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FORMULATION APPROACHES AND DEVELOPMENT OF NANOSTRUCTURED

LIPID CARRIER

Presented By

Mr. Rahul S. DalviM. Pharm. (SEM – II)Dept. of Pharmaceutics

Guided By

Dr. A. J. ShindeAsso. Professor Dept. of Pharmaceutics

BHARATI VIDYAPEETH COLLEGE OF PHARMACY, KOLHAPUR

2015-2016

Date:12/03/2016

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Contents Introduction

Types of NLC

Composition

Method of preparation

Characterization methods

Marketed products

Conclusion

References

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Introduction Lipid nanoparticles.

Second generation lipid nanoparticles.

Produced from blends of solid lipids and liquid lipids.

The blends obtained are also solid at room temperature and body

temperature.

Solid lipids are mixed with liquid lipids preferably in the ratio of

70:30 up to a ratio of 99.9:0.1.

Has lipid matrix with a special nanostructure which improve drug

loading and firmly incorporate the drug during storage.

Can be administered via oral, ocular, topical and intravenous

route.

Nanostructured Lipid Carrier ( NLC )

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Limitations Poor drug loading capacity.

Drug expulsion after polymeric transition during storage.

Relatively high water content of the dispersions (70-99.9%)

The low capacity to load water soluble drugs due to

partitioning effects during the production process.

NLC overcome these limitations

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Advantages Better physical stability.

Ease of preparation and scale-up.

Increased dispersability in an aqueous medium.

High entrapment of lipophilic drugs and hydrophilic drugs.

Controlled particle size.

An advanced and efficient carrier system in particular for

substances.

Increase of skin occlusion.

Extended release of the drug.

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Types of NLC Type 1: Imperfect type NLC Solid and liquid lipids are blended.

Small amount of liquid lipid.

The difference in the structures of the lipids and special

requirements in the crystallization process lead to a highly

disordered, imperfect lipid matrix structure offering space for drug

molecules and clusters of drugs.

Drug

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Type 2: Multiple type NLC The multiple oil/fat/water, drug can be accomodated in the solid,

but at increased solubility in the oily parts of the lipid matrix.

At high oil concentrations a miscibility gap of two lipids occurs

during the cooling phase, leading to phase separation, that means

precipitation of tiny oily nano compartments.

Drug

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Type 3: Amorphous type NLC Lipids are mixed in a way that prevents them from crystallizing.

The lipid matrix is solid but, in a amorphous state.

e g. Hydroxy octacosanylhydroxystearate.

Drug

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Composition

Lipids

Water

Emulsifier

Main Components of

NLC

Components Ingredients Materials Solid lipids Tristearin, stearic acid, cetyl palmitate, cholesterol,

Precirol® ATO 5, Compritol® 888 ATO, Dynasan®116, Dynasan® 118, Softisan® 154, Cutina® CP, Imwitor® 900 P, Geleol®, Gelot® 64, Emulcire® 61

Liquid lipids

Medium chain triglycerides, paraffin oil, 2-octyl dodecanol, oleic acid, squalene, isopropyl myristate,vitamin E, Miglyol® 812, Transcutol® HP, Labrafil Lipofile® WL 1349, Labrafac® PG, Lauroglycol® FCC,Capryol® 90

Hydrophilic emulsifier

Pluronic® F68 (poloxamer 188), Pluronic® F127 (poloxamer 407), Tween 20, Tween 40, Tween 80,polyvinyl alcohol, Solutol® HS15, trehalose, sodium deoxycholate, sodium glycocholate, sodium oleate,polyglycerol methyl glucose distearate

Lipophilic emulsifier

Myverol® 18-04K, Span 20, Span 40, Span 60

Amphiphilic emulsifier

Egg lecithin, soya lecithin, phosphatidylcholines, phosphatidylethanolamines, Gelucire® 50/13

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Method of Preparation Homogenization technique

Solvent evaporation technique

Microemulsion technique

Melting Dispersion Technique

Double emulsion technique

Spray Drying

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Homogenization techniques

Constant stirring with high shear device

Cool at room temperature

Use of piston gap homogenizer

Hot homogenization

Drug dispersed in lipid melt

Then rapid refrigeration

Use of ice or liquid nitrogen

Cold homogenization

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Factors Affecting technique

High temperature, low viscosity of lipid melt, lower particle size,

can lead to degradation of drug and carrier.

High homogenization, high kinetic energy of particles, particle

coalescence, higher particle size.

Factors

Temperature Homogenization speed

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Solvent Evaporation Technique

Drug Lipid

_-_-_-_-_-_-_-_-

_-_-_

H2O immiscible organic solvent

-_-_-_-_-_-_-

_-_-_-_

Emulsification with HPH

Micro fluidizer

Evaporation of organic solvent (at room temperature and reduced pressure)

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Concentration of lipid in organic solvent dictates particle size

Low lipid load, small particle size

Incorporation of thermolabile drugs

Disadvantages: use of organic solvent may interact with drug,

limited solubility of lipid in organic solvent.

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Microemulsion Technique The lipids are melted

Drug incorporated in molten lipid

A mixture is heated

Adding the melted lipid

Stirring

Transparent and thermodynamically are mixed

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Melting Dispersion Technique Melting of drug and lipids in organic solvent(oil phase)

Simultaneous heating of water at same temperature.

Addition of oil phase in small volume of water with stirring at

higher rpm for few hours.

Cooling down to room temperature.

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Double Emulsion Technique Drug dissolved in aqueous phase.

Then emulsification in melted lipids: Primary emulsion.

Add stabilizer: stabilized primary emulsion.

Dispersion in aq. phase containing hydrophilic emulsifier.

This double emulsion is stirred and filtered.

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Spray Drying Colloidal dispersion of NLC is spray dried

Cheaper than lyophilization

Disadvantages:

Particle aggregation due to high temperature

Shear forces

Partial melting of particles

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Characterization

Particle Size: Photon Correlation Spectroscopy

Zeta potential

Electron microscopy: SEM, TEM, AFM

Surface tension: Wilhemy plate method

DSC: Crystallinity

X-Ray Diffraction: Crystallinity

NMR: Mobility of materials in inner core of NLC

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Drug entrapment efficiency: Ultrafiltration, ultracentrifugation,

filtration by sephadex and dialysis

Drug release: Franz cell

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Case StudyTitle : ‘Nanostructured Lipid Carrier Gel for Topical Delivery of

Ketoconazole’

API : Ketoconazole

Other excipients : Compritol 888@ ATO, Precirol@ ATO 5, Stearic

acid, Clove oil, Tween 80, Transcutol P, Ethanol, Carbopol 934, etc.

Experimental and Evaluation Parameters

Preformulation study

Screening of surfactuctant and co-surfactuctant system

Preparation of NLCFormulation concentrations for NLC

Factorial design

Formulation development

Preparation of KNLC

KNLC were prepared by using mechanical agitation method. Method uses

ketoconazole in 200 mg and 400 mg concentration, 40 mg/ml and 20 mg/ml of

clove oil and 160 mg/ml and 80 mg/ml of solid lipid compritol 888 ATO.

Surfactant, co-surfactant system included tween 80 (0.3% w/v) and triton X-

100 (0.1% w/v) were used for KNLC. Antisolvent volume was 50 ml.

Preparation of KNLC Gel

KNLC gel was prepared by using mechanical agitation method. Method uses

KNLC system of volume 50 ml and carbomer 934 was used as gelling agent at

concentration 1.5%.

Evaluation and optimization of Ketoconazole NLC

Crystallographic investigations

Evaluation of Ketoconazole NLC Gel

Accelerated stability studies

Accelerated stability study carried out for three months period at 250C ±

2˚c/ 75 % ±5% RH. Sampling has been done after three months period.

These gels were evaluated for in vitro drug release study (ICH Q1A (R2) .

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Marketed ProductsProducts Producer

Cutanova Dr. Rimpler

SuperVital cream IOPE

Surmer Isabella Lancray

NanoLipid Restore CLR Chemisches Laboratorium Dr. Kurt Richter GmbH

NanoLipid Q 10 CLR Chemisches Laboratorium Dr. Kurt Richter GmbH

NanoRepair Q 10 Dr. Rimpler

NanoVital Dr. Rimpler

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Conclusion The lipid nanoparticles – NLC are carrier systems with good

perspectives to be marketed very successfully.

The reason for this is that they were developed considering

industrial needs e.g. scale up, qualification and validation,

simple technology, low cost, tolerability

NLCs can generally be applied where solid nanoparticles

possess advantages for the delivery of drugs.

NLCs are used in topical drug delivery, oral and parenteral

administration. They also have used in cosmetics, food and

agricultural products.

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References Mishra B, Patel BB, Tiwari S, Colloidal nanocarriers: a

review on formulation technology, types and applications

toward targeted drug delivery, Nanomedicine. 2010; 6: 9– 24.

Muller, R. H. et al., Solid lipid nanoparticles (SLN) for

controlled drug delivery – a review of the state of the art, Eur.

J. Pharm. Biopharm. 50, 161-177, 2000.

Carli, F., Physical Chemistry and Oral Absorption of the

Nanoparticulate Systems, 1999,158-160.

Joshi, M., Patravale, V., Nanostructured lipid carrier (NLC)

based gel of celecoxib, Int J Pharm, 2008, 346(1-2):124-32.

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