Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained.
Oral administration is the most commonly preferred route for drug delivery because of its simplicity, convenience, and patient acceptance, especially in the case of repeated dosing for chronic therapy [
Nanotechnology brings some advantages to the drug delivery, particular for oral drug. It allows (1) the delivery of poorly water-soluble drugs; (2) the targeting of drugs to specific parts of the gastrointestinal tract (GI); (3) the transcytosis of drugs across the tight intestinal barrier; and (4) the intracellular and transcellular delivery of large macromolecules [
A drug that is administered orally must survive transit through the gastrointestinal (GI) tract. Although part of the absorption process occurs in the oral cavity and stomach due to the presence of salivary amylase and gastric protease (pepsin), the small intestine remains the major site for absorption [
Schematic representation of the mechanisms involved in the absorption of exogenous drugs in the small intestine. (a) Transcellular transport; (b) active transport; (c) facilitated diffusion; (d) receptor-mediated endocytosis; (e) paracellular transport; (f) pinocytosis [
Although oral administration is the preferred route for drug delivery, and the mechanisms of drug absorption have been widely studied, there still exists the serious problem of low bioavailability which has severely impeded the development of oral therapy. The bioavailability of a drug strongly depends on its intrinsic properties and physiological conditions. A drug that is administered orally must survive transit through the chemical and enzymatic GI liquids, cross the mucus layer and the epithelium before being absorbed [
Therefore, to achieve good absorption and bioavailability, oral drugs should be stable at the low gastric pH and have a reproducible and good pharmaceutical dissolution profile and adequate hydrophilic/lipophilic balance to cross the intestinal epithelial membrane. Furthermore, they should not induce significant gastrointestinal toxicities, such as nausea, vomiting, loss of appetite, or diarrhea, that would limit continued oral administration or result in poor compliance [
PMs are self-assembled core-shell nanostructures formed in an aqueous solution consisting of amphiphilic block copolymers (see Figure
Formation and drug loading of PMs by self-assemble of amphiphilic block copolymers in aqueous solution.
Theoretically, the formation of micelles is driven by decrease of free energy. The removal of hydrophobic fragments from the aqueous environment and the reestablishing of hydrogen bond network in water decrease free energy of the system and finally form the micelles. The typical methods used for encapsulation of poorly water-soluble drugs are dialysis method, oil-in-water emulsion solvent evaporation method, and solid dispersion method [
PMs present a great potential as a drug delivery system for compounds that are hydrophobic and exhibit poor bioavailability which results from the unique core-shell structure. The inner hydrophobic core enables incorporation of poorly water-soluble drugs thus improving their stability and bioavailability. Typically, the inner core of the PMs was formed with hydrophobic blocks of the copolymers by hydrophobic interaction. Besides, it can also be formed by electrostatic interactions, using charged block copolymers of oppositely charged macromolecules, resulting in the formation of polyion complex (PIC) micelles [
Amphiphilic copolymers which constitute PMs are usually block copolymers [
The main mechanisms involved in the enhancement of drug absorption by PMs are: (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the loaded drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve drug accumulation [
As we discussed above, GI tract is the major barrier for oral drugs. After oral administration, drugs will encounter the harsh physicochemical environment of the GI tract and be degraded due to the variation of pH levels as well as the presence of enzymes or bile salts. To ensure delivery of the carried drugs to the absorption sites, PMs must be able to resist rapid dissociation upon dilution and retain the stable core-shell structure before target sites. It is known that PMs possess two aspects of structural stability, thermodynamic and kinetic, provided by the entanglement of polymer chains in the inner core [
For a micelle to be thermodynamically stable, the copolymer concentration should be above its CMC. The CMC is influenced by the hydrophilic-lipophilic balance (HLB) of the block copolymer [
It is indicated that non-pH-sensitive micelles may enhance drug solubilization but probably not necessarily the drug absorption. Free (readily absorbable) form of a drug is one of the most important requirements for absorption in the GI tract. However, drug release from such PMs will occur only by diffusion when polymer concentration is well above the CMC, preventing the complete drug release [
The potential disadvantage of normal PMs can be solved by application of additional stimuli that cause micelle destabilization in a specially controlled manner thus increasing the selectivity and efficiency of drug delivery to target sites. External factors such as heat [
As is known, blood and normal tissues have a pH of 7.23 [
Among the various polymers composed micelles, polyacids, or polybases may be used as building blocks that impart pH sensitivity to drug release [
Schematic representation of the mechanisms of pH sensitivity. (a) PMs with basic core units, (b) PMs with acidic core units.
Acrylic-based polymers are widely used in oral pH-sensitive drug delivery, such as poly(methacrylic acid) (PMAA). PMAA retains a collapsed state in the low pH of the stomach and swells as it transits through the intestines. Blends of this polymer with polyethylacrylate (PMAA-PEA) and polymethacrylate (PMAA-PMA) can be tailored to dissolve in specific pH ranges corresponding to specific locations in the GI tract [
Kim and his coworkers hypothesized that the physical stability of hydrotropic polymeric (HP) micelles containing AA moieties may decrease in the intestine, releasing the loaded drugs faster in the intestine than in the stomach [
Some other groups have also developed the pH-sensitive oral drug delivery systems. In an earlier report, Sant et al. prepared and characterized a pH-sensitive PMs incorporating poorly water-soluble model drugs [
Nanocarriers for oral administration should adhere to mucus and cross the mucus layer. Drugs delivered to mucosal surfaces are usually efficiently removed by mucus clearance mechanisms [
The ability to develop mucoadhesive interactions within the gut would be one of the key factors influencing their ability to promote oral absorption of the loaded drug. It was demonstrated that there exists a direct relationship between mucoadhesion and drug absorption [
Mucoadhesion is a complex phenomenon, and several steps have been suggested in mucoadhesive bond formation [
The fates of the mucoadhesive PMs in the GI tract include at least three different pathways: mucoadhesion, translocation through the mucosa or transit, and direct faecal elimination. Among the various factors, the surface charges of PMs seem to play an important role in particle uptake. On one hand, the negatively charged intestinal mucosa, due to the existence of glycocalyx, attracts more positively charged PMs. Therefore, a considerable number of studies have been conducted using positively charged polymers such as chitosan to increase residence time in the GI tract [
Polymers such as cross-linked polyacrylic acids (PAA) [
Other synthetic mucoadhesive polymers have been currently investigated in pharmaceutical formulations including PEG, cellulose derivatives (methylcellulose) [
Much stronger bioadhesion can be achieved by functionalizing polymers with targeting ligands (e.g., lectins) [
Besides uptake, drugs are often pumped out of enterocytes by efflux transporters on the surface of intestinal mucosa. The extent of absorption for poorly water-soluble drugs (and orally administered drugs in general) is affected by these efflux pathways [
The first P-gp inhibitors proposed were substrates that could bind to the protein and inhibit its activity. Several drugs, including cyclosporine A (cyA) and verapamil, have been studied for this purpose [
Pluronic block copolymers (also known under their nonproprietary name “poloxamers”) consist of hydrophilic ethylene oxide (EO) and hydrophobic propylene oxide (PO) blocks arranged in a basic A-B-A structure:
Pluronic block copolymers available from BASF (Wyandotte, MI, USA) contain two hydrophilic EO blocks and a hydrophobic PO block [
D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or simply TPGS) (see Figure
Structure of D-a-tocopheryl polyethylene glycol succinate (TPGS).
The effect of TPGS on the bioavailability of a P-gp substrate was first reported in enhancing CyA absorption. It was initially postulated that the improvement in oral availability was due solely to micelle formation and increased drug solubility. Subsequently, Chang and coworkers demonstrated an increased CyA absorption at TPGS concentrations below the CMC [
In addition, some other amphiphilic polymers have been reported as P-gp inhibitors, such as mPEG-block-polycaprolactone [
Oral administration is the most commonly preferred route for drug delivery, especially in the case of repeated dosing for chronic therapy. To achieve good oral absorption of poorly water-soluble drugs, the loaded drug should be protected from the harsh gastrointestinal environment and release in a controlled manner at the target sites. In this review article, we aim to illustrate the potential of PMs for delivery of poorly water-soluble drugs, especially in the areas of oral delivery. It was suggested that PMs could enhance the oral drug bioavailability probably because the special stability (thermodynamic and kinetic stability) facilitating the safe transport of PMs through the GI tract, the pH-sensitivity of PMs promoting the controlled release properties of loaded drugs at target region, the mucoadhesivity of PMs prolonging the residence time in the gut, and the P-gp inhibitors contributing to drug accumulation. To make a methodical layout, we introduced various kinds of PMs separately in this article. However, a possible direction of combining two or more properties, such as pH-sensitive and mucoadhesive PMs, has gained much attention and offers a promising way to enhance the bioavailability of oral delivery.
The authors would like to thank Mr. Lee Lankford from UC Davis for grammatical editing of the paper.