In the granule coating method using a centrifugal fluidized bed rotary granulator, cracking and abrasion of core particles is often caused by the spray air. A three-fluid nozzle spray gun, which has one more air line added to the outside of a two-fluid nozzle spray gun, was effective in reducing these problems. We developed a three-fluid nozzle spray gun, equipped at the centrifugal fluidized bed rotary granulator, and performed granule coating. As the result, use of the new spray gun prevented loss of yield, increased blocking and decrease of drug contents, and made it possible to produce high quality granules. The cracking and abrasion of particles were remarkably reduced by the effect of the air curtain. It was found that this phenomenon was due to an alleviative effect of the collision of rotating particles near the spray air outlet, so the new outermost air line of the three-fluid nozzle spray gun is used to create an air curtain. The air curtain enabled an increase of the spraying area to the maximum, and caused the spraying speed to be slower. This resulted in the reduction of cracking and abrasion of granules, and adhesion on the spray gun was prevented.

The dissolution behavior and pharmacokinetics of chlormadinone acetate (CMA) sustained-release tablets, a once daily medicine for prostatic hypertrophy, were investigated. Chlormadinone acetate and enteric polymer (Eudragit^®S) were adsorbed on magnesium aluminometasilicate, and the admixtures were crushed to the size of 80-110 μm in diameter. The powder obtained was mixed with low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium and magnesiumstearate, and compressed into tablets. The tablets were coated with enteric polymer (Eudragit^®LD) (Test tablet D). The dissolution characteristics of CMA from Test tablet D and a commercial tablet (Prostal^®L) were identical. The pharmacokinetics after a single oral administration of Test tablet D and the commercial tablet were examined in healthy adult male volunteers. Test tablet D and the commercial tablet were mutually bioequivalent. The influence of food on the bioavailability of these sustained-release tablets was observed; the extent of bioavailability of CMA after a meal was larger than that under fasting conditions. Judging from the simulated serum concentrations after multiple administration, Test tablet D is expected to be effective in a once-a-day dosing regimen as well as for immediate-release tablets in a twice-a-day dosing regimen. These results suggest that if a tablet exhibits the same in vitro dissolution profiles, it will exhibit the same in vivo pharmacokinetics.

The purpose of this study was to seek good in vitro-in vivo correlation (IVIVC) for enteric-coated multiple unit dosage forms. The gastric emptying (GE)-convolution method we had developed was applied to analyze data from bioavailability tests of enteric-coated aspirin granules that had been conducted with eight healthy male volunteers, four subjects having orthotonic stomachs and four hypotonic stomachs. Enteric-coated aspirin granules and enteric-coated BaSO₄ granules were administered concurrently, and the concentrations of salicylate in serum and urine were determined. The behavior of the BaSO₄ granules was traced by X-ray camera. The dissolution profiles of enteric-coated aspirin granules in the gastrointestinal (GI) tract were determined by combining in vitro dissolution data and gastric-emptying profiles of granules (GE-convolution). The cumulative absorption profiles of aspirin under usual and light meal conditions, calculated by the Wagner-Nelson method, closely coincided with the predetermined dissolution profiles from in vitro dissolution at pH 5.0. Dissolution profiles in vivo were successfully predicted by this novel method, which takes into account the great change in the gastric emptying rate of granules caused by food and interindividual variation.

A continuous microwave sterilizer (MWS) was developed. The MWS is a new sterilization system using microwave dielectric heating. Its temperature characteristics, selection of biological indicators, and sterilizing ability were reported in our previous papers. Here we report the application of the MWS to thermally labile drug solutions whose sterilization was not possible with conventional autoclaving. We selected nine strains of microorganisms with heat resistance close to that of microorganisms found in a bioburden. Each microbial suspension (10⁶ to 10⁷ cfu/ml) was heated for 12 sec with the MWS at 81-128°C. Six strains of vegetative-form cells and fungal spores were sterilized completely at 81-86°C. Bacillus subtilis spores and Clostridium sporogenes spores were sterilized at 117-119°C and 123-125°C, respectively. These results suggest that microorganisms detected in a bioburden can be reliably sterilized with the MWS at 81-125°C. The deterioration in quality of thermally labile drug preparations (ascorbic acid solution and pyridoxamine phosphate solution) following sterilization with the MWS or an autoclave was evaluated. When compared with the same Fo value, sterilization with an autoclave resulted in quality deterioration of both preparations, but sterilization with the MWS did not. These results suggest that the MWS allows reliable sterilization of thermally labile drug preparations without quality deterioration. When decompositions of the active ingredient following sterilization were compared, no differences were observed in decompositions induced by the two methods of sterilization, suggesting that the effects of microwave dielectric heating on chemical bonds are similar to the effects of conventional moist heat sterilization.

The heating characteristics, heating parameters, and sterilizing effect of a new type of sterilizer (microwave sterilizer) for the head space of ampules were investigated. A thermographic analysis of the temperature of the head space of the ampules revealed that this system can heat both the solution and the head space to the same level of accuracy, and that the neck of the ampules is a cold spot when they are heated with this device. The two hot-air heaters (X₁ and X₂) were used for heating the head space of the ampules, and the microwave output (X₃) was used for heating the solution within them. Multiple regression analysis was conducted to examine the relationship between the temperature of the cold spot of the head space (Y) and these three parameters (X₁, X₂, and X₃), using ampules containing physiological saline. This analysis yielded the following relationship: Y=0.357X₁-0.023X₂+0.026X₃+4.164 (R=0.998). The following biological indicators were put into the cold spot of the ampule head to evaluate the sterilizing effectiveness of this device: spores of Aspergillus niger (for the low temperature range from 60 to 100°C), spores of Bacillus subtilis (for the medium temperature range from 101 to 120°C), and spores of Bacillus stearothermophilus (for the high temperature range from 121 to 140°C). Challenge tests for these three temperature ranges indicated that this microwave sterilizing system can adequately sterilize the head space of ampules in all temperature ranges.

To evaluate the effects of amorphous alloy system (Ta-Fe-Ni-Cr: composition, 36:44:4:12 (%)) coating on tableting, we have investigated tablet compression by using a single-punch tableting machine whose upper and lower punch surfaces are coated with amorphous alloys (amorphous alloy-coated punch). The effects of amorphous alloy coating on the compression characteristics of pharmaceutical excipients (mixtures of lactose and crystalline cellulose with various amounts of magnesium stearate) in the presence or absence of drugs were compared with the effects observed when conventional hard chromium (Cr) plating (Cr-plated punch) was used. With the Cr-plated punch, the effect of magnesium stearate on the prevention of powder adhesion to the punch tip surface was minimal. On the other hand, powder adhesion did not occur even after 3,000 tablets were produced (running time of machine approximately 3.3 h) by using the amorphous alloy-coated punch. A marked improvement in the prevention of sticking was achieved even with the addition of only 0.1% magnesium stearate when the amorphous alloy-coated punch was used. A similar advantage in the prevention of powder adhesion was obtained by using an amorphous alloy-coated punch in a lactose and crystalline cellulose mixture containing a drug such as aspirin. The low values of surface roughness parameters and the scraper pressure, which is the shear stress between the tablet and the lower punch surface, were observed in the use of the amorphous alloy-coated punch. It seems that a high value of the contact angle of water to the amorphous alloy surface leads to high repellent characteristics and to an easy detachment of tablets from the punch tip surface.

The penetration of four drugs through a living skin equivalent (LSE) was compared with that via Wistar rat and human cadaver skins. Comparatively rapid penetration of 5-fluorouracil, indomethacin and dexamethasone through LSE was observed compared with that through rat and human skins, with flux 15-54 times larger than that of human skin and with a much shorter lag time. Penetration through LSE was enhanced by 2.5-4 times in the presence of d-limonene as compared with that without the enhancer. Scanning electron microscopic observations showed that the stratum corneum (SC) of LSE has many cracks and cell junctions were not fully closed, probably due to the lack of organized extracellular lipids, whereas rat skin had closed intercellular spaces and human skin was tightly closed. Thus, the LSE had an incomplete barrier function which was not fully equivalent to that of human SC. Our results attested that since permeability through LSE was much larger than that via Wistar rat and human skins, LSE was not a good model for evaluating skin permeation. The permeability coefficient (Kp) values predicted from physicochemical properties hardly agreed with experimental Kp for human skin.

We studied the validation for drug content of a new insulin cartridge (Humacart 3/7, 3.0 ml cartridge^®). The concentrations of total insulin, Zn, m-cresol, and phenol in the Humacart 3/7, 3.0 ml cartridge^® were consistent with the levels described in the interview form. To study the relationship between the mixing (0, 5, and 10 times) and the uniformity of the insulin suspension, a Humacart 3/7, 3.0 ml cartridge^® was set into the insulin delivery device specifically designed for this cartridge (Autopen^®). The total insulin concentrations of this preparation through Autopen^® varied from 30 to 150 U/ml without mixing, so mixing more than 10 times was necessary to make the suspension uniform. The total insulin concentrations through Autopen^® decreased with increased standing times after thorough mixing; thus the Humacart 3/7, 3.0 ml cartridge^® must be injected as soon as possible after mixing. The dimeric-hexameric insulin concentration in the Humacart 3/7, 3.0 ml cartridge^® was 10 times higher than the monomeric insulin concentration. Furthermore, the insulin concentration through Autopen^® with a 31-gauge needle was the same as the insulin concentration using a 30-gauge needle. These results indicate that the characteristics of a Humacart 3/7, 3.0 ml cartridge^® are equivalent to that of a Humacart 3/7, 1.5 ml cartridge^®.