Effect of formulation variableson solid lipid nanoparticles

Presented byMs. Amruta Sunil Ner

Guided byDr. Mrs. A. R. Madgulkar

AISSMS COLLEGE OF PHARMACY, PUNE-01

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Contents:Introduction to SLNsMethods of preparationFormulation variables which affect SLNs Properties affected by formulation variablesStabilityApplications

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Introduction:Definition:Nanoparticles: nanoparticles are solid colloidal

particles which ranging in size from 10 to 1000nm (1 μm). They consist of macromolecular materials such as adjuvant in vaccines or drug carriers in which the active principle (the drug or biologically active material) is dissolved, entrapped or encapsulated or to which active principle is adsorbed or attached.

Solid lipid nanoparticles: solid lipid nanoparticles are colloidal carriers which consist of spherical solid lipid particles in nanometer range. They are made up of lipid(s), emulsifier(s) and water.

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Advantages of SLN:Controlled drug releaseTargeting of drugIncreased drug stabilityHigh drug loading capacityLess toxicAvoidance of organic solventsProtection of drugLarge scale productionWide spectrum of application.

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Disadvantages:Particle growth.

Unpredictable gelation tendency.

Unexpected dynamics of polymorphic transitions.

Inherent low incorporation rate due to the

crystalline structure of the solid lipid.

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Components of solid lipid nanoparticles: Lipids: Selection of lipid is based on solubility of

drug in various Lipids. There are various lipid are used like Stearic acid, Glyceryl monostearate, Compritol ATO888(Glyceryl behenate),Precirol ATO5(Glyceryl palmitostearate),Gelucire, Emulcire.

Surfactants: Various lipophilic and hydrophilic surfactants are used. lipophilic surfactants are used to enhance drug solubility in lipid. Hydrophilic surfactants used to stabilize the formulation.Lipophilic surfactants: Span 60,Sodium cholate, Soya lecithin.Hydrophilic surfactants: Tween 80,Poloxamer 188.

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Types of solid lipid nanoparticles: The type of SLNs depends:The chemical nature of the active ingredient and

lipid, The solubility of actives in the melted lipid,Nature and concentration of surfactants, Type of production (hot vs. cold HPH), and the

production temperature.Fig. structural models for drug loading profiles in

SLNs

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Drug release: Types:

• Control release

• Burst release

• Enzyme dependent release

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Controlled release:

• This type of release showed with a uniform drug profile throughout the lipid shell or an enriched ‘core’.

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Burst release:

Affected by 2 factors:

• Processing temperature

• Concentration of surfactant

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Enzyme release:

• Enzymatic release of drug from SLN takes place by lipase/ colipase complex.

• Components accelerating degradation-Cholic acid sodium saltTween 80

• Components preventing degradation-Waxes (cetyl palmitate)Poloxamer 407

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Methods of SLN preparation: A. Mechanical methods: High shear homogenizationHigh pressure homogenizationUltrasonication

B. Chemical methods:Solvent evaporationMicroemulsions

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A. High pressure homogenization:Principle: It is based on principles of fluid

mechanics to produce extremely high fluid pressures, and, thus energy dissipation rates in the form of high shear stresses and cavitation forces that act to reduce the size of dispersed phase in emulsions.

• Two types:1.Hot pressure homogenization2.Cold pressure homogenization

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B. Probe sonication method:

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C) Micro-emulsion dilution method:Preparation of micro-emulsionDilution of micro-emulsion into near freezing

temperature at ratios of 1:25-1:50 to cold water to form lipid nanoparticles.

D) Solvent evaporation method:Lipid with drug mixed with water immiscible

solvent and then emulsified with water.Emulsion is then subject to reduced pressure

to evaporate solvent and precipitate lipid particles as aqueous dispersion.

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Methods of Preparation Strengths weaknessesHot Pressure homogenization Scalable

Mature technology Continuous operation Commercially

demonstrated

Extremely energy intensive process

Polydisperse distributions Biomolecule damage Not used for thermolabile

drugCold pressure homogenization Mature technology

Continuous operation Commercially

demonstrated Mainly used for the

thermolabile and hydrophilic drugs

Extremely energy intensive process

Polydisperse distributions Biomolecule damage

Ultrasonication Reduced shear stress Metal contamination potential

Energy intensive process Polydisperse distributions

Microemulsion dilution Low mechanical energy input

Theoretical stability

Extremely sensitive to change

Labor intensive formulation work

Low nanoparticles concentrations

Solvent evaporation No dilution solidification Residual organic solvent

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Formulation variables which affect SLN:

Lipids

Surfactants

Processing parameters (stirring time, stirring rate,

rate of cooling,

temperature)

Drug

Spray drying

Lyophilization

sterilization18

Factors which are affected by formulation variables:Particle size

Polydispersity index (P.I.)

Zeta potential

% entrapment efficiency

drug release

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Lipids:Properties of lipids which affect SLNs:

Melting point of lipid

Concentration of lipid

Composition of lipids

Combination of lipids

Lipid crystallinity

Chemistry of lipids

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Effect of lipid melting point (M.P.) on processing parameter

(In homogenization method)

lipid Stirring time Stirring rate Optimum cooling condition

Witepsol W 35(M.P. 450c)

8 minute 20,000 rpm 10 minute(in room temperature)

Dynasan 116(M.P. 640c)

10 minute 25,000 rpm 5 minute(in cool water)

Lipid crystalline state:Crystallization is a balance between attractive

intermolecular forces and entropic factors. SLNs exhibits in various crystalline structure:

1. α-form.2. β′-form.3. β -form.4. Super cooled melt

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Lipid crystallization depends on:• Rate of cooling• type of hydrophobic group in surfactant.

Lipid crystallization mainly affects:• Drug incorporation • Drug release characteristics.

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Effect of lipid matrix on drug release:

Different lipids give different release kinetics.

Example:

Release rate decreases in following order-

Triglyceryl stearate > triglyceryl palmitate >

myristin.

• Effect of waxes on drug release:

• Example – cetyl palmitate

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Effect of surfactants:Effects are due to:

• Temperature • Surfactant mixture/ cosurfactants, surfactant to cosurfactant molar ratio• HLB number• Surfactant number (CPP)• Amount of emulsifier, surfactant to lipid

molar ratio• Molecular weight and speed of redistribution• Varying rates of adsorption onto interface

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Effect of temperature: Ionic surfactants: becomes more hydrophilic.Non ionic surfactants: becomes more hydrophobic.

Effect of surfactant mixture on particle size:

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surfactant Particle size before freezing

Particle size after freezing

Tween 80(100%) 487.7 1459.7

Egg PC(100%) 397.1 440.3

Tween 80: Egg PC (46:56)

227.2 329.5

Effect of cosurfactant selection on lipid nanoparticle characteristics:

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cosurfactant Particle size (nm)

Polydispersity index

Sodium taurocholate

99 0.30

Sodium glycocholate

110 0.01

cholesterol 620 0.01

Effect of concentration of surfactant on:

Particle size

% entrapment efficiency

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Steric stabilizers:Ex. Poloxamer 407 PEG poloxamine 908Effect due ethylene oxide/ propylene oxide

copolymers

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Example No. of ethylene oxide chains

Molecular weight

Adsorbed layer thickness

Poloxamer 407 98 11500 12nm

Tween 80 20 1840 2nm

• Effect of type of surfactants on drug release:

• Effect on enzymatic release:• Enzymatic release of SLN takes place by lipase/

colipase complex

• Components accelerating degradation- Cholic acid sodium salt(bile salt) Tween 80(ethylene oxide propylene oxide copolymer)

• Components preventing degradation- Poloxamer 407(ethylene oxide propylene oxide

copolymer)

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Drug: Effect of drug nature:

• Lipophilic drug

• Hydrophilic drug

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Processing parameters:• Homogenization cycles

• Stirring time

• Stirring rate

• Rate of cooling

• Processing temperature

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Effect of processing temperature on:• Particle size• Degradation• Drug distribution• Increase of processing temperature causes

burst release to take place.1. burst release:Fig. drug enriched shell model

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Lyophilization:Following points considered:• Effect of drug• Effect of lipid content• Selection of cryoprotector• Concentration of cryoprotector• Time of addition of cryoprotector Effect of rate of cooling:• Rapid cooling- gives small crystals• Slow cooling- gives larger crystals

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Spray drying:• During spray drying particle aggregation is

the main problem.• Points to be considered to avoid particle

aggregation:

Selection of lipids

Concentration of lipids

Addition of carbohydrates

Use of ethanol-water mixture

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Sterilization:Autoclaving: Effect of surfactant- Poloxamer 188 Lecithin

Sterile filtration: use it if particle size is less than 200nm.

Gamma irradiation

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Stability: Properties considered:• Particle size distribution (increase particle

size, gelation)• Lipid crystallization state

Stability studies performed for effect of: • Light • Temperature• Packaging material

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• Example: poloxamer 188 stabilized compritol SLN:

• Stability achieved by: Temperature- 8oC Light- dark Container-siliconized vials.

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Effect of lipids and surfactants on SLNs stability:

Speed of lipid crystallinity and surfactant properties affect speed of degradation of SLNs.

Example:

degradation velocity can be modulated by changing surfactant ratio:

Degradation velocity: Cholic acid > Lipoid E 80 > Tween 80 >

Poloxamer 407. 39

Lipid Surfactant

1. Dynasan 116(Tripalmitin)

M.P.(640c)

1. Poloxamer 407

2. Dynasan 114(Trimyristin) M.P.(560c)

2. Sodium cholate

Applications:SLN can be given by various routs as follows:

• Oral route

• Intravenous route

• Transdermal route

• Occular route.

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References:1. Muller RH, Mäder K. Gohla S. Solid lipid

nanoparticles (SLN) for controlled drug delivery - A review of the state of art. Eur. J. Pharm. Biopharm 2000;50: 161-177.

2. Khar RK, Vyas SP. Targeted and Controlled Drug Delivery. CBS Publishers & Distributors.1st Edi,Vol.II,2002, 331-383.

3. Manjunath K, Reddy JS, Venkateswarlu V. Solid lipid nanoparticles as drug delivery systems. Methods Find. Exp. Clin. Pharmacol. 2005; 27:127-144. 

4. Mehnert W, Mäder K. Solid lipid nanoparticles - Production, characterization and applications. Adv. Drug Deliv. Rev 2001; 47:165-196.

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References:5) Gupta R.B., Kompella U.B., Nanoparticle technology for

drug delivery, Taylor and Francis group,Vol.159,pg no.1-45.

6) Tassu D., Deelers M., Pathak Y., Nanoparticulates drug delivery systems., Taylor and Francis group,Vol.166,pg no.89-98.

7) ) Freitas C, Muller RH, “Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle dispersions”, Int. J. Pharm., 168, 1998, 221-228.

8) Olbrich C, Muller RH, “Enzymatic degradation of SLN- effect of surfactant and surfactant mixtures”, Int. J. Pharm., 180, 1999, 31-39.

9) Attama AA, Christel C, Muller- Goymann, “Effect of beeswax modification on the lipid matrix and solid lipid nanoparticle crystallinity”, Colloids and Surfaces A: Physicochem. Eng. Aspects, 315, 2008, 189- 195.

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Thank you…