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 self-dispersible dry nanosuspension through wet milling and spray freeze-drying for poorly water-soluble drugs.

The purpose of the present research is to establish a novel nanosizing technique starting from wet nano-milling, named "dry nanosuspension" technique for poorly water-soluble drugs. The spray freeze-drying (SFD) method was applied instead of the spray-drying one previously developed. Drug particles were milled in the aqueous solution of dispersing agents using an oscillating beads-milling apparatus. The milled nanosuspension was sprayed to the surface of liquid nitrogen, and the resultant iced droplets were freeze-dried to obtain the powdery product. The loading ratio of a dispersing agent was investigated to enhance its redispersing property. Dry nanosuspension, which could be spontaneously dispersed into original nanosuspension in water, was obtained by SFD process. It was assumed that self dispersion property would be attributed to its structure with porous network, in which the primary milled drug crystals were embedded. Such unique structure contributed greatly to immediate release behaviors of the drug in gastrointestinal buffered media. These pharmaceutical properties were enhanced by increasing the ratio of the dispersing agent to the drug and the solid content in suspension to be sprayed. The present technique via wet milling and spray freeze-drying processes would be a novel dissolution-enhanced technology for poorly water-soluble drugs.

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.

[Effect of concomitant use of dental drug on the properties of recombinant human basic fibroblast growth factor formulation for periodontal disease].

We have discussed the essential property for periodontal disease medication using protein, such as recombinant human basic fibroblast growth factor (rhbFGF). In our previous study, the criteria of thickener for the medication, viscosity, flowability etc., were set. The aim of this study was to evaluate the physical and chemical effect of concomitant use of general dental drug or device on thickener properties for the clinical use of viscous rhbFGF formulation. Viscous formulation was prepared with six cellulose derivatives, two types hydroxy propyl cellulose (HPC), three types hydroxy ethyl cellulose (HEC) and methyl cellulose (MC). Antibiotic ointment, local anesthetic, bone graft substitute, agent for gargle and mouthwashes, were chosen as general dental drug and device. These drugs and device were mixed with the viscous formulations and the change of viscosity and flowability, the remaining ratio of rhbFGF were evaluated. When the various thickener solutions were mixed with the liquid drugs, viscosity and flowability did not changed much. However, in the case of MC solution, viscous property declined greatly when MC solution was mixed with cationic surfactant for gargle. The flowabilities of thickener solutions were declined with insoluble bone graft. The stabilities of rhbFGF in thickener solutions were no problem for 24 hours even in the case of mixing with dental drug or device. Our findings suggested that the viscous rhbFGF formulations prepared in this research were not substantially affected by the concomitant use of dental drug or device, especially the formulation with HPC or HEC was useful.

[Effect of crystalline metastasis of lactose on hardness of compressed baby milk powder].

The purpose of this study was to examine the relationship between the crystalline metastasis of lactose, which is a main component baby milk powder, and the hardness of baby milk powder compressed by humidification followed by drying. Because baby milk powder is manufactured using a spray dryer, lactose in compressed baby milk powder exists in an amorphous (solid dispersion) form. X-ray diffraction measurement showed that this amorphous lactose metastasized to ß-form crystalline lactose, and thereafter metastasized to the α-form during the humidification-drying process. As a result of this crystalline metastasis, the hardness of the compressed baby milk powder increased, and then decreased. Furthermore, scanning electron microscopy (SEM) showed bridging structures between the particles increased and then decreased during the humidification-drying process. This showed that bridging structures between the particles produced by crystalline metastasis of lactose as a result of the humidification-drying process, which leads to an increase in the hardness of the compressed baby milk powder. These results show that the necessary degree of hardness of the porous compressed baby milk powder (necessary for packaging and transportation) resulted from the humidification-drying process.

Evaluation of disintegration properties of orally rapidly disintegrating tablets using a novel disintegration tester.

This report describes a new disintegration tester that can determine not only the disintegration time of orally rapidly disintegrating tablets (ODT), but also the disintegration behavior and mechanism. Using the tester, the disintegration properties of the tablets prepared in a previous study were examined. The purpose of this study is to confirm the utility of the tester as an instrument for evaluating the disintegration properties of ODT and determine relations among time, behavior and mechanism of the disintegration. Results demonstrated that in vitro disintegration time in the tester is similar to that in the commercial disintegration tester for ODT and is highly correlated with oral disintegration time. Observations of disintegration process revealed that a difference in disintegration behavior between tablets compressed at 50-75 MPa and 100 MPa; the disintegration behavior of the tablets were designated immediate disintegrating type and gradual disintegrating type, respectively. The dynamic swelling profile and water absorption profile indicated that the disintegration mechanism of the tablets involved wicking action induced by swelling of the disintegrant; the disintegration time was closely related to the initial rates of swelling and water absorption. Furthermore, the mechanism of water absorption of tablets compressed at 50-75 MPa and 100 MPa shows anomalous diffusion and case-II transport, respectively. The shift in this mechanism is consistent with differences in disintegration time and behavior between the tablets. These findings suggest that information on disintegration properties obtained by our tester is useful for understanding of disintegration phenomena of ODT.

Investigation of surfactants suitable for stabilizing of latanoprost.

The content of latanoprost, a therapeutic drug for glaucoma, is likely to decrease in solution. In a previous study, we confirmed that this was associated with latanoprost adsorption to the container and hydrolysis of latanoprost, and established a formulation of latanoprost eye drop solution that can be stored at room temperature. In addition, we clarified that a surfactant added to the formulation stabilized latanoprost by forming complex micelle. In this study, we investigated the influence of structure of surfactants in the stabilization of latanoprost. Non-ionic surfactants involving the polyoxyethylene chain (additive mol number: 20 or more) and the straight-chain alkyl group, with an HLB of 15.0 or more, markedly inhibited a decrease in the latanoprost content and its degradation. These surfactants are soluble in the formulation of eye drop solution, leading to micelle formation even at a low concentration, and they are not influenced by the temperature. Therefore, they may exhibit marked stabilization effects. In addition, there was no influence on the stability of latanoprost when adding benzalkonium chloride, as a preservative, to a formulation involving these surfactants.

Spray freeze-dried porous microparticles of a poorly water-soluble drug for respiratory delivery.

Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.

Novel ultra-cryo milling and co-grinding technique in liquid nitrogen to produce dissolution-enhanced nanoparticles for poorly water-soluble drugs.

A novel ultra-cryo milling micronization technique for pharmaceutical powders using liquid nitrogen (LN2 milling) was used to grind phenytoin, a poorly water-soluble drug, to improve its dissolution rate. LN2 milling produced particles that were much finer and more uniform in size and shape than particles produced by jet milling. However, the dissolution rate of LN2-milled phenytoin was the same as that of unground phenytoin due to agglomeration of the submicron particles. To overcome this, phenytoin was co-ground with polyvinylpyrrolidone (PVP). The dissolution rate of co-ground phenytoin was much higher than that of original phenytoin, single-ground phenytoin, a physical mixture of phenytoin and PVP, or jet-milled phenytoin. X-Ray diffraction showed that the crystalline state of mixtures co-ground by LN2 milling remained unchanged. The equivalent improvement in dissolution, whether phenytoin was co-ground or separately ground and then mixed with PVP, suggested that even when co-ground, the grinding of PVP and phenytoin occurs essentially independently. Mixing original PVP with ground phenytoin provided a slight improvement in dissolution, indicating that the particle size of PVP is important for improving dissolution. When mixed with ground phenytoin, PVP ground by LN2 milling aided the wettability and dispersion of phenytoin, enhancing utilization of the large surface area of ground phenytoin. Co-grinding phenytoin with other excipients such as Eudragit L100, hypromellose, hypromellose acetate-succinate, microcrystalline cellulose, hydroxypropylcellulose and carboxymethyl cellulose also improved the dissolution profile, indicating an ultra-cryo milling and co-grinding technique in liquid nitrogen has a broad applicability of the dissolution enhancement of phenytoin.

Development of a novel ultra cryo-milling technique for a poorly water-soluble drug using dry ice beads and liquid nitrogen.

A novel ultra cryo-milling micronization technique has been established using dry ice beads and liquid nitrogen (LN2). Drug particles were co-suspended with dry ice beads in LN2 and ground by stirring. Dry ice beads were prepared by storing dry ice pellets in LN2. A poorly water-soluble drug, phenytoin, was micronized more efficiently using either dry ice beads or zirconia beads compared to jet milling. Dry ice beads retained their granular shape without pulverizing and sublimating in LN2 as the milling operation progressed. Longer milling times produced smaller-sized phenytoin particles. The agitation speed for milling was optimized. Analysis of the glass transition temperature revealed that phenytoin particles co-ground with polyvinylpyrrolidone (PVP) by dry ice milling were crystalline, whereas a planetary ball-milled mixtures process with zirconia beads contained the amorphous form. The dissolution rate of phenytoin milled with PVP using dry ice beads or zirconia beads was significantly improved compared to jet-milled phenytoin or the physical mixture. Dry ice beads together with LN2 were spontaneously sublimated at ambient condition after milling. Thus, the yield was significantly improved by dry ice beads compared to zirconia beads since the loss arisen from adhering to the surface of dry ice beads could be completely avoided, resulting in about 85-90% of recovery. In addition, compounds milled using dry ice beads are free from abraded contaminating material originating from the beads and internal vessel wall.

Development of formulation device for periodontal disease.

In addition to providing standard surgical treatment that removes the plaque and infected tissues, medications that can regenerate periodontal tissue are also required in the treatment of periodontal disease. As a form of regenerative medication, various growth factors are expected to be used while treating periodontal disease. A protein-like growth factor is often developed as a lyophilized product with dissolution liquid, considering its instability in the solution state. We have clarified that the formulation for periodontal disease needs to be viscous. When the lyophilized product was dissolved using a sticky solution, various problems were encountered, difficulty in dissolving and air bubbles, for example, and some efforts were needed to prepare the formulation. In this research, to identify the problem of preparing a viscous formulation, a lyophilized product (placebo) and sticky liquid were prepared by using vial and ampoule as the conventional containers. Based on these problems, a prototype administration device was developed, and its functionality was confirmed. As a result, it was suggested that the device with a useful mixing system that could shorten the preparation time was developed.

Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology.

In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).

[Making tablets of powdered milk and the physical properties].

Compressed baby milk powder has proven to be very convenient for parents due to the ease with which it can be handled, and the fact that use of a measuring scoop is not necessary. The purpose of this study was to develop a compressed baby milk powder and analyze the resulting physical properties. The basic production process consisted of the following steps: 1) molding milk powder by low compression pressure, 2) humidification at 25°C·97%RH and 3) drying with use of a desiccant. No chemical additives were used for solidification; therefore the chemical composition of the compressed milk powder is identical to the base milk powder. The important properties of the compressed milk powder are both ready solubility and the strength of the solid. The compressed milk powder obtained at low pressure was too brittle for practical use, but the strength was increased by humidification followed by drying. During the humidification process, the powder particles located close to the surface of the compressed milk powder partially dissolve resulting in bridging structures between the particles, leading to an increase in strength. Both specific surface area and the volume ratio of the compressed milk powder decreased. Testing showed that caking between the particles occurred following humidification, and that the volume of caking affected the ease with which the compressed milk powder dissolves in water.

Design of dry nanosuspension with highly spontaneous dispersible characteristics to develop solubilized formulation for poorly water-soluble drugs.

PURPOSE: The powderization of the aqueous nanosuspension of a poorly water-soluble drug, which was prepared by wet-milling technique developed by authors, was investigated to apply to the development of solid dosage forms. METHODS: Drug particles were suspended and milled in the aqueous medium using the oscillating beads-milling apparatus. The recovered nanosuspension was spray-dried 1) with no additive or 2) with co-dissolving mannitol as a nanoparticle carrier. As a control, the solution of the drug and additives with the same formulation as nanosuspension was also spray-dried. RESULTS: SEM observation and X-ray powder diffraction analysis revealed that the dried products from suspension formed a spherical particle with single-micron diameter, which was composed of thousands of nano-sized crystalline drug fragment. It was also found that the dried products from suspension could be spontaneously redispersed in water, transforming into nanosuspension with the original size distribution. Such dried powder with high dispersibility was named "dry nanosuspension." The dry nanosuspension had immediate release behaviors in gastrointestinal buffered media, whereas the dried product from solution showed the poor dispersion and dissolution properties even if same content of additives were loaded. CONCLUSIONS: The present technique with combination of wet nano-milling and spray-drying processes would be a novel approach to develop the pharmaceutical products with poorly water-soluble and oral-absorbable drugs.

Sugar ester J-1216 enhances percutaneous permeation of ionized lidocaine.

Percutaneous absorption enhancers affect not only the permeability of skin but also the thermodynamic properties of active ingredients in the vehicle. The present study examined the effect of J-1216, a sucrose laurate with hydrophilic-lipophilic balance = 16, on the percutaneous permeation of lidocaine (LC) from this point of view. The percutaneous permeation of LC from aqueous vehicles (pH 6.0, 7.0, 8.0, and 10.0) with or without 1.5% J-1216 was examined with excised hairless mouse skin mounted on flow-through-type diffusion cell. The permeation of LC without J-1216 increased with an increase in the vehicle pH and could be basically explained by pH-partition theory. J-1216 increased the LC permeation at pH 6.0 and 7.0 but decreased it at pH 8.0 and 10.0. The interaction between LC and J-1216 was examined using an ultrafiltration technique. J-1216 micelles interacted predominantly with unionized LC. A theoretical calculation suggested that J-1216 enhances the permeability coefficient of ionized LC, whereas it has almost no effect on that of unionized free LC. J-1216 directly affects the skin to increase the permeation of ionized LC, whereas J-1216 micelles interact with unionized LC to decrease the permeation. The effect of J-1216 is therefore a function of vehicle pH and LC concentration.

[Dissolution characteristics of composite particles using a spray freeze drying].

A spray freeze drying (SFD) method, using a spray nozzle, liquid N(2) and a lyophilizer, was developed to prepare composite particles of a poorly water-soluble drug. The resultant particles were found to have a porous structure. The purpose of the present research was to prepare a sustained release formulation using the SFD technique. Tolbutamide (TBM)and Eudragit S were used as model drugs and pH-dependent carrier, respectively. Eudragit S is a polymer that is soluble at or above pH 7.0. Morphological evaluation of the composite particles revealed that they had a porous structure with a significantly larger specific surface area than bulk TBM. The physicochemical properties of the particles were found to be dependent on the drug to carrier ratio, with the crystallinity of the TBM decreasing as the proportion of Eudragit S increased. Dissolution tests in solutions of pH 1.2 and pH 6.8 showed that the release profiles of TBM from the SFD composite particles were improved compared to bulk TBM, through the use of the pH-dependent carrier. On the other hand, following compression of the composite particles, sustained release was observed in a solution of pH 6.8, whereas almost no dissolution occurred in a solution of pH 1.2.

[Influence of compression pressure and die-wall pressure on tablet sticking].

An eccentric-type tablet machine fitted with 8-mm-diameter flat-faced punches was used to measure the forces of upper and lower punches, die-wall pressure, tablet ejection force, and scraper pressure (SCR), a type of shear stress, to evaluate sticking behavior. The shear stress between the surfaces of the tablet and lower punch was determined using an SCR detection system. Mean surface roughness (R(a)) of tablets, measured by laser scanning microscopy, was used to estimate the magnitude of sticking. Tablet tensile strength tended to increase with compression pressure, which is consistent with previous reports. SCR decreased with increasing compression pressure for samples at all formulations (i.e., for different kinds and percentages of lubricant). R(a) associated with sticking increased with SCR, indicating that the adhesive force between the particles of the tablet surface and the lower punch surface plays an important role in sticking. Multiple linear regression analysis with SCR as the response variable was conducted. Upper and lower punch force, die-wall pressure, tablet ejection force, SCR, percentage of lubricant, and tensile strength of tablet were selected as explanatory variables. Results of this analysis indicate that the incidence of sticking decreased when either the lower punch force or die-wall pressure increased, where, of these two, increasing the lower punch force had a stronger effect on decreasing SCR.

The stabilization mechanism of latanoprost.

The content of latanoprost is likely to decrease in solution because of the adsorption to eye drop containers and hydrolysis. We reduced these problems and established a formulation of latanoprost eye drops which is stable at room temperature. We assume that the additive surfactants form micelles and stabilize latanoprost in this formulation. In this study, we elucidated the latanoprost stabilization mechanism. It was revealed by Arrhenius analysis that the adsorption to eye drop containers and hydrolysis of latanoprost were temperature-dependent. In addition, polyethylene glycol monostearates inhibited the adsorption and hydrolysis of latanoprost at 1 mg/mL, which exceeded the critical micelle concentration. By the fluorescent probe method, it was suggested that the surfactants were associated with benzalkonium chloride and formed complex micelles consisting of about 10 molecules, and latanoprost interacted with the micelles at 1:1. By (1)H NMR, it was revealed that adsorption was inhibited by arranging the hydrophobic group toward the center of complex micelles and that hydrolysis was inhibited by interaction between the ester group and the complex micelles. It was shown that the latanoprost is stabilized by the interaction with complex micelles. It was effective for the inhibition of both adsorption and degradation.

Chitosan-interferon-ß gene complex powder for inhalation treatment of lung metastasis in mice.

We prepared gene powders with chitosan as a non-viral vector and mannitol as a dry powder carrier to compare their gene expression and therapeutic efficacy to intravenous or intratracheal gene solutions using mice burdened with pulmonary metastasis prepared by injecting CT26 cells. The expression of a luciferase expression plasmid driven by the cytomegalovirus promoter (pCMV-Luc) and plasmid DNA encoding farnesylated enhanced green fluorescent protein (pEGFP-F) suggested that the genes expressed in both normal and tumorous tissues and the intratracheal powder resulted in higher expression than the intravenous or intratracheal solution. The intravenous and intratracheal solutions and the intratracheal powder of pCMV-Muß encoding murine interferon-ß were administered the day after the inoculation of mice with CT26 cells. Lung weight and the number of pulmonary nodules at day 21 were significantly suppressed by the three formulations at a dose of 10 µg (N/P = 5). Reducing the dose to 1 µg resulted in a loss of effect by the intravenous solution; however, the intratracheal formulations, especially the powder, were still effective. The intratracheal powder of pCMV-Muß at a dose of 1 µg administered on day 1 significantly extended mean survival time compared to the untreated control. These findings showed that therapeutic gene powders are promising for gene therapy to treat lung cancer or metastasis.

Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method.

Simple and easy methods to prepare oral nanosuspension of a poorly water-soluble pharmaceutical candidate compound, called a candidate, have been developed to support the discovery and preclinical studies using animals. The different wet-milling processes in miniature, middle and large preparation scales have been established in order to cover the various types of studies with wide scale. The powder of phenytoin, a poorly water-soluble model drug candidate, was suspended in the aqueous medium, in which the appropriate dispersing agents were dissolved, and milled by agitating together with small hard beads made of zirconia. Three general-purpose equipments with stirring, oscillating and turbulent motions were applied instead of the specific milling machine with high power to avoid much investment at such early development stage. The operational condition and dispersing agents were optimized to obtain finer particles using the middle-scaled oscillating beads-milling apparatus in particular. It was found that the nanosuspension, which whole particle distribution was in the submicron range, was successfully produced within the running time around 10min. By applying the newly developed dispersing medium, the nanoparticles with identical size distribution were also prepared using the stirring and turbulent methods on miniature and large scales, respectively; indicating only 50mg to 30g or more amount of candidate could be milled to nanosuspension using three equipments. The crystalline analysis indicated that the both crystal form and crystallinity of the original bulk drug completely remained after wet-milling process. The results demonstrated that the wet-milling methods developed in this research would be a fundamental technique to produce nanosuspension for poorly water-soluble and oral absorbable drug candidates.