ABSTRACT
Polymer micelles have been used widely in the delivery of various therapeutic drugs, which are also known as active pharmaceutical ingredients (APIs). Recent advances in drug discovery technology, including an accumulated database on therapeutic targets, combinational chemistry, and high-throughput screening (HTS), have further increased the number of candidate compounds and constructed a huge pipeline for the discovery and development of new chemical entities (NCEs).1,2 A very large number of chemicals are hailed as new drug candidates, but almost one-third of them are poorly water soluble.3 Polymer micelles consisting of amphiphilic
19.1 Introduction .......................................................................................................................... 513 19.2 Drug Solubilization Methods................................................................................................ 515
19.2.1 Salt Formation .......................................................................................................... 516 19.2.2 Nanosizing ................................................................................................................ 517 19.2.3 Solubilizing Excipients ............................................................................................. 518 19.2.4 Liposomes ................................................................................................................. 519 19.2.5 Polymer-Drug Conjugates ........................................................................................ 520
19.3 Polymer Micelles as a Drug Carrier ..................................................................................... 521 19.3.1 Micellar Drug Solubilization Theory ....................................................................... 521 19.3.2 Hydrotropy ................................................................................................................ 524
19.3.2.1 Hydrotropes and Their Mechanism of Drug Solubilization ...................... 524 19.3.2.2 Hydrotropic Polymer Micelles ................................................................... 526 19.3.2.3 A Theory to Explain Hydrotropy ............................................................... 529
19.4 Stability of Polymer Micelle ................................................................................................. 531 19.4.1 Stability of Polymer Micelle in Water and Buffers .................................................. 531
19.4.1.1 Thermodynamic Stability .......................................................................... 531 19.4.1.2 Kinetic Stability ......................................................................................... 533 19.4.1.3 Drug Effect ................................................................................................ 535
19.4.2 Stability of Polymer Micelle in Biological Environments ........................................ 535 19.4.2.1 Micelle-Protein Interaction ....................................................................... 535 19.4.2.2 PEG-Protein Interactions .......................................................................... 536 19.4.2.3 Protein Penetration into Micelles ............................................................... 538
19.4.3 Micelle-Cell Interaction ........................................................................................... 538 19.4.4 In Vivo Stability of Polymer Micelles .......................................................................540
19.5 Perspectives and Conclusive Remarks ..................................................................................540 References ...................................................................................................................................... 543
block copolymers or lipids form a hydrophobic core, in which lipophilic drugs can be physically incorporated. Hydrophilic blocks or segments generate water-friendly corona and encapsulate the hydrophobic core. In this way, poorly soluble drugs can be successfully solubilized in aqueous media (Figure 19.1).
