Abstract
Purpose. The lack of water-solubility hampers the use of many potent pharmaceuticals. Polymeric micelles are self-assembled nanocarriers with versatile properties that can be engineered to solubilize, target, and release hydrophobic drugs in a controlled-release fashion. Unfortunately, their large-scale use is limited by the incorporation methods available, especially when sterile dosage forms are sought.
Methods. In this manuscript, we describe a straightforward, economical, and innovative drug-loading procedure that consists in dissolving both the drug and an amphiphilic diblock copolymer in a water/tert-butanol mixture that is subsequently freeze-dried.
Results. We demonstrate that monodisperse 20-60 nm-sized drug-loaded polymeric micelles are produced directly and spontaneously upon rehydration of the freeze-dried cake. To establish the proof-of-principle, two hydrophobic taxane derivatives were solubilized in the micelles, and their partition coefficient was determined.
Conclusions. This approach is efficient yet astonishingly simple and may be of great interest for scientists working in nanotechnology and pharmaceutical sciences.
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References
X. Duan, Y. Huang, Y. Cui, J. Wang, and C. M. Lieber. Indium phosphide nanowires as building blocks for nanoscale electronic and optoelectronic devices. Nature 409:66-69 (2001).
A. T. Woolley, C. Guillemette, C. Li Cheung, D. E. Housman, and C. M. Lieber. Direct haplotyping of kilobase-size DNA using carbon nanotube probes. Nat. Biotechnol. 18:760-763 (2000).
L. Zhang and A. Eisenberg. Multiple morphologies of “crew-cut” aggregates of polystyrene-b-poly(acrylic acid) block copolymers. Science 268:1728-1731 (1995).
L. F. Zhang, K. Yu, and A. Eisenberg. Ion-induced morphological changes in crew-cut aggretates of amphiphilic block copolymers. Science 272:1777-1779 (1996).
A. Harada and K. Kataoka. Chain length recognition: core-shell supramolecular assembly from oppositely charged block copolymers. Science 283:65-67 (1999).
D. E. Discher and A. Eisenberg. Polymer vesicles. Science 297:967-973 (2002).
A. Kabanov, P. Lemieux, S. Vinogranov, and V. Alakhov. Pluronic block copolymers: novel functional molecules for gene therapy. Adv. Drug Deliv. Rev. 54:223-233 (2002).
V. P. Torchilin, A. N. Lukyanov, Z. Gao, and B. Papahadjopoulos-Sternberg. Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc. Natl. Acad. Sci. USA 100:6039-6044 (2003).
C. Allen, D. Maysinger, and A. Eisenberg. Nano-engineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces 16:3-27 (1999).
M. C. Jones and J. C. Leroux. Polymeric micelles—a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101-111 (1999).
M. H. Dufresne, E. Fournier, M. C. Jones, M. Ranger, and J. C. Leroux. Block copolymer micelles—engineering versatile carriers for drugs and biomacromolecules. In R. Gurny (ed.), Challenge in Drug Delivery for the New Millenium, Bulletin technique Gattefosse 96 (R. Gurny, ed.), Saint-Priest, 2003, pp. 103-118.
G. Kwon, S. Suwa, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly (ethylene oxide-aspartate) block copolymer-adriamycin conjugates. J. Control. Rel. 29:17-23 (1994).
R. Savic, L. Luo, A. Eisenberg, and D. Maysinger. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science 300:615-618 (2003).
G. S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Physical entrapment of adriamycin in AB block copolymer micelles. Pharm. Res. 12:192-195 (1995).
S. B. La, T. Okano, and K. Kataoka. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(beta-benzyl L-aspartate) block copolymer micelles. J. Pharm. Sci. 85:85-90 (1996).
X. Zhang, J. K. Jackson, and H. M. Burt. Development of amphiphilic diblock copolymers as micellar carriers of taxol. Int. J. Pharm. 132:195-206 (1996).
A. Benahmed, M. Ranger, and J. C. Leroux. Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide). Pharm. Res. 18:323-328 (2001).
L. Luo, M. Ranger, D. G. Lessard, D. Le Garrec, S. Gori, J. C. Leroux, S. Rimmer, and D. Smith. Novel amphiphilic diblock copolymer of low molecular weight poly(N-vinylpyrrolidone)-block-poly(D,L-lactide): Synthesis, characterization and micellization. Macromolecules (2004).
F. M. Winnik, A. Adronov, and H. Kitano. Pyrene-labeled amphiphilic poly-(N-isopropylacrylamides) prepared by using a lipophilic radical initiator: synthesis, solution properties in water, and interactions with liposomes. Can. J. Chem. 73:2030-2040 (1995).
A. K. Krishna and D. R. Flanagan. Micellar solubilization of a new antimalarial drug, beta-arteether. J. Pharm. Sci. 78:574-576 (1989).
R. O. R. Costa and R. F. S. Freitas. Phase behaviour of poly(N-isopropylacrylamide) in binary aqueous solutions. Polymer 43:5879-5885 (2002).
D. L. Teagarden and D. S. Baker. Practical aspects of lyophilization using non-aqueous co-solvent systems. Eur. J. Pharm. Sci. 15:115-133 (2002).
U. Isele, P. Van Hoogevest, R. Hilfiker, and H. G. Capraro. and Schieweck. Large-scale production of liposomes containing monomeric zinc phthalocyanine by controlled dilution of organic solvents. J. Pharm. Sci. 83:1608-1616 (1994).
V. J. Stella, K. Umprayn, and W. N. Waugh. Development of parenteral formulations of experimental cytotoxic agents. I. Rhizoxin (NSC-332598). Int. J. Pharm. 43:191-199 (1988).
K. Kasraian and P. P. DeLuca. Thermal analysis of the tertiary butyl alcohol-water system and its implications on freeze-drying. Pharm. Res. 12:484-490 (1995).
K. Kasraian and P. P. DeLuca. The effect of tertiary butyl alcohol on the resistance of the dry product layer during primary drying. Pharm. Res. 12:491-495 (1995).
B. Nuijen, M. Bouma, R. E. Henrar, P. Floriano, J. M. Jimeno, H. Talsma, J. J. Kettenes-van den Bosch, A. J. Heck, A. Bult, and J. H. Beijnen. Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine. PDA J. Pharm. Sci. Technol. 54:193-208 (2000).
N. Ni, M. Tesconi, S. E. Tabibi, S. Gupta, and S. H. Yalkowsky. Use of pure t-butanol as a solvent for freeze-drying: a case study. Int. J. Pharm. 226:39-46 (2001).
C. Kim, S. C. Lee, J. H. Shin, and J. S. Yoon. Amphiphilic diblock copolymers based on poly(2-ethyl-2-oxazoline) and poly(1,3-trimethylene carbonate): synthesis and micellar characteristics. Macromolecules 33:7448-7452 (2000).
E. A. Grulke. Solubility parameter values. In J. Brandrupand and E. H. Immergut (eds.), Polymer Handbook, Vol. 7, John Wiley and Sons Inc., New York, 1989, pp. 519-559.
D. V. Krevelen. Cohesive properties and solubility. In D. V. Krevelen (ed.), Properties of Polymers: Ttheir Correlation with Chemical Structure; Their Numerical Estimation and Prediction from Additive Group Contributions, Elsevier Scientific, New York, 1990, pp. 189-225.
L. Zhang, H. Shen, and A. Eisenberg. Phase separation behaviour and crew-cut micelle formation of polystyrene-b-poly(acrylic acid) copolymers in solutions. Macromolecules 30:1001-1011 (1997).
I. C. Riegel, D. Samios, C. L. Petzhold, and A. Eisenberg. Self-assembly of amphiphilic di and triblock copolymers of styrene and quaternized 5-(N,N-diethylamino) isoprene in selective solvents. Polymer 44:2117-2128 (2003).
International Conference on Harmonization (ICH), Harmonized Tripartite guidlines. Impurities: residual solvent. Step 4, Consensus guideline, 17 July 1997.
J. F. Douglas, J. Roovers, and K. F. Freed. Characterization of branching architecture through ‘Universal’ ratios of polymer solution properties. Macromolecules 23:4168-4180 (1990).
A. Harada and K. Kataoka. Novel polyion complex micelles entrapping enzyme molecules in the core. 2. Characterization of the micelles prepared at nonstochiometric mixing ratios. Langmuir 15:4208-4212 (1999).
S. C. Lee, Y. Chang, J. S. Yoon, C. Kim, I. C. Kwon, Y. H. Kim, and S. Y. Jeong. Synthesis and micellar characterization of amphiphilic diblock copolymers based on poly(2-ethyl-2-oxazoline) and aliphatic polyesters. Macromolecules 32:1847-1852 (1999).
C. Allen, J. Han, Y. Yu, D. Maysinger, and A. Eisenberg. Polycaprolactone-b-poly(ethylene oxide) copolymer micelles as a delivery vehicle for dihydrotestosterone. J. Controlled Release 63:275-286 (2000).
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Fournier, E., Dufresne, MH., Smith, D.C. et al. A Novel One-Step Drug-Loading Procedure for Water-Soluble Amphiphilic Nanocarriers. Pharm Res 21, 962–968 (2004). https://doi.org/10.1023/B:PHAM.0000029284.40637.69
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DOI: https://doi.org/10.1023/B:PHAM.0000029284.40637.69