Encapsulation and Controlled Release of Rapamycin from Polycaprolactone Nanoparticles Prepared by Membrane Micromixing Combined with Antisolvent Precipitation.

Rapamycin-loaded polycaprolactone nanoparticles (RAPA-PCL NPs) with a polydispersity index of 0.006-0.073 were fabricated by antisolvent precipitation combined with micromixing using a ringed stainless steel membrane with 10 µm diameter laser-drilled pores. The organic phase composed of 6 g L-1 PCL and 0.6-3.0 g L-1 RAPA in acetone was injected through the membrane at 140 L m-2 h-1 into 0.2 wt % aqueous poly(vinyl alcohol) solution stirred at 1300 rpm, resulting in a Z-average mean of 189-218 nm, a drug encapsulation efficiency of 98.8-98.9%, and a drug loading in the NPs of 9-33%. The encapsulation of RAPA was confirmed by UV-vis spectroscopy, XRD, DSC, and ATR-FTIR. The disappearance of sharp characteristic peaks of crystalline RAPA in the XRD pattern of RAPA-PCL NPs revealed that the drug was molecularly dispersed in the polymer matrix or RAPA and PCL were present in individual amorphous domains. The rate of drug release in pure water was negligible due to low aqueous solubility of RAPA. RAPA-PCL NPs released more than 91% of their drug cargo after 2.5 h in the release medium composed of 0.78-1.5 M of the hydrotropic agent N,N-diethylnicotinamide, 10 vol % ethanol, and 2 vol % Tween 20 in phosphate buffered saline. The dissolution of RAPA was slower when the drug was embedded in the PCL matrix of the NPs than dispersed in the form of pure RAPA nanocrystals.

Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes.

Co-encapsulation of drugs in the same carrier, as well as the development of microencapsulation processes for biomolecules using mild operating conditions, and the production of particles with tailored size and uniformity are major challenges for encapsulation technologies. In the present work, a suitable method consisting of the combination of membrane emulsification with solvent diffusion is reported for the production of multi-core matrix particles with tailored size and potential application in multi-therapies. In the emulsification step, the production of a W/O/W emulsion was carried out using a batch Dispersion Cell for formulation testing and subsequently a continuous azimuthally oscillating membrane emulsification system for the scaling-up of the process to higher capacities. In both cases precise and gentle control of droplet size and uniformity of the W/O/W emulsion was achieved, preserving the encapsulation of the drug model within the droplet. Multi-core matrix particles were produced in a post emulsification step using solvent diffusion. The compartmentalized structure of the multicore-matrix particle combined with the different chemical properties of polycaprolactone (matrix material) and fish gelatin (core material) was tested for the simultaneous encapsulation of hydrophilic (copper ions) and hydrophobic (α-tocopherol) test components. The best operating conditions for the solidification of the particles to achieve the highest encapsulation efficiency of copper ions and α-tocopherol of 99 (± 4)% and 93(± 6)% respectively were found. The multi-core matrix particle produced in this work demonstrates good potential as a co-loaded delivery system.

Hydrothermal carbonisation of sewage sludge: effect of process conditions on product characteristics and methane production.

Hydrothermal carbonisation of primary sewage sludge was carried out using a batch reactor. The effect of temperature and reaction time on the characteristics of solid (hydrochar), liquid and gas products, and the conditions leading to optimal hydrochar characteristics were investigated. The amount of carbon retained in hydrochars decreased as temperature and time increased with carbon retentions of 64-77% at 140 and 160°C, and 50-62% at 180 and 200°C. Increasing temperature and treatment time increased the energy content of the hydrochar from 17 to 19 MJ/kg but reduced its energy yield from 88% to 68%. Maillard reaction products were identified in the liquid fractions following carbonisations at 180 and 200°C. Theoretical estimates of the methane yields resulting from the anaerobic digestion of the liquid by-products are also presented and optimal reaction conditions to maximise these identified.

Preparation of liposomes: a novel application of microengineered membranes--from laboratory scale to large scale.

A novel ethanol injection method using microengineered nickel membrane was employed to produce POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and Lipoid(®) E80 liposomes at different production scales. A stirred cell device was used to produce 73ml of the liposomal suspension and the product volume was then increased by a factor of 8 at the same transmembrane flux (140lm(-2)h(-1)), volume ratio of the aqueous to organic phase (4.5) and peak shear stress on the membrane surface (2.7Pa). Two different strategies for shear control on the membrane surface have been used in the scaled-up versions of the process: a cross flow recirculation of the aqueous phase across the membrane surface and low frequency oscillation of the membrane surface (∼40Hz) in a direction normal to the flow of the injected organic phase. Using the same membrane with a pore size of 5µm and pore spacing of 200µm in all devices, the size of the POPC liposomes produced in all three membrane systems was highly consistent (80-86nm) and the coefficient of variation ranged between 26 and 36%. The smallest and most uniform liposomal nanoparticles were produced in a novel oscillating membrane system. The mean vesicle size increased with increasing the pore size of the membrane and the injection time. An increase in the vesicle size over time was caused by deposition of newly formed phospholipid fragments onto the surface of the vesicles already formed in the suspension and this increase was most pronounced for the cross flow system, due to long recirculation time. The final vesicle size in all membrane systems was suitable for their use as drug carriers in pharmaceutical formulations.

PLGA particle production for water-soluble drug encapsulation: degradation and release behaviour.

Particles for subcutaneous depot use encapsulating a model water-soluble drug have been produced from poly(lactic-glycolic acid) (PLGA) using a membrane emulsification-solvent evaporation technique. The release behaviour, mainly the change in size and inner morphology are reported. During release, the particles initially swelled in size, then reduced. A diffusion based model, taking in to account the change in particle size, is presented. Surface erosion is evident from the particle size and image evidence, and the diffusion model provides a fit to the data even during the surface erosion period, suggesting that the model drug diffuses before the particle degrades.

Preparation and characterization of PLGA particles for subcutaneous controlled drug release by membrane emulsification.

Uniformly sized microparticles of poly(D,L-lactic-co-glycolic) (PLGA) acid, with controllable median diameters within the size range 40-140 microm, were successfully prepared by membrane emulsification of an oil phase injected into an aqueous phase, followed by solvent removal. Initially, simple particles were produced as an oil in water emulsion, where dichloromethane (DCM) and PLGA were the oil phase and water with stabiliser was the continuous phase. The oil was injected into the aqueous phase through an array type microporous membrane, which has very regular pores equally spaced apart, and two different pore sizes were used: 20 and 40 microm in diameter. Shear was provided at the membrane surface, causing the drops to detach, by a simple paddle stirrer rotating above the membrane. Further tests involved the production of a primary water in oil emulsion, using a mechanical homogeniser, which was then subsequently injected into a water phase through the microporous membrane to form a water in oil in water emulsion. These tests used a water-soluble model drug (blue dextran) and encapsulation efficiencies of up to 100% were obtained for concentrations of 15% PLGA dissolved in the DCM and injected through a 40 microm membrane. Solidification of the PLGA particles was followed by removal of the DCM through the surrounding aqueous continuous phase. Different PLGA concentrations, particle size and osmotic pressures were considered in order to find their effect on encapsulation efficiency. Osmotic pressure was varied by changing the salt concentration in the external aqueous phase whilst maintaining a constant internal aqueous phase salt concentration. Osmotic pressure was found to be a significant factor on the resulting particle structure, for the tests conducted at lower PLGA concentrations (10% and 5% PLGA). The PLGA concentration and particle size distribution influence the time to complete the solidification stage and a slow solidification, formed by stirring gently overnight, provided the most monosized particles and highest encapsulation efficiency.

Reversible adsorption inside pores of ultrafiltration membranes.

A range of experiments were performed on the dead-end ultrafiltration (UF) of poly(ethylene glycol) (PEG) of different molecular weights. Deviations from a linear dependence of the filtration rate with the applied membrane pressure difference were found. It is shown that these deviations are not caused by an osmotic pressure influence but determined by the reversible adsorption of PEG molecules inside the pores of the ultrafiltration membranes used. A theoretical model of the process is suggested, which describes the reversible adsorption inside the membrane pores and the corresponding reduction of the filtration velocity. Comparison of the theory predictions with experimental data on the ultrafiltration of PEG shows a good agreement between the theoretical predictions and experimental data. A theory is presented for calculation of the PEG rejection coefficient in the case of ultrafiltration.