A Method for the Tensile Strength Prediction of Tablets with Differing Powder Plasticities.

Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (Ep/Ee) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and Ep/Ee obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.

Enhancement of cell membrane permeability by using charged nanoparticles and a weak external electric field.

Because the cell membrane is the main barrier of intracellular delivery, it is important to facilitate and control the translocation of extracellular compounds across it. Our earlier molecular dynamics simulations suggested that charged nanoparticles under a weak external electric field can enhance the permeability of the cell membrane without disrupting it. However, this membrane permeabilization approach has not been tested experimentally. This study investigated the membrane crossing of a model compound (dextran with a Mw of 3000-5000) using charged nanoparticles and a weak external electric field. A model bilayer lipid membrane was prepared by using a droplet contact method. The permeability of the membrane was evaluated using the electrophysiological technique. Even when the applied electric field was below the critical strength for membrane breakdown, dextran was able to cross the membrane without causing membrane breakdown. These results indicate that adding nanomaterials under a weak electric field may enhance the translocation of delivery compounds across the cell membrane with less damage, suggesting a new strategy for intracellular delivery systems.

Development of a Simple In-Die Method for Determination of Capping Tendency in Rotary Tableting Machines.

A rotary tableting machine is used for the continuous tableting process. Tableting conditions often result in capping, leading to serious problems during production. Several studies have been conducted to predict the tablet capping tendency. However, as most previous studies were conducted using a compaction simulator, there is a lack of technology that can be readily applied during actual production. Therefore, the present study aimed to develop a novel method for predicting tablet capping in a rotary tableting machine. We hypothesized that capping occurs when residual stress of the tablet inside a die exceeds the critical stress immediately before ejection. Residual stress was evaluated by measuring the in-line die-wall pressure in a rotary tableting machine. Additionally, critical stress was estimated from the tablet strength inside the die using the Rumpf's equation. The critical and residual stresses were compared to determine the capping tendency to some extent. The findings of this study will substantially contribute to the rapid detection of tablet capping during tablet production.

Continuous measurement of die wall pressure in a rotary tablet machine.

In the pharmaceutical industry, tablets are manufactured using rotary tableting machines. Recently, die wall pressure in a single-punch press was measured to understand the compaction mechanism and predict tableting failure. However, die wall pressure measurements in rotary tableting machines have not been studied. Two challenges exist in measuring die wall pressure in these machines, viz. (i) lack of space inside the machine to set up the measurement equipment and (ii) difficulty in installing wired measurement hardware because the die rotates with the rotary plate. This study aimed to continuously measure die wall pressure in a rotary tableting machine and investigate the effect of high compression speed on die wall pressure. Die wall pressure at tableting speeds of up to 140 mm/s was successfully determined using a wireless telemeter. Residual die wall pressure for plastic materials was strongly dependent on the tableting speed, although the tableting speed affected the maximum die wall pressure minimally. This novel measurement technique can be used to study the effect of tableting speed on die wall pressure, which can be applied in solving the problems of capping and lamination during tablet production.

Mechanism of Solubility Enhancement of Poorly Water-Soluble Drugs Triggered by Zeolitic Imidazolate Frameworks.

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

Direct translocation of a negatively charged nanoparticle across a negatively charged model cell membrane.

Nanoparticles have attracted much attention as a carrier for drug, gene, and macromolecule delivery in next-generation biomedical and therapeutic technologies. In delivery applications, nanoparticles tend to have negative charge due to the negative charge of biomolecules used as delivery cargo, while biological cell membranes are also negatively charged. This means that negatively charged nanoparticles (NC-NPs) are required to translocate across these negatively charged cell membranes (NC-CMs). However, this translocation is unlikely to occur because of electrostatic interactions. Here, we investigated the translocation of a NC-NP across a NC-CM under a transmembrane electric potential through coarse-grained molecular dynamics simulations. To model the transmembrane potential, two approaches were adopted: externally applied electric field and ionic charge imbalance. We showed that a NC-NP can directly translocate across a NC-CM via a non-disruptive pathway under a weak external electric field with an ionic charge imbalance. It was also found that the ionic charge imbalance contributes to the membrane crossing of a NC-NP as well as the self-resealing of the cell membrane after a NC-NP translocation. Our findings imply that NC-NPs can be delivered into a cell by combining applied electric field with membrane hyperpolarization/depolarization induced by an external stimulus.

Numerical Study on Spray Drying Process: Effect of Nonuniform Temperature Field and Interaction between Droplets on Evaporation Rates of Individual Droplets.

Spray drying process is widely used to produce particulate materials in the pharmaceutical industries, such as porous materials for direct compression, solid dispersion for improvement of drug dissolution properties, micro encapsulation to stabilize active compounds, taste masking, preparation of dry powder for inhalation. However, as many factors affect the physical properties of dried particles and the spray drying processes have complex behaviors in which heat and mass transfer occur simultaneously, the detailed mechanisms of dry particle generation have yet to be sufficiently elucidated. In this study, computational fluid dynamics was used to simulate water droplet evaporation in a spray dryer, and the evaporation kinetics of "individual droplets" in the droplet aggregate (group) were analyzed. The numerical simulation revealed that each droplet had different evaporation rates owing to the following two reasons. First, the driving force of evaporation, ΔT, changed every moment as the droplets traveled through different temperature fields in the drying tower. Second, it was calculated the driving force for droplet evaporation differed from the ideal system because the evaporation of other droplets changed the fluid characteristics around the droplets. The obtained results are important findings that lead to the understanding the spray drying process to design and manufacture the pharmaceutical products.

Numerical Study on Particle Adhesion in Dry Powder Inhaler Device.

This study investigated the particle adhesion mechanism in a capsule of dry powder inhaler (DPI) based on a combined computational fluid dynamics and discrete element method (CFD-DEM) approach. In this study, the Johnson-Kendall-Roberts (JKR) theory was selected as the adhesion force model. The simulation results corroborated the experimental results-numerous particles remained on the outlet side of the capsule, while a few particles remained on the inlet side. In the computer simulation, the modeled particles were placed in a capsule. They were quickly dispersed to both sides of the capsule, by air fed from one side of the capsule, and delivered from the air inlet side to the outlet side of the capsule. It was confirmed that vortex flows were seen at the outlet side of the capsule, which, however, were not seen at the inlet side. Numerous collisions were observed at the outlet side, while very few collisions were observed at the inlet side. These results suggested that the vortex flows were crucial to reduce the amount of residual particles in the capsule. The original capsule was then modified to enhance the vortex flow in the area, where many particles were found remaining. The modified capsule reduced the number of residual particles compared to the original capsule. This investigation suggests that the CFD-DEM approach can be a great tool for understanding the particle adhesion mechanism and improving the delivery efficiency of DPIs.

Numerical study for tableting process in consideration of compression speed.

A numerical study of the tableting process using a finite element method (FEM) is important to quantitatively understand the structural change inside the tablet and the mechanism of tableting failures such as capping, picking, lamination, and sticking. In the pharmaceutical field, the Drucker-Prager Cap (DPC) model is used most widely to demonstrate the mechanical behavior of the powder during tableting. The DPC model, however, cannot consider compaction speed, although the compaction speed has a large impact on the tablet strength and tableting failures. In the present study, a combined novel model using both the DPC and Perzyna models, which incorporates a visco-plastic behavior considering the compression speed, was proposed and numerical simulation was conducted. Cellulose, lactose, and acetaminophen were selected as model powders. The DPC-Perzyna model parameters were determined from experimental compaction tests, unconfined compression tests, and tension tests. The calculated loading curves agreed with the experimental data under different compaction speeds, in addition the high compression speed resulted in less plastic deformation and much residual stress. It was demonstrated that the DPC-Perzyna model proposed in the present study was useful to analyze the tableting process when considering compression speed.

Effect of Particle-Wall Interaction and Particle Shape on Particle Deposition Behavior in Human Respiratory System.

Dry powder inhalation (DPI) has attracted much attention as a treatment for respiratory diseases owing to the large effective absorption area in a human respiratory system. Understanding the drug particle motion in the respiratory system and the deposition behavior is necessary to improve the efficiency of DPI. We conducted computer simulations using a model coupling a discrete element method and a computational fluid dynamics method (DEM-CFD) to evaluate the particle deposition in human respiratory system. A simple artificial respiratory model was developed, which numerically investigated the effect of particle properties and inhalation patterns on the particle deposition behavior. The DEM-CFD simulations demonstrated that the smaller- and lower-density particles showed higher reachability into the simple respiratory model, and the particle arrival ratio to the deep region strongly depended on the aerodynamic diameter. The particle arrival ratio can be described as an exponential function of the aerodynamic diameter. Furthermore, the exponential relationship between the particle reachability into the depth of the simple respiratory model and the aerodynamic diameter predicted the particle aerodynamic diameter based on the required reachability. The particle shape also had an impact on the particle deposition behavior. The rod-like particles with a larger aspect ratio indicated higher reachability into the depth of the simple respiratory model. This was attributed to the high velocity motion of the particles whose long axis was in the direction of the deep region.

Direct translocation of nanoparticles across a model cell membrane by nanoparticle-induced local enhancement of membrane potential.

In biomedical technologies that use nanoparticles, the nanoparticles are often required to translocate across a cell membrane. Application of an external electric field has been used to increase the cell membrane permeability; however, damage to the cell is of great concern. Using a molecular dynamics simulation, we show that even under a weak external electric field that is lower than the membrane breakdown intensity, a cationic nanoparticle will directly translocate across a model cell membrane without membrane disruption. We then reveal its physical mechanism. At the contact interface between the nanoparticle and the cell membrane, the electric potential across the membrane is locally enhanced by superimposing the nanoparticle surface potential on the externally applied potential, resulting in its direct translocation. Our finding implies that, by controlling the nanoparticle-induced local enhancement of the membrane potential, the cellular delivery of nanoparticles via a non-endocytic and non-disruptive pathway can be realized.

Development of a Novel Milling System Using Supercritical Carbon Dioxide for Improvement of Dissolution Characteristics of Water-Poorly Soluble Drugs.

The aim of this study is to develop a novel milling system using supercritical carbon dioxide (SC-CO2) for the improvement of dissolution characteristics of water-poorly soluble drugs. SC-CO2 possesses high potential in the application of nanotechnology, due to the attractive properties of SC-CO2 fluid such as cheap, inert and non-polluting. In addition, SC-CO2 has density comparable to a liquid, viscosity similar to a gas, and high diffusion capacity. Most of all, carbon dioxide exists as gas in room temperature and pressure, which enables the removal of fluid instantaneously. In this study, a novel method of milling using SC-CO2 was proposed to produce fine-drug particles. SC-CO2 milling was conducted and its performance was compared with the ones by various milling methods such as jet milling, dry milling and wet milling. A comparison on the effect of each milling medium on its milling performance, drug size distribution, and particle morphology was conducted. Operating variables of the SC-CO2 milling system were also investigated to clarify the factors affecting the milling properties and to improve drug release characteristics of water-poorly soluble drugs.

MD simulation study of direct permeation of a nanoparticle across the cell membrane under an external electric field.

Nanoparticles (NPs) have been attracting much attention for biomedical and pharmaceutical applications. In most of the applications, NPs are required to translocate across the cell membrane and to reach the cell cytosol. Experimental studies have reported that by applying an electric field NPs can directly permeate across the cell membrane without the confinement of NPs by endocytic vesicles. However, damage to the cell can often be a concern. Understanding of the mechanism underlying the direct permeation of NPs under an external electric field can greatly contribute to the realization of a technology for the direct delivery of NPs. Here we investigated the permeation of a cationic gold NP across a phospholipid bilayer under an external electric field using a coarse-grained molecular dynamics simulation. When an external electric field that is equal to the membrane breakdown intensity was applied, a typical NP delivery by electroporation was shown: the cationic gold NP directly permeated across a lipid bilayer without membrane wrapping of the NP, while a persistent transmembrane pore was formed. However, when a specific range of the electric field that is lower than the membrane breakdown intensity was applied, a unique permeation pathway was exhibited: the generated transmembrane pore immediately resealed after the direct permeation of NP. Furthermore, we found that the affinity of the NP for the membrane surface is a key for the self-resealing of the pore. Our finding suggests that by applying an electric field in a suitable range NPs can be directly delivered into the cell with less cellular damage.

Simple and rapid synthesis of magnetite/hydroxyapatite composites for hyperthermia treatments via a mechanochemical route.

This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate-substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments.

In-die evaluation of capping tendency of pharmaceutical tablets using force-displacement curve and stress relaxation parameter.

A novel in-die evaluation method of tablet capping tendency was proposed based on a force-displacement curve and stress relaxation parameter in a tableting process. In our previous study (Chem. Pharm. Bull., 59, 2011, Nakamura et al.), the phase diagram consisting of elastic recovery energy (E(e)) and plastic deformation energy (E(p)) of compressed powder, named as the E(e)-E(p) diagram, was proposed. However, it was found that capping tendency of tablets prepared by double-compression with multi-component powder formulations cannot be discriminated using the E(e)-E(p) diagram. To improve the capping discrimination ability, we here proposed a novel corrected phase diagram consisting of the E(e) and an interparticle bonding parameter E(b)(t), named as the E(e)-E(b)(t) diagram. The E(b)(t) was proposed as a new parameter expressing strength of the interparticle bonding formed by the stress relaxation inside compressed powder. The E(b)(t) was defined as a product of the E(p) and the stress relaxation parameter Y(t), estimated from the force-displacement curve and the stress relaxation test. The capping discrimination ability of the diagrams was evaluated using a hierarchical-clustering analysis. The results exhibited that the capping tendency could be clearly discriminated using the proposed E(e)-E(b)(t) diagram at the double-compression and the multi-component powder formulations, as compared to the E(e)-E(p) diagram. This proposed diagram can be used for screening of the powder formulations to avoid the capping.

Development of a novel tablet machine for a tiny amount of powder and evaluation of capping tendency.

A novel single punch tablet machine was developed for a tiny amount of powder sample. This tablet machine mainly consists of upper and lower punches, single die, and conical powder feeder equipped with micro-vibrators. By using the powder feeder, mass of discharged powder can be maintained constant even if a tiny amount of powder having poor flowability is used. Motions of both upper and lower punches can be set arbitrarily. Thus, this machine enables us to prepare tablets with a tiny amount of powder sample under the same compression mechanism as conventional rotary tablet machines. Performance of the developed tablet machine was evaluated in a continuous direct tableting using a model powder with poor flowability. Thirty-four tablets (195 mg×34) having acceptable properties can be successfully prepared using no more than 10.0 g of a powder sample. We then proposed a novel in-die evaluation method of capping tendency. A new phase diagram consisting of the elastic recovery energy and the plastic deformation energy was proposed. These energies were calculated from a force-displacement profile, continuously monitored by the developed tablet machine. The results indicate that by using the new diagram the capping tendency of tablets prepared from various model powders can be well discriminated. The developed tablet machine and proposed evaluation method can contribute to a significant cost reduction and speeding up of formulation studies of oral dosage form.

Polyhydroxy fullerenes (fullerols or fullerenols): beneficial effects on growth and lifespan in diverse biological models.

Recent toxicological studies on carbon nanomaterials, including fullerenes, have led to concerns about their safety. Functionalized fullerenes, such as polyhydroxy fullerenes (PHF, fullerols, or fullerenols), have attracted particular attention due to their water solubility and toxicity. Here, we report surprisingly beneficial and/or specific effects of PHF on model organisms representing four kingdoms, including the green algae Pseudokirchneriella subcapitata, the plant Arabidopsis thaliana, the fungus Aspergillus niger, and the invertebrate Ceriodaphnia dubia. The results showed that PHF had no acute or chronic negative effects on the freshwater organisms. Conversely, PHF could surprisingly increase the algal culture density over controls at higher concentrations (i.e., 72% increase by 1 and 5 mg/L of PHF) and extend the lifespan and stimulate the reproduction of Daphnia (e.g. about 38% by 20 mg/L of PHF). We also show that at certain PHF concentrations fungal growth can be enhanced and Arabidopsis thaliana seedlings exhibit longer hypocotyls, while other complex physiological processes remain unaffected. These findings may open new research fields in the potential applications of PHF, e.g., in biofuel production and aquaculture. These results will form the basis of further research into the mechanisms of growth stimulation and life extension by PHF.

Numerical simulation of film coating process in a novel rotating fluidized bed.

In this study, numerical simulation of film coating process in a novel rotating fluidized bed (RFB) was conducted by using a Discrete Element Method (DEM)-Computational Fluid Dynamics (CFD) coupling model. Particle movements and fluid motions in a centrifugal force field were simulated at three-dimensional cylindrical coordinate, and this model was applied to film coating process. Film coating process in a RFB was numerically analyzed by using a simplified assumption that a particle was coated only when a particle existed within a spray zone. The experiments were also conducted and uniformity of sprayed material was evaluated by investigating color difference of the coated particles. As a result of the numerical simulation, three-dimensional bubble movements and particle circulation could be well simulated. In addition, mass of the sprayed material on a single particle in a RFB could be visualized by using our proposed model. The relationship between distribution of the sprayed material and the coating time was also analyzed. Calculated mass distributions of the sprayed material could be expressed by a normal distribution function, showing qualitative good agreement with the previous studies. Effect of the operating parameters, such as gas velocity and centrifugal acceleration, on the uniformity of the sprayed material was also investigated by both numerical and experimental approaches. Comparison of the coating process in a RFB with that in a conventional fluidized bed was also conducted by the numerical simulation. The result showed that uniformity of the sprayed material was greatly improved in a RFB due to the much smaller circulation time.

Gastric cancer screening of a high-risk population in Japan using serum pepsinogen and barium digital radiography.

With the aim of developing more efficient gastric cancer screening programs for use in Japan, we studied a new screening program that combines serum pepsinogen (PG) testing and barium digital radiography (DR). A total of 17 647 middle-aged male subjects underwent workplace screening over a 7-year period using a combination of PG testing and DR. This program's effectiveness, as well as other characteristics of the program, was analyzed. Forty-nine cases of gastric cancer were detected (comprising 88% early cancer cases). The detection rate was 0.28%, and the positive predictive value was 0.85%. The PG test detected 63.3% of cases, DR detected 69.4% of cases, and both tests were positive in 32.7% of cancer cases. The two methods were almost equally effective, and were considerably more effective than conventional screening using photofluorography. Each screening method detected a distinct gastric cancer subgroup; the PG test efficiently detected asymptomatic small early cancer with intestinal type histology, while DR was efficient at detecting cancers with depressed or ulcerated morphology and diffuse type histology. The cost for the detection of a single cancer was much less than that for conventional screening. In fact, it is possible to further reduce the cost of detecting a single cancer to a cost comparable to that of surgically resecting a single gastric cancer. Thus, it is probable that a highly efficient gastric cancer screening system can be implemented by combining the two screening methods. Such a screening program would be beneficial in a population at high risk for gastric cancer.

Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer.

We conducted a longitudinal cohort study to determine the association of Helicobacter pylori infection and the progression of chronic atrophic gastritis (CAG) with gastric cancer. A cohort of 4655 healthy asymptomatic subjects was followed for a mean period of 7.7 years. H. pylori infection was established by serum specific antibodies and the presence of CAG was confirmed by serum pepsinogen. During the follow-up period, 45 gastric cancer cases were detected (incidence rate, 126/100000 person-years). A univariate analysis after adjustment for age showed that both H. pylori and CAG were significantly associated with gastric cancer. To clarify the interaction between H. pylori and CAG, an analysis stratified by H. pylori- and CAG-status was performed. No cancer developed in the H. pylori(-)/CAG(-) group during the study period. This supports the theory that it is quite rare for any type of gastric cancer to develop in an H. pylori-free healthy stomach. With the progression of H. pylori-induced gastritis, the risk of gastric cancer increased in a stepwise fashion from CAG-free gastritis [H. pylori(+)/CAG(-) group] (HR=7.13, 95%CI=0.95-53.33) to CAG [H. pylori(+)/CAG(+) group] (HR=14.85, 95%CI=1.96-107.7) and finally to severe CAG with extensive intestinal metaplasia [H. pylori(-)/CAG(+) group] (HR=61.85, 95%CI=5.6-682.64) in which loss of H. pylori from the stomach is observed. Therefore, it is probable that H. pylori alone is not directly associated with stomach carcinogenesis. Instead, H. pylori appears to influence stomach carcinogenesis through the development of CAG. The observed positive correlation between the extent of H. pylori-induced gastritis and the development of cancer was strong, especially for the intestinal type. These results are compelling evidence that severe gastritis with extensive intestinal metaplasia is a major risk factor for gastric cancer, and they confirm the previously described model of stomach carcinogenesis: the gastritis-metaplasia-carcinoma sequence.