ANWESHA DANDAPATH

M.PHARM,1st YEAR,2nd SEMESTER

INTRODUCTION

SLN OVER EMULSION & LIPOSOME

SOLID LIPID AS MATRIX MATERIAL

LIST OF EXCIPIENTS USED IN SLN PREPARATION

ADVANTAGES & DISADVANTAGES

METHODS OF PREPARATION

DRUG RELEASE

CHARACTERIZATION OF SLN

PURIFICATION OF SLN

STEALTH SLN

APPLICATION

SLN ARE

Colloidal carrier system(1-

100nm)

Composed of a high melting point lipid as a solid core &

coated by aqueous surfactant.

Made up of drugs usually of

BCS class п & ІV

Lipid emulsion contain a neutral lipophilic core surrounded by a monolayer of amphiphilic lipid.

Liposome contain an outer bilayer of amphilphilic molecule such as phospholipid with an aqueous compartment inside.

SLN contain a solid lipid core surrounded by phospholipid

The term lipid in broad sense includes triglycerides ,partial glycerides ,fatty acids , fats

& waxes.

ADVANTAGES OF SOLID LIPID OVER LIQUID LIPID

1)Mobility of reactive agents in a solid matrix is

lower than in a liquid matrix .so that the rate of

chemical degradation reactions may be

regarded.

2)Micro phase seperations of the active ingredients &

carrier lipid within the individual liquid particles can be controlled, thereby

preventing the accumulation of active

compounds at the surface of lipid particles where

chemical degradation often occurs

3)The absorption of poorly absorbed bio active

compounds has been shown to be increased after incorporation into solid lipid nanoparticle

LIPIDS SURFACTANTS

TriglyceridesTricaprinTrimyristinTrilaurinHard fat types witepsolO W35witepsolO H35Acyl glycerolGlyceryl monostearateGlyceryl monooleateWaxesFatty acidsCetyl palmitateFatty acidsStearic acid

PhospholipidsSoy lecithinEgg lecithinEthylene oxide/propylene oxide copolymersPolyoxamer188Polyoxamer407Sorbitan ethylene oxide/propylene oxide co polymerPolysorbate20Polysorbate60Polysorbate80Bile saltsSodium cholateSodium glycholate

Use of biodegradable physiological lipids which decreases the danger of acute and chronic toxicity and avoidance of organic solvents in production method.

Improved bioavailability of poorly water soluble molecules

Site specific delivery of drugs, enhanced drug penetration into the skin via dermal application

Chemical protection of labile incorporated compound.

Large scale production is possible

Long term stability

DISADVANTAGES Poor loading capacity

Drug expulsion after polymeric transition during storage

Relatively high water content of the dispersions(70%-90%)

THERE ARE SEVERAL METHODS FOR PREPARATION OF SLN.THOSE ARE:

1)HOT HOMOGENIZATION TECHNIQUE

2)COLD HOMOGENIZATION TECHNIQUE

3)ULTRASONICATION OR HIGH SPEED HOMOGENIZATION

4)SOLVENT EMULSIFICATION-EVAPORATIO TECHNIQUE

5)SOLVENT EMULSIFICATION –DIFFUSION TECHNIQUE

6)MICRO EMULSION BASED METHOD

7)SUPERCRITICAL FLUID TECHNOOGY

a)IGA/SAS

b)PGSS

8)DOUBLE EMULSION TECHNIQUE

9)MEMBRANE CONTACTOR TECHNIQUE

8)SOLVENT INJECTION TECHNIQUE

SOLIDIFICATION OF THE NANO EMULSION BY COOLING DOWN TO ROOM TEMPERATURE TO FORM SLN

O/W –NANO EMULSION

HIGH PRESSURE HOMOGENIZATION AT A TEMPERATURE ABOVE THE LIPID MELTING POINT

PREMIX USING A STIRRER TO FORM A COARSE PRE EMULSION

MIXING OF THE PREHEATED DISPERSION MEDIUM AND DRUG LIPID MELT

DISSOLUTION OF THE DRUG IN THE MELTED LIPID

MELTING OF THE LIPID

SOLID LIPID NANOPARTICLES

DISPERSION OF THE LIPID IN THE COLD AQUEOUS DISPERSION MEDIUM

GRINDING IN A POWDER MILL(50-100 MICROMETER PARTICLES)

SOLIDIFICATION OF THE DRUG LOADED LIPID IN LIQUID NITROGEN OR DRY ICE

DISSOLUTION/SOLUBILIZATION OF THE DRUG IN THE MELTED LIPID

MELTING OF THE LIPID

ADVANTAGES:

a)Low capital cost

b)Demonstrated at lab scale

DISADVANTAGES:

a)Energy intensive process

b)Demonstrated at lab scale bimolecular damage

c)Polydisperse distribution

d)Unproven scalability

1)Drug is added to previously melt solid lipid.2)The heated aqueous phase (heated to same temperature)

is added to the melted lipid .3)Emulsified by probe sonication or by using high speed

stirrer or aqueous phase added to lipid phase drop by drop followed by magnetic stirring

4)The obtained pre emulsion is then ultrasonicated using probe sonicator with water bath(0◦).

In order to avoid recrystallization during the process the production temperature kept at least 5◦ C above the lipid melting point.

5)Emulsion is filtered through a .45 micrometer in order to remove inpurities carried in during sonication

6)SLN are produced and is stored at low temperature

Precipitate of SLN is formed

Coarse emulsion is passed through microfluidizer & organic solvent is being evaporated at room temperature under reduced pressure(e.g.rotary evaporator)

Emulsified in an aqueous phase using high speed homogenizer

Lipophilic material & hydrophobic drug are dissolved in a water immiscible organic solvent(e.g.cyclohexane,toluene,chloroform)

The solvent used(e.g. benzyl alcohol, butyl lactate) in this technique is partially miscible with water and this technique can be carried out either in aqueous phase or in oil.

Initially ,both the solvent and water are mutually saturated in order ensure the initial thermodynamic eqillibrium of both liquid

Heating is required to solubilize the lipid ,the saturationship was performed at that temperature

STEPS: a)The lipid & drugs were dissolved in water saturated solvent

b) organic phase was emulsified with solvent saturated aqueous solution containing the stabilizer

c)Formation of o/w emulsion

d)Water in typical ratio ranges 1:5 to 1:10 were added to the system in order to allow solvent diffusion into the continuous phase

e) Aggregation of the lipid in nanoparticles.

Liquid phase was pressed at a temperature above the melting point of the lipid through the membrane pore allowing the formation of small droplets.

The aqueous phase was stirred continuously and circulates tangentially inside the membrane module & sweeps away the droplets being formed

SLN were prepared after cooling at room temperature

B=tangential flow of the aqueous phase

A=lipid phase, permeation under applied pressure

There are mainly 3 drug incorporation models which describe the incorporation of drug into SLN

1)Homogenous matrix model

2)Drug enriched shell ,core shell model

3)Drug enriched core ,core shell model

DIFFERENT TYPES These are

HOMOGENOUSMATRIX

DRUG ENRICHED SHELL WITH LIPID CORE

DRUG ENRICHED CORE WITH LIPID SHELL

Obtained by incorporating highly lipophilic drugs into SLN using hot homogenization technique or cold homogenization technique.

e.g. etomidate SLN

Obtained during the

production ,when the drug partitioned to water phaseUpon cooling ,the lipid precipitates first ,forming a drug free lipid coreDrug reprecipitates in the remaining liquid lipid phase Increase in drug concentration in the outer shellCrystallization of drug enriched shelle.g. Tetracycline SLN

Cooling of the formed nanoemulsion will lead to supersaturation of drug in melted lipidIt leads to drug precipitation prior to lipid precipitationFurther cooling leads to precipitation of lipid surrounding the drug enriched core.

Parameters used for characterization are

Particle size & size distribution

Charge determination

Surface hydrophobicity

Chemical analysis of surface

Carrier drug interaction

Nanoparticle dispersion stability

Release profile

Drug stability

PHOTON CORRELATION SPECTROSCOPY: Suitable for particle size in the range of 3nm-3mm.

Method is based on the dynamic scattering of laser light due to Brownian motion.

ELECTRON MICROSCOPY: Measures individual paticles for size & its distribution

Transmission electron microscopy(TEM):Uses electrons transmitted through the sample.

Permits differentiation among nanocapsules & emulsion droplets

Scanning electron microscopy(SEM):Uses electrons transmitted from the surface of the sample

Atomic force microscopy(AFM):Measures the force acting between surface of the sample and tip of the probe.

2)DENSITY:

Helium or air using a gas pycnometer

Density gradient centrifugation

3)Molecular weight:

Gel permeation chromatography by using a refractive index detector

4)Specific surface area: specific surface area is determined by sorptometer

specific surface area=6/(Density*Diameter of the particle)

SURFACE HYDROPHOBICITY:

Regulates the extent & type of hydrophobic interactions of SLN with blood components & determines its biofate.

METHODS:

1. Hydrophobic interaction chromatography

2. Rose bengal(dye) binding

3. Water contact angle measurements

SURFACE CHARGE & ELECTRONIC MOBILITY:

1. Laser doppler anemometry

2. Zeta potentiometer

INVITRO RELEASE:

1. Dialysis technique

2. Ultrafiltration technique

NANOPARTICLE YIELD:

%Yield=(Actual weight of the product/total weight of drug & excipient)

%Drug Entrapment=(mass of the drug in nanoparticles/Mass of the drug used in formulation)*100

DRUG STABILITY: Bioassay of the drug extracted from nanoparticles

Chemical ananlysis of the drug

There are 3 laboratory scale method of purification. These are

GEL FILTRATION

•REMARKS:

•High molecular weight substances & impurities are difficult to remove

DIALYSIS

•REMARKS:• Time consuming

process

• Scaling up is difficult

• High molecular weight substances are difficult to remove

ULTRA-CENTRIFUGATION

•RE

•R

•REMARKS

• Aggregation of the particle

• Time consuming process

INDUSTRIAL STAND POINT METHOD:

Known as cross fitration method

Nano particle suspension is filtered through membrane,with the direction of the fluid being tangential to the surface of he membrane

Clogging is avoided

STEALTH SLNs are one kind of shielded SLN , produced to avoid opsonization & to prolong circulation lifetime

The hydrophilic & flexible polymer coating on SLN is thought mask the surface from opsonins.

STEALTHING AGENTS:

1. Dipalmitoyl phosphatidylethanolamine-PEG-2000

2. Stearic acid-PEG2000

3. Polyoxamer

PEG-2000 represents hydrophilic part & long PEG form hydrophilic cloud over SLN & protect the nanoparticle by steric repulsion or lowering protein adsorption

APPLICATION PURPOSE MATERIAL

1. Cancer therapy

2. Intracellular tergating

3. Prolonged systemic circulation

1. Targeting ,reduced toxicity, enhanced uptake of anti cancer drug, improved in vitro & in vivo stability

2. Target reticulo endothelial systems for intracellular infections

3. Prolonged systemic drug effect ,avoid uptake by reticuloendothelial system

1. Poly(alkylcyanoacrylate) nanoparticles with anticancer agents ,oligonucleotides

2. Poly(alkylcyanoacrylate) polyester nanoparticles with anti parasistic or anti viral agents

3. Polyesters with adsorbed polyethylene glycols or pluronics or derivatized polyesters

APPLICATION* PURPOSE MATERIAL

4)Vaccine adjuvant

5)Peroral absorption

6)DNA Delivery

7)Oligonucleotide delivery

4)Enhances immune response ,alternate acceptable adjuvant

5)Enhanced bio availability ,protection from GI enzymes

6)Enhanced delivery & significantly higher expression level

7)Enhanced delivery of oligonucleotide

4)Poly(methyl methacrylate) nanoparticles with vaccines(oral & intramuscular immunization)

5)Poly (methylmethacrylate) nanoparticles with protein & therapeutic agents

6)DNA –gelatin nanoparticle, DNA –chitosan nanoparticle ,PDNA –(DL-lactide-co-glycolide) nanoparticle)7)Alginate poly(D,L),Lactic acid nanoparticles