Polymeric Micelles

• PM are formed from the association of block copolymers.

• Block copolymers micelles have the capacity to increase the solubility of hydrophobic molecules due to their unique structural composition, which is characterized by a hydrophobic core sterically stabilized by a hydrophilic shell.

The hydrophobic core serves as a reservoir in which the drug molecules can be incorporated by means of chemical, physical or electrostatic interactions, depending on their physicochemical properties.

Block vs. Random

Diblock vs Multiblock

natural (dextran) and synthetic (polystyrene) polymeric micelle.Daniel Taton and co-workers at the University of Bordeaux, France, 2007

According to the type of intermolecular forces driving the micelle formation, PM are classified as:

• amphiphilic micelles; formed by non polar hydrophobic interactions,

• polyion complex micelles, PICM; resulting from electrostatic interactions,

• micelles formed by metal complexation.

Non polar hydrophobic interactions Micellization is driven by a gain in entropy of the solvent

molecules as the hydrophobic components withdraw from the aqueous media.

Examples: Polymers contain• polyester as Poly(lactic acid) (PLA),…• poly(amino acid) PAA derivative as Poly(aspartic acid)

(PAsp),… (neutral or conjugated to hydrophobic group). ,…....

• Polyethers as the poloxamer family { (poly(ethylene glycol)-b-poly(propylene oxide)-bpoly( ethylene glycol)) (PEG-b-PPO-b-PEG)

All are biocompatible and biodegradable approved by the FDA for biomedical applications in humans.

Electrostatic interactions

The self-assembly of PICM, proceedsthrough the electrostatic interaction betweenpolycations and polyanions leading toneutralization of oppositely chargedpolyions.

The presence of the polymer hydrophilic segment prevents precipitation.

Examples:• Polymers having protonated amines at physiological pH

like poly(ethyleneimine) (PEI),…..

Micelle PreparationAmong the methods used in PM preparation are

1. Direct dissolution method

Suitable for moderately hydrophobic copolymers, such as poloxamers, and for PICM.

dissolving the block copolymer along with the drug in an aqueous solvent.

The copolymer and drug are dissolved separately in an injectable aqueous vehicle.

Micelle formation is induced by combining the two solutions to appropriate drug–polymer /charge ratios.

2. Indirect method using organic solvent

Applies to amphiphilic copolymers which are not readily soluble in water.

Organic solvent common to both the copolymer and the drug

is used. (such as dimethylsulfoxide, acetone,….

The mechanism by which micelle formation is induced depends on the solvent-removal procedure.

a. Dialysis method: the copolymer mixture can be dialyzed against water. Slow removal of the organic phase triggers micellization.

b. Solution-casting method: evaporation of the organic phase to yield a polymeric film where polymer–drug interactions are favored. Rehydration of the film with a heated aqueous solvent produces drug-loaded micelles.

c. Emulsion (O/W) method using non-water-miscible organic solvent like dichloromethane.

d. Freeze drying method:

one-step procedure based on the dissolution of both the polymer and the drug in a water/tert-butanol (TBA) mixture with subsequent lyophilization of the solvents.

Drug-loaded micelles are formed spontaneously upon reconstitution of the freeze-dried polymer–drug cake in an injectable vehicle.

Common drug-loading procedures: (A) simple equilibrium, (B) dialysis, (C) O/W emulsion, (D) solution casting, and (E) freeze-drying.Journal of Controlled Release 109 (2005) 169–188

Ref.: © 2004 IUPAC, Pure and Applied Chemistry 76, 1321–1335