In vitro human plasma distribution of nanoparticulate paclitaxel is dependent on the physicochemical properties of poly(ethylene glycol)-block-poly(caprolactone) nanoparticles

In this study, we synthesized and characterized two methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) amphiphilic diblock copolymers, both based on MePEG with a molecular weight of 5000 g/mol (114 repeat units) and PCL block lengths of either 19 or 104 repeat units. Nanoparticles were formed from these copolymers by a nanoprecipitation and dialysis technique. The MePEG₁₁₄-b-PCL₁₉ copolymer was water soluble and formed micelles that had a hydrodynamic diameter of 40 nm at all copolymer concentrations tested, and displayed a relatively low core microviscosity. The practically water insoluble MePEG₁₁₄-b-PCL₁₀₄ copolymer formed nanoparticles with a larger hydrodynamic diameter, which was dependent on copolymer concentration, and possessed a higher core microviscosity than the MePEG₁₁₄-b-PCL₁₉ micelles, characteristic of nanospheres. The micelles solubilized a maximum of 1.6% w/w of the hydrophobic anticancer agent, paclitaxel (PTX), and released 92% of their drug payload over 7 days, as compared to the nanospheres, which solubilized a maximum of 3% w/w of PTX and released 60% over the same period of time. Both types of nanoparticles were found to be hemocompatible, causing only minimal hemolysis and no changes in plasma coagulation times as compared to control. Upon in vitro incubation in human plasma, PTX solubilized by micelles had a plasma distribution similar to free drug. The majority of PTX was associated with the lipoprotein deficient plasma (LPDP) fraction, which primarily consists of albumin and alpha-1-acid glycoprotein. In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction.     

In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration.

Methoxy poly(ethylene glycol)-b-poly(caprolactone) (MePEG-b-PCL) copolymers with varying PEG block lengths and a constant PCL block length were synthesized by cationic ring-opening polymerization and used to form nano-sized micelles. Due to their small size and superior in vitro stability, the MePEG(5000)-b-PCL(5000) micelles were selected for further in vitro characterization and an in vivo evaluation of their fate and stability following intravenous (i.v.) administration. Specifically, (3)H-labelled MePEG(5000)-b-PCL(5000) micelles were i.v. administered to Balb/C mice at copolymer doses of 250, 2 and 0.2 mg/kg in order to examine the distribution kinetics of (1) copolymer assembled as thermodynamically stable micelles, (2) copolymer assembled as thermodynamically unstable micelles and (3) copolymer unimers, respectively. Overall, it was found that when the copolymer is assembled as thermodynamically stable micelles the material is effectively restricted to the plasma compartment. Interestingly, the copolymer was found to have a relatively long circulation half-life even when administered at a dose that would likely fall to concentrations below the CMC following distribution. Analysis of plasma samples from this group revealed that even 24 h post-administration a significant portion of the copolymer remained assembled as intact micelles. In this way, this study demonstrates that the hydrophobic and semi-crystalline nature of the PCL core imparts a high degree of kinetic stability to this micelle system.     

Comparison of two pegylated copolymeric micelles and their potential as drug carriers

The aim of this study was to evaluate the ability of forming micelles from two types of synthesized diblock pegylated amphiphilic copolymers and their potential as a drug carrier. Two lactone monomers, ε -caprolactone (CL) and δ -valerolactone (VL), were copolymerized with methoxy poly(ethylene glycol) (MePEG), respectively. The properties of copolymers were investigated and their biocompatibility was tested through an in vitro cytotoxicity study. The influences of the type of lactone monomer (CL and VL) and the feed molar ratios of lactone/MePEG (50/1, 80/1, 160/1) on the performance and release behavior of drug-loaded micelles were investigated. The opening of CL and VL rings by MePEG was efficient, and the pegylation of poly(lactone)s allowed copolymers possessing amphiphilic property and efficiently self-assembled to form micelles with a low critical micelle concentration (CMC) in the range of 10 ^{- 7}-10^{- 8} M. The nano-sized micelles were able to incorporate hydrophobic drug and regulate drug release, and the release of drug was dominated by the hydrophobic poly(lactone) chain length. Although both amphiphilic copolymers exhibited similar controlled release character, the PCL/MePEG micelles possessed lower CMC, higher biocompatibility, and higher drug loading than PVL/MePEG micelles. These suggested that results choosing pegylated PCL as a drug carrier could be better than PVL/MePEG.     

Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymer micelles: theoretical and experimental data and correlations

The solubilization of five model hydrophobic drugs by a series of micelle-forming, water-soluble methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymers (MePEG-b-PCL) with varying methoxy poly(ethylene glycol) (MePEG) and polycaprolactone (PCL) block lengths was investigated. Variation of the feed weight ratio of MePEG to caprolactone resulted in the synthesis of copolymers with predictable block lengths. The micelle diameter and pyrene partition coefficient (Kv) were directly related to the PCL block length whereas the critical micelle concentrations (CMC) were inversely related to the PCL block length. The aqueous solubilities of the model hydrophobic drugs, indomethacin, curcumin, plumbagin, paclitaxel, and etoposide were increased by encapsulation within the micelles. Drug solubilization was directly related to the compatibility between the solubilizate and PCL as determined by the Flory-Huggins interaction parameter (chisp). Furthermore, the concentration of solubilized drug was also directly related to the PCL block length.     

Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations

A number of hypersensitivity reactions have been attributed to the presence of Cremophor((R)) EL in the current formulation for paclitaxel. This has led to the development of formulations for paclitaxel employing polyether-polyester diblock copolymers as micelle forming carriers. Diblock copolymers of methoxypolyethylene glycol-block-poly(D,L-lactide) (MePEG:PDLLA) were synthesized from monomers of D,L-lactide and MePEG by a ring opening bulk polymerization in the presence of stannous octoate. Up to 25% paclitaxel could be loaded into matrices of MePEG:PDLLA (60:40, MePEG molecular weight of 2000) using the solution casting method. Dissolution of paclitaxel/copolymer matrices in aqueous media resulted in complete solubilization of paclitaxel within the hydrophobic PDLLA core of the micelles. This review article describes the synthetic reaction conditions influencing the degree of conversion of monomer to copolymer, thermal properties, critical micelle concentrations of copolymers, methods of incorporation of paclitaxel into copolymer matrices and subsequent constitution in aqueous media and biological evaluations of micellar paclitaxel.     

Block copolymer micelles as long-circulating drug vehicles

The development of block copolymer micelles as long-circulating drug vehicles is described. As well, a recent fundamental study of block copolymer micelles, where much insight into their structures and properties has been realized, is briefly summarized in order to shed light on their properties in vivo. There is emphasis on block copolymer micelles having poly(ethylene oxide) as the hydrophilic block and poly(l-amino acid) as the hydrophobic block, with some discussion on the properties of poly(ethylene oxide). Comparisons are drawn with other drug vehicles and with micelles formed from low molecular weight surfactants. Micelle-forming, block copolymer-drug conjugates are described. Hydrophobic drugs, such as doxorubicin, distribute into block copolymer micelles, and details of several examples are given. Finally, the paper presents studies that evidence the long circulation times of block copolymer micelles. Like long-circulating liposomes, block copolymers that form micelles accumulate passively at solid tumors and thus have great potential for anti-cancer drug delivery.     

Micelle formation and drug release behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer

Self-association behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer and drug carrier capability of the formed micelles was examined. The results gained through fluorescence spectroscopy, transmission electron microscopy and nuclear magnetic resonance spectroscopy revealed that both polypeptide graft copolymer and its mixture with polypeptide block copolymer can self-assemble to form polymeric micelles in aqueous media. The molecular structure of the graft copolymer and blending the graft with block copolymer exert marked effects on the critical micelle concentration and the shape of formed micelles. It was found that the hydrophobic inner core of the micelles formed either by graft copolymer or mixture of graft and block copolymers can act as an incorporation site for the hydrophobic drugs. The drug loading content of the graft copolymer micelles tends to be larger when the content of the polypeptide segments in the copolymer increases. The results obtained from the drug-release studies showed that the drug-release rates are dependent on the chemical nature of the graft copolymer, the composition of the graft and block copolymer mixture, and also the pH value of the release media.     

紫杉醇Pluronic P105聚合物胶束的制备、表征与逆转肿瘤多药耐药性的体外研究

药物递送系统是克服肿瘤多药耐药性(MDR)的一种新策略。本文以聚合物胶束系统和难溶性药物紫杉醇(PTX)为研究对象，旨在制备一种新型的PTX给药系统，既能增溶难溶性药物，又具有克服肿瘤MDR的能力。以Pluronic P105为载体，采用固体分散-水化法制备PTX聚合物胶束，并以星点设计-效应面优化法进行处方优化。对其粒径、体外释放等性质进行表征后，以人耐药卵巢癌细胞SKOV-3/PTX为细胞模型，体外评价PTX聚合物胶束的细胞摄取及其逆转肿瘤细胞耐药性的作用。结果显示，聚合物胶束制剂的载药量约为1.1%、药物浓度约为700 μg·mL^-1、平均粒径约为24 nm。胶束制剂与普通制剂(Taxol)在6 h内的累积释放分别为45.4%和95.2%，前者具有较强的缓释作用；胶束制剂与Taxol对SKOV-3/PTX的IC₅₀值分别为1.14和5.11 μg·mL^-1，二者的耐药逆转指数(RRI)分别为9.65和2.15。胶束制剂可促进耐药细胞对P-糖蛋白(P-gp)底物(PTX或Rhodamine-123)的摄取。结果表明，Pluronic P105可有效增溶难溶性药物PTX，并形成具有较强缓释作用的纳米级聚合物胶束制剂，该制剂可显著提高PTX对人卵巢癌耐药细胞的细胞毒性，能逆转其耐药性。     

Methoxypolyethylene glycol-block-polycaprolactone diblock copolymers reduce P-glycoprotein efflux in the absence of a membrane fluidization effect while stimulating P-glycoprotein ATPase activity

We have previously shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-b-polycaprolactone (MePEG-b-PCL) increased the cellular accumulation and reduced the basolateral to apical flux of the P-glycoprotein substrate, rhodamine 123 (R-123) in caco-2 cells. The purpose of this study was to investigate membrane perturbation effects of MePEG-b-PCL diblock copolymers with erythrocyte membranes and caco-2 cells and the effect on P-gp ATPase activity. The diblock copolymer MePEG(17)-b-PCL(5) induced increasing erythrocyte hemolysis at concentrations which correlated with increasing accumulation of R-123 into caco-2 cells. However, no increase in cellular accumulation of R-123 by non-P-gp expressing cells was observed, suggesting that diblock did not enhance the transmembrane passive diffusion of R-123, but that the accumulation enhancement effect of the diblock in caco-2 cells was likely mediated primarily via P-gp inhibition. Fluorescence anisotropy measurements of membrane fluidity and P-gp ATPase activity demonstrated that MePEG(17)-b-PCL(5) decreased caco-2 membrane fluidity while stimulating ATPase activity approximately threefold at concentrations that maximally enhanced R-123 caco-2 accumulation. These results suggest that inhibition of P-gp efflux by MePEG(17)-b-PCL(5) does not appear to be related to increases in membrane fluidity or through inhibition in P-gp ATPase activities, which are two commonly reported cellular effects for P-gp inhibition mediated by surfactants.     

Preparation,characterization, and drug release behaviors of drug nimodipine-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles

Amphiphilic triblock copolymers, poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring opening polymerization of epsilon-caprolactone initiated with the hydroxyl functional groups of poly(ethylene glycol) at both ends of the chain. The micelles composed of this type of copolymer had such a structure that both ends of the PEO chain were anchored to the micelle. The critical micelle concentration of the block copolymer in distilled water was determined by a fluorescence probe technique using pyrene. As the hydrophobic components of the block copolymer increased, the critical micelle concentration value decreased. To estimate the feasibility as novel drug carriers, the block copolymer micelles were prepared by precipitation of polymer from acetone solution into water. From the observation of transmission electron microscopy, the micelles exhibited a spherical shape. Nimodipine was incorporated into the hydrophobic inner core of micelles as a lipophilic model drug to investigate the drug release behavior. The PEO/PCL ratio of copolymer was a main factor in controlling micelle size, drug-loading content, and drug release behavior. As PCL weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

P-glycoprotein efflux inhibition by amphiphilic diblock copolymers: relationship between copolymer concentration and substrate hydrophobicity

The utilization of surfactants to increase intestinal absorption of drugs is a viable strategy that benefits from increases in drug solubilization and the potential for inhibition of P-glycoprotein (P-gp) mediated efflux. However, the effective concentration range for P-gp inhibition of most surfactants is defined over a narrow concentration range, below the critical micelle concentration (CMC), as a result of significant micelle sequestration of drug. Therefore, the objectives of these studies were to assess if association of P-gp substrates differing in hydrophobicity will impact the effective concentration range for P-gp inhibition by amphiphilic diblock copolymers based on methoxypolyethylene glycol-block-polycaprolatone (MePEG-b-PCL). Comparisons between the micelle association and Caco-2 cellular accumulation were evaluated using two structurally homologous P-gp substrates, the relatively hydrophobic R-6G and the hydrophilic R-123, over concentrations above and below the CMC for MePEG-b-PCL diblock copolymers. An approximately 3.75-fold enhancement of R-123 accumulation occurred with 2 mM MePEG17-b-PCL5, compared to approximately 1.25-fold for R-6G. This decrease in the accumulation enhancement corresponds with the higher R-6G fraction (0.75) associated at 2 mM MePEG17-b-PCL5 compared with R-123 (0.25). Interestingly, R-6G accumulation was enhanced over a very broad range of MePEG17-b-PCL5 concentrations below the CMC. This was in contrast to R-123, which demonstrated no enhancement below the CMC. A similar concentration dependent accumulation profile was seen with other surfactants such as vitamin E TPGS and Cremophor EL and with two other P-gp substrates differing in hydrophobicity, the relatively hydrophobic paclitaxel and hydrophilic doxorubicin. In conclusion, the effective concentration range for surfactant mediated inhibition of P-gp appears to depend on the P-gp substrate hydrophobicity.     

Evidence for Modulation of P-glycoprotein-Mediated Efflux by Methoxypolyethylene Glycol-block-Polycaprolactone Amphiphilic Diblock Copolymers

PURPOSE: The purpose of this study was to investigate the pathways involved in rhodamine 123 (R-123) accumulation enhancement in Caco-2 cells with a low molecular-weight methoxypolyethylene glycol-block-polycaprolactone (MePEG-b-PCL) diblock copolymer. METHODS: R-123 accumulation by Caco-2 cells with MePEG17-b-PCL5 was measured in the presence of endocytosis inhibitors or under ATP depletion conditions. Directional flux studies were conducted with cell monolayers on Transwell plates. RESULTS: Endocytosis inhibitors had no effect on reducing R-123 accumulation with MePEG17-b-PCL5. The apical to basolateral (AP-->BL) flux of R-123 with MePEG17-b-PCL5 or verapamil was similar to R-123 alone. However the BL-->AP flux was significantly decreased with MePEG17-b-PCL5 and verapamil. The efflux ratio for R-123 flux was 3.2 and was reduced to 1.06 with MePEG17-b-PCL5 confirming the inhibition of P-glycoprotein (P-gp)-mediated efflux. R-123 accumulation at the conclusion of each of the flux experiments was similar for MePEG17-b-PCL5 and verapamil in the BL-->AP direction. The AP-->BL direction demonstrated a 2-fold increase for verapamil and a 5-fold increase with MePEG17-b-PCL5. This difference in R-123 accumulation was possibly due to the diblock enhancing passive membrane diffusion of R-123. CONCLUSIONS: MePEG17-b-PCL5 diblock reduced R-123 efflux through inhibition of P-gp efflux, and unimers may interact with cell membranes, increasing permeability and enhancing R-123 influx through increased transmembrane diffusion.     

Filamentous, mixed micelles of triblock copolymers enhance tumor localization of indocyanine green in a murine xenograft model

Polymeric micelles formed by the self-assembly of amphiphilic block copolymers can be used to encapsulate hydrophobic drugs for tumor-delivery applications. Filamentous carriers with high aspect ratios offer potential advantages over spherical carriers, including prolonged circulation times. In this work, mixed micelles composed of poly(ethylene oxide)-poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127 (PF-127) were used to encapsulate a near-infrared fluorophore. The micelle formulations were assessed for tumor accumulation after tail vein injection to xenograft tumor-bearing mice by noninvasive optical imaging. The mixed micelle formulation that facilitated the highest tumor accumulation was shown by cryo-electron microscopy to be filamentous in structure compared to spherical structures of pure PF-127 micelles. In addition, increased dye loading efficiency and dye stability were attained in this mixed micelle formulation compared to pure PEO-PHB-PEO micelles. Therefore, the optimized PEO-PHB-PEO/PF-127 mixed micelle formulation offers advantages for cancer delivery over micelles formed from the individual copolymer components.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the 'stealth' properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

Amphiphilic block copolymers for drug delivery

Amphiphilic block copolymers (ABCs) have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery. The utility of ABCs for delivery of therapeutic agents results from their unique chemical composition, which is characterized by a hydrophilic block that is chemically tethered to a hydrophobic block. In aqueous solution, polymeric micelles are formed via the association of ABCs into nanoscopic core/shell structures at or above the critical micelle concentration. Upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate. Although the Pluronics, composed of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), are the most widely studied ABC system, copolymers containing poly(L-amino acid) and poly(ester) hydrophobic blocks have also shown great promise in delivery applications. Because each ABC has unique advantages with respect to drug delivery, it may be possible to choose appropriate block copolymers for specific purposes, such as prolonging circulation time, introduction of targeting moieties, and modification of the drug-release profile. ABCs have been used for numerous pharmaceutical applications including drug solubilization/stabilization, alteration of the pharmacokinetic profile of encapsulated substances, and suppression of multidrug resistance. The purpose of this minireview is to provide a concise, yet detailed, introduction to the use of ABCs and polymeric micelles as delivery agents as well as to highlight current and past work in this area.     

PEG-b-PPS diblock copolymer aggregates for hydrophobic drug solubilization and release: cyclosporin A as an example

Micelles formed from amphiphilic block copolymers have been explored in recent years as carriers for hydrophobic drugs. In an aqueous environment, the hydrophobic blocks form the core of the micelle, which can host lipophilic drugs, while the hydrophilic blocks form the corona or outer shell and stabilize the interface between the hydrophobic core and the external medium. In the present work, mesophase behavior and drug encapsulation were explored in the AB block copolymeric amphiphile composed of poly(ethylene glycol) (PEG) as a hydrophile and poly(propylene sulfide) PPS as a hydrophobe, using the immunosuppressive drug cyclosporin A (CsA) as an example of a highly hydrophobic drug. Block copolymers with a degree of polymerization of 44 on the PEG and of 10, 20 and 40 on the PPS respectively (abbreviated as PEG44-b-PPS10, PEG44-b-PPS20, PEG44-b-PPS40) were synthesized and characterized. Drug-loaded polymeric micelles were obtained by the cosolvent displacement method as well as the remarkably simple method of dispersing the warm polymer melt, with drug dissolved therein, in warm water. Effective drug solubility up to 2 mg/mL in aqueous media was facilitated by the PEG- b-PPS micelles, with loading levels up to 19% w/w being achieved. Release was burst-free and sustained over periods of 9-12 days. These micelles demonstrate interesting solubilization characteristics, due to the low glass transition temperature, highly hydrophobic nature, and good solvent properties of the PPS block.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the ‘stealth’ properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic^® (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs

INTRODUCTION: Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo. AREAS COVERED: In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed. EXPERT OPINION: During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.     

Solubilisation in aqueous micellar solutions of block copoly(oxyalkylene)s

The solubilisation capacities of micellar solutions of diblock and triblock copolymers composed of hydrophilic poly(ethylene oxide) and hydrophobic poly(styrene oxide) have been compared using the poorly water-soluble drug griseofulvin as a model solubilisate. Our results showed an increase of solubilisation capacity (expressed as mg griseofulvin per gram of hydrophobic block) with temperature and, for spherical micelles, with core volume before reaching limiting values. A change of micelle shape from spherical to cylindrical (or worm-like) resulting from an increase in micelle aggregation number was accompanied by a further enhancement of solubilisation capacity. Comparison with the solubilisation of the same drug in micellar solutions of block copolymers of poly(ethylene oxide) and poly(1,2-butylene oxide) showed that the solubilisation capacity of a poly(styrene oxide) block was approximately four times that of a poly(1,2-butylene oxide) block for spherical micelles. Solubilisation capacity at 25 degrees C was approximately doubled when griseofulvin was incorporated into a copolymer melt and micelles initially formed from the drug-loaded melt at 65 degrees C rather than by loading the drug into pre-micellised solution at 25 degrees C in the usual manner.