Department of Pharmacy (Pharmaceutics) | Sagar savale

NANOPARTICULATE
DRUG DELIVERY SYSTEM

Mr. Sagar Kishor Savale

[Department of Pharmaceutics]
avengersagar16@gmail.com
2015-2016
 Introduction
‫ סּ‬NANOTECHNOLOGY 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 : Consists 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.

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.
 there are mainly 2 type of nanoparticles
NANOPARTICLES
MATRIX RESERVIOR
type type

NANOSPHERES NANOCAPSULES

‫סּ‬ 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)
 DEFINITION :
 SUBNANOSIZED STRUCTURES C CONTAIN
DRUG OR BIOACTIVE SUBS. WITHIN THEM

 SIZE RANGE : 5nm – 300 nm

 ADVANTAGES:

 IMPROVED EFFICACY
 REDUCED TOXICITY
 ENHANCED DISTRIBUTION
 IMPROVED PATIENT COMPLIANCE
 EXAMPLE :
 IN CANCER CHEMOTHERAPY, CYTOSTATIC
DRUGS DAMAGE BOTH MALIGNANT AND
NORMAL CELLS ALIKE . BUT NANODRUG
DELIVERY SELECTIVELY TARGETS
MALIGNANT TUMOR ONLY…..
 TYPES OF NANOPARTICLES :
1. POLYMERIC NANOPARTICLE
2. SOLID LIPID NANOPARTICLE
3. NANOSUSPENSION
4. POLYMERIC MICELLES
5. CERAMIC NANOPARTICLES
6. LIPOSOMES
7. DENDRIMERS
8. MAGNETIC NANOPARTICLES
9. NANOSHELLS COATED WITH GOLD
10. NANOWIRES
11. NANOPORES
12. QUANTUM DOTS
13. FERROFLUIDS
1. POLYMERIC NANOPARTICLES

 SOLID COLLOIDAL PARTICLES

 SIZE : 10 nm – 1000 nm

 NANOCAPSULES : DRUG IS IN CAVITY

SURROUNDED BY UNIQUE POLYMER
MEMBRANE

 NANOSPHERES : MATRIX SYSTEM IN C

DRUG IS DISPERSED
NANOCAPSULE NANOSPHERE
 Advantages:
 Small size → Easy penetration through capillaries
→ Drug accumulation at target site
 Use of biodegradable material for preparation →
Sustained drug release

Application :
• Controlled & targetted drug delivery
2. SOLID LIPID NANOPARTICLES
 Colloidal Carrier System
 Size : 100 – 500 nm
 Delivery medium for lipophilic drugs

ADVANTAGES :
 Good Biocompatibility, low toxicity & stability
 3. NANOSUSPENSION
 Good for poorly soluble drugs
 Size : 200 – 600 nm
 Drug powder + surfactant in high pressure
homogenisation → Nanoparticles
 4. POLYMERIC MICELLES
• Miceller systems for systemic delivery of water-
insoluble drugs
• Amphiphilic copolymer self associate to form
micelles in water.
• Small size < 100 nm in diameter leads to avoiding of
renal excretion and RES
• Small size also leads to endothelial cell
permeability
• Accumulate greatly in tumor cells than in normal
 ADVANTAGES :
 Better thermodynamic stability in physiological
solution
 Stable & prolonged systemic circulation time
 Rapid invivo dissociation is prevented
 5. CERAMIC NANOPARTICLES
 SIZE : < 50 nm

 Ceramic particles with entraped biomolecules

 ADVANTAGES :
 Easy preparation process as similar to sol-
gel process
 No swelling or porosity changes with pH
 Protection for doped molecules (enzymes ,
drugs )against denaturation caused by pH &
temp.
 Compatible with biological systems
 Easy conjugation to variety of monoclonal
antibodies to target desired sites invivo
 6. LIPOSOMES
 Small artificial spherical shape vesicles
 Prepared from natural non toxic phospholiids and
cholesterol
 Classification :
 Based on size & no. of bilayers ::
1. Small unilamellar vesicles [ SUV ]
Size : 25-50 nm in diameter
2. Large unilamellar vesicles [ LUV ]
3. Multilamellar vesicles [ MLV ]
Several lipid layers separated by layer of aq.
solution
• Drugs in liposomes reduce systemic toxicity &
prevent early degradation
• Liposome surface can be modified by attaching
PEG to bilayer to enhance circulation time in
blood.
 7. Dendrimers
 Tree like molecules with defined cavities
 8. Magnetic Nanoparticles
• Powerful versatile diagnostic tool in medicine
Use :
1. To label sp molecule , cell population or
microorganisms by binding to suitable Ab
2. As contrast agents in MRI
3. As a drug delivery medium
Magnetic immunoassay :
Magnetic field generated by magnetically labelled
targets is detected by a sensitive magnetometer
 Composition :
Iron oxide [magnetite Fe203 or maghemite ]
coated with polymer such as dextran.
Commercial products :
1. Lumiren ( silicon coated iron oxide)
Diameter : 300 nm
2. Endorem ( dextran coated magnetite)
Diameter : 150 nm
9. NANOSHELLS COATED WITH GOLD
 Infrared optical activity combine with properties of
gold colloid
 Consist of :
1. Dielectric core ( gold sulfide or silica or silica )
2. Metal shell (gold)
 Particle < 75 nm diameter absorb & others scatter
the incidence light
 Surface properties of gold nanoshells = gold
colloid.
 Use :
 Destroy breast cancer cells
Antibodies to breast cancer can be directly
attached to gold nanoshells
 Nanoshells strongly absorb infrared light while
normal tissue is transparent to it
 Nanoshell-antibody complex binds only to cancer
cells
 Infrared laser heats up the nanoshells and thus
cancer cells are destroyed.
 10. Nanowires & Carbon nanotubes
 Linear nanostructures made from metals,
semiconductors or carbon .
 Modifications : Single- or multi-walled,
Filled or surface modified
 Use : Fillers for nanocomposites for material with sp
properties
 11. NANOPORES

 Eg : Aerogel produced by sol-gel chemistry

 Applications :
1. Catalysis
2. Thermal insulation
3. Electrode material
4. Environment filters
5. Controlled release drug carriers
 12. Quantum Dots
 Highly light absorbing luminescent
semiconductor nanoparticles
 Size : 2-8 nm in diameter
 Luminescence properties of semiconductor is
sensitive to local envrm and nanocrystal surface
prepartion.
 CdSe-CdS core shell
Range : 550nm to 630 nm
 InP & InAs
Range : Near infrared region
 Fuctionalisation with mercaptoacetic acid or thin
silica layer makes it water soluble
 Covalent attachment of proteins to mercaptoacetic
acid makes it biocompatible
 Binding to cell surface, insertion in cell surface &
binding to cell nucleii is possible due to
conjugation of nanoparticle with targeting protein
 13. Ferrofluids
 Colloidal solutions of iron oxide magnetic
nanoparticle covered by polymer layer coated with
affinity molecules s/a Ab
 Size: 25-100 nm radius
Hence they behave as a solution rather than
suspension
ADVANTAGES OF NANOSIZING OF DRUGS
 Increase surface area
 Enhances solubility
 Increase rate of dissolution
 Increase oral bioavailability
 More rapid onset of therapeutic action
 Decreased dose
 Decreased patient-to-patient variability
 Target specificity
 Limited side effects
 Limitations
 Expensive therapy
 Excess use of PVA as a detergent issues with
toxicity
 Limited targeting abilities
 Discontinuation of therapy is not possible
Conclusion
 Polymeric systems have great potential in drug
delivery application
 Still none of this systems is applied in practice to
patients- FDA approval requires extensive toxicity
investigations
Approaches for the preparation
Methods of preparation
1) Amphiphilic macromolecule cross-linking
a) Heat cross-linking.
b) Chemical cross-linking.

2) Polymerization based methods

a) Polymerization of monomers in situ.
b) Emulsion (micellar) polymerization.
c) Dispersion polymerization.
d) Interfacial condensation polymerization.
e) Interfacial complexation.

3) Polymer precipitation methods

a) Solvent extraction/Evaporation.
b) Solvent displacement (Nanoprecipitation).
c) Salting out.
PREPARATION METHODS OF
NANOPARTICLES

(Polymers for nanoparticles)

Proteins polysaccharides
 Gelatin  Alginate
 Albumin  Dextran
 Lectins  Chitosan
 Legumin  Agarose
 Vicilin  Pullulan
 Various synthetic polymers used for
prepration of nanoparticles

Prepolymerised Polymerised in process

 Poly(e-caprolactone)  Poly(isobutylcynoacrylate)
 Polylactic acid  Poly(butylcynoacrylate)
 Poly(lactide-co-  Poly(hexylcynoacrylate)
glycolide)  Polymethylmethacrylate
 Polystyrene
Polymers used for preparation of nanoparticles& nanocapsules

Polymer use Technique Candidate drug

Hydrophilic Heat denaturation & cross Hydrophilic
linking in w/o emulsion
Albumin, gelatin Desolvation &cross linking in Hydrophilic & protein affinity
aqueous medium

Alginate,chitosan Cross linking in aq. medium Hydrophilic & protein affinity

Dextran Polymer precipitation in an Hydrophilic

organic solvent

Hydrophobic Emulsion polymerization Hydrophilic

Poly(alkylcyanoacrylates) Interfacial/polymerization Hydrophobic

Polyesters Solvent extraction-evaporation Hydrophilic ,Hydrophobic

Poly(lactic acid,poly(lactide-co- Solvent displacement Soluble in polar solvent
glycolide)poly(€-caprolactone) Salting out Soluble in polar solvent
Method of preparation for nanoparticles

 Amphillic macromolecules that undergo a crosslinking

reaction during preparation of nanospheres

 Monomers that polymerize during formation of nanospheres

 Hydrophobic polymers which are initially dissolved in

organic solvents & then precipitated under controlled
conditions to produce nanospheres
 Nanoparticles preparation by cross linking of amphiphilic
macromolecules
 It can be prepared from amphiphilic macromolecules, proteins &
polysaccharides which have affinity for aq.&lipid solvents.
 The tech.of their preparation involves the aggregation of amphiphiles followed
by further stabilization either by heat denaturation or chemical cross linking.

 Cross linking in w/o emulsion

1. The method involves the emulsification of bovine serum albumin/human
serum albumin or protein aq. solution in oil using high pressure
homogenization or high frequency sonication
2. The w/o emulsion so formed is poured into preheated oil. The suspension in
preheated oil maintained above 1000C is held stirred for time in order to
denature & aggregate the protein contents of aq. pool completely & to
evaporate water
3. The particles are finally washed with organic solvent to remove any oil traces
& collected by centrifugation
4. The main factors are emulsification energy & temperature (used for
denaturation & aggregation
 Phase separation in aqueous medium (desolvation)

 The protein or polysaccharide from an aq. phase can be desolvated by

PH change or temp change or by adding counter ions. Cross linking may
be affected simultaneously or next to the desolvation step

 Steps are protein dissolution, protein aggregation & protein

deaggregation

 Solvent competing agent ,sodium sulphate is mainly used as a

desolvating agent while alcohol are added as desolvating or
deaggregating agent

 Addition can be optimized turbidometrically using Nephelometer.

 Aqueous phase (Protein
aq.solution)

Desolvation (solvent
competing agent)
Protein aggregates (coacervates)
Resolvation
(alcohol)
Protein colloidal dispersion
Crosslinking
(aldehyde)

Nanoparticle suspension (external aq.

Phase)

Nanoparticle preparation by desolvation in an aq. medium technique

 PH induced aggregation

 Gelatin & Tween 20 were dissolved in aq. phase & PH was adjusted to
optimum value. Solutions were heated ,then quenching at 4oC for 24h.The
leads to colloidal dispersion of aggregated gelatin. The aggregates were
finally cross linked using glutaraldehyde.The size of nanospheres were of
200 nm. The ideal PH range is 5.5-6.5.

 Counter ion induced aggregation

Separation of protein phase may occur by the presence of counter ions in

the aqueous medium.

The aggregation can be propagated by adding counters ions followed by

rigidization step.

Chitosan nanospheres can be prepared by adding tripolyphosphate to the

medium.

Alginate nanoparticles can be prepared by gelation with calcium ions

Nanoparticles prepared by polymerization methods

 The polymers used for nanospheres preparation include poly

(methylmethacrylate) poly(acrylamide)poly(butyl cyanoacrylate).

 The different methods using in situ polymerization tech. are

 Methods in which the monomer to be polymerised is emulsified in a non

solvent phase or (emulsion polymerization)
 Methods in which the monomer is dissolved in a solvent that is non
solvent for the resulting polymer (Dispersion polymerization)
 In EP method the monomer is dissolved in an internal phase while in
case of DP it is taken in dispersed phase
 In both cases after polymerization polymer tends to be insoluble in
internal phase & results into suspension of nanospheres
Emulsion polymerization
Micellar polymerization

 The mechanism involved are micellar nucleation & polymerization &

homogenous nucleation & polymerization

 The first includes swollen monomer micelles as the site of nucleation &
polymerization.

 The monomer is emulsified in the non solvent phase with the help of
surfactant molecules.

 The process leads to formation of monomer swollen micelles which has

size in nanometric range.

 The polymerization reaction proceeds through nucleation & propogation

in the presence of chemical or physical initiator
 Homogeneous polymerization
 Monomer is sufficiently soluble in the continuous outer phase

 Formation of primary chains (oligomers)

 At certain length oligomers precipitate & forms primary particles

which are stabilized by surfactant

 Addition of monomer input or fusion of primary particles forms

nanoparticles
 Water soluble drugs may be associated with PACA
nanoparticles either by dissolving the drug in the
aqueous polymerization medium or by incubating the
blank nanospheres with an aq. solution of drug

 Drug molecules may be entrapped within the polymer

matrix & are also adsorbed onto the surface of
nanoparticles

 Drug molecules may be physically adsorbed on the

surface
Dispersion polymerization

 In emulsion polymerization monomer is emulsified in an

immiscible phase using surfactant.In case of dispersion
polymerization monomer is dissolved in an aqueous
medium which acts as precipitant for polymer

 The monomer is introduced into the dispersion medium.

Polymerization is initiated by adding a catalyst &
proceeds with nucleation phase followed by growth
phase.
Inverse emulsification polymerization mechanism
Emulsion polymerization process
 The nucleation is directly induced in the aqueous
monomer solution & the presence of stabilizer or
surfactant is not required
 The acrylamide or methyl methacrylate monomer is
dissolved in aqueous phase & polymerized by gamma
irradiation
 By chemical initiation (ammonium or potassium
peroxodisulphate) combined with heating to temp. above
65 0C
 PMMA nanoparticles can be prepared by gamma
irradiation in the presence of antigenic material
e.g. influenza virion, influenza sub unit antigen, bovine
serum albumin, HIV-1 & HIV-2 antigens
Interfacial polymerization
 The preformed polymer phase is finally transformed to an
embryonic sheath.

 The polymer & drug are dissolved in a volatile solvent. The

solution is is poured into a non solvent for both polymer & core
phase.

 The polymer phase is separated as as a coacervate phase at o/w

interface. The mixture turns milky due to formation of
nanocapsules.

 This method is used for proteins, enzymes, antibodies, & cells

 Interfacial polymeric condensation of 2,2-bis-(4hydroxyphenyl)

propane & sebacoyl chloride
 The size of nanocapsules ranges from 30-300nm
Nanoparticle preparation using emulsion solvent evaporation
method
 Hydrophobic polymer & or hydrophobic drug is dissolved in a organic
solvent followed by its dispersion in a continuous aq. Phase in which the
polymer is insoluble. External phase contains stabilizer.

 Depending upon solvent miscibility tech.may called as solvent extraction

or evaporation method

The polymer precipitation is done by

 Increasing the solubility of organic solvent in the external medium by

adding an alcohol (isopropanol)

 By incorporating water into ultraemulsion(to extract solvent)

 By evaporation of solvent at room temp. by using vacuum

 Using an organic solvent which is completely soluble in the continuous

aq.phase(acetone)nanoprecipitation
Solvent extraction method

 This method involves the preparation of o/w emulsion

 The subsequent removal of solvent or the addition of water to the

system so as to affect diffusion of solvent to external phase
(emulsification diffusion method)

 The solvent used for polymer is poorly miscible with dispersion phase &
thus diffuses & evaporates out slowly on continual stirring

 Dispersion medium miscible polymer solvent (alcohol & acetone

instantaneously diffuses into the aq. phase & polymer precipitates as
tiny nanospheres
Solvent evaporation method
 Solvent evaporation done by altering pressure or high speed
homogenization.
 E.g. Testosterone, Indomethacin.
Organic phase Aqueous phase
Chlorinated Solvent Distilled water
Polymer Surfactant

Emulsification

O/W emulsion
Solvent evaporation

nanospheres

Emulsification solvent evaporation method 64

Solvent displacement method
Salting out
Solvent displacement method

 It is based on interfacial deposition of a polymer following

displacement of a semi polar solvent miscible with water
from a lipophilic solution

 The organic solvent diffuses instantaneously to the external

aq. Phase inducing immediate polymer precipitation
because of complete miscibility of both the phases
 If drug is highly hydrophilic it diffuses out into the external
aq. phase while if drug is hydrophobic it precipitates in aq.
medium as nanocrystals
Solvent displacement method
 Review on Nanoparticulate
carriers
Nanocarrier Preparation Polymer/ Lipid Drug Advantage/
system method based system Application

Polymeric Solvent evaporation PEG with PEO Protein Fast drug release
coating for 4 hours

nanoparticles Solvent evaporation PLGA Dexamethasone Sustain release for

10 days

nanoprecipitation PLGA Docetaxel Minimized

cytotoxicity

Solvent evaporation PLGA-co-PCL Diphtheria toxoid Improved drug uptake

Solid lipid Hot homogenization Stearic acid in 0.1% Insulin 80% entrapment
poloxamer 188 efficiency

nanoparticles Emulsion solvent Stearic acid in 1% Antitubercular drug Sustained plasma

diffusion wt/vol aq.PVA level over 8 day

Magnetic Bottom up fabrication Metallic Fe with Cancer treatment Parenteral

activated carbon administration

nanoparticles Co-precipitation Dextran coated iron Cancer treatment 74% to 95% drug
followed by separation oxide entrapment
Contd.
Nanocarrier Preparation Polymer/lipid Drug Advantage/
system method based system Application
Quantum dots Modified one pot Positively charged Gene delivery Imaging agents
method CdTe QD’s

Colloidal CdSe-ZnS core shell In-vitro imaging 10% to 20% higher

nanosuspension nanocrystals of QD’s gene silencing
activity

Polymeric Co-polymerization Pluronic-PPA Solid tumor Increased sol. of

micelles treatment hydrophobic drugs

micelles Co-solvent PEO-PPO-PEO Solid tumor Minimized

evaporation treatment cytotoxicity

Nanosized

Colloidal Dehydration- DOPE-glycol Nasal DNA vaccine 53% entrapment

Rehydration chitosan liposome efficiency
liposome's methods

Suspension and PC/Chol/PEGDSPE Gene delivery Prolonged plasma

subsequent circulation(24hr)
extrusion
 Schematic diagram for the development of targeted
nanoparticles

 Using a platform technology we first generate an activated nanoparticle.

 In a second reaction the targeting agent (antibodies) is conjugated to
the outer surface of the nanoparticle with the help of Linkers or Spacers.
• The nanoparticle now produced is ready for its specific target.
 MODE OF ACTION

 The targeted nanoparticle finds the specific cellular target.

 The nanoparticle binds to the surface of the cell

 If the target is internalized (i.e. folate receptors) the nanoparticle

is carried to the intracellular environment

 If the target is not internalized (i.e. annexin A2) the delivery

system has been engineered to release the nanoparticle at the
surface of the cell allowing for endocytosis to occur.
The potential of Nanocarriers as Drug Delivery Systems.
 Stimuli that can be utilized to control the behavior and
properties of drug delivery systems.

Stimuli Site Stimuli origin

pH Internal Decreased pH in pathological areas, such as tumors, infarcts, and

inflammations, because of hypoxia and massive cell death.

Temperature Internal hyperthermia associated with inflammation.

Can be caused inside target tissues by locally applied ultrasound or by

Temperature External locally applied high frequency causing the oscillation of target-
accumulated magneto-sensitive nanoparticles with heat release.

Magnetic field External Magnetic field of different gradients and profiles applied to the body can
concentrate magneto-sensitive DDS in required areas.

Sonication can be applied to the body to get a diagnostic signal from

Ultrasound External echogenic contrast agents and can also facilitate DDS penetration into
cells and drug/gene release from ultrasound-sensitive DDS.
CHALLENGES

Prevention of drug from biological degradation

Effective Targeting

Patient Compliance

Cost effectiveness

Product life extension

20/03/2008 Dept. of Pharmaceutics 75

Where all the action is the
 Block copolymer micelles for gene
therapy
 Transfection of plasmid
DNA using diblock
copolymer.

 DNA is released inside

the cytosol and appears
in the nucleus to express
a desired protein.
 PHARMACEUTICAL ASPECTS OF NANOPARTICLES

 The important process parameters performed are Purification, Freeze

drying, Sterilization.
1) Purification of nanoparticles:-Toxic impurities includes organic solvents,
residual monomers, polymerization initiators, electrolytes, stabilizers &
large polymer aggregates. Most commonly used method is gel filtration,
dialysis & ultra centrifugation.
 But a new methodology called as cross flow filtration method is used.

2) Freeze drying of nanoparticles

 It includes freezing of nanoparticle suspension & sublimation of water to
produce free flowing powder.
Advantages are
a) Prevention from degradation and/or solubilization of the polymer.
b) Prevention from drug leakage, drug desorption, drug degradation.
c) Readily dispersible in water without modifications in their physicochemical
properties.
 Nanocapsules containing oily core may be processed in the presence
of mono or disaccharides (glucose or sucrose).

3) Sterilization of Nanoparticles

 Nanoparticles for parenteral use should be sterilized to be pyrogen free

before animal or human use.

 Sterilization in nanoparticles is achieved by using aseptic

tech.throughout their preparation & processing & formulation & by
sterilizing treatments like autoclaving or gamma- irradiation.
Characterization of nanoparticles
Parameter
Particle size & size distribution
Charge determination
Surface hydrophobicity
Chemical analysis of surface
Carrier-drug interaction
Nanoparticle dispersion stability
Release profile
Drug stability
Characterization method
Photon correlation spectroscopy,
Transmission electron microscopy,
Scanning Electron Microscopy,
Atomic force microscopy.
Laser doppler anemometry,
Zeta potentiometer.
Water contact angle measurements, rose
bengal binding X-ray photoelectron
spectroscopy
Static secondary ion mass spectrometry,
Sorptometer
Differential scanning calorimetry
Critical flocculation temp (CFT)
In vitro release characteristic under
physiologic & sink conditions
Bioassay of drug extracted from
nanoparticles,
Chemical analysis of drug
1) Size & morphology
 EM(SEM & TEM) are widely used for determining particle size & its
distribution.
 Freeze fracturing of particles allows for morphological determination of
inner structure of particles.
 TEM permits differentiation among nanocapsules, nanoparticles, &
emulsion droplets
 Atomic force microscopy (AFM) images can be obtained in an
aq.medium hence used for investigation of nanoparticle behavior in
biological environment.

2) Specific surface:- Is determined with the help of Sorptometer.

A = 6/ density x D
3) Surface charge & electrophoretic mobility:-The nature & intensity of
surface charge determines their interaction with biological environment
as well as with bioactive compounds.It is determined by measuring the
particle velocity in an electric field. (Laser doppler anemometry)
 The surface charge of colloidal particles is measured as electrophoretic
mobility which is determined in phosphate saline buffer & human serum
4) Surface hydrophobicity:-influences in interaction with biological
environment ( Protein particles & cell adhesion).
 It is determined by two phase partition,contact angle measurements,
adsorption of hydrophobic fluorescent or radiolabelled probes.
 X-ray photoelectron spectroscopy permits the identification of specific
chemical groups on the surface of nanoparticles.
4) Density:-The density of nanoparticles is determined with helium or air
using a gas Pycnometer
5) Molecular weight measurement of nanoparticles:- Molecular weight of
the polymer & its distribution in the matrix can be evaluated by gel
permeation chromatography using a refractive index detector.
6) Nanoparticle recovery & drug incorporation efficiency:-Nanoparticle
yield can be calculated as

nanoparticles recovery(%) = Conc. of drug in nanoparticles *100

conc of nanoparticles recovered
7) Drug incorporation efficiency or drug content:-
Drug content(% w/w) = Conc of drug in nanoparticles *100
conc of nanoparticles recovered

8) In vitro release:-In vitro release profile can be determined using

standard dialysis, diffusion cell or modified ultrafiltration technique
 IN VIVO FATE & BIODISTRIBUTION OF NANOPARTICLES

 The plasma proteins (opsonins) adsorb on to the surface of colloidal

carriers & render particles recognizable to RES.

 Phagocytosis of particulates by elements of RES( liver, spleen, bone

marrow), liver( Kupffer cells )is regulated by opsonins & dysopsonins (IgA).

SURFACE ENGINEERING OF NANOPARTICLES

1) Stearic stabilized(stealth) nanoparticles

2) Biomimetic nanoparticles
3) Antibody coated nanoparticles
4) Magnetically guided nanoparticles
5) Bioadhesive nanoparticles
Methods of drug delivery
 APPLICATIONS OF NANOPARTICLES
1) Oral Drug Delivery.
 Nanosizing of drug lead to dramatic increase in their oral absorption and subsequent
bioavailability because of-
 Increase surface area.
 Increase saturation solubility.
 Looareesuwan et al 1999, Atovaquinone an antibiotic indicated for Pneumnocystis carinii
showed 2.5 fold increase in oral bioavailability used in the treatment of PCP.
 Other drugs studied include Danazol, Amphotericin B (kayser et al 2003).

2) Parenteral Drug Delivery.

 Taxanes has been found useful in the treatment of various cancers .As Taxanes are
insoluble in water, TAXOL Nanoemulsion containing Paclitaxel with polyethoxylated castor oil in
ethanol was prepared.

 A vitamin E-based Nanoemulsion of Paclitaxel (TOCOSOL paclitaxel) was developed by

SONUS Pharmaceuticals. It is a Cremophor-free formulation of paclitaxel, a ready-to-use injectable
product that incorporates high drug loading (8–10 mg/ml) . Based on the data to date, TOCOSOL
paclitaxel shows greater tumor accumulation than Taxol® and antitumor efficacy. TOCOSOL
paclitaxel nanodroplets manufactured by proprietary high shearing homogenization have a mean
droplet diameter in the range of 40–80 nm, are stable and neutrally charged, which allows for
diffusion into the tumor interstitium.

REF; Advances in lipid nanodispersions for parenteral drug delivery and targeting by Panayiotis P.
Constantinides, Mahesh V. Chaubal, Robert Shorr. Biopharmaceutical and Drug Delivery Consulting, LLC,
Gurnee, IL, USA; Baxter Healthcare, Round Lake, IL, USA.
3) Ocular Drug Delivery.
Biodegradable as well as water soluble polymer possessing ocular tolerability can be used to
sustain the release of the drug.

(Bucolo et al. 2002) successfully formulated FLURBIPROFEN & IBUFROFEN Nanosuspension

using acrylate polymers such as Eudragit RS 100 & Eudragit RL 100.

4) Pulmonary drug delivery.

Increase adhesiveness of drug to mucosal surface, prolongs the residence time of drug at
absorption site.

It offers quick onset of action initially and then control release of active moiety which is required
by most pulmonary disorders.

Budesonide is poorly water soluble corticosteroid has been successfully formulated as a

Nanosuspension for pulmonary drug delivery.

5) Targeted drug delivery.

This system has showed tremendous potential in target drug delivery, especially to brain.

Successful targeting of peptide Dalargin to brain by employing surface modified poly (isobutyl
cyanoacrylate) Nanoparticle has been the major achievement in target drug delivery.

Natural targeting of RES by nanosuspension has been already described.

Stealth nanoparticles are also produce to avoid RES.

Mucoadhesive bupravaquone nanosuspension reveled 10 fold reductions in infectivity score of

Cryptosporidium parvum.
 Brain targetting
 BBB is one of the hurdles for the antineoplastics, antibiotics
and neuroleptic agents.
 Drugs like hexapeptide dalargin, tubocurarine ,doxorubicin
have been targetted by the following approaches
1) Higher concentration gradient across the BBB,
2) Solubilization of endothelial cell membrane by surfactants,
3) Loosening of the tight junction between endothelial cells,
4) Endocytosis of nanoparticles and
5) Transcytosis of the nanoparticles.

 Kreuter and co-workers 1995,reported the transport of the

hexapeptide dalargin across the blood-brain-barrier using
poly(butylcyanoacrylate) nanoparticles, which were coated
with polysorbate80.
 Enhanced Permeability and Retention (EPR) effect
-Nanoparticle entry and accumulation in tumors PEGylated particles, in the
desired size range, leaks out of the microvasculature and accumulates into the
tumor site.
-Insufficient lymphatic drainage favors retention of PEGylated Particles within
the tumor site.
 Various therapeutic applications of
nanoparticles /nanocapsules
Application Material Purpose

Cancer therapy Poly(alkylcyanoacrylate)nanoparticle Targeting,reduced toxicity,

swith anticancer enhanced uptake of
agents,oligonucleotides antitumour agents,
improved in vivo & in vitro
stability
Intracellular Poly(alkylcyanoacrylate) Target RES for intracellular
targeting Polyester nanoparticles with anti interactions
parasitic or antiviral agents

Prolonged systemic Polyesters with adsorbed Prolong systemic drug

circulation polyethylene glycols or pluronics effect,avoid uptake by RES

Vaccine adjuvant Poly Enhances immune

(methylmetghacrylate)nanoparticles response
with vaccines(oral & IM injection)
 Application Material
Peroral Poly(methylmetghacrylate)nanopart
absorption icles with proteins & therap.agents
Ocular delivery Poly(alkylcyanoacrylate)with
steroids,antiinflammatory
agents,antibacterial agents for
glaucoma
DNA delivery DNA gelatin nanoparticles, DNA
chitosan nanoparticles,
Oligonucleotide Alginate nanoparticles,
delivery poly(D,L)lactic acid nanoparticles
Other Poly(alkylcyanoacrylate)nanoparticl
applications es with peptides
For transdermal application
Nanooparticles with radioactive or
contrast agents
Copolymerized peptide
nanoparticles of n-butyl
cyanoacrylate & activated peptides
Purpose
Enhanced bioavailability
&protection from GI enzymes
Improved retention of
drugs/reduced wash out
Enhanced delivery & higher
expression levels
Enhanced delivery of
oligonucleotide
Crosses blood brain barrier
Improved absorption & permeation
Enzyme
immunoassays,Radioimaging
Oral delivery of peptides
The six major challenge areas of
emphasis
1. Prevention and Control of Cancer
Developing nanoscale devices that can deliver
cancer prevention agents and anticancer vaccines
using nanoscale delivery vehicles.
2. Early Detection and Proteomics
Creating implantable molecular sensors that can
detect cancer-associated biomarkers(MEMS).
3. Imaging Diagnostics
Designing “smart” injectable,targeted contrast
agents that improve the resolution of cancer to
the single cell level. i.e. Quantum Dots.
 .

4. Multifunctional Therapeutics
Developing nanoscale devices that integrate
diagnostic and therapeutic functions.
5. Quality of Life Enhancement in Cancer Care
Designing nanoscale devices that can optimally
deliver medications for treating side effects due to
chronic anticancer therapy, including pain, nausea,
loss of appetite, depression,difficulty in breathing
and emesis.
6. Interdisciplinary Training
Coordinating efforts to provide cross-training in
molecular and systems biology to nanotechnology
engineers and in nanotechnology to cancer
researchers.
 Recent advances
 An emerging, interdisciplinary science
 Integrates chemistry, physics, biology, materials engineering,
earth science, and computer science.

 The power to collect data and manipulate particles at such a

tiny scale will lead to
 New areas of research and technology design
 Better understanding of matter and interactions
 New ways to tackle important problems in healthcare,
energy, the environment, and technology
 A most practical applications now, but problems in preparing
at large level.
 Example : Clottocyte, Respirocyte
 Artificial platelets (Clottocyte)
An artificial mechanical platelet appears to halt bleeding 100-1000 times
faster than natural hemostasis. A single clottocyte, upon reliably detecting a
blood vessel break, can rapidly communicate this fact to its neighbors,
immediately triggering a progressive controlled mesh-release cascade.
 Respirocyte
 The artificial red bloodcellor "respirocyte”
Proposed here is a bloodborne spherical 1-
microndiamondoid 1000-atmpressure vessel with
active pumping powered by endogenous serum
glucose, able to deliver236 times more oxygen to
the tissues per unit volume than natural red cells
and to manage carbonic acidity.
 An onboard nanocomputer and numerous
chemical and pressure sensors enable complex
device behaviors remotely reprogrammable by
the physician via externally applied acoustic
signals.
Primary
applications will
include:
1) Transfusable blood
substituent's.
2) Partial treatment for
anemia,
3) Perinatal/neonatal and
lung disorders;
4) Tumor therapies and
diagnostics;
5) Artificial breathing and
6) Prevention of asphyxia.
REFERENCES
 Swarbrick J, Boylan J. Encyclopedia of pharmaceutical technology. 2nd ed.;
Marcel Dekker, New York, 2002, pp : 443.

 Targetted and controlled drug delivery, Novel carrier systems; S.P Vyas and
R.K.Khar , CBS publishers and distributors, New Delhi, pg no : 331-385.

 Pharmaceutical dosage form and drug delivery; Ram I. Mahato, CRC press;
pg no : 258-260.

 Advances in controlled and novel drug delivery ; Jain N.K. ,CBS publishers and
distributors, New Delhi, pg no : 408-426.

 www. nanoproject.org

 www.nanomanufacturing.eu

 NANOPARTICLES & NANOTECHNOLOGY by Dr Paranjothy Kanni*, Health

Administrator , Vol : XX, Number 1&2, pg no : 26-28.
 1) Kreuter J, Ramge P, Petrov V, Hamm S, Gelperina SE, Engelhardt B, Alyautdin R,
von Briesen H, Begley DJ. Direct evidence that polysorbate-80-coated
poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms
requiring prior binding of drug to the nanoparticles .Journal of Pharmaceutical science
2003; pg no. 409-16.

2) Chen Y, Dalwadi G, Benson H. Drug delivery across the blood-brain barrier. Current
Drug Delivery 2004; vol .1, pg no.361-376.

3) Binding and release of drugs into and from thermo sensitive poly(N-vinyl
caprolactam) nanoparticles.
* Henna Vihola , Antti Laukkanen , Jouni Hirvonen , Heikki Tenhu .
Division of Pharmaceutical Technology, Viikki Drug Discovery Technology Center,
University of Helsinki, PB 56, FIN-00014, Helsinki, Finland.
Journal of pharmaceutical science.

4) Colloidal Nanocarriers: a review on formulation technology, types and applications

toward targeted drug delivery.
B. Mishra , PhD; Bhavesh B. Patel; Sanjay Tiwari.
Department of Pharmaceutics, Institute of Technology, Banaras Hindu University,
Varanasi, India.
.

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