Polylactide-Poly(ethylene glycol) Copolymers as Drug Delivery Systems. 1. Characterization of Water Dispersible Micelle-Forming Systems S. A. Hagan, A. G. A. Coombes, M. C. Garnett, S. E. Dunn, M. C. Davies, L. Illum, and S. S. Davis* The Department of Pharmaceutical Sciences, The University of Nottingham, Nottingham NG7 2RD, U.K. S. E. Harding Physical Biochemistry Laboratory, The Department of Applied Biochemistry and Food Science, The University of Nottingham, Sutton Bonnington LE12 5RD, U.K. S. Purkiss and P. R. Gellert Zeneca Pharmaceuticals, Alderley Park, Macclesfield, U.K. Received August 1, 1995. In Final Form: January 31, 1996 X Copolymers of polylactide and poly(ethylene glycol) (PLA-PEG), which self-disperse in water to form spherical nonionic micelles, have been investigated as a novel biodegradable drug delivery system. These copolymers are defined by the molecular weight ratios of their polylactide to poly(ethylene glycol) components (1.5:2 PLA-PEG and 2:5 PLA-PEG) and gave two peaks when purified by gel permeation chromatography (GPC). The first peak consisted of spherical micelles with a diameter of 15.6 nm for 1.5:2 PLA-PEG, and 18.9 nm for 2:5 PLA-PEG micelles after analysis by dynamic light scattering (DLS) and by transmission electron microscopy (TEM). The second peak was a PLA-depleted species resulting from the synthesis and did not form micelles. Testosterone and sudan black B (SBB), which have different hydrophobicities, were used as “model drugs” to evaluate the drug loading ability of the micelles. Ultracentrifugation sedimentation velocity studies confirmed that solubilization of the model drugs had occurred by micellar incorporation. Higher drug loading was obtained for the 1.5:2 PLA-PEG micelles (63.9% (w/w) of SBB, 0.74% (w/w) of testosterone) than for the 2:5 PLA-PEG micelles (59.0% (w/w) of SBB, 0.34% (w/w) of testosterone). The amount of testosterone solubilized was therefore significantly lower than SBB for both copolymers. Stability testing in the presence of salt suggested that the micelles had sterically stabilized surfaces. In vivo studies in the rat, using a radioactive marker, showed that PLA-PEG micelles demonstrated extended circulation times in the blood during the period of study (3 h). The 1.5:2 PLA-PEG showed increased blood levels and lower uptake of the micelles by the liver compared to the 2:5 PLA-PEG micelles. This is thought to be due to differences in the packing density of the copolymer molecules on the micelle surface. Introduction Colloidal carriers display good potential as drug delivery systems due to the ease of both preparation and incor- poration of drug molecules as well as a potential for high drug loading and possibilities for sustained systemic release. However, the effectiveness with which colloidal carriers are captured by the mononuclear phagocytic system (MPS) presents a major obstacle to the use of such vehicles for site-specific drug delivery. Extensive inves- tigations have shown that this barrier can be overcome and particles can be directed away from the liver to other sites if the carrier surface is modified by hydrophilic poly- (oxyethylene) chains. 1,2 There is a significant interest in micelles or “self- assembling, supramolecular complexes” as microcontain- ers for drug targeting. For nonionic micelles produced from poloxamers, which are based on blocks of hydrophilic poly(oxyethylene) (PEO) and hydrophobic poly(oxypro- pylene) (PPO), molecules of the drug can be solubilized in the inner hydrophobic PPO core, with the PEO blocks forming the outer hydrophilic shell. It has been reported, for example, that the neuroleptic action of haloperidol, injected into mice in highly concentrated aqueous micellar solutions of PEO-PPO-PEO block copolymer surfactant (Pluronic P-85), was increased relative to aqueous halo- peridol solutions. 3 Targeting of so-called “microcontain- ers” to specific cells has been attempted by Kabanov et al. 4 who conjugated the poloxamer molecules with anti- bodies against a target-specific antigen or with protein ligands selectively interacting with target cell receptors. These same authors also reported the ability of a low molecular weight compound (ATP), solubilized in polox- amer micelles, to penetrate an intact cell in vitro. Micellar complexes are, however, in dynamic exchange with free copolymer molecules in solution, continuously breaking and re-forming. 5 This property will be of particular consequence in vivo under dilution and will have an important influence on the drug carrying capacity of amphiphilic polymers which show this micelle-type association behavior. * To whom correspondence should be addressed. X Abstract published in Advance ACS Abstracts, April 1, 1996. (1) Illum, L.; Davis, S. S. Life Sci. 1987, 40, 1553-1560. (2) Gref, R.; Minamitake, Y.; Peracchia, M. T.; Trubetskoy, V.; Torchilin, V.; Langer, R. Science 1994, 263, 1600-1603. (3) Kabanov, A. V.; Chekhonin, V. P.; Alakhov, V. Y.; Batrakova, E. V.; Lebedev, A. S.; Melik-Nubarov, N. S.; Arzakov, S. A.; Levashov, A. V.; Morozov, G. V.; Severin, E. S.; Kabanov, V. A. FEBS Lett. 1989, 258, 343-345. (4) Kabanov, A. V.; Batrakova, E. V.; Melik-Nubarov, N. S.; Fedoseev, N. A.; Dorodnich, T. Y.; Alakhov, V. Y.; Chekhonin, V. P.; Nazarova, I. R.; Kabanov, V. A. J. Controlled Release 1992, 22, 141-158. (5) Hall, D. G.; Pethica, B. A. In Nonionic Surfactants; Schick, M. J., Ed.; Marcel Dekker Inc.: New York, 1967; pp 516-557. 2153 Langmuir 1996, 12, 2153-2161 S0743-7463(95)00649-4 CCC: $12.00 © 1996 American Chemical Society