The global market for drugs for the central nervous system
(CNS) is greatly under-penetrated, and would have to grow
by >500% just to equal the cardiovascular drug market.
More than 98% of the newly developed agents for CNS do not
Molecules should possess low molecular weight (<500 Da) and
high lipophilicity in order to cross blood-brain barrier (BBB).
There are only a few diseases of the brain that are currently
treated by CNS drugs.
› Only affective disorders, insomnia, pain, and epilepsy respond to
› Most other brain diseases such as Alzheimer’s,Parkinson’s,Brain
Cancer, Stroke, Neuro-AIDS etc do not respond to small
Recently developed large molecules such as therapeutic
proteins, peptides, genes, monoclonal antibodies,
cannot cross BBB.
Development of drugs for brain is incomplete without a
parallel approach in brain drug delivery.
Ref: Pardridge, W.M. Brain Drug Targeting: The Future of Brain
Drug Development, Cambridge University Press, 1, (2001), pp 3-
Oral bioavailability of proteins and peptides is severely
limited due to the epithelial barriers of the GIT and
degradation by digestive enzymes.
GI passage of particles can be achieved by formulation
of fine size ranges of approximately below 200 nm.
A Nano-size range favors uptake through
› Absorptive Enterocytes
› Intestinal M cells
Also, a size range below 200 nm favors escape from
spleenic filtration effects thereby enhancing circulation
half-life of nanoparticles.
Polymeric nanoparticles can allow loading of such molecules
within a polymeric matrix, protecting from enzymatic
degradation and hydrolysis, as well as targeting to brain
However, application of nanoparticles as oral drug delivery
systems are restricted due to their
› Limited absorption across GIT.
› Short circulation half-life.
(The peptide drug chosen for this study is dalargin, a
hexapeptide with amino acid sequence Tyr-D-Ala-Gly-Phe-
Leu-Arg which does not cross the BBB. It is an Leu-Enkephalin
analog which binds with opioid receptors in brain and causes
Nanoparticles can be “double-coated” with a
combination of Tween 80 and PEG 20,000 successively to
achieve “stealth” targeting properties.
Role of Tween 80
A Tween 80 coating over a polymeric nanoparticle leads
to the adsorption of Apo lipoprotein E (Apo E) from
plasma upon the nanoparticle surface.
Such nanoparticles interacts with Low Density
Lipoproteins (LDL) receptors in BBB and reaches the brain
interior by endocytic uptake mechanism.
Nanoparticles degrade in brain interior and peptide is
Role of PEG 20,000
Poly (ethylene) glycol (PEG) is known to protect labile
drugs against enzymatic degradation in GIT.
Higher molecular weight PEGs such as PEG 20,000, forms
a protective “brush” against the digestive enzymes.
High molecular weight PEGs also provides “dysopsonic”
effect against macrophageal clearance in the blood
Emulsion (Anionic) polymerization
Medium (pH 2.5, 0.01N HCl) containing Dextran 70 (1.5%) as
Polymerization for 4 hours with constant magnetic stirring at
Medium was neutralized using 0.1 N NaOH until the final pH
Size excluded by multi-filtration steps using successive filters of
5 µ, 1.2 µ and 0.7 µ pore size diameters.
Unreacted monomers and agglomerations removed by 3 cycles
of washing and ultracentrifugation at 76,500 g for 1 hour.
Nanoparticles collected as wet pellets.
Immediately kept in lyophilizer at -40ºC and 130 × 10-4
mbar for 12
hours for freeze drying.
Finally, nanoparticles were obtained as free flowing, white
powder and stored at 4ºC for further use.
The nanoparticle yield was 23% w/w.
Entrapment efficiency (EE %) was found to be 39.84 ± 4 % w/w
Double-coated PBCA-NDSs with overcoats of Tween 80
and PEG 20,000 represent a feasible method to deliver
and target peptides to brain via the oral route.
Coating of nanoparticles with 2% Tween and 2% PEG
represents the optimal formulation for PBCA
PBCA-NDSs with average diameter of 100 nm represents a
satisfactory size for oral and targeted peptide delivery to