Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability.

The aim of this study was to develop antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPßCD) was used as a stabilizer and as an electrospinning matrix. In order to optimize the morphology of the fibers, electrospinning of various formulations was carried out using water, methanol/water (1:1), and methanol as solvents. The results showed that using methanol could be advantageous due to the lower viscosity threshold for fiber formation enabling higher potential drug loadings by using less excipient. To increase the productivity of electrospinning, high-speed electrospinning technology was utilized and HPßCD fibers containing 9.1% antisense oligonucleotide were prepared at a rate of ~330 g/h. Furthermore, to increase the drug content of the fibers, a formulation with a 50% drug loading was developed. The fibers had excellent grindability but poor flowability. The ground fibrous powder was mixed with excipients to improve its flowability, which enabled the automatic tableting of the mixture by direct compression. The fibrous HPßCD-antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPßCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning such as scale-up and downstream processing of the fibers.

Modulating protein release profiles by incorporating hyaluronic acid into PLGA microparticles Via a spray dryer equipped with a 3-fluid nozzle.

PURPOSE: The purpose of this study was to modulate the release profiles of the model protein drug from spray dried poly(DL-lactic-co-glycolic acid) (PLGA) microparticles by incorporating hyaluronic acid (HA) in the formulation. METHODS: Bovine serum albumin (BSA)-loaded PLGA microparticles with or without HA were prepared using a spray dryer equipped with a 3-fluid nozzle. The effects of HA on the surface tension and the rheological behavior of the inner feed solution were investigated. The physicochemical properties of the resulting microparticles were characterized using scanning electron microscopy (SEM), laser diffraction (LD), confocal laser scanning microscopy (CLSM) and X-ray photoelectron spectroscopy (XPS). Circular dischoism (CD) was used to characterize conformational integrity of BSA released from the microparticles. RESULTS: Spherical microparticles with D50 of 5-10 µm were obtained. Addition of HA in inner feed solutions increased the feed viscosity, but with no influence on the surface tension. All inner feed solutions showed non-Newtonian shear thinning behavior and the rheological properties were not time dependent. The CLSM and XPS analyses suggested a core-shell like structure of the microparticles when HA was incorporated. The release profiles of BSA were extended and the initial burst releases were suppressed with an increase in HA in the microparticle formulations. In addition, HA seemed to protect BSA from degradation upon the spray-drying process. CONCLUSIONS: The present work demonstrates the potential of HA to modulate protein release profile from PLGA microparticle formulations produced via spray drying using 3-fluid nozzle.

One-step production of protein-loaded PLGA microparticles via spray drying using 3-fluid nozzle.

PURPOSE: The aim of this study was to investigate the potential of using a spray-dryer equipped with a 3-fluid nozzle to microencapsulate protein drugs into polymeric microparticles. METHODS: Lysozyme and PLGA were used as a model protein and a model polymer, respectively. The effects of process and formulation variables, such as i) the type of organic solvent, ii) the feeding rate ratio of the outer PLGA-containing feed solution to inner lysozyme-containing feed solution, and iii) the mass ratio of PLGA to protein, on the properties (morphology, internal structure, protein surface enrichment and release profiles) of the spray dried microparticles were investigated to understand protein microencapsulation and particle formation mechanisms. RESULTS: The spherical, condensed microparticles were obtained with D50 of 1.07-1.60 µm and Span in the range of 0.82-1.23. The lysozyme surface content decreased upon different organic solvents used as follows: acetonitrile > acetone > dichloromethane. Additionally, the lysozyme surface enrichment decreased slightly when increasing the feeding rate ratio of the outer feed solution to the inner feed solution from 4:1 to 10:1. Furthermore, it was observed that there was a correlation between the degree of burst release and the lysozyme surface enrichment, whereas the lysozyme loading content had no substantial impact on the release kinetics. CONCLUSIONS: The present work demonstrates the potential of spray dryer equipped with a 3-fluid nozzle in microencapsulation of proteins into PLGA matrices with different characteristics by varying process and formulation parameters.

Droplet size measurements for spray dryer scale-up.

This study was dedicated to facilitate scale-up in spray drying from an atomization standpoint. The purpose was to investigate differences in operating conditions between a pilot and a production scale nozzle. The intension was to identify the operating ranges in which the two nozzles produced similar droplet size distributions. Furthermore, method optimization and validation were also covered. Externally mixing two-fluid nozzles of similar designs were used in this study. Both nozzles are typically used in commercially available spray dryers, and they have been characterized with respect to droplet size distributions as a function of liquid type, liquid flow rate, atomization gas flow rate, liquid orifice diameter, and atomization gas orifice diameter. All droplet size measurements were carried out by using the Malvern Spraytec with nozzle operating conditions corresponding to typical settings for spray drying. This gave droplets with Sauter Mean Diameters less than 40 microm and typically 5-20 microm. A model previously proposed by Mansour and Chigier was used to correlate the droplet size to the operating parameters. It was possible to make a correlation for water incorporating the droplet sizes for both the pilot scale and the production scale nozzle. However, a single correlation was not able to account properly for the physical properties of the liquid to be atomized. Therefore, the droplet size distributions of ethanol could not be adequately predicted on the basis of the water data. This study has shown that it was possible to scale up from a pilot to production scale nozzle in a systematic fashion. However, a prerequisite was that the nozzles were geometrically similar. When externally mixing two-fluid nozzles are used as atomizers, the results obtained from this study could be a useful guideline for selecting appropriate operating conditions when scaling up the spray-drying process.

Scaling up the spray drying process from pilot to production scale using an atomized droplet size criterion.

PURPOSE: The purpose of this study was to investigate the possibility of producing identical powders in pilot and production scale spray drying equipment by matching the droplet size distributions produced by two differently sized atomizers. METHODS: Particles were prepared by spray drying solutions of acetaminophen and polyvinylpyrrolidone K-30. The success of the up-scaling was evaluated by comparing the powders in terms of particle size distribution (laser diffraction), crystallinity (XPRD) and morphology (SEM). Furthermore, the influence of process parameters on other product characteristics such as stability and residual volatile content was also evaluated. RESULTS: The spray drying experiments resulted in spherical, amorphous particles with volumetric median diameters of typically 4-10 microm for pilot scale and 4-30 microm for production scale. The results showed that particles with similar morphology and crystallinity could be produced in the two applied spray dryers. However, scale-up based purely on matching droplet size distributions was not feasible. CONCLUSIONS: The scale-up criterion did not account for the differences between the droplet-drying gas mixing and residence time distribution within the two spray dryers. Therefore, production scale experiments are required in order to obtain similar product characteristics as in pilot scale.