Technology of micro and nanoencapsulation

John Rojas, PhD

Pharmaceutical technology I
 Microcapsules vs microspheres
A Microcapsule has a drug A Microsphere has its drug dispersed
located centrally within the throughout the particle i.e. the
particle, where it is encased
within a unique polymeric internal structure is a matrix of drug
membrane and polymeric excipients

2
 Advantages vs Disadvantages
 Protection of the drug from the surrounding environment, hence
improving the shelf-life, and stability
 Protection of environment from product, where active core material is
hazardous or toxic
 Separation of components, allowing control of incompatibility of
components
 Control rate of release of core material, by rupture of polymer wall e.g.
by impact or long acting sustained release e.g. solution or diffusion
 Masking undesired properties of active component e.g. odour, taste
 Formation of solid systems e.g. retention of liquid or volatile
compounds
 Targeting of site of release of active material
 Small size and large surface area improving bioavailability
 Low yield (API loss)
 Cost and Complexity
 Scale up 3
 Types of microencapsulation techniques

 Coacervation
 Solvent extraction
 Supercritical fluid  Inclusion complexes
 polycondensation
 Suspension/emulsion
 spray-congealing
 Hot-melt extrusion

*yhors ciro & john rojas, STABILIZATION OF ASCORBIC ACID BY MICROENCAPSULATION FOR COSMETIC
PREPARATIONS, IN: ASCORBIC ACID, USES AND APPLICATIONS, NOVA SCIENCE PUBLISHERS
*Microcapsules of Vit. C
Supercritical fluids (CO2) techniques
Supercritical fluids (CO2) techniques
 Spray congealing/Spray-drying
The transition of a melt from a
soft or fluid state to a rigid or
solid state by cooling is called
congealing. The various droplet
formation techniques & the
efficient droplet/air contact
make the spray cooling concept
ideal for making spherical
particle powder by congealing
of melts. On the other hand,
spray-drying implies the rapid
drying of a dispersion into
droplets which then are
converted into spheres.
7
 Internal/external gelation
HPMC, alginate dispersion is added
to CaCl2. Alginates can be cross-
linked by external or internal
gelation method using polyvalent
cations, such as Ca2+. In the
production of micropellets by
external gelation, the alginate-
drug solution is extruded as
droplets into a solution of calcium
salt.

AM Naranjo-Durán, J Quintero-Quiroz, J Rojas, GL Ciro-Gómez

2021. Modified-release of encapsulated bioactive compounds from annatto seeds produced by optimized ionic gelation techniques
 Internal/external gelation
A B

(a) No CaCl2 is added to alginate dispersion

(b) CaCl2 is added to alginate dispersion
For internal gelation, an insoluble calcium salt is added to the alginate-drug
solution and the mixture extruded into oil. The latter is acidified to bring about
the release of Ca2+ from the insoluble salt for cross-linking with the alginate.
 Internal/external gelation
(i) Polyelectrolyte complex
formation between carboxylate
ion of alginate and protonated
amino group of chitosan to form
an outer membrane. (ii) Calcium
mediated gelation of alginate in
which calcium slowly diffused Coat Core
through cross linking barrier to
attach two alginate strand
together to form core. (iii)
Polyelectrolyte complex
formation between chitosan and
alginate to form coat or outer
polymeric membrane. (iv) "Egg
box model" in which alginate
cross-linked with CaCl2 to form
inner core
 Shaheen Sultana, Sushma Talegaonkar, Aseem Bhatnagar, Farhan J Ahmad, Gaurav Mittal2. 2013. Optimization of nifedipine loaded gastroretentive
microcapsules for biliary colic 10
 Inclusion complexes
 These complexes can be prepared
with β-cyclodextrin and HP-β-CD.
 The required quantity of β-CD is
weighed and water added to get
consistency.
 To the mass weighed a quantity of
the drug (pyronine) is added. The
mixture is kneaded in a glass
mortar for 1 h and then dried in
hot air oven at 60◦C for 2 h. The
dried mass is sieved through mesh
no. 120
 Other inclussion complexes are
given by polymaleic acid
derivatives
Y Ciro, rojas J, Salamanca C. 2021. Production and characterization of nanometric systems of chitosan crosslinked with different polianionic
agents for the modified reléase of anticancer and antimicrobial agents 11
 Centrifugal extrusion
It is a centrifuge-based method of monodisperse hydrogel microspheres possessing
multiple compartments under ultra-high centrifugal gravity. It enables gelification of
droplets of sodium alginate solution into microparticles without oil, heat or UV, is easy to
use, simple and biocompatible. Centrifuge-based Droplet Shooting Device (CDSD) and a
tabletop centrifuge. It is composed of a capillary, an acrylic holder, and a microtube. The
barrel-configuration of the capillary gives designated compartmentalization in the
hydrogel spheres. Firstly, sodium alginate solutions are introduced in each capillary barrel.
We set the capillary in the acrylic holder and insert the holder in a microtube whose
bottom is filled with a 500 mM CaCl2 solution. Then we conducted centrifugation on the
microtube. The sodium alginate solutions in capillary-barrels are pushed out by centrifugal
gravity and synthesized into pendant-drop at the orifice. Finally, the drop gets detached
and forms a droplet .

12
Maeda et al., 2011. A centrifuge based shooting device for the synthesis of multicompartmental microspheres ultra high gravity
 Hot-melt extrusion & ASD
It is used to prepare solid dispersions of poorly soluble active
pharmaceutical ingredients, and for creating controlled-release
medications. In this process, APIs are compounded with polymers
that have suitable glass transition temperatures and extruded at
an appropriate temperature to form a solid dispersion. This
polymer matrix acts as a solid solvent for the drug molecules.

Rojas, J. 2015. Excipient Design by Co-processing for Direct Compression Applications. In: Excipient Applications in Formulation Design
and Drug Delivery. 978-3-319-20205-1. Edited by Ajit S. Narang, Sai H.S. Boddu. Springer. NY. 589-612 p.
13
Hot melt extrusion (HME)

The API can be

amorphous, molecularly
dispersed or crystalline
dispersed within the
polymer.
 HME: processing regimes

A complete melting is important for obtaining a ASD

Thermal behavior of drugs with different crystallization
tendency
 Amorphous solid dispersions (ASD)
It is the dispersion of one or
more active ingredients in an
inert carrier or matrix at solid
state prepared by the fusion or
melting solvent method.
Carriers for solid dispersions:
• Sugars: dextrose, sorbitol,
mannitol.
• Acids: Citric acid, tartaric
acid, succinic acid.
• Polymeric materials: PEG
4000, PEG 6000, HPMC,
polyvinyl pyrrolidone.

Solid dispersions. Fundamental aspects of…http://www.yxxb.com.cn:8081/apsb/EN/abstract/html/20140105.htm

17
 Pathways of crystallinity in ASD

The polymer acts as solvent for the drug, has especific interactions,
decreases drug mobility, & awards steric hyndrance & thus controls
dissolution rate and drug crystallization in solution
 Dispersion of drug in hydrophilic carrier

Solubility advantage
 Drug: amorphous state
 Polymer as hydrophilic matrix:
 Enhance wettability
 Precipitation inhibition and
maintenance
Stability advantage
 Low molecular mobility (high
Tg)
 Drug-polymer interactions
(e.g. hydrogen bonds)
 Phase diagrams of ASD
If the formulation is amorphous,
such as when the API is
dispersed in an amorphous
polymer, the API is distributed
at random between the
excipient molecules, and can be
present as crystalline or
amorphous particles, or in
molecular solution.

Molecular properties depends on:

 Polymer selection
 Drug loading
 Ancilliary fromulation
compounds

 Solid solutions and dispersions: http://www.particlesciences.com/news/technical-briefs/2012/solid-solutions-dispersions.html20

 Solid dispersions: and overview. http://www.pharmainfo.net/reviews/solid-dispersions-overview
 Production of ASD

SMEEDDS: self microemulsifiying drug delivery system

Carrier: Magnesium Aluminometasilicate or linseed oil

21
Taken from: http://www.neusilin.com/library/application_data.php
 Crystallinity of ASD nanoparticles- PXRD
ASD of poorly soluble drugs always render more soluble products
 Lyophilation of probucol nanoparticles (example)
Several formulations of probucol nanoparticles were made and
sucrose laurate was used as crioprotectant. Once redisperse in
several media particle size varied.

Conditions of the dissolution test:

 20 mg of lyophilized nanoparticles were mix with 2% SLS. The

apparatus II was employed in 250 mL, 50 rpm, & 37°C
 First HCl at pH of 1.2 for 120 min followed by pH of 6.8 adjusted with 1
M NaOH
Dispersibility of nanoparticles with and without sucrose
laurate
 Lack of redispersion of dried
solids into primary
nanoparticles is the most
difficult development
challenge
 Use of sucrose or lactose as
stabilizers produces dried
nanoparticles that readily
disperses into primary particles
upon mild agitation
 Drying method (lyophilation or
spray drying) does not have an
impact on redispersion
Formulation of sucrose laurate in lyophilation
 Sucrose moiety in sucrose laurate
acts like cryoprotectant by
adsorption on nanoparticle
surfaces
 This explains why large amounts
of sucrose is needed in marketed
nanoparticle products

 Sucrose alone cannot guarantee

redispersion into primary particles
 Amorphous nature of sucrose
laurate form films on particle
surface (does not crystallize)
 Sucrose laurate provides the right
HLB value for redispersion
 26
Soli-lipid nanoparticles (example)

Doxetaxel
(API)

Triestearin
Polyethylenglicol succinate-
tocoferol 1000 (surfactant)
http://www.sigmaaldrich.com/catalog/product/sial/y0001466?lang=en&region=CO
 27
Solid lipid nanpoparticles (process)

API+acetone & ethanol (1: 1, Dilute in 100 mL of

v/v) mix at 70ºC aqueous phase having
0,01% (p / v) TPGS 1000

Sonication at 30 W for 10 Stiring at 400 rpm at 70

minutes then in ice bath ° C for 5 min

Dialisis for 12 h (purification) Centrifugation(1.600 rpm, 5 min)

Lyophilization

https://www.dovepress.com/surface-modified-solid-lipid-nanoparticles-for-oral-delivery-
of-doceta-peer-reviewed-fulltext-article-IJN
 AMS current status
• 1985-2006: 3 products
• 2007-2019: 20 products
• 2019 onwards: several approved and other in
clinical trials
 Coacervation (phase separation)
They are prepared by controlled precipitation of polymers solubilized in one
of the phases of an emulsion. Ejem. By thermal change, adding
noncompatible polymers, addition of a non-solvent, salt addition, charge
interaction between polymers by solvent evaporation.

Materials:
Poly(vinyl alcohol)
Gelatin
Gelatin-Acacia
Polyvinyl methyl ether

Applications:
Encapsulation of enzymes for liquid
detergents.
Fragrances, dyes, flavors
encapsulation.

The oil droplets can contain a

dispersion of hydrogel particles
loaded with an active ingredient.
29
Complex coacervation (phase separation)

30
Taken from: http://microencapsulationinnovations.com/Chemical.html
 Coacervation (crosslinking)

Effect of crosslinking
with glutaraldehyde
Coacervation (solvent evaporation)

(a) With span®

(b) span® and homogenized

Coacervation (solvent evaporation)
Polymer is
dissolved in
organic solvent
and then the API
is added then
water is added
with a surfactant
to form the
emulsion
http://www.ehu.eus/reviberpol/pdf/JUL04/Saez.pdf
Precipitation Polymerization
Monodisperse microgels in the
micron or submicron size range.

Precipitation polymerization starts

from a homogeneous monomer
solution in which the synthesized
polymer is insoluble.

The particle size of the resulting

microspheres depends on the
polymerization conditions, including
the monomer/comonomer
composition, the amount of initiator
and the total monomer
concentration.

AIBN: Azobisisobutyronitrile

34
 Electrospinning
PLLA fibers
pump syringe
needle fibers
l = 3,0 – 5,0
mm
Ø = 1,0 – 2,0
µm
Rotary
ring
voltage

axis
Water
pool

Electrospinning is a fiber production method that uses electric force to draw charged
threads of polymer solutions or polymer melts up to fiber diameters in the order of
some hundred nanometers. Electrospinning shares characteristics of both
electrospraying and conventional solution dry spinning of fibers 35
Zuo et al, 2010.
 Polymeric micelles
 Small, spherical structures
composed of from a few
dozen to thousand molecules
that attract one another to
reduce surface tension within
the membrane of a cell.
 They must be sufficiently
stable in blood circulation
and should not disintegrate
upon contact with blood
components. Therefore the
CMC should be low as
possible.
 For poorly soluble drugs it uses a lecithin and gelatin based water soluble coating
to improve dissolution and hydration of lecithin-gelatin coat to form micelles
which improve oral bioavailability of insoluble drugs.
36
 Micelle formation
 When amphipathic molecules are
dispersed in water, micelles are
formed above the Critical Micelle
Concentration (CMC).
 A high CMC causes rapid exchange
of the constitution components,
fast disintegration upon dilution
and less stability. The molecules
will rearrange themselves to form a
micelle.
 A low CMC indicates that the
micelles are stable and hence do
not disintegrate readily.
37
 Micelles (examples)
 Konakion (phyto methadione) micelles are
produced from lecithin and glycocholic acid
compounds.
 Used in treatment of Vitamin K deficiency
bleeding in neonates and infants.

PolyGlycolic acid

38
 Micelle functionalization

 Micelles made of block co-polymers are used as drug carriers, i.e.,

doxorubicin
 These block-copolymers are composed of a hydrophilic PEG block
and a hydrophobic block based on poly(aspartic acid) or poly(β-
benzyl L-aspartate) with doxorubicin conjugation.
 The diameter of the micelles can be manipulated so that the
resulting particle size is <200 μm. This will allow accumulation of
the drug in target site, such as tumor tissue, inflamed tissue.

39
 Liposomes
 Microscopic spherical vesicles
composed of a phospholipid bilayer
that are capable of encapsulating active
drugs. Spontaneously orientate in
water to give a bilayer. Tails are
rearranged away from the water.
Spherical structure reduces exposure at
the edges and produces a
thermodynamically stable structure
 Size varies from 20-20000 nm
 Depending on the solubility of the
drug, can be: Encapsulated in aqueous
core, Interacting with surface of
liposome via Electrostatic interaction
and Taken up by bilayer
40
 Advantages & Disadvantages of
Liposomes
Advantages Disadvantages
 High drug loading  Inability to cross the
capacity, and doesn’t endothelial barrier,
affect the overall property difficult to
of the carrier extravasate
 Drug can be physically  Subject to
entrapped
phagocytosis as
 The system confer
recognized by the
protection to the drug
RES as a foreign
 Biodegradable, non-toxic
body
 Carry both water and oil
soluble drugs
41
 Types according to size

Small unilamellar
vesicles (SUV): 20-100
nm
Large unilamellar
vesicles (LUV): >100 nm
Giant unilamellar
vesicles (GUV):>1000
nm
Oligolamellar vesicles
(OLV): 100-1000 nm
Multilamellar vesicles
(MLV): >500 nm
Production techniques

Dying down lipids

from organic solvent
Dispersing the lipids
in the aqueous
media
Purifying the
resulting liposome
Analyzing the final
product
(i) Mechanical agitation: Film hydration method
(ii) Detergent removal method
Particle size before and after dialysis
Monitoring dialysis process

Decrease in particle size

after 4h and decrease in
zeta potential reaming
detergent detection after
4h
 Liposomes: Cosmetic application

 Cesar A. Londoño, John Rojas, Cristhian J. Yarce and Constain H. Salamanca

Design of Prototype Formulations for In Vitro Dermal Delivery of the Natural Antioxidant Ferulic Acid Based on
Ethosomal Colloidal Systems Cosmetics 2019, 6(1), 5
Types of Liposomes according to ligands

49
Conventional liposomes: examples
 These are rapidly taken up by
phagocytic cells of the RES,
localized predominately in the
liver and spleen, therefore used
when targeting RES as the
therapeutic goal. i.e.,
Amphotericin B
 Ambisome has a size of 50-100
nm and have low toxicity and
hence allow higher doses to be
given.
 It is used to treat drug resistant
Leismaniasis, a parasitic infection
of the RES.
 Ideal for use in treatment of
diseases of the liver and spleen.
50
 Long Circulating sterically stable (‘Stealth’) liposomes
 Carry hydrophilic coatings, and used to obtain
prolonged circulation times
 It is produced by covalently attach the
hydrophilic polymer i.e., polyethylene glycol
(PEG) to the liposome bilayer. i.e., Doxil
 Reduced toxicity: it alters the biodistribution
of many therapeutic agents, by directing them
away from organs responsible for side effects.
 This liposome has segments of hydrophilic
methoxypolyethylene glycol (mPEG) grafted
onto the surface.
 This creates a physical barrier that inhibits the
approach of other liposomes or macrophages,
protecting it from detection and destruction
via phagocytosis.

51
 Long Circulating sterically stable liposomes: Doxorubicin
example

 It is used for metastasis breast cancer,

bladder cancer, aids related Kaposi's
sarcoma (KS), and ovarian cancer.
 Doxorubicin.HCl binds to DNA and is a
topoisomerase II enzyme inhibitor,
and generates oxygen free radicals
which damage tumour cell DNA.
 Doxorubicin generates hydrogen
peroxides and hydroxyl radicals which
are highly cytotoxic destroying cells.
 A lipid membrane has hydrogenated
soy phosphatidyl choline &
cholesterol segments of PEG (2000
Da) are grafted to the membrane

52
Long Circulating sterically stable liposomes: Doxorubicin
example

Doxorubicin liposomes showed higher concentrations at tumour

sites compared. Treatment resulted in a 5 -11 fold higher drug
levels in Kaposi's Sarcoma lesions in humans.
53
 Immunoliposome (antibody targeted)
 They have antibody fragments on their surface which aids and
enhances target site binding

(left) antibodies attached to the surface of stealth liposomes; (center)

antibodies attached to the distal ends of polyoxyethylene chains in stealth
liposomes; (right) antibodies attached to the surface of non-stealth liposomes
 Gene delivery i.e., delivery of plasmid DNA oligonucleotides to bind ribosomal
mRNA
 Folate receptors are over expressed in ovarian carcinoma and liposomes bearing
specific ligands, (i.e., folate), may be used to target ovarian carcinomas.
54
 Cationic liposomes
 These are positively charged liposomes, and
are used to deliver genetic material
 The cationic lipid components of the
liposomes interact with, and neutralize,
negatively charged DNA, thereby
condensing the DNA into a more compact
structure
 Cationic liposomes are used to deliver DNA
to the required site in the respiratory
system, where the liposome fuse to the cell
membrane and incorporate DNA into the
cell
 Involves the delivery of DNA of Cystic
Fibrosis Transmembrane Conductance
Regulator (CFTR) to epithelial tissue of the
respiratory system. In Cystic Fibrosis there is
a lack of this channel which results in
massive production and accumulation of
sticky purulent mucus, characteristic of the
55
disease.
Liposomal formulation example (Rendesimir )
Application in Lung: key for covid treatment
In vitro cytotoxicity and cellular uptake
of rendisimir
 Niosomes/ethosomes
 Niosomes are non-ionic surfactant vesicles. A large number of surfactants have been
found to self assemble into bilayer vehicles which can be used as drug delivery.
Surfactant screening showed that only Span 60, Span 20, and Tween 20 with
cholesterol have capability of nano size vesicle formation.
 Niosomes encapsulation of methotrexate and doxorubicin increase drug delivery to
tumor cells.
 Unlike non-stealth liposomes, 800 nm doxorubicin niosomes possessing a triglycerol
or 200 nm doxorubicin niosomes possessing a muramic acid surface are not
significantly taken up by RES. These triglycerol niosomes accumulate in the tumor.
 The encapsulation of these polymeric prodrugs within 200 nm niosomes provides a
depot system within the liver from which the free drug is gradually cleaved off and
the liver level of drug is increased over a 24 h period.
 The activity of other anticancer drugs, such as Vincristine, Bleomycin are also
improved with niosomes encapsulation.
 Niosomes are reported to increase the skin permeation and bioavailability of
topically applied drug molecules.

Mali N, Darandale S, Vavia P. 2012. Niosomes as a vesicular carrier for topical administration of minoxidil: formulation and in vitro59
assessment. Drug Del Trans Res.
 Niosomes/ethosomes
 The uptake of Niosomes by the liver and
spleen, makes them ideal for targeting disease
manifesting in these organs, i.e. Leismaniasis.
 A number of studies have shown that niosomal
formulations of sodium stibogluconate
improves parasite suppression upon
intramuscular administration.
 Niosomal antigens are potent stimulators of
the cellular and immune response.
 The formulation of antigens as a niosome in a
W/O emulsion further increases the activity of
antigens.
 Enhancement of the immunological response is
due to the controlled release property of the
emulsion formulation.
60
 Applications: Reticuloendothelial system (RES)
 It is composed of phagocytic cells which
have the ability to phagocytosis inert
particles. These cells are Macrophages
and Monocytes, hence the system is
also referred to as the Mononuclear
Phagocytic System (MPS). These cells are
either freely circulating within the blood
or are fixed to various connective tissue
i.e., spleen, liver sinusoids, joints, skin,
bone marrow.
 The RES makes up part of the immune
system, where the cells mostly
accumulate in the lymph node, spleen,
and Kuppfer cells of the liver.

61
Lymphatic system and RES
Macrophages:
Mononuclear
phagocytes found in
tissue. Arise from
stem cells in bone
marrow. They develop
into monocytes and
circulate in blood for
about 40 h.
Monocytes: non-
granular white blood
cells that function as
phagocytes in blood.
They mature into
macrophages after
leaving bloodstream
and move into the
connective tissue,
where they undergo
metamorphosis
(increase in size and
phagocytic activity.)
 Applications: Vaccines

 Antigens are either adsorbed onto their

surface or entrapped in the matrix of
polymethylmethacrylate nanoparticles.
i.e., they may contain the influenza
antigen.
 By decreasing the particle size and
increasing the hydrophobicity, the
particles offer a prolonged and a
controlled release of the antigen in the
immune system.
 supramolecular assemblies comprising
quillaja saponins, cholesterol,
phospholipids, and hydrophobic
antigens. They are used as parenteral
and non-parenteral immunoadjuvants
and are currently undergoing clinical
trials. 63
 Applications: Peptide Formulations

 Leuprorelin acetate and triptoreline, both are

luteinising hormone releasing hormone agonists.
 Angiotensin receptor antagonist L-158809 for
treatment of hypertension
 Thyrotropin releasing hormone
 Salmon calcitonin for treatment of hypercalcemia
and postmenopausal osteoporosis
 Immunosuppressant drug. i.e., Cyclosporin A

64
Applications: Scaffold for bone regeneration
prehardering

Powder F Líquid Powder Líquid F Polvo Líquido

a) b)
CPC
CPC with API
c) F F d)

a) Within pores, b) on the crystal surface c) aggregated crystals.

Ginebra et al, 2012. 65
 Bone regeneration examples

API Use References

Gentamicine U. Joosten et al 2004; C. Flores et al 2016

Vancomicin antibiotic T. Sasaki et al 2005; K. Urabe et al 2009.

Doxiciclin (Doxy-h) Pastorino et al 2015; M. Hamdan et al 2010.

Alendronate Osteoporosis V. Schnitzler et al 2011

Zoledronate anticancer B. Peter et al 2005.

Lactoferrin (hLFI-II) antibiotic H. Stallman et al 2008.

Cefalexin antibiotic A. Akashi et al 2001

Metotrexate D. Li et al 2010
anticancer
Cis-Platin Y. Tahara 2001

Ibuprofen Anti inflammatory S. Girod et al 2010

Paclitaxel anticancer M. Lopez-Heredia et al 2011

Y. Raymond, M. Bonany, C. Lehmann, E. Thorel, R. Benítez, J. Franch, M. Espanol, X. Solé-Martí, M.C. Manzanares, C. Canal, M.P. Ginebra. Hydrothermal processing of 3D-printed calcium phosphate scaffolds
enhances bone formation in vivo: a comparison with biomimetic treatment. Acta Biomateriaia Volume 135, November 2021, Pages 671-688. doi: doi.org/10.1016/j.actbio.2021.09.001. OPEN ACCESS.

M.Á. Brennan, D.S. Monahan, B. Brulin, S. Gallinetti, P. lHumbert, Ch. Tringides, C. Canal, M.P. Ginebra, P. Layrolle. Biomimetic versus sintered macroporous calcium phosphate scaffolds enhanced bone
regeneration and human mesenchymal stromal cell engraftment in calvarial defects. Acta Biomaterialia Volume 135, November 2021, Pages 689-704. doi: doi.org/10.1016/j.actbio.2021.09.007. 66
 Tumor growth

 Cancerous cells replicate at a rate

higher than normal healthy cells.
They compete with healthy cells for
nutrients and elimination of waste
products. Once a small tumor mass
has formed, healthy tissue will not
be able to compete with cancer
cells for adequate supply of
nutrients from the blood stream.
 Tumor development is driven by
three key processes: initiation of
angiogenesis, maintenance of
angiogenesis and tumor growth.
67
 Tumor growth
Tumor cells with continue to divide and
increase in size using growth factors. The
tumor cells at the outer edge of the mass
have the best access to nutrients, while
the cells in the core die due to the lack of
nutrients supplied with increasing mass of
the tumor. This will form a necrotic core
within tumors that rely on diffusion to
deliver nutrients and eliminate waste
products.

Growth factors are small proteins or

steroid hormones. They may be secreted
by the same cells on which they act or by
cells that may reside in a different part of
the body than the target cells. i.e.,
estrogens, a growth factor for breast cells
and VEGF, a growth factor that causes the
68
development of blood vessels.
 Enhanced Permeability Retention
(EPR) Effect
 In normal tissue, the cells lining the blood vessels are continuous,
without any gaps between them. Hence particles present in the
circulation are unable to extravasate into the surrounding tissue.
 In tumor tissue (and inflamed tissue), there is damage of endothelial
cells and tissue, which results in gaps between cells.
 The leaky blood vessels in tumor tissue allows big polymeric molecules
to extravasate from the blood stream and accumulate at the site of the
tumor. This accounts for the enhanced permeability of molecules into
the target site.
 Accumulation and retention of these particles at the tumor site is due
to deficient lymphatic system in the tumor, which is unable to drain the
particles out from site. Thus leads to entrapment of molecules within
the tumor.
Y Ciro, J Rojas, AL Di Virgilio, MJ Alhajj, GA Carabali, CH Salamanca
Production, physicochemical characterization, and anticancer activity of methotrexate-loaded phytic acid-chitosan nanoparticles on HT-29 human colon
adenocarcinoma cells 69
Carbohydrate polymers 243, 116436
Enhanced permeability & retention in tumor

70
 References
 Simon Benita. 2005. Microencapsulation: Methods and Industrial Applications,
Second Edition (Drugs and the Pharmaceutical Sciences). CRC Press.
 Donald L. Wise. 2000. Handbook of pharmaceutical controlled release
technology. Marcel Dekker.
 Leon Lachman. 1976. The theory and practice of industrial pharmacy. Lean &
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