1: Pharm Res. 2004 Sep;21(9):1581-90. 

Biodegradable self-assembling PEG-copolymer as vehicle for poorly water-soluble
drugs.

Ould-Ouali L, Arien A, Rosenblatt J, Nathan A, Twaddle P, Matalenas T, Borgia M,
Arnold S, Leroy D, Dinguizli M, Rouxhet L, Brewster M, Preat V.

Universite Catholique de Louvain, Department of Pharmaceutical Technology,
Brussels, Belgium.

PURPOSE: To develop self-assembling systems increasing the solubility of poorly
water-soluble drugs. METHODS: Low molecular weight liquid biodegradable
copolymers were synthesized by ring-opening polymerization using caprolactone
(CAP) and trimethylenecarbonate (TMC) as monomers. Various initiators were
evaluated. The emulsifying and self-assembling properties were investigated by a
water titration method. The self-assembling systems were characterized for size,
shape, isotropic behavior, cloud point, surface charge, and critical micellar
concentration in order to optimize the polymer synthesis. Finally, the
improvement of solubility of model drugs was assessed. RESULTS: Only diblock
monomethyl ether PEG-CAP/TMC copolymers synthesized with monomethyl ether
polyethyleneglycol 550 to 2000 as initiator have shown self-assembling
properties: upon dilution, these copolymers formed an isotropically clear
solution with droplet sizes in the range of 20 to 100 nm. The hypothesis that
these diblock polymers form micelles was confirmed by their low critical
micellar concentration (10(-5) g/ml). The copolymers initated with mmePEG750 had
a higher cloud point and better colloidal stability than those initiated with
mmePEG 550. The solubility of the poorly water-soluble drugs was increased by 1
to 2 orders of magnitude. Good reproducibility was observed from batch to batch.
CONCLUSIONS: The polyester diblock copolymer mmePEG750-CAP/TMC forms
spontaneously stable micelles in aqueous medium and increases the solubility of
lipophilic drugs. They are very promising vehicles for the oral delivery of
poorly water-soluble drugs.

PMID: 15497683 [PubMed - in process]