Unified Scaling of the Structure and Loading of Nanoparticles Formed by Diffusion-Limited Coalescence.

The present study establishes the scaling laws describing the structure of spherical nanoparticles formed by diffusion-limited coalescence. We produced drug-loaded nanoparticles from a poly(ethylene glycol)-poly(d,l-lactic acid) diblock polymer (PEG- b-PLA) by the nanoprecipitation method using different types of micromixing chambers to explore multiple mixing regimes and characteristic times. We first show that the drug loading of the nanoparticles is not controlled by the mixing time but solely by the drug-to-polymer ratio (D:P) in the feed and the hydrophobicity of the drug scaled via the partition coefficient P. We then procure compelling evidence that particles formed via diffusion/coalescence exhibit a relative distribution of PEG blocks between the particle core and its shell that depends only on mixing conditions (not on D:P). Scaling laws of PEG relative distribution and chain surface density were derived in different mixing regimes and showed excellent agreement with experimental data. In particular, results made evident that PEG blocks entrapment in the core of the particles occurs in the slow-mixing regime and favors the overloading (above the thermodynamic limit) of the particles with hydrophilic drugs. The present analysis compiles effective guidelines for the scale up of nanoparticles structure and properties with mixing conditions, which should facilitate their future translation to medical and industrial settings.

Design of PEG-grafted-PLA nanoparticles as oral permeability enhancer for P-gp substrate drug model Famotidine.

Bioavailability of oral drugs can be limited by an intestinal excretion process mediated by P-glycoprotein (P-gp). Polyethylene glycol (PEG) is a known P-gp inhibitor. Dispersion of Famotidine (a P-gp substrate) within PEGylated nanoparticles (NPs) was used to improve its oral bioavailability. In this work, we evaluated the potential impact of NPs prepared from a grafted copolymer of polylactic acid and PEG on P-gp function by studying in vitro permeability of Famotidine across Caco-2 cells. Copolymers of PEG grafted on polylactic acid (PLA) backbone (PLA-g-PEG) were synthesised with 1 mol% and 5 mol% PEG vs. lactic acid monomer using PEG 750 and 2000 Da. The polymers were used to prepare Famotidine-loaded NPs and tested in vitro on Caco-2 cells. Significant decrease in basolateral-to-apical transport of Famotidine was observed when Famotidine was encapsulated in NPs prepared from PLA-g-PEG5%. NPs prepared from PLA-g-PEG5% are promising to improve oral bioavailability of P-gp substrates.

Effect of various formulation parameters on the properties of polymeric nanoparticles prepared by multiple emulsion method.

This work evaluates and interprets underlying mechanisms behind various aspects related to preparation and physical characteristics of polymeric nanoparticles (NP). These were prepared from different biodegradable polymers according to a water-in-oil-in-water emulsion solvent evaporation method. Polymers used were poly(lactic-co-glycolic) acid (PLGA), poly (lactic acid) (PLA), (PLA-PEG-PLA) triblock and (PLA-PEG-PLA)n multi-block co-polymers. A model DNA, as an example of a hydrophilic drug, was encapsulated in the internal aqueous phase. The primary emulsion was prepared using a high shear turbine mixer. The secondary emulsion was prepared by high-pressure homogenization. Surface morphology and internal structure were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Influence of process variables on the physical properties of NP has been studied. Release of DNA was evaluated. In addition, changes occurring to NP porosity and surface area during degradation were followed. Nanoparticle size was ranging between 200-700 nm, according to the preparation conditions. Homogenizing pressure, concentration of the emulsifying agent used, polymer concentration and type and the concentration of a cryoprotectant had variable effects on NP size, surface area and porosity. Batches of NP where no emulsifying agent was added were obtained successfully. The release rate of the DNA from NP was mainly dependent on porosity, which varied significantly among used polymers. The preparation technique was efficient in encapsulating the model DNA and will be used for plasmid encapsulation in a future work.

Physicochemical evaluation of carbamazepine microparticles produced by the rapid expansion of supercritical solutions and by spray-drying.

PURPOSE: To compare the physical and physicochemical characteristics of carbamazepine microparticles prepared using two different methods: (1) the rapid expansion of supercritical solutions (RESS) and (2) the spray-drying process. METHODS: For both processes, microparticles were produced over a range of different temperatures (35 to 100 degrees C). For the RESS method, carbon dioxide was the solvent used over a pressure range of 2500 to 3500 psi. As for the spray-drying method, different organic solvents were used at atmospheric pressure. Comparison was based on morphology, crystalline structure, mean particle size, and size distribution of processed particles. The influence of process parameters on microparticles' characteristics was also investigated. Particles were analyzed using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), thermogravimetric analyzer (TGA), and differential scanning calorimetry (DSC). RESULTS: The carbamazepine particles used as unprocessed starting material had a mean diameter of approximately 85 microm with a size distribution range between 15 and 336 microm. Microparticles produced by either the RESS or spray-drying method had a mean diameter smaller than 2 microm and a narrower size distribution range between 0.25 and 2.5 microm. SEM photomicrographs, X-ray diffractograms, and DSC spectra revealed that modification of crystal morphology was dependent on the operating conditions. CONCLUSIONS: Significant reduction in mean particle size and size distribution range of carbamazepine particles was observed by RESS and spray-drying methods. The results also demonstrate that the crystalline nature of carbamazepine particles depends on the method of production and on the operating parameters of pressure and temperature.