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SOLID LIPID NANOPARTICLES

Content::

Content: Introduction of Nanoparticles Solid lipid Nanoparticles Advantage &

disadvantages of SLNs Methods of Preparation Sterilization Criteria Characterization
of SLNs Applications of SLNs References 2

Introduction :

Introduction NANOTECHNOLOGY comprises technological developments on the

nanometer scale, usually 0.1 to 100 nm. Nanotechnology , the science of the small.
Nano is Greek for dwarf, and nanoscience deals with the study of molecular and
atomic particles. The application of nanotechnology in pharmaceutical field includes
formulation of Nanoparticles , Nanosuspension , Nanospheres , Nanocapsules , and
Nanoemulsion . NANOSUSPENSIONS : They are colloidal dispersions of nanosized
drug particle that are produced by suitable method and stabilized by suitable
stabilizer . NANOPARTICLES : They are solid colloidal particles sized from 30-100
nm . NANOSPHERES : Polymer matrices in which drug is dissolved or dispersed .
NANOCAPSULES : C onsists of polymer wall entrapping an oily core in which the
drug is dissolved

HISTORY -Nanoparticles as a drug delivery vehicle were first developed by Spieser

and co-workers in the late 1960s. -In early 1970s the cross linked polyacrylamide
nanoparticles were produced. -Scheffel et al. developed a process for production of
radiolabelled albumin particles for imaging purpose in nuclear medicines. -Widder et
al incorporated magnetic particles into the nanoparticles for targeting of these
particles by means of magnetic field. . :

H ISTORY - Nanoparticles as a drug delivery vehicle were first developed by Spieser

and co-wor kers in the late 1960s. -In early 1970s the cross linked polyacrylamide
nanoparticles were produced. -Scheffel et al. developed a process for production of
radiolabelled albumin particles for imaging purpose in nuclear medicines. -Widder e t
a l incorporated magnetic particles into the nanoparticles for targeting of these
particles by means of magnetic field. . NANOPARTICLES : Nanoparticles are
particles made of natural or synthetic polymers ranging in size from 50 to 500 nm.
They consist of macromolecular materials in which the active principle ( drug or
biologically active material ) is dissolved, entrapped, and or to which the active
principle is adsorbed or attached.

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there are mainly 2 type of nanoparticles NANOPARTICLES Nanospheres are solid

core spherical particulates, which contain drug embedded within the matrix or
adsorbed onto the surface.(Matrix type) Nanocapsules are vesicular system in which
drug is essentially encapsulated within the central core surronded by a polymeric
sheath.(Reservoir type) MATRIX type RESERVIOR type NANOSPHERES
NANOCAPSULES

.:

. NANOPARTICULATE CARRIERS NANOSHELLS DENDRIMERS QUANTUM

DOTS CARBON NANOTUBES SOLID LIPID NANOPARTICLES LIPOSOMES
NIOSOMES POLYMERIC NANOPARTICLES

Solid lipid nanoparticles:

Solid lipid nanoparticles The solid lipid nanoparticles (SLN’s) are submicron colloidal
carriers which are composed of physiological lipid, dispersed in water or in an
aqueous surfactant solution. They consist of macromolecular materials in which the
active principle ( drug or biologically active material ) is dissolved, entrapped, and or
to which the active principle is adsorbed or attached. Nanoparticles are particles
made of natural or synthetic polymers ranging in size from 50 to 500 nm. No
potential toxicity problems as organic solvents are not used. SLNs are new
generation of submicron sized lipid emulsion where the liquid lipid(oil) has been
substituted by a solid lipid. Phospholipids monolayer

Advantages:

Advantages Small size & narrow size distribution provides for site specific drug
delivery by SLNs Controlled release of active drug over a long period can be
achieved Protection of incorporated drug against chemical degradation SLNs can be
lyophilized & spray dried No toxic metabolites are produced Sterilization can be done
by autoclaving or gamma irradiation Surface modification can be easily done

Disadvantages::

Disadvantages: 9 Drug Loading capacity is limited High pressure induce drug

degradation Coexistences of several colloidal species Lipid crystallization & drug
incorporation - supercooled melts - gelation phenomenon Drug expulsion

Types and proposed structured of SLN:

Types and proposed structured of SLN According to drug incorporation mechanism,

SLN based system can classified into: Classical SLN Lipid drug conjugate (LDC)
Nonostructured lipid carriers (NLC) Polymer-lipid hybrid SLN (PLN) 10

Classical SLN:
Classical SLN Based on the difference melting point (MP) between drug and lipid
matrix together with consideration on the release kinetics of SLN, 3 hypothetical
model : Solid solution model – M.P. drug ≈ M.P. lipid Core-shell model, drug
enriched shell- M.P. drug < M.P. lipid 11

3) Core-shell model, drug-enriched core.:

3) Core-shell model, drug-enriched core. 12 Lipid drug conjugates (LDC) It should

similar to classical SLN with the loaded drug evenly distributed within the lipid matrix
because they are directly bonded to the lipid molecule M.P. drug > M.P. lipid

Nonostructured lipid carriers (NLC):

Nonostructured lipid carriers (NLC) In this case, the lipid matrix is composed of
binary mixture of a solid lipid and a medium chain triglyceride or liquid oil. Based on
the lipid matrix of NLC, Jenning et al. proposed two drug model : In the first model,
liquid oil molecularly dispersed within the solid lipid matrix when the concentration of
the liquid oil is below its solubility in the liquid. In the second model, liquid oil is
distributed in the solid lipid in droplet form. 13

Polymer-lipid hybrid Nanoparticle (PLN):

Polymer-lipid hybrid Nanoparticle (PLN) In order to deliver the hydrophilic drugs with
a high drug loading capacity and simultaneously control the kinetics of SLN, a new
variation SLN, PLN was developed . + D + D+ D+ D + D+ Water-soluble Water-
soluble drug-polymer drug loaded polymer-lipid Counter polymer ionic drug complex
hybrid nanoparticle Proposed formation mechanism & structure of polymer-lipid
hybrid Nanoparticles (PLN) 14 D+

Composition of SLNs:

Composition of SLNs General ingredients include solid lipid, surfactant, co-surfactant

& water Lipid used may be triglycerides (eg. Tristearin, Tripalmitin , Trimyristin)
partial glycerides (glyceryl monostearate, glyceryl behenate,) fatty acids (eg. stearic
acid, Lauric acid etc) waxes (ex- carnauba wax) Charge modifier may be used, eg.
stearylamine Combination of surfactant enhances stability by preventing particle
agglomeration Surfactant eg. soybean lecithin, egg lecithin, Poloxamers etc. 15

Method of preparation::

Method of preparation : High pressure homogenization: Hot homogenization Cold

homogenization Ultrasonication /high speed homogenization: Solvent
emulsification/evaporation Micro emulsion based SLN preparations SLN preparation
by using supercritical fluid Spray drying method 16
Hot homogenization:

Hot homogenization Melting of the lipid & dissolving/dispersing of the drug in the lipid
Dispersing of the drug loaded lipid in a hot aqueous surfactant mixture. Premix using
a stirrer to form a coarse preemulsion High pressure homogenization at a
temperature above the lipid M.P. Hot O/W nanoemulsion Solid Lipid Nanoparticles
Disadvantages: 1) temperature induce drug degradation 2) partioning effect 3)
complexity of the crystallization 17

Cold homogenization:

Cold homogenization Melting of lipid & dissolving/dispersing of the drug in the lipid
Solidification of the drug loaded lipid in liquid nitrogen or dry ice Grinding in a powder
mill Dispersing the powder in a aqueous surfactant dispersion medium High pressure
homogenization at room temperature or below. Solid Lipid Nanoparticles
Disadvantages: 1) Larger particle sizes & broader size distribution 2) does not avoid
thermal exposure but minimizes it 18

Ultrasonication/ high speed homogenization ::

Ultrasonication/ high speed homogenization : SLN were also developed by high

speed stirring or sonication Adv. : 1) Equipment used is very common 2) No
temperature induced drug degradation Disadv .: 1) Potential metal contamination 2)
Broader particle size distribution ranging into micrometer range. 19

Solvent emulsification/ evaporation ::

Solvent emulsification/ evaporation : Lipophilic material is dissolved in a water

immiscible organic solvent ( e.g.cyclohexane ) that is emulsified in an aqueous
phase. Upon evaporation of solvent, a nanoparticle dispersion is formed by
precipitation of lipid in aq. Medium. The mean diameter of the obtained particles was
25 nm with cholesterol acetate as model drug and lecithin/sodium glycocholate blend
as emulsifier. Adv:- Avoidance of any thermal stress. Disadv:- use of organic
solvents. 20

Micro emulsion based SLN preparations:

Micro emulsion based SLN preparations Preparation by stirring optically transparent

mixture at 65-70 o c composed of a low melting fatty acid, emulsifier, coemulsifier &
water. This hot microemulsion dispersed in cold water (2-3 o c) & stirring . By using
Supercritical fluid Can be prepared by Rapid Expansion of Supercritical Carbon
dioxide solution methods(RESS) Carbon dioxide with 99.99% is good solvent. Adv:-
1) Solvent less processing. 21

By Spray drying method:

By Spray drying method Alternative procedure to lyophilization in in order to
transform an aqueous SLN dispersion into a drug product. Disadvantages:- 1)
particle aggregation due to high temp., shear forces & partial melting of particles. 2)
Recommended use of lipid with M.P. >70 0 c for spray drying. 22

Sterilization of SLNs:

Sterilization of SLNs For parentral & ocular administration SLNs must be sterile. For
lecithin stabilized SLNs autoclaving is possible & it is not possible for sterically
stabilized polymers. Physical stability during autoclave can not be stated, it depends
on composition. SLN dispersion can also be sterilized by filtration. 23

Characterization of SLNs::

Characterization of SLNs: [I] Measurement of particle size Photon correlation

spectroscopy Transmission electron microscopy Scanning electron microscopy [II]
Measurement of Zeta Potential Allows predictions about the storage stability of
colloidal dispersion Zeta potential under 30 mV are required for full electrostatic
stabilization . 24

[III] Molecular weight :

[III] Molecular weight Gel chromatography Atomic force microscopy [IV] Surface
element analysis X-ray photoelectron spectroscopy Electrophoresis Laser Doppler
anaemometry [V] Density Helium compression pychnometry Contact angle
measurement 25

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[VI] Molecular analysis H-NMR Infra red analysis [VI] Measurement of Crystallinity ,
Lipid modification DSC and X-ray scattering used to investigate status of lipid 26

APPLICATIONS:

APPLICATIONS Solid lipid Nanoparticles possesses a better stability and ease of up

grad ability to production scale as compared to liposomes . SLNs form the basis of
colloidal drug delivery systems, which are biodegradable and capable of being
stored for at least one year . 27

SLNS AS COSMECEUTICALS:

SLNS AS COSMECEUTICALS Applied in the preparation of sunscreens. SLN has

UV reflecting properties. ORAL SLN IN ANTITUBERCULAR THERAPY Anti-
tubercular drugs such as rifampicin , isoniazide , loaded SLNs able to decrease
dosing frequency and increase bioavailability. SLN AS A GENE VECTOR CARRIER
Several recent reports of SLN carrying genetic materials such as DNA, plasmid
DNA, & other nucleic acid have been reported. 28

SLNS FOR POTENTIAL AGRICULTURE ::

SLNS FOR POTENTIAL AGRICULTURE : Essential oil in SLN, were able to reduce
the rapid evaporation compared with emulsions. The systems have been used in
agriculture as a suitable carrier of ecologically safe pesticides. POTENTIAL OF SLN
IN BRAIN TARGETING: SLNs taken up readily by the brain due to their lipidic nature
by passing the BBB via CTZ. High potential to treat brain cancer. New formulations
of neuroactive drugs into SLN are expected to improve their pharmacokinetic profile.
29

SLNs AS A TARGETED CARRIER FOR ANTICANCER DRUG TO SOLID

TUMORS:

SLNs AS A TARGETED CARRIER FOR ANTICANCER DRUG TO SOLID TUMORS

SLNs have been reported to be useful as drug carriers to treat neoplasm. Tamoxifen,
anticancer drug incorporated in SLN to prolong release of drug after i.v.
administration in breast cancer and to enhance the permeability and retention effect.
Tumors targeting has been achieved with SLNs loaded with drugs like methotrexate
and camptothecin. 30

SLNS IN BREAST CANCER AND LYMPH NODE METASTASES::

SLNS IN BREAST CANCER AND LYMPH NODE METASTASES : Mitoxantrone-

loaded SLN local injections were formulated to reduce the toxicity and improve the
safety and bioavailability of drug. Efficacy of doxorubicin (Dox) has been reported to
be enhanced by incorporation in SLNs. In the methodology the Dox was complexed
with soybean-oil-based anionic polymer and dispersed together with a lipid in water
to form Dox-loaded solid lipid nanoparticles. 31