taken by enteric route becoz they are formulated with surfactants, which are approved for human  consumption (GRAS),

Stability of Nanoemulsion: 

Stability of Nanoemulsion Brownian movement Low rate of sedimentation – due to the small particle size low gravitational force As particle s become smaller, the attractive force of van der waals will be smaller. High Zeta potential- more electrostatic repulsive forces ;resulted in reducing the coalescence or coagulation of emulsion droplets Optimum Thermodynamically stability ;but high kinetic stability

Preparation of Nanoemulsion: 

Preparation of Nanoemulsion Drug poorly water soluble drug eg: Diclofenac,Ramipril Oil phase eg: dimethicone oil , castor oil , Soyabean oil Aqueous phase Surfactant Cremphore,lecithin Cosurfactant : Propylene glycol, polysorbate 80, cetylphosphate,hydrogenated caster oil

Methods Of Preparation Of Nanoemulsions:: 

Methods Of Preparation Of Nanoemulsions : High-Energy 1. High pressure homogenization 2 Microfludization 3 Ultrasound energy Undesirable for labile drugs and macromolecules (proteins and nucleic acids) (for lab & industrial preparation) Low-Energy 1. Spontaneous 2. Solvent-diffusion 3. Phase inversion temperature (PIT) a. Rapid cooling of selected ME state b. Dilution with water (for lab preparation)

1.High-Pressure Homogenisation : 

1.High-Pressure Homogenisation In a high-pressure homogenizer, the dispersion of two liquids (oily phase and aqueous phase) is achieved by forcing their mixture through a small inlet orifice at very high pressure (500 to 5000 psi), which subjects the product to intense turbulence and hydraulic shear resulting in extremely fine particles of emulsion.

2.Microfluidization : 

2.Microfluidization patented mixing technology, use of a device called microfluidizer. This device uses a high-pressure positive displacement pump (500 to 20000psi), which forces the product through the interaction chamber, which consists of small channels called ‘microchannels’. The product flows through the microchannels on to an impingement area resulting in very fine particles of sub-micron range.

Evaluation Parameter: : 

Evaluation Parameter: Transmission Electron Microscopy Droplet size Analysis Viscosity determination Refractive Index Zeta potential measurement In vitro drug release Analytical test (UV,HPLC) Biological studies

Transmission Electron Microscopy : 

Transmission Electron Microscopy Morphology and structure of the nanoemulsion were studied using transmission electron microscopy (TEM) To perform the TEM observations, a drop of the nanoemulsion was directly deposited on the holey film grid and observed after drying

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eg:TEM positive image of aceclofenac nanoemulsion showing the size of some oil droplets. . Scanning Electron Microscopy picture of nanoemulsion .

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Droplet size Analysis Determined by photon correlation spectroscopy that analyzes the fluctuations in light scattering due to Brownian motion of the particles, using a Zetasizer 1000 HS (Malvern Instruments) Brookfield viscometer Refractive Index Abbe-type refractometer Zeta potential measurement The zeta potential was measured by electrophoretic mobility using Malvern Nanosizer/Zetasizer ® nano-ZS ZEN 3600 (Malvern Instruments, USA). Skin Irritation Test Plasma-time profile

Advances in Nanoemulsion : 

Advances in Nanoemulsion

1.Use Of Nanoemulsions In Cosmetics : 

1.Use Of Nanoemulsions In Cosmetics Due to their lipohilic interior, nanoemulsions are more suitable for the transport of lipophilic compounds High skin penetration due to small size Body Moisturiser Nanoemulsion Face Lotion with Vitamin Nanoemulsion

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2.Antimicrobial Nanoemulsions Antimicrobial nanoemulsions are oil-in-water droplets that range from 200-600 nm. The nanoemulsion has a broad spectrum activity against -bacteria (e.g., E. coli, Salmonella, S. aureus), -enveloped viruses (e.g., HIV, Herpes simplex), -fungi (e.g., Candida, Dermatophytes), -spores (e.g., anthrax).

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In the case of spores

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Nanoemulsions as a prophylactic medication A human protective treatment, to protect people exposed to bio-attack pathogens such as Anthrax ,Hepatitis and Ebola . The technology has been tested on gangrene and clostridium botulism spores and even used on contaminated wounds to salvage limbs

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3.Nanoemulsions As Mucosal Vaccines (Under Trial) Nanoemulsions are being used to deliver either recombinant proteins or inactivated organisms to a mucosal surface to produce an immune response. The first applications, an influenza vaccine and an HIV vaccine, can proceed to clinical trials. nanoemulsion causes proteins applied to the mucosal surface facilitates uptake by antigen presenting cells systemic and mucosal immune response that involves the production of specific IgG and IgA antibody as well as cellular immunity

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4.Nanoemulsions In Cell Culture Technology Cell cultures are used for in vitro assays or to produce biological compounds, such as antibodies or recombinant proteins Nanoemulsions are a new method for the delivery of oil-soluble substances to mammalian cell cultures. These nanoemulsions are transparent and can be passed through 0.1 µm filters for sterilization. Nanoemulsion droplets are easily taken up by the cells. The advantages of using nanoemulsions in culture technology are · Better uptake of oil-soluble supplements in cell cultures. · Improve growth and vitality of cultured cells.

References : 

44 44 References Vyas S. P. And Khar R. K., Targeted And Controlled Drug Delivery System, 1 st Edition , 2002, CBS Publication; 303-329. Jain N. K., Controlled And Novel Drug Delivery, 1 st Edition 2001, CBS Publication; 381-399. Internet Information

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