Encapsulation of amphotericin B in poly(ethylene glycol)-block-poly(epsilon-caprolactone-co-trimethylenecarbonate) polymeric micelles.

The aim of this work was to evaluate the potential of self-assembling poly(ethyleneglycol)(750)-block-poly(epsilon-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

Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-trimethylene carbonate) for drug solubilization

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of F-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 24h 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 11 (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 di-block 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

Self-assembling PEG-p(CL-co-TMC) copolymers for oral delivery of poorly water-soluble drugs: a case study with risperidone.

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 degrees C than at 4 degrees 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

Monoglyceride-based self-assembling copolymers as carriers for poorly water-soluble drugs

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 10,000 g/mol containing a minimum of 40 mol% PEG and a maximum of 10 mol% MOG self-assembled spontaneously in aqueous media upon gentle mixing. They formed particles with a diameter of 10 nm although some aggregation was evident. The critical micellar concentration varied between 3 x 10(-4) and 4 x 10(-3) g/ml, depending on the polymer. The cloud point (>= 66 degrees C) and flocculation point (>= 0.89 M) 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. (C) 2009 Elsevier B.V. All rights reserved

Biodegradable self-assembling PEG-copolymer as vehicle for poorly water-soluble drugs.

PURPOSE: To develop self-assembling systems increasing the solubility of poorly water-soluble drugs. METHODS: Low molecular weight liquid biodegradable copolymers were synthesized by ring-opening polymerization using caprolactone (CAP) and trimethylenecarbonate (TMC) as monomers. Various initiators were evaluated. The emulsifying and self-assembling properties were investigated by a water titration method. The self-assembling systems were characterized for size, shape, isotropic behavior, cloud point, surface charge, and critical micellar concentration in order to optimize the polymer synthesis. Finally, the improvement of solubility of model drugs was assessed. RESULTS: Only diblock monomethyl ether PEG-CAP/TMC copolymers synthesized with monomethyl ether polyethyleneglycol 550 to 2000 as initiator have shown self-assembling properties: upon dilution, these copolymers formed an isotropically clear solution with droplet sizes in the range of 20 to 100 nm. The hypothesis that these diblock polymers form micelles was confirmed by their low critical micellar concentration (10(-5) g/ml). The copolymers initated with mmePEG750 had a higher cloud point and better colloidal stability than those initiated with mmePEG 550. The solubility of the poorly water-soluble drugs was increased by 1 to 2 orders of magnitude. Good reproducibility was observed from batch to batch. CONCLUSIONS: The polyester diblock copolymer mmePEG750-CAP/TMC forms spontaneously stable micelles in aqueous medium and increases the solubility of lipophilic drugs. They are very promising vehicles for the oral delivery of poorly water-soluble drugs