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