1. Int J Pharm. 2009 Dec 1;382(1-2):244-53. Epub 2009 Aug 8.

Monoglyceride-based self-assembling copolymers as carriers for poorly
water-soluble drugs.

Rouxhet L, Dinguizli M, Latere Dwan'isa JP, Ould-Ouali L, Twaddle P, Nathan A,
Brewster ME, Rosenblatt J, Ariën A, Préat V.

Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340
Beerse, Belgium.

To develop self-assembling polymers forming polymeric micelles and increasing the
solubility of poorly soluble drugs, amphiphilic polymers containing a hydrophilic
PEG moiety and a hydrophobic moiety derived from monoglycerides and polyethers
were designed. The biodegradable copolymers were obtained via a polycondensation 
reaction of polyethylene glycol (PEG), monooleylglyceride (MOG) and succinic
anhydride (SA). Polymers with molecular weight below 10,000 g/mol containing a
minimum of 40 mol% PEG and a maximum of 10 mol% MOG self-assembled spontaneously 
in aqueous media upon gentle mixing. They formed particles with a diameter of 10 
nm although some aggregation was evident. The critical micellar concentration
varied between 3x10(-4) and 4x10(-3) g/ml, depending on the polymer. The cloud
point (> or = 66 degrees C) and flocculation point (> or = 0.89 M) increased with
the PEG chain length. At a 1% concentration, the polymers increased the
solubility of poorly water-soluble drug candidates up to 500-fold. Drug
solubility increased as a function of the polymer concentration. HPMC capsules
filled with these polymers disintegrated and released model drugs rapidly.
Polymer with long PEG chains had a lower cytotoxicity (MTT test) on Caco-2 cells.
All of these data suggest that the object polymers, in particular PEG1000/MOG/SA 
(45/5/50) might be potential candidates for improving the oral biopharmaceutical 
performance of poorly soluble drugs.

PMID: 19666096 [PubMed - in process]