To develop self-assembling polymers forming polymeric micelles and increasing the solubility of poorly soluble drugs, amphiphilic polymers containing a hydrophilic PEG moiety and a hydrophobic moiety derived from monoglycerides and polyethers were designed. The biodegradable copolymers were obtained via a polycondensation reaction of polyethylene glycol (PEG), monooleylglyceride (MOG) and succinic anhydride (SA). Polymers with molecular weight below 10,000g/mol containing a minimum of 40mol% PEG and a maximum of 10mol% MOG self-assembled spontaneously in aqueous media upon gentle mixing. They formed particles with a diameter of 10nm although some aggregation was evident. The critical micellar concentration varied between 3×10−4 and 4×10−3g/ml, depending on the polymer. The cloud point (≥66°C) and flocculation point (≥0.89M) increased with the PEG chain length. At a 1% concentration, the polymers increased the solubility of poorly water-soluble drug candidates up to 500-fold. Drug solubility increased as a function of the polymer concentration. HPMC capsules filled with these polymers disintegrated and released model drugs rapidly. Polymer with long PEG chains had a lower cytotoxicity (MTT test) on Caco-2 cells. All of these data suggest that the object polymers, in particular PEG1000/MOG/SA (45/5/50) might be potential candidates for improving the oral biopharmaceutical performance of poorly soluble drugs.

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di-block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation.

Monomethylether poly(ethyleneglycol)(750)-poly(caprolactone-co-trimethylene carbonate) (mmePEG750)P(CL-co-TMC)) which spontaneously form micelles, can cross lipid bilayers via passive diffusion and demonstrate an oral bioavailability of 40% in rats. The aim of the current work was to study the transport mechanism(s) of drug-loaded mmePEG750P(CL-co-TMC) micelles across the intestinal barrier. The transport of radiolabelled polymer across Caco-2 cell monolayer was investigated by disrupting tight junctions and by inhibiting endocytosis. The polymer and drugs loaded in micelles independently crossed Caco-2 cell monolayers and did not use either the paracellular route or M-cells. The polymer did not affect P-gp pumps. This mechanistic study suggests that whereas drug-loaded micelles were absorbed by fluid-phase endocytosis, polymeric unimers diffused passively across the membrane concomitantly with micellar endocytosis.

The goal of the current study was to assess the value of predictive computational approaches for estimating drug solubility in hydrated micelles formed from di-block copolymers of polyethylene glycol (PEG) and random copolyesters of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) using drug-polymer compatibility as assessed through the Flory-Huggins interaction parameter (chi). In order to accomplish this, the compatibility of several well-known model drugs (associated with the four biopharmaceutics classification system (BCS) classes) was assessed with both segments of the amphiphilic di-block copolymer PEG-b-P(CL-co-TMC). Compatibilities were estimated based on the Hansen modification of the Hildebrand approach using Molecular Modeling Pro software. Experimental solubilities for model drugs were determined using a shake-flask technique at various polymer concentrations. The solubilities of 8 compounds in 10% w/v micelle solutions were in relatively good agreement with the predicted drug-polymer compatibility. In addition, the approach allows for the selection of a suitable di-block copolymer for optimal solubilization of a specific drug. Furosemide was assessed as a model with results suggesting that it can be best entrapped in a di-block copolyester containing a relatively high CL content. The data suggests that prediction of drug solubilization of block copolymer-based micelles may be facilitated by assessing the compatibility of the drug for the component polymeric domains.

Self-assembling polymeric surfactant, mmePEG(750)P(CL-co-TMC) [monomethylether poly(ethylene glycol)(750)-poly(caprolactone-co-trimethylene carbonate)], increases drug solubility and crosses an enterocyte monolayer both in vitro and in vivo. The aims of the present work were to investigate whether mmePEG(750)P(CL-co-TMC) polymers can diffuse passively through lipid bilayer using parallel artificial membrane permeability assay (PAMPA) and affect membrane properties using liposomes as model. The mmePEG(750)P(CL-co-TMC) polymer was able to cross by passive diffusion an enterocyte-mimicking membrane in PAMPA at concentration which did not perturb membrane integrity. A weak rigidification associated with a low increase in permeability of liposomal lipid bilayers was observed. These data suggest that polymeric surfactants can cross the lipid membrane by passive diffusion and interact with lipid bilayers.

The aim of this work was to evaluate the potential of self-assembling poly(ethyleneglycol) 750-block-poly(-caprolactone-co-trimethyl- enecarbonate)4500 50/50 copolymers (PEG-p(CL-co-TMC)) to solubilize amphotericin B in polymeric micelles and to disaggregate the drug to the less toxic monomeric form. Amphotericin B was encapsulated in the micelles upon dilution of a mixture of the liquid polymer and the drug in water. Its solubility was increased by two orders of magnitude depending on polymer concentration. The aggregation state of amphotericin B was decreased by PEG-p(CL-co-TMC). The preparation method and the loading of the polymeric micelles influenced it. The antifungal activ- ity of the drug was reduced by encapsulation in the polymeric micelles whereas the onset of amphotericin B-induced hemolysis was delayed. PEG-p(CL-co-TMC) micelles could be an easy method for amphotericin B encapsulation. © 2005 Published by Elsevier B.V.

The aim of this work was to evaluate the potential of self-assembling poly(ethyleneglycol)750-block-poly(ɛ-caprolactone-co-trimethylenecarbonate)4500 50/50 copolymers (PEG-p(CL-co-TMC)) to solubilize amphotericin B in polymeric micelles and to disaggregate the drug to the less toxic monomeric form. Amphotericin B was encapsulated in the micelles upon dilution of a mixture of the liquid polymer and the drug in water. Its solubility was increased by two orders of magnitude depending on polymer concentration. The aggregation state of amphotericin B was decreased by PEG-p(CL-co-TMC). The preparation method and the loading of the polymeric micelles influenced it. The antifungal activity of the drug was reduced by encapsulation in the polymeric micelles whereas the onset of amphotericin B-induced hemolysis was delayed. PEG-p(CL-co-TMC) micelles could be an easy method for amphotericin B encapsulation.

To determine the fate of polymeric micelles after oral administration, we investigated the possible transport of polymeric micelles across Caco-2 monolayers and their biodistribution in rats after per os administration of [14C]-labelled mmePEG750P(CL-co-TMC) micelles containing risperidone (BCS Class II drug). mmePEG750P(CL-co-TMC) was able to cross Caco-2 monolayer via a saturable transport mechanism. The oral bioavailability of the polymer was 40%. Polymeric micelles based on mmePEG750P(CL-co-TMC) showed very low clearance by the reticuloendothelial system (RES) and a renal excretion. A sustained release of risperidone was observed.

Electron Paramagnetic Resonance and fluorescence spectroscopy have been used to determine the micropolarity and microviscosity of self-assembling systems based on mmePEG-p(CL-co-TMC) having different PEG chain lengths and different CL/TMC ratios and PEG/MOG/SA (45/5/50) polymers with different PEG chain lengths. Four reporter probes have been used: two spin probes, 16-doxyl stearic acid and 5-doxylstearic acid, and two fluorescent probes, pyrene and 1,3-bis(1-pyrenyl) propane (P3P). We found that the micelles based on mmePEG-p(CL-co-TMC) polymers are of a biphasic nature. The micelles are made of a hydrophilic corona with low viscosity while the core of the micelle is more hydrophobic and more viscous. The outer shell is made up of PEG chains, the hydrophobic part of the chains making the core. The partial hydration of the shell seems to lead to a looser chain network than that associated with deeper domains in the micelles. By contrast, in micelles composed of PEG/MOG/SA, there is no clear domain separation. This is consistent with a spatial configuration of random polymeric chains forming a loose network. In these micelles, the microviscosity is low and the hydrophobicity is high.

Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum based chemotherapy, frequent recurrence and subsequent acquired chemoresistance are responsible for the therapeutic failure, leading to an overall 5 years survival rate of 30%. Considering the usual initial sensitivity of the ovarian tumors to chemotherapy, over the past decade efforts have been focused over the past decade to cure ovarian cancer using the currently available chemotherapeutic agents in various combinations, dosages, schedules (durations and/or routes of administration). However, with such a systemic chemotherapeutic approach, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Considerable efforts are implemented to engineer systems capable of ferrying large doses of cytotoxic agents specifically into targeted malignant cells while sparing healthy cells. The purpose of the present review is to index the main targeted colloidal systems used for drug delivery to ovarian tumors. These nanocarriers will be analyzed by citing examples of their use in preclinical development.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer as well as to produce a foamed extrudate. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. The physicochemical characteristics of the extrudates with and without injection of carbon dioxide were evaluated with reference to the morphology of the solid dispersion and dissolution behaviour and particle properties. Carbon dioxide acted as plasticizer for itraconazole/PVP-VA 64, reducing the processing temperature during the hot stage extrusion process. Amorphous dispersions were obtained and the solid dispersion was not influenced by the carbon dioxide. Release of itraconazole from the solid dispersion could be controlled as a function of processing temperature and pressure. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.

Diblock PEG-p(CL-co-TMC) [methoxypoly(ethylene glycol)-poly(caprolactone/trimethylene carbonate)] copolymers form micelles spontaneously and significantly increase the solubility of poorly water-soluble drugs. The aim of this work was to assess these diblock copolymers as oral drug delivery systems in both in vitro and in vivo experiments using risperidone as a model drug. The permeation of risperidone through Caco-2 cell monolayers showed that the apparent permeation coefficient (Papp) was slightly reduced when risperidone was formulated with the copolymer. Based on the higher apparent drug solubility, the copolymer increased drug flux or the total amount of drug which crossed the Caco-2 monolayers. The Papp of the micelle formulation was higher at 37 °C than at 4 °C. After oral administration to rats, the pharmacokinetic parameters and the pharmacological effect were evaluated. Time courses of receptor occupancy by risperidone after oral administration were similar when risperidone was encapsulated in PEG-p(CL-co-TMC) micelles or solubilized in an aqueous tartaric acid vehicle. The areas under the curve (AUC) were not significantly different although the maximal concentration (Cmax) was twofold lower with the copolymer. The polymeric micelles of PEG-p(CL-co-TMC) seem to be a good candidate for oral drug delivery of poorly soluble drugs.

Micelles obtained from block copolymers of polyethylene glycol and random copolyesters of q-caprolactone and trimethylene carbonate (50/50) can be used as carriers for hydrophobic drugs. We show in this study that the drug loading into the micelles depends strongly on the compatibility of both blocks with the drug considered. Using modeling, we developed a methodology that opens the way to qualitatively predict the drug solubility in polymeric micelles based on polymer–drug interaction parameters.

Electrostatic spinning was applied to the preparation of drug-laden nanofiber for potential use in oral and topical drug delivery. While this technique is in its infancy with regard to pharmaceutical applications, a number of recent publications suggest that it may be of high value in the formulation of poorly water-soluble drugs by combining nanotechnology and solid solution/dispersion methodologies. The purpose of this article is to describe some of these recently published applications. For immediate release oral application, a water-soluble cellulose polymer was selected (i.e., hydroxypropylmethylcellulose, HPMC) while for topical application, a nonbiodegradable, water-insoluble polymer was investigated (i.e., a segmented polyurethane, SPU). Solutions of the polymer and the drugs in appropriate solvents could be spun across various potentials (16-24 kV) generating nanofibers with diameters ranging from 300 to 2000 nm. Dissolution studies found that the non-woven fabrics derived from HPMC and containing itraconazole dissolved over a time course of minutes to hours depending on the formulation used as well as the drug/polymer ratios. Drug release from the SPU samples was dependent on the incorporated drug as well as nanostructure obtained.

Purpose . Nanoparticles can be utilised for targeting drugs to the regional lymph nodes or as diagnostic agents. The surface modification of magnetite nanospheres with poly(ethylene glycol) (PEG) has been assessed by in vitro characterisation and in vivo studies following subcutaneous administration to the rat. Methods . Magnetite nanospheres were prepared with a grafted PEG layer using various PEG lengths from 350 to 1000 Da. Thermogravimetric analysis was utilised to measure the adsorbed amount of PEG. Colloid stability was confirmed by measurement of the particle size and electrophoretic mobility. The kinetics of injection site drainage and lymph node retention were determined 2 hours after subcutaneous administration, for nanospheres coated with PEG lengths of 350, 550, 750, and 1000 Da. For the 750 PEG coated nanospheres, the kinetics of distribution was determined over a 48–hour time course. Results . The distribution of the nanospheres was modified and the lymph node localisation enhanced by altering the surface coverage of PEG on the magnetic surface. Conclusions . PEG–coated magnetite nanospheres with different surface characteristics can be utilised to target a diagnostic agent to regional lymph nodes.

Poloxamer 407 was adsorbed onto the surface of model colloidal drug carriers, polystyrene nanoparticles of 40, 70 and 137 nm in diameter, and the effect of the degree of surface coverage and the conformation of the poly(ethylene oxide) (PEO) chains on biological fate was studied. The relationship between the physicochemical and the biological properties of the nanoparticle systems was also investigated. The adsorbed layer of poloxamer 407 was characterised in terms of percentage surface coverage, thickness of the adsorbed layer and average surface area per PEO chain. Computer modelling of the adsorbed layer was performed (applying the self-consistent field technique), to obtain the structural information of the PEO chains in the layer. The in vitro interaction of the nanoparticles with different degrees of poloxamer 407 surface coverage with serum components and the in vivo biodistribution in the rat model were assessed. The results demonstrated that an increase in the surface coverage with poloxamer 407 resulted in an increased volume fraction of the PEO in the adsorbed layer, further extension of the PEO chains from the surface and closer packing of the chains at the surface. With regard to the interaction with the serum components, an increased surface coverage resulted in a reduction of the amount of serum proteins adsorbed, and, importantly, affected the type of proteins adsorbed. High molecular weight proteins were not adsorbed onto the nanoparticles with a surface coverage above approx. 25%. Following the intravenous administration to rats, even the nanoparticles with the lowest degree of surface coverage (approx. 5%) showed improved circulation profiles relative to the uncoated nanoparticles. The effect was more pronounced for the 40 nm nanoparticles. A further increase in the surface coverage to approx. 25% resulted in a significant increase in circulation time, as compared to uncoated and 5% coated systems, for all sizes of nanoparticles. Importantly, it was found that a long in vivo blood circulation time could be achieved for nanoparticles with a relatively low degree of surface coverage with PEO chains.

Calcitonin-loading was studied in liposomes composed of phosphatidylcholine, cholesterol and stearylamine in relation to the vesicle preparation method. Liposomes entrapping calcitonin were prepared by extrusion, sonication or from mixed micelles through the elimination of cholate by gel filtration. To understand the mode of calcitonin encapsulation in the vesicles, riboflavin was entrapped within the vesicles and taken as a simple model for the encapsulation of molecules in the aqueous phase. Interactions of calcitonin with the liposomal membranes were evaluated by studying the fixation of radiolabelled calcitonin to the outer surface of empty liposomes, and by preparing calcitonin-loaded LDL-like nanoparticles composed of phosphatidylcholine and cholesteryl-oleate. Calcitonin entrapment in the vesicles depends largely on the vesicle preparation method. When vesicles are prepared by removal of cholate from mixed micelles, relatively little calcitonin entrapment in the liposomes is obtained. In this type of vesicle, calcitonin is exclusively embedded in the vesicle bilayer. When vesicles are prepared by extrusion or sonication, calcitonin is found both in the aqueous and lipidic phases of the vesicles. Optimal calcitonin encapsulation was obtained when the liposomes were prepared by sonication.

Purpose. The work was performed to obtain a better understanding why the oral administration of calcitonin (CT)-loaded liposomes to rats results in a hypocalcemia, while liposomes are normally disrupted in the gastro-intestinal tract and cannot protect the hormone from enzymatic digestion.