Design of easily swallowable xerogel pill with enough physical strength through hardening-process under heating and humidification.

The xerogel pill has been developed as a novel dosage form with dose-adjusting and swallow-assisting functions by using drop freeze-drying (DFD) technique. It was double-structured small sphere composed of an inner drug core and an outer dried-gel layer, however, had problem of insufficient physical strength. In this study, it was attempted to use dextrin (DEX), one of oligosaccharides, to strengthen the xerogel pill. DEX was co-dissolved in the dropping fluid in the DFD process and co-loaded in the conventional pill, which was mainly composed of mannitol (MNT) as a filler, to prepare the rigid body. DEX-loaded pill could be successfully prepared with high recovery (>90 %) by optimizing the ratio of DEX and MNT. Further, the representative pills with and without DEX (P-DEX and P-MNT, respectively) were hardening-processed under humidification. The physical strength of P-DEX pill was significantly increased when humidified under severe condition, resulting in enough hardness (>5N) and friability (<1.0 %). Processed P-DEX was found to have dense structure covered with a thick outer shell, which would be formed by interparticle bridge of DEX. It was also found that processed P-DEX pill suppressed initial drug dissolution significantly and exhibited sustained dissolution behavior, suggesting the potential function of bitter taste masking. Processed P-DEX pill had excellent sliding behavior with low friction forces as a result of lubricant effect of xanthan gum (XG) surrounding the pills. Furthermore, the sliding test also suggested that processed P-DEX pill had hard candy-like texture, in contrast unprocessed P-DEX pill had orally disintegrating (OD) tablet-like texture. Various xerogel pills with such different swallowing texture would have a potential to accommodate the children's preferences when taking medication.

[Homogeneity of Two Semisolid Formulations Using Simple In-tube Mixing Method].

To accelerate therapeutic effects, the mixtures of two or more topical pharmaceutical products having different medicinal purposes are often applied in the medical field. In this study, we aimed to develop a simple mixing method/procedure to achieve excellent homogeneity in the mixture of two topical products, a steroidal ointment and a skin moisturizer. To assess an in-tube mixing method as a simple mixing procedure, we injected both topical products into an empty resin tube, a flexible hollow tube with an open end that can be closed on one side, and a closed end on the other, removed as less air as possible inside the tube, and then thermocompressed (sealed) the open end to close it. The two topical products were then mixed uniformly by repeated finger pressure along the longitudinal axis of the tube. The homogeneity of the two topical products in the tube was evaluated by measuring the content of methyl paraoxybenzoate (MP), an additive loaded in the skin moisturizer. In addition, the mixability was qualitatively evaluated from the distribution of white petrolatum, another additive loaded in the steroid ointment, using Raman spectroscopy. As a result, the measured value of MP relative to the label claim was in the range of 100±12%, and the coefficients of variation value was also less than 12%. These results indicate that the in-tube mixing method using two topical products is approximately hologenetic preparations that do not cause therapeutic problems.

Preparation of sustained-release tablets using a solventless-mixing tablet coating technique: Particle design of dry ammonioalkyl methacrylate copolymer latex with high coating performance using sodium lauryl sulfate.

The aim of this study was to produce sustained-release tablets by V-shaped blending of polymer and tablets without using solvents or heating, and we investigated the design of polymer particles with high coating performance by modifying the structure of the particles using sodium lauryl sulfate. Dry-latex particles of ammonioalkyl methacrylate copolymer were prepared by adding the surfactant into aqueous latex, followed by freeze drying. The resulting dry latex was mixed with tablets (1:10) using a blender and the resulting coated tablets were characterized. Tablet coating by the dry latex was promoted as the weight ratio of surfactant to polymer increased. At a surfactant ratio of 5%, deposition of the dry latex was most effective and the resulting coated tablets (annealed at 60 °C/75%RH for 6 h) exhibited sustained-release characteristics over a period of 2 h. The addition of SLS prevented coagulation of colloidal polymer in the freeze drying, resulting in a loose-structured dry latex. This latex was easily pulverized by V-shaped blending with tablets and the resulting fine particles with high adhesiveness were deposited on the tablets. However, at a surfactant ratio of 10%, the coating of dry latex decreased due to reduced adhesiveness.

Design of xerogel pill with good swallowing performance through wet milling and drop freeze-drying processes.

A novel dosage form with dose-adjusting and swallow-assisting functions, named "xerogel pills," was developed for pediatric or geriatric patients. It is a multiple-unit dosage form in which a single dose is divided into several pills. The pills are double-structured small spheres with an inner drug core and an outer dried-gel layer (xerogel shell). In this research, the preparing method (formulation and process) of the xerogel pills was established by using a combination of wet-milling and drop freeze-drying (DFD) techniques. Fexofenadine hydrochloride (FXF) was used as a poorly water-soluble model drug. Xanthan gum (XG), a gelling agent, was formulated to attain a smooth and soft mouth-feeling. The internal fluid consisting of the FXF nanosuspension prepared through the wet-milling process and the external fluid consisting of an XG solution were separately fed to a two-fluids nozzle composed of central and peripheral nozzles. Both fluids were concentrically dropped together into liquid nitrogen to construct double-structured droplets. After the freeze-drying process, the xerogel pills were formed. Mannitol (MNT), as a filler, was co-formulated with both fluids to strengthen the pills physically. The resultant pills were around 5-6 mm in diameter with a spherical shape, uniform size, and low density, enabling them to be easily swallowed, and quickly gelled upon contact with water. The FXF amount in one pill was 7-9 mg, depending on the XG loading in the external fluid. The relative standard deviation (RSD) of the FXF amount were varied in the range of around 3-10%, suggesting that the content uniformity would be acceptable as a composite dosage unit containing five or more pills. It was assumed that further improvements of the physical strength and drug content uniformity would be required to introduce the xerogel pills to practical use.

Preparation of Fine-Drugs Layered Spherical Particles with Good Micromeritic and Dissolution Properties through Ultra Cryo-Milling and Mechanical Powder Processing.

The particles of phenytoin (Phe), a poorly water-soluble model drug, were bead-milled alone or co-milled with a hydrophilic waxy additive using an ultra cryo-milling technique in liquid nitrogen (LN2) to improve its dissolution properties. However, the micronized drug particles adhered and aggregated, resulting in poor handling in manufacturing processes such as blending or tableting. To improve the dissolution profile and powder properties of the drug simultaneously, the milled products were secondarily processed together with larger spherical particles by mechanical powder processing. These secondary products were composite particles with a core-shell structure, with fine drug particles adhered and deposited on the core, based on order mixing theory. As a core, three types/sizes of spherical pharmaceutical excipient particles were applied. The resultant composite particles produced much faster release profiles than just milled or co-milled mixtures. In addition, the composite particles showed good micromeritic properties depending on the size of the core particles. These results indicate that the ultra cryo-milling and subsequent dry composite mixing is a potential approach for developing drug particles with improved dissolution.

Design of taste-masked swellable drug particles using dry-coating technology with mechanical curing.

A novel dry coating technique for fine particles that does not require any liquids has been developed. Swellable ordered-mixed drug particles (Swell-OM-spheres, SOS), using a modified starch as the core particle and a drug coating layer have been previously developed. In the present work, SOS particles were further processed to generate 100-µm taste-masking particles using an all dry coating processes. SOS particles were coated with a gastric-soluble powder using a mechanical powder processor. The coated particles (CPs) were subsequently heated while rotating in the same powder processor, completing film formation by a process termed dynamic curing. As a control, conventional film formation (static curing) was performed using a drying oven. The CPs obtained by these two curing processes had distinct appearances, but exhibited equivalent dissolution suppression effects in a medium at pH 6.8 (the pH of the oral cavity). The suppression effect was further improved by adding a plasticizer to the coating powder, even though a lower heating temperature was required. Orally disintegrating tablets incorporating these CPs exhibited excellent taste-masking performance, i.e., suppressing taste in saliva while accelerating dissolution in gastric juice. The dissolution behavior indicated that the CPs can provide an ON/OFF switching function in drug release.

Solventless granulation and spheronization of indomethacin crystals using a mechanical powder processor: Effects of mechanically induced amorphization on particle formation.

Our aim was to reveal the effects of mechanically-induced amorphization on the solventless agglomeration and spheronization of drug crystals using a mechanical powder processor. This process can provide spherical particles comprising 100% drug. Indomethacin crystals were mechanically treated using various jacket temperatures and the resulting particles were characterized using particle and crystalline analyses. Also, the adhesive and mechanical properties of amorphous indomethacin were examined. At 20 °C, the indomethacin crystals fragmented and amorphized during processing, indicating that glassy-state indomethacin with no adhesiveness does not contribute to agglomeration or spheronization. At 40 °C, agglomeration occurred due to the transformation of mechanically-induced amorphous phases from non-adhesive glass to an adhesive supercooled liquid at around the glass transition temperature. However, at higher temperatures, the formation of agglomerates was suppressed by recrystallization of the amorphous surface. At 60 °C, the indomethacin crystals compacted and spheronized due to deformation of the particle surface, consistent with results showing that the stiffness of amorphous indomethacin decreased suddenly above 60 °C. The lifespan of the amorphous phase decreased due to enhanced recrystallization as the temperature increased, thereby reducing the degree of spheronization. In conclusion, agglomeration and spheronization are affected by the glass transition temperature and recrystallization of the mechanically-induced amorphous phase.

[Research on Gliding and Discharge Performance of Suspended Injection from Syringe -Effect of Diameter Ratio of Suspending Particle against Needle Hole on Needle Passageability].

Suspended injectable formulations such as sustained-release luteinizing hormone-releasing hormone (LH-RH) analogue loaded in polylactic acid-glycolic acid copolymer (PLGA) particles have been developed on market. Such formulations have potential issue of suspended particles blocking the injection needle. In this research, two types of injectability tests (gliding force, particles discharge) were developed to evaluate the needle passageability of suspended particles. The model suspension was newly designed using mono-dispersed polyethylene (PE) spheres and qualified dispersing fluid to enhance universality and validity of the test. The suspension-filled syringe, in which three sizes of spheres (L, M, S) were dispersed, was vertically fixed and pushed by auto-compression/tensile tester. The gliding force was continuously detected during testing time and all discharged PE spheres were collected and weighed. The combination of sphere (L, M, S) and injection needle were varied to evaluate the effect of the diameter ratio of sphere against needle hole (D/W) on passageability through needle. These injectability tests revealed that the blockage of a needle hole was occasionally observed when the D/W value increased up to 0.35-0.5, which was detected by jump-up of gliding force and drastic decrease of discharged sphere. In addition, the effect of the formulation properties (concentration of suspended spheres, viscosity of dispersing fluid) and operational factor (injection speed) on injectability was also investigated. The results from this study would be valuable in developing suspended injections and predicting injection trouble at the medical scene.

Cryo-milling with spherical crystalline cellulose beads: A contamination-free and safety conscious technology.

Crystalline cellulose is a common inactive pharmaceutical additive. If this material can also be used to construct beads for the wet milling of pharmaceutical compounds, it could possibly address issues related to wear and contamination associated with zirconia and polyethylene beads. In this study, the model drug phenytoin was milled with spherical crystalline cellulose (SCC) in liquid nitrogen. The particle size of the milled product was found to be comparable to that obtained using zirconia beads, verifying the feasibility of using SCC beads for this purpose. Using a design of experiment approach, the bead amount, agitation speed, and milling time were all determined to have a significant effect on the milled particle size, giving a D50 value as low as 0.3 µm. No breakage of the SCC beads was observed during the milling process in durability tests under conditions that will degrade spherical D-mannitol beads, showing that this material exhibits sufficient durability. In addition, the variation in elastic modulus between beads was minimal. Because SCC is commercially available and easy to handle, the present wet milling technique is considered to have potential applications to the manufacture of pharmaceuticals on an industrial scale, as it shows sufficient milling capability and durability.

Solventless-mixing tablet coating technique using a V-shaped blender; investigation using methyl methacrylate and diethylaminoethyl methacrylate copolymer powder.

Our aim was to investigate the feasibility of a tablet coating mixing technique using a V-shaped blender to produce coated tablets by mixing only tablets and polymer powder. Tablet coating was achieved as follows. First, polymethacrylate latex was freeze-dried to prepare a coating powder. Second, tablets and polymer powder were mixed using the blender, yielding coated tablets. Two types of coating powder, composed of colloidal or non-colloidal particles of the same polymer, were prepared and used in the mixing treatment. Colloidal powder was rapidly pulverized due to impact by falling tablets in the blender and adhered to tablet surface. The powder on tablets was easily consolidated due to compression by tumbling tablets, yielding a polymer layer that can suppress drug release after curing. In contrast, non-colloidal powder was insufficiently pulverized and densified, and its deposition did not occur. Therefore, tablets are mechanically coated using a V-shaped blender by using colloidal polymer powder with high grindability and compactability. The impact rose by increasing rotation speed of the blender and promoted deposition of the polymer. Appropriate collision impacts of tablet-tablet and tablet-wall are required for successful tablet coating, although too intense impacts lead to tablet breakage and removal of the membrane.

Cryo-milling using a spherical sugar: Contamination-free media milling technology.

Milling beads experience wear upon repeated use. And milling beads made of material that is safe when ingested have not yet been developed. The present report describes the development and characteristics of spherical d-mannitol (SDM) beads, which would be safe when ingested. The model drug phenytoin was dispersed in liquid nitrogen along with SDM and the materials were agitated at high speed. The effects of the amount of beads, agitation speed, and milling time on phenytoin particle size, yield, and bead fractures were investigated using a central composite experimental design. The diameter of milled phenytoin particles decreased significantly as the amount of SDM beads and agitation speed increased. In contrast, no difference was found in the diameter with milling time. Although the fractured SDM ratio increased slightly at higher agitation speeds, the SDM was not broken and was durable enough for milling. This milling technique was applicable not only to phenytoin but also to other drug substances. Bead durability and applicability indicated that SDM can be used as wet milling beads that are considered safe for use if ingested.

Novel contamination-free wet milling technique using ice beads for poorly water-soluble compounds.

The aim of this study is to establish a contamination-free milling method using ice beads instead of conventional hard beads such as metal or ceramics. Ice beads, which melt after the milling process to form water, would solve the contamination issue attributed to bead breakage or abrasion. The technique/method for preparing spherical ice beads of mono-dispersed size ranging from 150 to 3000 µm was newly developed. An oscillation beads milling apparatus was used for pulverization. In the initial stages of ice beads milling, the process is dry, but as time passes, the surface of the ice beads begins to melt, resulting in a transition to wet beads milling. It was found that ice beads are an effective milling media for beads milling, and that milling efficiency is strongly affected by the temperature of the coolant, with the peak efficiency occurring when the temperature was set to -2 °C and ice beads around 1500 µm in diameter were used. The spray-dried powder obtained from suspension after ice beads milling had dissolution improvement equivalent to that obtained after zirconia beads milling, resulting from its spontaneous rapid dispersion into nanosuspension.

Mechanical particle coating using ethylcellulose nanoparticle agglomerates for preparing controlled release fine particles; effect of coating temperature on coating performance.

This study describes the effect of coating temperature on the performance of mechanical particle coating using ethylcellulose, which was done to produce controlled-release particles (diameters less than 100 µm) with different release rates. First, theophylline crystals were spheronized using a mechanical powder processor, yielding theophylline spheres (used as core particles). Second, ethylcellulose aqueous dispersion was powdered by spray-freeze drying to prepare colloidal agglomerates (used as coating powder). Finally, the spheres and agglomerates were mechanically mixed at various temperatures using the processor to produce composite particles. The ethylcellulose agglomerates were pulverized during processing to coat the theophylline spheres effectively. When the coating temperature was higher than the glass transition temperature (Tg) of ethylcellulose, the amount of coated polymer increased significantly due to plastics deformation, causing thickening of the coated layer. The porosity of the coated layer decreased upon coalescence of coated polymer particles due to plastic deformation, which prevented the appearance of cracks in the film during curing. Therefore, controlled-release fine particles with various release rates can be produced effectively by mechanical particle coating at temperatures higher than the Tg of the polymer.

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.

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.

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.

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.

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.

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.