Formulation Exercise – Replication Of A Marketed Product
Use Of Liposomes & Nanoparticles In Brain Drug Targeting
1. Use of Liposomes &
Nanoparticles in Brain Drug
Targeting - Recent Trends
Presented by Debanjan Das
2. Changing face of CNS drug
development
Chemically driven to biologically driven
Delivery of large molecule
pharmaceuticals(>500 Daltons) such as
recombinant proteins,monoclonal
antibodies,antisense drugs,gene medicines
The horse & the cart science,where horse is
the carrier dosage form and the cart is the
large molecule pharmaceutical
3. Application of Liposomes
Remarkable structural versatility
Targeting to specific organs or cells by coupling
with a carrier moiety
Biodegradable,shows good drug
entrapment(water & oil soluble drugs),and
physicochemically stable
Inherent efficiency of CNS drug development is
increased by incorporating structure transport
relationship(STR) during formulation
development phase
4. Recent trends: PEGylation
Brain cancer treatment,AIDS related Kapsoi’s
sarcoma,solid brain tumors
Coating with PEG which confers optimal
protection from RES mediated clearance; long
acting type
Bilayer rigidification using phospholipid reduces
chances of leakage
Localization in brain tumors due to enhanced
extravasations through abnormally permeable
microvasculature and impaired lymphatic
drainage
5. ATP supply to brain
Potential application in human
resuscitation from deep brain hypogeric
states
Experimented intracarotidally &
cerebroventricularly into rats subjected to
brain ischaemia
ATP entrapped in liposomes decreases
ischaemic episodes in brain
6. Transfecting neurons & glia
Use of pH sensitive immunoliposomes
Effective transfection system for gene
delivery to brain
Liposomes constructed with N-glutaryl-
phosphatidylethanolamine conjugated
antibodies & a beta galactosidase plasmid
under the control of cytomegalo virus
7. AZT oral dosage
Chemical delivery of AZT (AZT-CDS) orally
shows poor bioavailability in brain due to its acid
lability in the intestine
AZT-CDS in Dimethyl Sulfoxide did not reach
brain
Liposome formulation of AZT was absorbed
from jejunum
Liposome formulation in enteric coated AZT-
CDS might be promising for oral dosage
8. Cationic liposome complex for
gene transfer
Improvement over previously done direct in vivo
gene transfer by continuous injection of plasmid
DNA
Plasmid DNA-cationic liposome complex
contained a reporter gene coding for E.Coli beta
galactosidase
Improved liposome mediated gene transfer
technology helpful for treating brain disorders &
analysis of gene functions
9. Vector mediated brain drug
delivery
Chimeric peptide technology where a non-
transportable drug is conjugated to a BBB vector
Vector can be receptor specific Mabs which will
undergo receptor mediated transcytosis across
BBB
Delivery of wide variety of liposomes such as
peptide based pharmaceuticals,brain derived
neutropic factors,anti sense therapeutics etc
10. Application of Nanoparticles
Like liposomes nanoparticles are rapidly cleared
from blood
PEGylation is done to prolong circulation time in
blood
Unexpected finding with dalargin,where 230nm
nanoparticles crossed BBB,whereas 40-80 nm
liposomes doesn't
Recent studies show that detergents like Tweens
enhance BBB transport
11. Recent trends-use of surfactants
Drug+nanoparticles+Tween complexes
cross BBB
Polysorbate 20/40/60/80 were tested for
efficiency,of which 80 showed best effect
Experiment done in rats where these
complexes were injected i.v. & nociceptive
analgesia was measured by tail flick test
12. Use of surfactants (Continued)
Formulation consisted of dalargin bound to poly
butyl cyanoacrylate nanoparticles by
sorption,then coated with polysorbate 80
Simple mixture of the above three components
showed no effect
Fluorescent & electron microscopic studies show
that the passage of particle bound drug occurred
by phagocytic uptake of polysorbate 80 coated
nanoparticles by brain blood vessel endothelial
cells
13. Enhanced brain targeting using
DO-FudR-SLN
DO-FudR-SLN is 3,5-dioctanoyl-5-fluro-2
deoxyuridine,conjugated into solid lipid
nanoparticles(SLN)
Prepared by thin layer ultrasonication technique
with median particle size of 76nm,drug loading of
29.02% & entrapment efficiency of 96.62%
Excellent penetration through BBB
Promising drug targeting system to treat brain
disorders
14. Use of SLN
SLN loaded with tobramycin showed
increased concentration in brain
However,concentration was much less
when given intraduodenally than via iv
route
Hence,oral route seems unsuitable but iv
route provided much greater tissue
distribution of SLN in brain
15. Delivery of AZT by oral route
Use of hexacyanoacrylate nonaparticles as
colloidal drug carriers of AZT to brain
The AUC for treated nanoparticles when used in
above formulation showed 30% increase than the
control confirmed by use of 14C radioactive
tracers
Shows promising delivery system for nucleoside
analogs
Abundance of macrophages in BBB actually
helps in greater uptake,and hence lowers the
dosage & systemic toxicity
16. Use of magnetic materials
Nanodisperesed iron preparations accumulated in
brain following iv injection to rats
Magnetite-dextran nanoparticle injection in
carotid artery
Penetration of particles in brain tumor &
peritumoral tissue of rats bearing glial brain
tumor
Accumulation in brain confirmed by MRI
imaging
17. Lipid Drug Conjugate Liposomes
(LDC)
Particles incubated in mouse & human serum for
adsorption of plasma proteins
Showed preferential adsorption of
apolipoproteins,specially ApoE,which proves to
be a decisive factor for brain uptake
In vivo localization in brain confirmed by marker
Nile Red & confocal laser scanning microscopy
18. Summary
Liposomes show steric stabilization,remote
loading of drugs by pH & ionic gradients, form
lipoplexes based on complexes of cataionic
liposomes with anionic nucleic acids or proteins
Excellent vehicle for delivery of large volume
pharmaceuticals to brain
Do not cross BBB inherently excepting BBB
disruption or structural modifications(STR)
19. Summary (Continued)
Nanoparticle mediated transport depends on
overcoating of particles with polysorbates, which
provides an anchor for plasma protein
They mimic LDL particles & interact with LDL
receptors leading to accumulation in brain by
diffusion or transcytosis
BBB tight junctions are modified by
phosphoglycoprotein inhibition
Above mechanisms run in parallel or in
combination for brain drug uptake
20. Conclusion
Nanoparticles can be regarded as better tools of
brain drug targeting
They cross BBB with little modifications
Drugs successfully tried out are dalargin,
loperamide, tubocurarine, doxorubicin & NMDA
receptor antagonist MRZ2/576
However,more studies need to be done in finding
its ability to carry large volume pharmaceuticals