A mechanistic study of the formation of polymer nanoparticles by the emulsification-diffusion technique

The mechanism of formation of polymer nanoparticles prepared by the emulsification-diffusion method was evaluated under different preparation conditions and by turbidimetry measurements. Biodegradable poly (D,L-lactic acid) was used as the polymer model. The results show that each emulsion droplet will form several nanoparticles and that the interfacial phenomena during solvent diffusion determine the size properties of the resulting colloid particles. These phenomena cannot be entirely explained by the convection effects caused by interfacial turbulence. We suggest that nanoparticle formation is due to diffusion alone, and we propose a mechanism based on the "diffusion-stranding” mechanism for spontaneous emulsification. In this mechanism, the diffusion of solvent causes local supersaturation near the interface, and nanoparticles are formed, due to the phase transformation and polymer aggregation that occur in these regions. This interpretation is supported by the turbidity measurements made at different polymer concentrations and stirring rate

Novel injectable urethral bulking agents for the treatment of urinary incontinence

Stress urinary incontinence is a highly prevalent disorder resulting from weak urethral closure mechanisms. Endoscopic injection of a urethral bulking agent (UBA) under the urethral mucosa increases coaptation, which improves continence. Collagen is an efficient agent, although its effects are limited in time. Other materials still suffer either from a short-lasting effect or migration in distant organs. We evaluated here novel UBAs using an ex vivo model, with respect to criteria of ease of injection, ability to form a high and stable tissue bulking, implant elasticity and tissue reaction. One approach involves solutions of polymers in water-miscible organic solvents that precipitates in situ. In this manner, high and stable bulks were routinely obtained using various commercial polymers. Selected solvents reduced the tissue reaction to the implant. Microsphere suspensions in hydrogels also proved to be efficient UBA, although less stable bulks were obtained. Thermosetting chitosan hydrogels showed promising results with respect to bulk stability and isoelasticity with surrounding tissues. Different strategies have thus been compared and optimised ex vivo. Further experiments are required to compare the ability of these materials to induce a sustained in vivo bulking effec

Influence of the Organization of Binary Mixes on Their Compactibility

Purpose. Elucidate the compactibility of binary mixes from their organization as compared to the traditional approach involving the different behavior of the materials under compression (plastic or brittle). Methods. Several materials were selected from their surface energies. Binary mixes 50/50 v/v were prepared from different sieved or freeze-milled fractions. The tensile strengths of the tablets obtained at two compression forces were compared with those of series of compacted binary mixes containing different proportions of the raw materials (concept of equivalent media). Results. In the case of interacting mixes, when the differences in particle size between the fractions blended increased, the material with the lowest particle size coated the largest particles more efficiently. Consequently, the tensile strengths of the tablets obtained became closer to the tensile strengths obtained from the pure coating material. For the non-interacting systems, the experimental tensile strengths were very close to the values calculated from the tensile strengths of the pure materials. Conclusions. This study clearly demonstrates the influence of the organization of binary mixes on their compactibility. The adhering material makes a percolating network governing the tensile strength of the tablet. From an industrial point of view, it is possible to improve the compactibility of binary mixes without changing their composition by selecting the appropriate organizatio

Comparative Study of Chemoembolization, Loadable Beads: In vitro Drug Release and Physical Properties of DC Bead and Hepasphere, Loaded with Doxorubicin and Irinotecan

Purpose To characterize in vitro the loadability, physical properties, and release of irinotecan and doxorubicin from two commercially available embolization microspheres. Materials and Methods DC Bead (500-700 μm) and Hepasphere (400-600 μm) microspheres were loaded with either doxorubicin or irinotecan solutions. Drug amount was quantified with spectrophotometry, bead elasticity was measured under compression, and bead size and loading homogeneity were assessed with microscopy image analysis. Drug release was measured over 1-week periods in saline by using a pharmacopeia flow-through method. Results Almost complete drug loading was obtained for both microsphere types and drugs. Doxorubicin-loaded DC Beads maintained their spherical shape throughout the release. In contrast, Hepaspheres showed less homogeneous doxorubicin loading and, after release, some fractured microspheres. Incomplete doxorubicin release was observed in saline over 1 week (27% ± 2 for DC beads and 18% ± 7 for Hepaspheres; P = .013). About 75% of this amount was released within 2.2 hours for both beads. For irinotecan, complete release was obtained for both types of beads, in a sustained manner over 2-3 hours for DC Beads, and in a significantly faster manner as a 7-minute burst for Hepaspheres. Conclusions The two drug-eluting microspheres could be efficiently loaded with both drugs. Incomplete doxorubicin release was attributed to strong drug-bead ionic interactions. Weaker interactions were observed with irinotecan, which led to faster drug release

In vitro characterization of sunitinib eluting beads.

Purpose: To load embolization particles (DC-Beads, Biocompatibles, UK) with an anti-angiogenic agent (sunitinib) and to characterize the in vitro properties of the Beads-drug association.Materials: DC Beads of 100-300µm were loaded using a specially designed 10mg/ml sunitinib solution. Loading profile was studied by spectrophotometry of the supernatant solution at 430nm at different time points. Release experiment was performed using the USP method 4 (flow-through cell). Spectrophotometric determination at 430nm was used to measure drug concentration in the eluting solution.Results: We were able to load >98% of the drug in the DC-Beads in 2 hours. The maximum concentration was 20mg sunitinib/ml DC Beads. Loaded Beads gradually released 59% of the loaded drug in the eluting solution, by an ionic exchange mechanism,over 6 hours.Conclusions: DC Beads could be loaded with the multi tyrosine kinase inhibitor sunitinib using a specially designed solution. High drug payload can be achieved. The loaded DC Beads released the drug in an ionic eluting solution with an interesting release profile

Freeze-drying and lyopreservation of diblock and triblock poly(lactic acid)poly(ethylene oxide)(PLA-PEO) copolymer nanoparticles

In this study, the formulation and process parameters that determine successful production and long-term stability of freeze-dried poly(lactic acid) (PLA) nanoparticles with “hairy-like” poly(ethylene oxide) (PEO) surfaces were investigated. Nanoparticles with grafted (covalently bound) PEO coatings were produced by the salting-out method from blends of PLA and PLA–PEO diblock or triblock copolymers. PLA nanoparticles with physically adsorbed PEO were also produced. The redispersibility of the nanoparticles after freeze-drying under various conditions was assessed. The surface of the nanoparticles was characterized and classified in terms of “brush” and “loop” conformations. Upon freeze-drying, it appeared that the presence of PEO at the nanoparticle surface could severely impair the redispersibility of the particles, especially in the PEO-grafted systems. This effect was shown to be related to the amount and molecular weight of PEO in the various formulations. In most cases, particle aggregation was prevented by use of trehalose as lyoprotective agent. Increasing the concentration of particles in the suspension to be freeze-dried was shown to induce much less damage to the nanoparticles, and freezing the suspension at a very low temperature (−196°C) was found to further improve the lyoprotective effect. Most of the lyoprotected nanoparticles remained stable for at least 12 weeks at 4 and −25°C. The production and preservation of freeze-dried PLA–PEO diblock and triblock copolymer nanoparticles is feasible under optimized lyoprotective conditions