cyclodextrin-gantrez nanoparticles as bioadhesive … · zeta pot. (mv) cd loading ... sin título...
TRANSCRIPT
M. Agüeros1, M.A. Campanero2, J.M. Irache1
1 Departamento de Farmacia y Tecnología Farmaceutica. Universidad de Navarra.2 Departamento de Farmacología Clínica. Clínica Universitaria.
CYCLODEXTRIN-GANTREZ NANOPARTICLES AS BIOADHESIVE CARRIERS FOR ORAL DRUG DELIVERY
Introduction: the oral route
Mayor drawbacks:
Low water solubility
Instability in the GIT
Slow dissolution rate
The preferred way for drug administration
Easy way
Economical advantages
Patient compliance
BIOADHESIVE
NANOPARTICLES
Release /Absorption
Adhesion
• Improve drug solubility
• Increase loading capacity of liposomes and microparticles
CYCLODEXTRINS: β-CD and OHβ-CDGANTREZ AN
CH3 CH CH CH
C
O
C OO
OCH3
n
• Biodegradable polymer
• Low oral toxicity (DL50= 8-9 g/Kg)
Hidrophobic cavity
Lipophilic drug
Design and characterization
12.4±1.168.4±4.3-52.1±3.7140±713.3±2.188.4 ±9.9-51.1±8.8144±610.9±0.3--48.1±0.8179±2
Size (nm)
Zeta pot.(mV)
CD loading(μg/mg NP)
RBITC content (μg/mg NP)
NPCD-NPOH-CD-NP
SEM for CD-NP
NPCD-NPOH-CD-NP
% C52.5242.3741.27
% H5.095.945.92
% O42.4651.6152.84
ELEMENTAL ANALYSIS
Purification CD-NPLiophilization
5% sucrose
EvaporationEtOH / water
Gantrez® AN / Acetone
β-CD
OH β CDsonication
OH-CD-NP
Sto I1 I2 I3 I4 Ce 0,5h
3h0
0,5
1
1,5
2
2,5
1h
8h
Sto I1 I2 I3 I4 Ce 0,5h
3h1h
8h
βCD-NP
Sto I1 I2 I3 I4 Ce 0,5h
3h0
0,5
1
1,5
2
2,5
1h
8h
Sto I1 I2 I3 I4 Ce 0,5h
3h0
1
1,5
2
2,5
1h
8h
OHCD-NP
Sto I1 I2 I3 I4 Ce
0
0,5
1
1,5
2
2,5
0,5h
3h1h
8h
Control NP
In vivo studies: distribution within the gut
washGut segments
Non-adheredfraction
Adheredfraction Spectrofluorimetry
RBITC-NPDose: 10 mg per rat (45 mg/kg)
Extraction Me OH
Digestion NaOH 3MRats sacrificed at 0.5, 1, 3 and
8 h
Centrifugation / digestion / extraction
Adhe
red
amou
nt(m
g)
Sto I1 I2 I3 I4 Ce 0,5h
3h0
0,5
1
1,5
2
2,5
1h
8h
Sto I1 I2 I3 I4 Ce 0,5h
3h1h
8h
βCD-NP
Sto I1 I2 I3 I4 Ce 0,5h
3h0
0,5
1
1,5
2
2,5
1h
8h
Sto I1 I2 I3 I4 Ce 0,5h
3h0
1
1,5
2
2,5
1h
8h
OHCD-NP
Sto I1 I2 I3 I4 Ce
0
0,5
1
1,5
2
2,5
0,5h
3h1h
8h
Control NP
In vivo studies: distribution within the gutAd
here
dam
ount
(mg)
KINETIC PARAMETERS
AUCadh
(mg h)
β-CD-NP 13.86
OHCD-NP 18.16*
NP 10.49
MRT(h)
3.53
3.41
2.74Adh
ered
frac
tion
Time
AUCadh
kadh
Qmax
AUMCadh (mg h)
AUCadh (mg)MRTadh (h) =
Fluorescence microscopy
OHCD-NP: Strong affinity
for the intestinal mucosa
Mucosal Layer(intestinal villy)
Lumen
ENTEROCYTES
OHCD- NP (x100)
LumenMucosal Layer(intestinal villi)
OHCD- NP
Control NP
Conclusions1. The association between CDs and Gantrez nanoparticles may be of
interest for the oral delivery of lipophilic drugs, included antitumoral
drugs.
2. The rationale selection of the cyclodextrin can, not only modify the drug
loading and modulate its release, but also improve the residence of the
drug delivery system in intimate contact with the gut mucosa.
Acknowledgements• Gobierno de Navarra (Departamento de Educación)
• ISP Corporation
• Ministerio de Ciencia y Tecnología (SAF2001-0690-C03)
• Instituto de Salud Carlos III (Grant RITC Cancer C1/03)
• Fundación Universitaria de Navarra; Asociación de Amigos