Masayasu Sugihara

Pulsed dextran release from calcium-alginate gel beads

Abstract Sodium alginate forms a hydrogel upon contact with calcium ions in aqueous solution due to the physical crosslinking (chelation) between the carboxylate anions of guluronate units in alginate and the calcium ions. Alginate disintegration (dissolution) in phosphate buffered saline solution (pH 7.4, Ca 2+ -, Mg 2+ -free) occurs completely in a short time period after a certain lag time. Calcium ion release from the alginate gels is believed to be an influential factor in alginate dissolution. Using this alginate dissolution mechanism, we tried to release macromolecular dextran (nominal molecular weight of 145 000) in a pulsatile manner. As was expected, dextran with molecular weight of 145 000 was released completely in a short time range after a certain lag time. The lag time could be controlled by either alginate molecular weight, alginate concentration in the preparation, or gel beads size. The larger the diameter of the alginate gel beads, the later the observed release time onset. Thereafter dextran was released without changing release rate. Furthermore, we have succeeded to release dextran in a pulsatile fashion using calcium-alginate gel beads by mixing different bead sizes. These results indicate that pulsatile release of macromolecular drugs such as peptides and proteins could be achieved using calcium-alginate gel beads.

Preparation and characterization of sealed heated mixture of sublimable compound and porous calcium silicate II: Investigation of the interaction between maltol and porous calcium silicate surface

Abstract A sealed heated mixture of maltol (Mal) and porous calcium silicate (Florite® RE:FR) was prepared by heating the physical mixture in a sealed container. The amorphization of the Mal crystals in the sealed heated mixture (FR:Mal=9:1 or 7:3) was observed by X-ray diffraction and differential scanning calorimetric measurements. At the same time, a marked discoloration was also observed in the sealed heated mixture, which showed a color change from initially white to yellow or light brown. On the basis of Fourier transform infrared spectroscopy, the discoloration seems to be due to the ionization of Mal molecules on the FR surface. The discoloration of the mixture during heating was accelerated by increasing the heating temperature and the heating time. The addition of colloidal silicon dioxide (Reolosil® QS-102:REO) affected the discoloration. It was found that an increase in an amount of REO added inhibited the discoloration during sealed heating.

Development and pharmaceutical properties of a new oral dosage form of theophylline using sodium caseinate for the possible use in elderly patients

Abstract As a new oral dosage form which elderly patients could handle and swallow more easily, a solid mass containing theophylline was formed by treatment of a powder mixture of sodium caseinate, microcrystalline cellulose and theophylline with moist heat in the form of saturated steam under pressure. The physical and chemical stability of theophylline in solid mass form was confirmed on the basis of data obtained by infrared spectroscopy, X-ray powder diffractometry and high-performance liquid chromatography. The solid mass containing theophylline showed lower water absorption and reduced swelling tendency compared to the theophylline-free solid mass, whereas the slope of the gel destruction curve of swollen mass containing theophylline was similar to that of the theophylline-free solid mass. Therefore, it appeared that elderly patients could swallow this dosage form easily. The rate of release of theophylline from the swollen mass decreased in the order of distilled water, JP XII disintegration test fluid no. 2 (pH 6.8), and JP XII disintegration test fluid no. 1 (pH 1.2). The profiles of theophylline release from the swollen mass demonstrated non-Fickian diffusional behavior. In JP XII disintegration test fluid no. 1, theophylline was released slowly from the whole swollen mass, but rapidly from the destroyed swollen mass. The presence of digestive enzyme (pepsin) increased the release rate of theophylline from the swollen mass gradually. Thus, the structure of the polymer network in the swollen mass was considered to influence the release profile of theophylline. Although the biopharmaceutical parameters of this new oral dosage form should be further examined, the dosage form using sodium caseinate seems to be useful for medication in elderly patients.

The Pulsatile Release System of Macromolecular Drugs from Alginate Gel Beads

We investigate the possible applicability of alginate gel beads for controlled release system of water-soluble macromolecular drugs, using Fluorescein Isothiocyanate Dextran (FITC-dex) as the model compound. Lower molecular weight dextran was released via the diffusion through alginate matrix, while alginate erosion strongly affected dex release with increasing molecular weight. For FITC-dex (MW: 145,000), pulsatile release was observed after a lag time of 90 min. The lag time could be controlled not only by molecular weight and concentration of alginate but also by particle size of beads. We have also succeeded to alter the release profile of FITC-dex (MW: 145,000) from pulsatile to sustained release by adding styrene-maleic anhydride copolymer (SMA) to alginate. These results suggest that alginate gel beads are utilized as vehicle for a delivery of bioactive compounds.

Estimation of the Child Resistant Characteristics of Reclosable Packagings of Safty Closure by Sequential Test Method.

The required forces for opening the safety closures of three reclosable packagings were measured at initial and after 60 opening and closing, and child resistant characteristics of those packagings were estimated by sequential test method, which reduces test subjects without changing the statistical parameters while permitting the same prediction accuracy with the PPPA (Poison Prevention Packaging Act) test method. As the results of the sequential tests, these packagings were statistically confirmed as child resistant materials under given conditions.Trials had shown that people in the age group over 61 had not great difficulty in opening child resistant packagings. Then it seemed that there was no need for the age group (61-65 years) to be tested specially.

Development of Oral Preparation for Elderly Patients. Water Absorption and Swelling Profiles of Dried Gel Sheet Prepared with Carrageenan.

The effects of gel concentration before drying, thickness of the dried gel sheet and the additives on the water absorption and swelling profile of the dried gel sheet prepared with carrageenan were investigated. The following results were obtained.The higher gel cocentaration before drying demonstrated the faster water absorption and swelling rate in the carrageenan sheet. The water absorption and swelling rate became 1.3-1.5 times faster with the addition of potassium citrate, sodium citrate and gulcose. However, the thickness of the sheet and the amount of additives scarcely affected the water absorption and swelling profiles.

Water Vapor Permeation of Child Resistant Package.

The water vapor permeation behavior of the child resistant package (CRP) with a pressand-turn closure, the polyethylene bottle with a screw cap and the glass bottle with a screw cap was investigated. The water vapor permeation increased in the order of the glass bottle, polyethylene bottle and CRP. The amount of water vapor permeated through the CRP showed a linear increment with the passage of time. The effect of applied sealing torques on the water vapor permeation was also investigated. There was not affect on the water vapor permeation of glass bottle and little influence on the of the polyethylene bottle. On the contrary, the water vapor permeation of the CRP showed dependency on the applied sealing torque. These results suggest that the differences in water vapor permeation were due to the specific structure of the CRP closure. Additionally revealed was that in the CRP the relationship between the log applied sealing torque and the water vapor permeation rate produced a nearstraight curve.

Decrease of Crystallization of Triturated Mixtures of Mefenamic Acid and Sodium Starch Glycolate by Heating at a Reduced Pressure.

The triturated mixtures of mefenamic acid (MFA) and Explotab ® (EX) were prepared by means of powder/powder mixing technique.After storage under reduced pressure at 60°C for 5 hr, with scanning electron microscopy, it seemed likely that EX was transformed to a porous powder.The crystal peaks of MFA by X-ray diffraction had almost disappeared.The dissolution profiles of MFA from the triturated mixtures stored under reduced pressure at 60°C for 5 hr were enhanced in comparison with that from a freshly prerared mixture.With the increase of either the storage temperature or the time under reduced pressure, the particle size of MFA tended to increase on the surface of EX, and MFA also tended to peel from the surface of EX.Consequently, the crystallization of MFA was accelerated.

Effect of Position of Nonflat Punch on-Dividing Properties of Scored Tablet in One Side Compaction Method

The significance of the position of nonflat punch on dividing prcperties of scored tablets was investigated in several tablets prepared from excipients or granules by one side compaction method.For the excipients, lactose, perfiller®and microcrystalline cellulose were used.For the granules, sieved granules in 12-16, 16-32 and 32-48 mesh incorporating either hydroxy propyl cellulose or potato starch as binder was used.Different influence of the position of nonflat punch on dividing strength of scored tablets was observed between the case of excipients and granules.Dividing strength of scored tablets made from excipients was not affected by the position of nonflat punch.But tablets made from granules had a tendency to show high dividing strength when tablets were compressed by nonflat upper punch.Then weight variation of divided tablets showed a tendency to become less when compressed by nonflat upper punch in both tablets made from excipients and granules.It was suggested that the effect of the position of nonflat punch on dividing properties of scored tablets was caused by different pressure lines during tablet compression.

Dividing Property of Scored Tablet Produced by Direct Compression Method.

Dividing property was investigated in scored tablets compressed by direct compression method. For the excipients, lactose (SL), corn starch (CS), synthetic aluminum silicate (SAS), hydroxy propyl starch (HPS), microcrystalline cellulose (MCC) and Perfiller® were used.Dividing strength of tablet was in the order MCC tablet>Perfiller® tablet>SAS tablet>SL, HPS and CS tablets.The dividing strength of SL-MCC and SL-Perfiller® mixture tablets increased with an increase of the mixing rate.But the dividing strength of SL-CS mixture tablet was unchanged.Weight variation of tablet halves was affected by compaction profiles of excipients alone. MCC, SAS and Perfiller® showed straight compaction profiles, these tablets had little weight variation of tablet halves.But in the case of SL-CS, SL-MCC and SL-Perfiller® mixture, no difference of compaction profiles was shown and SL-MCC mixture tablet alone decreased the weight variation of tablet halves of SL tablet. Then a correlation between dividing strength of tablet and weight variation of tablet halves was found in SL-MCC and SL-Perfiller® mixture tablets.