Particulate Systems

Particulate drug delivery
Drug Delivery Carriers

Particulate Drug Delivery
Microparticles
Microspheres
Microcapsules
Micro beads
Micro granules
Nanoparticles
Nanospheres
Nanocapsules
Liposomes
Dendrimers
GENERAL MERITS
Selective targeting
Organs
Pathogens
Cancer Cells
Protects deliverable
Less Medicine Wasted
Controlled drug release
Localization at region
Improves bioavailability
Prolongs residence time at site of application
Types
Nonbiodegradable
ceramic particles
polyethylene co-vinyl acetate
polymethacrylic acid/PEG
Biodegradable (preferred)
gelatin
polylactic-co-glycolic acid (PLGA)
Mode of release / Features
Hydrophilic (i.e. gelatin)

best for burst release
Hydrophobic (i.e. PLGA)
good sustained release (esp. vaccines)
tends to denature proteins
Hybrid (amphipathic)
good sustained release
keeps proteins native/active
Release Mechanisms
Rate of drug release depends on:

Size of drug
Solubility of drug
Molecular weight of polymer
Composition of polymer
Nanoparticles
Nanoparticles are Particulate Drug delivery systems
with a size range of 10 - 1000 nm in which the
drug may be dispersed, encapsulated or adsorbed.
Nanoparticles are subdivided into two main groups.

1) Nanospheres 2) Nanocapsules
Nanospheres are small solid monolithic spheres

constituted of a dense solid polymeric network.
Nanocapsules are small reservoirs consisting of a

central cavity surrounded by a polymeric membrane.
NANOPARTICLE STRUCTURES
Definitions- Particle Size
Nano = Ultrafine = < 100 nm

(Conventional)
Nano = <10 nm (suggested by unique
quantum and surface-specific functions)
Fine = 100 nm - 3 m
Respirable (rat) = < 3 m (max = 5 m)
Respirable (human) = < 5 m (max = 10
m)
Inhalable (human) = ~ 10 - 50 m
Potential bio-uptake of nanoscale
particulates
Nanoparticles may enter living cells

via:
Endocytosis
Receptor activation for initiation
Membrane penetration
Generally occurs with very
hydrophobic particles
Transmembrane channels
May be seen with very small
nanoparticles (< 5 nm)
Nanoparticles for drug delivery
The particles should be able to protect the
drug in-vivo
The particle should be able to chemically

sustain in the entire pathway
Site of administration to targeted site
The particle should be able to release the

drug at the targeted site
The particle should be eliminated from the

body after delivery
Nanoparticles for drug delivery
The material should be biocompatible
The material should be biodegradable &/or

bioeliminable
The material should be non-antigenic
The particle surface should be amenable to

chemical modifications
The particle should be able to encapsulate

as much drug as possible
Advantages of nanoparticles as drug
carriers
Large surface-to-volume ratio
resulting enhanced interaction sites
Surface functionalization for targeting
Suitable encapsulation
Release drugs in controlled manner
More efficient uptake by cells

Advantages of local drug
release
Lower doses required
Greater control over toxicity and bioavailability of

dose
Extended duration of release
Possibilities to combine local and systemic drugs

with different kinetics
Controlled release directly to site
Avoidance of systemic drug exposure

ROUTES OF ADMINISTRATION
PARENTERAL
ORAL
OCULAR
TOPICAL
BUCCAL
NASAL
PULMONARY
Nanoparticles for Drug Delivery
Metal-based nanoparticles
Lipid-based nanoparticles
Polymer-based nanoparticles
Biological nanoparticles
NANOPARTICLE COMPONENTS
INORGANIC MATERIALS
Polymers:
Natural (chitosan, sodium alginate, agarose)
Synthetic (PLGA, PVP, PMMA)
Proteins: gelatin, albumin
Lipids: triglycerides, fatty acids, sterols
ORGANIC MATERIALS
Calcium phosphate
Silica
Iron oxide
Polymers
Poly Caprolactone
Poly Lactic Acid
Poly Lactic Glycolic Acid
Polystyrene
Poly Methyl Metha Acrylate
Poly Vinyl Alcohol
Polyamides
Polycarbonates
Polyalkalene glycols
Polyvinyl ethers
MC, HPC, HPMC, SCMC
Polymers selection is based on:
Surface characteristics
Force of mucoadhesion
Release pattern
Clearance
Soluble or Insoluble
Biodegradable or non-biodegradable
Natural or synthetic
Polymeric Nanoparticles
Preparation of Nanoparticles
Emulsion polymerization
Nanoprecipitation
Micro encapsulation
Salting out
Solvent emulsification-evaporation method
Solvent-diffusion method
Interfacial polymerization
Coacervation
Spray-drying Or Spray-congealing
Supercritical fluid method
Hot and cold homogenization
Microemulsion technique
Ball milling
Equipments used for Nanoparticles
Homogenizer
Ultra Sonicator
Ball Mill
Spray Mill
Supercritical Fluid Technology
Electrospray
Ultracentrifugation
Nanofiltration
Solvent emulsification - evaporation
method
Polymer + Hydrophobic drug -- dissolved
in organic solvent.
This solution dispersed in an aqueous
surfactant solution by using a high speed
homogenizer at 10000 rpm for 2 min.
Organic solvent evaporated by mechanical
stirring (600 rpm) for 12 h at room
temperature.
The aqueous suspensions is concentrated
under low-pressure and filtered in a 0.8 m
membrane.
Solvent-diffusion method
Emulsion solvent diffusion method in
water
Polymers generally dissolved in the
organic phase.
On the other hand, the lipid dissolved in
the organic phase in water bath at 50C
and used as an acidic aqueous phase in
order to adjust the zeta potential to form
coacervation of polymeric nanoparticles
Drug dissolved completely in a mixture of
acetone and ethanol in water bath at 50C.
Organic solution was poured into an acidic
aqueous phase containing dispersing
agent under mechanical agitate with 400
rpm at room temperature for 5 min.
The pH value of the acidic aqueous phase
was adjusted to 1 by addition of 0.1 M
hydrochloric acid.
The PN suspension was quickly produced.
The entire dispersed system was then
centrifuged (4000 rpm for 10 min, and re-
suspended in distilled water. The resultant
dispersion was dried by lyophilization.
Nanoprecipitation
Polymer and a specified quantity of
drug were accurately weighed and
dissolved in organic solvent.
The organic phase was added
dropwise into the aqueous phase
and
Stirred magnetically at room
temperature until complete
evaporation of the organic solvent
had taken place.
Nanoprecipitation
Coacervation
Salting out
Freeze drying of nanoparticles
Advantages
Prevention from degradation and/or solubilization of
polymer
Prevention from drug leakage,drug desorption,drug

degradation
Easy to handle and store
Readily dispersible in water without modification in

their physicochemical properties
Characteristics of nanoparticles
Particle size and Surface properties
Drug-polymer interactions
Drug loading
In-vitro drug release

Evaluation Methods
Particle Size (Dynamic light scattering, PSA)
Zeta potential (Zeta Sizer)
Particle morphology (SEM, TEM)
Determination of drug incorporation efficiency
Drug Content (% w/w) =
(mass of drug in nanoparticles / mass of
nanoparticles recovered) X 100
Drug Entrapment (%) =
(mass of drug in nanoparticles / mass of drug
used in formulation) X 100
In-vitro drug release (Dialysis Membrane)
Crystallinity (XRD)
Drug loaded Polymeric Nanoparticles
Polymer Drug Observation

Albumin Piroxicam Increased bioavailability
compared to commercial
eye drops
Albumin Ganciclovir The residence time is
prolonged (2 weeks)
Chitosan Cyclosporine A Therapeutic concentrations
in cornea and conjunctiva
during at least 48 hrs
Carrageenan gelatin Timolol Higher bioavailability in
aqueous humor compared
to commercial eye drops
and insitu gelling system
Eudragit Ibuprofen Improved ocular
bioavailability
Applications of nanoparticles
Polymeric Trade Name Status Target Disease
Compounds
Polyglutamate- CT-2103 Phase II/III Cancer-
paclitaxel XYOTAX particularly lung
cancer, ovarian
Albumin Abraxane Market Breast cancer
nanoparticle
containing
paclitaxel
PEG-L- Oncasper Market Acute
asparaginse lymphoblastic
Leukemia.
Poly (alanine, Copaxone Market Multiple sclerosis
lysine,
glutamicacid,
tyrosine )
Potential Application Areas
Cancer chemotherapy
Vaccines
Gene therapy/ DNA delivery
Delivery to Brain
Metabolic Disorders
Inflammation, Pain Management
Lymphatic System
Protein & peptide delivery
Targeting specific tissues
Eg:
1. Lupron depot
Luprolide acetate (Peptide hormone) - PLGA (75% + 25%)
Treatment of Prostrate Cancer
Constant drug release for 1 month
2. Microparticle Vaccine
Malarial Vaccine - PLA + PLGA microparticles
Burst release of antigen at different time
PLGA + PCL (Diblock co-polymer) with PEG surface
modification Long acting nanospheres
Potential human hazards for nanoscale
particulates.
Inhalation: Inhaled particles induce
inflammation in respiratory tract,
causing tissue damage.
Example: Inhalation of silica particles
in industrial workers causes silicosis.
Dermal exposure: Particles may enter

body through the skin. Potential
hazards are unknown at present.
Ingestion: Nanoparticles may cause liver

damage. Ingested nanoparticles (i.e. for
oral drug delivery) have been found to
accumulate in the liver. Excessive
immune/inflammatory responses cause
permanent liver damage.
Potential bio-accumulation of nanoscale
particles.
Accumulation of a substance within a species

can occur due to lack of degradation or
excretion.
Many nanoparticles are not biodegradable.
If nanoparticles enter organisms, they may be

expected to accumulate higher.
Very little is understood about possible health

effects of nanoparticle exposure!
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Particulate drug delivery

Drug Delivery Carriers

Hydrophilic (i.e. gelatin)

Rate of drug release depends on:

Nanoparticles are subdivided into two main groups.

Nanospheres are small solid monolithic spheres

Nanocapsules are small reservoirs consisting of a

Nano = Ultrafine = < 100 nm

Nanoparticles may enter living cells

The particle should be able to chemically

Site of administration to targeted site

The particle should be able to release the

The particle should be eliminated from the

The material should be biodegradable &/or

The material should be non-antigenic

The particle surface should be amenable to

The particle should be able to encapsulate

Surface functionalization for targeting

Release drugs in controlled manner

More efficient uptake by cells

Greater control over toxicity and bioavailability of

Extended duration of release

Possibilities to combine local and systemic drugs

Controlled release directly to site

Avoidance of systemic drug exposure

Prevention from drug leakage,drug desorption,drug

Easy to handle and store

Readily dispersible in water without modification in

Particle size and Surface properties

In-vitro drug release

Polymer Drug Observation

Dermal exposure: Particles may enter

Ingestion: Nanoparticles may cause liver

Accumulation of a substance within a species

Many nanoparticles are not biodegradable.

If nanoparticles enter organisms, they may be

Very little is understood about possible health

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