Monoglyceride-based self-assembling copolymers as carriers for poorly water-soluble drugs.
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.
Rouxhet
L
L
Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
Dinguizli
M
M
Latere Dwan'isa
J P
JP
Ould-Ouali
L
L
Twaddle
P
P
Nathan
A
A
Brewster
M E
ME
Rosenblatt
J
J
Ariën
A
A
Préat
V
V
D018938:Caco-2 Cells; D002214:Capsules; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D005427:Flocculation; D006801:Humans; D065347:Hypromellose Derivatives; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008823:Micelles; D008970:Molecular Weight; D050178:Monoglycerides / Q000138:chemical synthesis* / Q000633:toxicity; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000633:toxicity; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013387:Succinic Anhydrides / Q000138:chemical synthesis* / Q000633:toxicity; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry*
D002214:Capsules; D004337:Drug Carriers; D008823:Micelles; D050178:Monoglycerides; D004364:Pharmaceutical Preparations; D012997:Solvents; D013387:Succinic Anhydrides; D014867:Water; D065347:Hypromellose Derivatives; D011092:Polyethylene Glycols; C031801:succinic anhydride; D008747:Methylcellulose