A theoretical approach to evaluate the release rate of acetaminophen from erosive wax matrix dosage forms.

To predict drug dissolution and understand the mechanisms of drug release from wax matrix dosage forms containing glyceryl monostearate (GM; a wax base), aminoalkyl methacrylate copolymer E (AMCE; a pH-dependent functional polymer), and acetaminophen (APAP; a model drug), we tried to derive a novel mathematical model with respect to erosion and diffusion theory. Our model exhibited good agreement with the whole set of experimentally obtained values pertaining to APAP release at pH 4.0 and pH 6.5. In addition, this model revealed that the eroding speed of wax matrices was strongly influenced by the loading content of AMCE, but not that of APAP, and that the diffusion coefficient increased as APAP loading decreased and AMCE loading increased, thus directly defining the physicochemical properties of erosion and diffusion. Therefore, this model might prove a useful equation for the precise prediction of dissolution and for understanding the mechanisms of drug release from wax matrix dosage forms.

Stabilization mechanism of clarithromycin tablets under gastric pH conditions.

It has been reported that tablets of clarithromycin (CAM), a 14-membered macrolide antibiotic, are especially stable under low pH conditions such as in gastric fluid, and showed excellent antibacterial efficiency even though CAM molecules themselves are rapidly decomposed. Therefore, we aimed to clarify the stabilization mechanism of CAM tablets under low pH conditions. From the results of stability and dissolution tests, the optimal decomposition rate constant (K(dec)) and dissolution rate constant (K(dis)) at various pH values were calculated by curve-fitting to consecutive reactions. Consequently, log(K(dec)) increased as pH decreased. On the other hand, log(K(dis)) increased as pH decreased from 3.0 to 1.5, but decreased as pH decreased from 1.5 to 1.0. In addition, the disintegration time of commercially available tablets at pH 1.0 and 1.2 was found to be delayed, resulting in a decrease of K(dis). Furthermore, from powder X-ray diffraction, HPLC and elemental analysis, the delay in disintegration time might be attributable to the formation of a transparent gel, formed by the reaction between CAM molecule and hydrochloric acid under low pH conditions, on the surface of CAM tablet. On the basis of these results, this report can be considered the first case where a transparent gel prevents gastric fluid from penetrating the tablet, resulting in reduced decomposition of CAM following oral administrating.

Application of principal component analysis enables to effectively find important physical variables for optimization of fluid bed granulator conditions.

Principal component analysis was applied to effectively optimize the operational conditions of a fluidized bed granulator for preparing granules with excellent compaction and tablet physical properties. The crucial variables that affect the properties of the granules, their compactability and the resulting tablet properties were determined through analysis of a series of granulation and tabletting experiments. Granulation was performed while the flow rate and concentration of the binder were changed as independent operational variables, according to a two-factor central composite design. Thirteen physicochemical properties of granules and tablets were examined: powder properties (particle size, size distribution width, Carr's index, Hausner ratio and aspect ratio), compactability properties (pressure transmission ratio, die wall force and ejection force) and tablet properties (tensile strength, friability, disintegration time, weight variation and drug content uniformity). Principal component analysis showed that the pressure transmission ratio, die wall force and Carr's index were the most important variables in granule preparation. Multiple regression analysis also confirmed these results. Furthermore, optimized operational conditions obtained from the multiple regression analysis enabled the production of granules with desirable properties for tabletting. This study presents the first use of principle component analysis for identifying and successfully predicting the most important variables in the process of granulation and tabletting.

A comparative study of glycerin fatty acid ester and magnesium stearate on the dissolution of acetaminophen tablets using the analysis of available surface area.

To study the effect of glycerin fatty acid ester (Poem TR-FB) concentrations on the dissolution rate of acetaminophen (APAP), the dissolution and disintegration behaviors of APAP tablets formulated using various lubricants were examined. The change over time in the available surface area of APAP (S(t)), which is in direct contact with solvent, was also analyzed using these dissolution data. In the dissolution tests, a retarded dissolution of APAP was not observed with TR-FB, whereas magnesium stearate (Mg-St), which is widely used as a lubricant, retarded the dissolution. However, no significant difference in the disintegration time between the two lubricants was observed. With regard to the time course of the S(t), Mg-St at 0.1% gave a maximum surface area value at 9.19 min (peak time); however, the profiles for APAP with Mg-St at greater than 0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value that was more than twice that of APAP with that of 0.5-3.0% of Mg-St. Scanning electron microscopy (SEM) observations showed that the differences in the dissolution rate and S(t) patterns between Mg-St and TR-FB could be explained by differences in extensibility deriving from their morphology. Therefore, it was concluded that TR-FB does not cause retardation of drug dissolution and may prove to be a superior alternative lubricant to Mg-St.

Optimization of a novel wax matrix system using aminoalkyl methacrylate copolymer E and ethylcellulose to suppress the bitter taste of acetaminophen.

The purpose of the present study was to design and evaluate a novel wax matrix system containing various ratios of aminoalkyl methacrylate copolymer E (AMCE) and ethylcellulose (EC) as functional polymers in order to achieve the optimal acetaminophen (APAP) release rate for taste masking. A two factor, three level (3(2)) full factorial study design was used to optimize the ratios of AMCE and EC, and the release of APAP from the wax matrix was evaluated using a stationary disk in accordance with the paddle method. The disk was prepared by congealing glyceryl monostearate (GM), a wax with a low melting point, with various ratios of polymers and APAP. The criteria for release rate of APAP from the disk at pH 4.0 and pH 6.5 were calculated to be more than 0.5017 microg/(mlxmin) and less than 0.1414 microg/(mlxmin), respectively, under the assumption that the particle size of spherical matrix should be 100 microm. In multiple regression analysis, the release of APAP at pH 4.0 was found to increase markedly as the concentration of AMCE increased, whereas the release of APAP at pH 6.5 decreased as the EC concentration increased, even when a high level of AMCE was incorporated. Using principle component analysis, it was found that the viscosity of the matrix affects the pH-dependent release of APAP at pH 4.0 and pH 6.5. Furthermore, using multiple regression analysis, the optimum ratio of APAP:AMCE:EC:GM was found to be 30:7:10:53, and the release pattern of APAP from the optimum wax formulation nearly complied with the desired criteria. Therefore, the present study demonstrated that the incorporation of AMCE and EC into a wax matrix system enabled the appropriate release of APAP as a means of taste masking.

Novel mathematical model for predicting the dissolution profile of spherical particles under non-sink conditions.

A mechanistic mathematical model was designed to predict dissolution patterns under non-sink conditions. Sulfamethoxazole was used as a model drug, and its physico-chemical properties such as solubility, density, and intrinsic dissolution rate constant etc., were investigated in order to apply these experimental values to the proposed model. Dissolution tests were employed as a way of validating the mathematical model, and it was found that the predictions given by the model were surprisingly accurate for all particle sizes. In addition, a simulation focused on forecasting the fraction of the drug that was dissolved at a certain time point when various initial particle diameters were used was also particularly valuable. Therefore, these results demonstrated that the model enables dissolution profiles to be analyzed under non-sink conditions.

Optimal conditions to prepare fine globular granules with a multi-functional rotor processor.

The optimal manufacturing conditions to obtain fine globular granules with a narrow size of particle distribution were investigated for a multi-functional rotor processor. A fractional factorial design analysis was undertaken to find out the significant operational conditions influencing the following physical characteristics of the obtained granules: size distribution, roundness and water content. Operational conditions tested were binder flow rate, atomization pressure, slit air flow rate, rotating speed and temperature of inlet air. It was observed that: the proportion of fine particles (106-212 microm) was positively affected by the atomization pressure, while negatively affected by the slit air flow rate; and roundness and water content were positively affected by the binder flow rate. Furthermore, the multiple regression analysis enabled the identification of an optimal operating window for production of fine globular granules. Therefore, the present study demonstrated that the combination of experimental design and multiple regression analysis allows a better understanding of complicated granulating process of multi-functional rotor processor to obtain fine globular granules.

Lubrication properties of potential alternative lubricants, glycerin fatty acid esters, to magnesium stearate.

To study the usefulness of glycerin fatty acid ester Poem TR-FB (TR-FB) and Poem TR-HB (TR-HB) as lubricants, pressure transmission ratio, ejection force, disintegration time, and tensile strength were measured at different concentrations and mixing times for granules and tablets. When each lubricant was mixed at 0.1-3.0%, the increase in the pressure transmission ratio that was equal to or greater than that of Mg-St as well as the reduction in the ejection force was observed at a low concentration in both TR-FB and TR-HB, proving that they have excellent lubrication performance. The granules that were lubricated with TR-FB and TR-HB at even low concentration of 0.4% showed a more stable and sufficiently lower ejection force than with Mg-St from the first tablet after the start of compression. When they were mixed for 5-60 min, while the mixture with Mg-St showed a low pressure transmission ratio of 82% and a high ejection force of 500 N in the first tablet even when the mixing time was 60 min, a high pressure transmission ratio and a low ejection force were observed in TR-FB and TR-HB from the first tablet after mixing for 5-60 min, and these were maintained thereafter. As for the disintegration time and the tensile strength, a prolonged disintegration time and a decreased tensile strength, which are disadvantages of Mg-St, were not observed in TR-FB and TR-HB. Based on these results, it was concluded that TR-FB and TR-HB are useful as alternative lubricants to Mg-St.

Physical properties of griseofulvin-lipid nanoparticles in suspension and their novel interaction mechanism with saccharide during freeze-drying.

Size reduction of drug particles to the nanoscale is important in improving the dissolution rate of poorly water-soluble drugs. The aim of this study was to investigate the physicochemical properties of griseofulvin (GF)-lipid nanoparticles and the interactions between GF-lipid nanoparticles and various saccharides during freeze-drying. The phase transition temperature of the GF-lipid nanoparticle suspension was 56.8 degrees C, whereas that of the lipid nanoparticle suspension alone was 57.9 degrees C, indicating that the GF crystals were incorporated into the lipid phase. The mean particle size of a rehydrated suspension of xylose-containing freeze-dried GF-lipid nanoparticles was about 220 nm. However, the mean particle size on the rehydration of nanoparticles containing mannose (monosaccharide), fructose (disaccharide), lactose (disaccharide), or raffinose (trisaccharide) was about 60 nm, suggesting that these saccharides prevented aggregation during the freeze-drying process. Powder X-ray diffraction revealed that xylose existed in the crystalline state in the freeze-dried nanoparticles, whereas the other saccharides existed in amorphous states. Thus, the crystallization of the saccharide was found to be strongly correlated with the aggregation property of the nanoparticles. In the case of freeze-dried xylose, the nanoparticles were squeezed out as the saccharine crystal lattice arranged itself regularly. Then, the ejected nanoparticles were aggregated. In contrast, in the case of the other freeze-dried saccharide, the saccharide remained incorporated with the GF-lipid nanoparticles because its crystal lattice was arranged irregularly. Thus, the particle size was maintained.

Preparation of griseofulvin nanoparticle suspension by high-pressure homogenization and preservation of the suspension with saccharides and sugar alcohols.

AIM: We have attempted to micronize drug particles with a particle size of less than 100 nm and maintain the particle size of their suspension to improve the solubility and bioavailability of poorly water-soluble drugs. Furthermore, the method of freeze-drying nanoparticles was applied to maintain particulate nature of nanoparticles containing various saccharides and sugar alcohols for a long time. METHOD: Griseofulvin (GF)-lipid nanoparticle suspension is prepared using GF and a lipid by high-pressure homogenization. The particle size of the obtained GF-lipid nanoparticle suspension is maintained constant by freeze-drying. RESULT: The mean particle size of GF-lipid nanoparticles prepared by high-pressure homogenization is approximately 60 nm. The mean particle size remains less than 100 nm for 1 month. The GF-lipid nanoparticle suspension containing xylitol, trehalose, or sucrose is freeze-dried to maintain the particulate nature. The mean particle size of the rehydrated suspension is lower than that of the rehydrated suspension containing erythritol or lactose. In particular, it is new knowledge to have found that an aggregation is minimized by adding xylitol which is sugar alcohol. The minimum concentration of xylitol, trehalose, and sucrose required to maintain a constant particle size by rehydration is 3%, 3%, and 5% (w/v), respectively.

Freeze-dried nifedipine-lipid nanoparticles with long-term nano-dispersion stability after reconstitution.

Nifedipine (NI) is a poorly water-soluble drug and its oral bioavailability is very low. To improve the water solubility, NI-lipid nanoparticle suspensions were prepared by a combination of co-grinding by a roll mill and high-pressure homogenization without any organic solvent. The mean particle size and zeta potential of the NI-lipid nanoparticle suspensions were about 52.6 nm and -61.8 mV, respectively, and each parameter remained extremely constant during a period of 4 months under 6 degrees C and dark conditions, suggesting that the negative charge of the phospholipid, dipalmitoyl phosphatidylglycerol, is very effective in preventing coagulation of the particles. In order to assure the nano-order particle size of the suspensions in view of long-term stability, a freeze-drying technique was applied to the NI-lipid nanoparticle suspensions. The mean particle size of freeze-dried NI-lipid nanoparticles after reconstitution was significantly increased in comparison to that of the preparations before freeze-drying. It was found, however, that the addition of sugars (glucose, fructose, maltose or sucrose) to the suspensions before freeze-drying inhibited the aggregation of nanoparticles, suggesting that the long-term stability storage of freeze-dried NI-lipid nanoparticles after reconstitution would be overcome. In addition, freeze-dried nanoparticles with 100mg sugar (glucose, fructose, maltose or sucrose) showed excellent solubility (>80%), whereas without sugar, as a control, showed low solubility (<20%). It was found that negatively charged phospholipids and sugars prevent coagulation of NI nanoparticle suspensions, and reproduce the nanoparticle dispersion after reconstitution; and remarkably increase the apparent solubility of nifedipine.

Preparation and stabilization of nifedipine lipid nanoparticles.

Design methods of nanoparticle formulations are divided into a break-down method and a build-up method. Furthermore, the former is further divided into dry and wet processes. For drug nanoparticle preparations, the wet process is generally employed, and organic solvents are used in most formulations. In this study, we investigated the preparation of nifedipine (NI) nanoparticles without using any organic solvent. NI nanoparticles with a mean particle size of approximately 50 nm could be prepared without organic solvent by a combination of roll mixing and high-pressure homogenization. The X-ray diffraction peak of the sample prepared by roll mixing was present at an identical position (2theta) to that of NI crystals, showing that no peak shift was induced by interaction with lipid. These findings clarified that most NI remained as crystals in lipid. To maintain the particle size of the nanoparticles in suspension for a long time, a method of adding gelatin powder to the NI-lipid nanoparticle suspension, dissolving the mixture by heating, and then solidifying by cooling was investigated. The mean particle size of the sample was about 55 nm, and that after heat-liquefaction of the NI-lipid nanoparticle suspension gelated at 5 degrees C for 24h was also about 55 nm, showing that the nanoparticle condition was retained.

A dosage design of mitomycin C tablets containing finely powdered green tea.

We previously reported a method of preparing finely powdered green tea (PT), powder characteristics and release profiles of green tea components from PT. In this study, we performed formulation studies of PT tablets containing mitomycin C (MMC), expecting its combined antitumor effects with mitomycin C and green tea components. The hardness of PT tablets was low (22-50 N) and the disintegration time was about 180 min regardless of hardness or tabletting pressure (15-200 MPa). Perfiller-101 improved tablet characteristics practically into 90 N of hardness and 18.5 min of disintegration time. Release rates of MMC, caffeine and EGCG from the tablets were similar, and depended on the disintegration time. PT and epigallocatechin gallate (EGCG) increased significantly in MMC uptake in Ehrlich ascites carcinoma cells as compared with the control dose-dependently in vitro.

Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides.

To improve the solubility of poorly water-soluble drugs, we studied physical characteristics of griseofulvin (GF) solid dispersions with saccharides as the dispersion carrier using a roll mixing method. In all carriers tested, roll mixtures of GF and saccharides gradually became amorphous, and the solubility of GF increased. The solubility of GF was higher in the mixtures with higher molecular weight carriers such as corn starch and processed starch. The dissolution of GF was markedly improved by the GF-Britishgum roll mixture. The initial dissolution rate of these mixtures was 170-fold higher than GF alone. The surface tension of carrier aqueous solutions was low in the processed starch with branched sugar chains. The initial dissolution rate of GF in physical mixtures was correlated with the surface tension of carrier aqueous solutions. The stability of the amorphous state of GF at a high humidity was maintained in the mixtures with carriers with a high molecular weight. These results indicated that the solubility of GF was markedly improved in the roll mixtures. It was suggested that the saccharides with a high molecular weight are useful carriers for solid dispersions.

Effects of mixed polyethyleneglycol modification on fixed aqueous layer thickness and antitumor activity of doxorubicin containing liposome.

Polyethyleneglycol (PEG) has often been used for the modification of liposomes, but it is difficult to insert PEG on the surface of liposomes, and the effects of modification are not marked enough. In this study, we examined the fixed aqueous layer thickness (FALT) of single or mixed PEG (molecular weight, 340, 500, 900, 2000)-modified doxorubicin (DOX) liposomes, and physical character and biological properties of these liposomes. On single PEG-modification, as the PEG-molecular weight increased, FALT also increased, but the ratio of the increase was reduced. While on modification by a mixture of PEG2000 and PEG with a short polyoxyethylene chain (PEG340 or PEG500), FALT increased compared with the single PEG2000-modified value. Moreover, when liposomes were modified by mixture of PEG2000 and PEG500, we recognized the most suitable mixed rate (PEG2000, 500=2:1), showed the maximum FALT. On the other hand, in vivo, as increase of FALT, DOX concentrations increased in the plasma and in the tumor, decreased in the liver. Furthermore, liposomes with remarkable increase of FALT showed enhancement of antitumor activity. As a result, the connection among increase of FALT and improvement of circulation in blood, the involvement of antitumor activity of DOX of these liposomes was suggested.