Keita Kondo

Preparation of sustained-release coated particles by novel microencapsulation method using three-fluid nozzle spray drying technique

We prepared sustained-release microcapsules using a three-fluid nozzle (3N) spray drying technique. The 3N has a unique, three-layered concentric structure composed of inner and outer liquid nozzles, and an outermost gas nozzle. Composite particles were prepared by spraying a drug suspension and an ethylcellulose solution via the inner and outer nozzles, respectively, and mixed at the nozzle tip (3N-PostMix). 3N-PostMix particles exhibited a corrugated surface and similar contact angles as ethylcellulose bulk, thus suggesting encapsulation with ethylcellulose, resulting in the achievement of sustained release. To investigate the microencapsulation process via this approach and its usability, methods through which the suspension and solution were sprayed separately via two of the four-fluid nozzle (4N) (4N-PostMix) and a mixture of the suspension and solution was sprayed via 3N (3N-PreMix) were used as references. It was found that 3N can obtain smaller particles than 4N. The results for contact angle and drug release corresponded, thus suggesting that 3N-PostMix particles are more effectively coated by ethylcellulose, and can achieve higher-level controlled release than 4N-PostMix particles, while 3N-PreMix particles are not encapsulated with pure ethylcellulose, leading to rapid release. This study demonstrated that the 3N spray drying technique is useful as a novel microencapsulation method.

Design of sustained release fine particles using two-step mechanical powder processing: Particle shape modification of drug crystals and dry particle coating with polymer nanoparticle agglomerate

We attempted to prepare sustained release fine particles using a two-step mechanical powder processing method; particle-shape modification and dry particle coating. First, particle shape of bulk drug was modified by mechanical treatment to yield drug crystals suitable for the coating process. Drug crystals became more rounded with increasing rotation speed, which demonstrates that powerful mechanical stress yields spherical drug crystals with narrow size distribution. This process is the result of destruction, granulation and refinement of drug crystals. Second, the modified drug particles and polymer coating powder were mechanically treated to prepare composite particles. Polymer nanoparticle agglomerate obtained by drying poly(meth)acrylate aqueous dispersion was used as a coating powder. The porous nanoparticle agglomerate has superior coating performance, because it is completely deagglomerated under mechanical stress to form fine fragments that act as guest particles. As a result, spherical drug crystals treated with porous agglomerate were effectively coated by poly(meth)acrylate powder, showing sustained release after curing. From these findings, particle-shape modification of drug crystals and dry particle coating with nanoparticle agglomerate using a mechanical powder processor is expected as an innovative technique for preparing controlled-release coated particles having high drug content and size smaller than 100 μm.

Design of Highly Dispersible PLGA Microparticles in Aqueous Fluid for the Development of Long-Acting Release Injectables

In this study, we developed highly dispersible polylactic glycolic acid (PLGA) copolymer microparticles (MRPs) in aqueous fluid. A solution containing both dissolved aripiprazole as a model drug and PLGA were spray-dried to make MRPs. The resultant MRPs were further co-processed with water-soluble additives and a surfactant to improve their dispersion behavior. The granules containing MRPs and additives, termed granulated microparticles (G-MRPs) were prepared by a newly established drop freeze-drying technique. The physicochemical properties of MRPs and G-MRPs were evaluated as a long-acting release depot injectable. The MRPs were spherical particles with diameters of approximately 1 to 20 µm and strongly assembled to one another in the aqueous phase, forming large aggregations. In contrast, the G-MRPs were spherical granules with diameters of approximately 200 to 400 µm that displayed a microparticles-in-granule structure in which small MRPs were embedded in the porous matrix inside the granules. When the G-MRPs were placed in water, the porous matrix base was immediately dissolved, and each embedded MRP was individually released, thus inducing monodispersion and significantly improved dispersibility. The excellent dispersibility was attributed to the water-soluble porous network structure mainly composed of D-mannitol and the steric hindrance effects derived from the polymeric molecular chains. These properties may give rise to the excellent passage of PLGA microparticles through needles for use in depot formulation suspensions. A crystalline evaluation of the G-MRPs suggested that the drug and PLGA molecularly interacted and that their thermodynamic stability was improved.

Development of a novel pelletization technique through an extremely high-shear process using a mechanical powder processor to produce high-dose small core granules suitable for film coating.

We established an extremely high-shear melt pelletization technique using a mechanical powder processor to produce high-dose granules smaller than 300 μm with properties suitable for film coating. A mixture of ethenzamide and polyethylene glycol (used as a low-melting binder) at various weight ratios was mechanically treated under various jacket temperatures. When the jacket temperature was set to 50 °C or greater, the product temperature reached the melting point of the binder, resulting in pelletization. The drug powder were pelletized with a small amount of binder to yield pellets of approximately 150 μm with a drug content of more than 90%. The mechanism of melt pelletization through ultrahigh shearing involves a series of nucleation, consolidation, coalescence and breakage stages. The power consumption profile corresponding to each stage in the pelletization revealed that pellets between 75 and 300 μm were effectively obtained at a large power consumption peak. The resultant pellets showed comparative sphericity and smoothness, and higher durability than commercial core granules for film coating. In conclusion, this study demonstrates that the extremely high-shear melt pelletization technique can give drug pellets with desirable properties as core particles for the coating process.

One step preparation of spherical drug particles by contamination-free dry milling technique with corn starch beads

The novel dry milling technique has been developed by using a mechanical powder processor for improving the dissolution properties of poorly water-soluble drugs. It was found that the drug crystals were well pulverized by co-processing with fine particles of corn starch (CS). The morphological observation and particle size evaluation revealed that the processed products formed the composite particles with ordered-mixed structure, having double-layered particles with a core of CS and a coating layer of phenytoin (Phe), as a model drug. This result suggested that the drug crystals were selectively micronized and the resultant miniaturized Phe particles were adhered/fixed on the surface of un-milled CS particles. The mechanical characteristics detected by the indentation test assumed that the brittle Phe crystals sandwiched between elastic CS particles would be successfully crushed down by high shearing stress in the processor. The newly-established dispersion-sedimentation test indicated that the fine Phe particles were immediately detached from the composite particles in aqueous phase, constructing the suspension. The dissolution behavior from the processed particles was found to be improved and strongly dependent on the size and amount of detached Phe particles. Such milling and ordered-mixturization have been also successfully done by using recrystallized larger Phe particles than 100μm. These results would propose the contamination-free dry milling technique without using hard milling balls or beads. The mechanism of the current milling and ordered-mixing phenomena is also provided in this report.

Spheronization mechanism of pharmaceutical material crystals processed by extremely high shearing force using a mechanical powder processor

We aimed to elucidate the mechanism of the spheronization of pharmaceutical material crystals through extremely high shearing force using a mechanical powder processor, which produces spherical crystals without a solvent. The spheronization of theophylline, acetaminophen, clarithromycin, ascorbic acid and lactose was investigated, and the relationship between the spheronization mechanism and material characteristics was also examined. Theophylline and ascorbic acid crystals were partially destroyed during mechanical processing, yielding large particles and dust, and the large fragments were then layered with powder to produce spheres with a core-shell structure. Acetaminophen crystals were completely fragmented under stress, yielding fine particles to which powder then agglomerated to produce spheres with a mosaic structure. Clarithromycin and lactose crystals were not spheronized. Our results showed that the fracture strength of intact material may be closely related to the size of intermediate fragments, determining spheronization mechanism. Furthermore, the results for powder cohesiveness suggest that the materials with moderate-to-high cohesiveness (theophylline, acetaminophen and ascorbic acid) are finally spheronized regardless of the degree of the strength, whereas those with low cohesiveness (clarithromycin and lactose) are not spheronized due to poor granulation. Hence, the cohesiveness of a material has a significant effect on the success of mechanical spheronization processes.

Ultra Cryo-Milling with Liquid Nitrogen and Dry Ice Beads: Characterization of Dry Ice as Milling Beads for Application to Various Drug Compounds

Ultra cryo-milling using liquid nitrogen (LN2) and dry ice beads has been proposed as a contamination-free milling technique. The morphological change of dry ice beads was visually monitored in LN2 to clarify their production process and cryo-milling process. We found that dry ice pellets, which are starting material of beads and available on the market, immediately disintegrate in LN2, resulting in the spontaneous production of dry ice beads. In addition, the resultant beads maintain their size and shape even under vigorous agitation in LN2, demonstrating that they could play a role of milling media in the milling process. The driving conditions of this cryogenic milling process including beads size were optimized to enhance the milling efficiency. Dry ice beads provided superior milling efficiency compared to original pellets. The milling efficiency increased as the size of the dry ice beads decreased; furthermore, the larger the amount of beads used, the finer the milled particles. Any crystals of three drug compounds were effectively pulverized to the sub- or single-micron range. Cryo-milling with dry ice beads is valuable on pharmaceutical field because it does not contaminate the product with fractured and/or eroded beads.

Mechanical particle coating using polymethacrylate nanoparticle agglomerates for the preparation of controlled release fine particles: The relationship between coating performance and the characteristics of various polymethacrylates

We aimed to understand the factors controlling mechanical particle coating using polymethacrylate. The relationship between coating performance and the characteristics of polymethacrylate powders was investigated. First, theophylline crystals were treated using a mechanical powder processor to obtain theophylline spheres (<100μm). Second, five polymethacrylate latexes were powdered by spray freeze drying to produce colloidal agglomerates. Finally, mechanical particle coating was performed by mixing theophylline spheres and polymethacrylate agglomerates using the processor. The agglomerates were broken under mechanical stress to coat the spheres effectively. The coating performance of polymethacrylate agglomerates tended to increase as their pulverization progressed. Differences in the grindability of the agglomerates were attributed to differences in particle structure, resulting from consolidation between colloidal particles. High-grindability agglomerates exhibited higher pulverization as their glass transition temperature (Tg) increased and the further pulverization promoted coating. We therefore conclude that the minimization of polymethacrylate powder by pulverization is an important factor in mechanical particle coating using polymethacrylate with low deformability. Meanwhile, when product temperature during coating approaches Tg of polymer, polymethacrylate was soften to show high coating performance by plastic deformation. The effective coating by this mechanism may be accomplished by adjusting the temperature in the processor to the Tg.