Factors Influencing Drug Release from Polymeric Micelles

A drug can be localized in potentially three different areas in a block copolymer micelle: in the core, at the core-corona interface, and at the corona.53 The drug in the micelle core has a longer diffusion path relative to the drug that is located at the core-corona interface or the corona. The drug that is released from the core-corona interface or the corona is typically referred to as a burst release, an initial discharge of drug in a relatively short period of time (typically hours). For example, Bromberg et al. observed a burst release (5-11%) of b-estradiol from the poly(acrylic acid) (PAA) corona of Pluronic®-PAA micelles.61 In most cases, after a burst release, a slower and more consistent release that typically lasts for a longer period of time (typically days to months) is observed. For example, Kim et al. demonstrated slow release of indomethacin (i.e., less than 30% released over a period of approximately 100 h) from Pluronicw/PCL micelles.62

The kinetics of drug release from micellar systems has been studied extensively by many groups.36,45,61,63-65 Despite the extensive release studies, the mechanism of drug release from block copolymer micelles is not fully understood. However, many groups believe that diffusion and copolymer degradation are the two principal mechanisms of release provided that the micelles are stable under the release conditions investigated.63 If the interaction between the polymer and the drug is strong and the rate of biodegradation is fast, then the degradation rate would govern the rate of drug release. However, the rate of drug release from micelles, as observed in vitro, usually exceeds the rate of copolymer degradation. As a result, polymer degradation can most often be ruled out as one of the main mechanisms of drug release. Therefore, diffusion of the drug may be considered the principal mechanism of release from micelles.

Drug release is influenced by three main factors: the characteristics of the drug (amount of drug, molecular weight of the drug, and molecular volume of the drug), the properties of the core-forming block (molecular weight of the core, nature of the core, and physical state of the core), and the degree of polymer-drug compatibility.

The amount of drug present in the micelle has been found to influence the release. Most often it has been found that an increase in the concentration of drug present results in a decrease in the rate of drug release.36,65-67 For example, Gref et al. reported that higher concentrations of lidocaine in PEG-b-poly(D,L-lactide-co-glycolide) (PEG-b-PLGA) micelles resulted in a slower release rate for the drug.66 Similarly, Lim Soo et al. observed that increasing the amount of estradiol in PEG-b-PCL micelles decreased the rate of drug release.65

The physical properties of the drug, including molecular weight and molecular volume have also been shown to influence their rate of release from micelles. An increase in the molecular weight of the drug forces a greater reorientation of the polymer chains for movement of the drug molecules through the polymer matrix. An increase in the volume of the drug will also require a greater effort to reorganize the polymer to accommodate its movement. As a result, larger or heavier molecular weight drugs will tend to have lower diffusion coefficients as opposed to smaller molecular weight agents.

The rate of diffusion of a drug in and out of the micelle is also greatly influenced by the properties of the micelle core. In general, increasing the molecular weight of the core-forming block will increase the size of the core provided that the hydrophilic block length is held constant. This increase in the molecular weight of the hydrophobic block and the size of the core has been found to decrease the overall rate of release rate of the entrapped agent.63,68-71

The nature of the core, specifically the hydrophobicity and/or polarity of the core, influences the release rate of the drug as it determines the permeability of the core to aqueous media. Micelles with a highly hydrophobic core will likely have less aqueous fluid in the core in comparison to micelles that have a more hydrophilic or polar core. Therefore, micelles prepared from more hydrophilic cores will likely have an accelerated rate of drug release. The physical state of the core will also affect the diffusion of drug from the micelles. Polymers that have a high Tg or bulky groups present on their backbone are limited in terms of their ability to reorient. As a result, these polymers will form micelle cores with a high microscopic viscosity, resulting in a low diffusion coefficient for the drug that is incorporated because of limited movement.72 This is in contrast to polymers that are more rubbery or gel-like that will tend to form cores that have a low microscopic viscosity and a higher rate of diffusion for the incorporated drugs.

Finally, the degree of polymer-drug compatibility greatly influences the rate of drug release from the micelles. Drugs that are highly miscible with the core-forming block have a high degree of polymer-drug compatibility. It is expected that these drugs would be molecularly dissolved in the core and not exhibit any crystallinity such that the release would be relatively fast. However, it is necessary to consider that the actual effect of a high degree of miscibility on drug release depends on the strength and extent of the core-drug interactions.36,45 An increase in the extent of interaction between a drug and the polymer will result in a decrease in the diffusion coefficient of the drug (slower release).73 The ability to provide sustained release of the drug from micelle systems is particularly beneficial for their use in therapeutic applications.

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