Yorinobu Yonezawa’s research while affiliated with Meijo University and other places

The object of this study was to prepare high drug content core particles that are suitable for the coating process. Ethenzamide (ETZ) of fine grade (mean median diameter 7.3 μm) was used as a model drug, and core particles before layering (core particles-N) were prepared by using an agitating fluidized bed granulator. To obtain core particles with a smooth surface, layering was carried out by spraying the core particles-N with a suspension of ultrafine grade (mean median diameter 2.8 μm) ETZ in the binder (hydroxypropylcellulose) solution. The size distribution, tensile strength, and bulk density of the core particles-N and core particles after layering (core particles-L) were measured, and surface shape of each particle was observed. To further evaluate the smoothness of the obtained core particles-N and core particles-L, coating was performed by using hydroxypropylmethylcellulose (HPMC)-base Opadry® and ethylcellulose (EC)-base Aquacoat® and dissolution test was carried out. The dissolution of ETZ from the coated core particles-L was less than from core particles-N even though the amount of the coating agent used was the same; this resulted from the core particles-L being coated more evenly because of their smoother surfaces. Thus a method to obtain high drug content core particles that can be coated with less coating agent was established.

Recently tablets that can rapidly disintegrate in the oral cavity have attracted attention as a novel dosage form that can be taken easily and safely even by infants and elderly people. In this research, rapidly disintegrating tablets containing a model drug with relatively low solubility were prepared by the wet compression method. Then, the optimal formulation for tablets having a tensile strength greater than 5 kg/cm² and disintegration time shorter than 15s was examined, and the mechanisms involved in the disintegration of these tablets were clarified. Using a binary system composed of highly soluble trehalose (Tre) and low solubility lactose (Lac) as excipients, optimal formulations for rapidly disintegrating tablets were investigated by changing Tre/Lac mixing ratios. It became clear that the incorporation of 10-20% Tre made tablets rigid without causing a significant delay in disintegration time, and the tablets had a high water penetration rate because of the large pore size. When Tre content was more than 50%, however, a remarkable delay in disintegration time was observed because of the decrease in both water penetration rate and water uptake ability of the disintegrant.

Highly functional excipients including cellulose derivatives have been developed recently, and it has been reported that the use of these materials may make tablets show excellent workability as well as disintegration. Microcrystalline cellulose and powdered cellulose, in general, are representative excipients using cellulose as the raw material. In this study, powdered cellulose in particular was examined. The workability and disintegration of powdered cellulose were measured to examine its usefulness as an excipient. A standard formulation (prepared by mixing and granulating lactose and corn starch in a ratio of 7:3) was used as the control material. As a result, the addition of powdered cellulose made it possible to obtain functionally excellent tablets. In other words, tablets containing powdered cellulose showed higher hardness and faster disintegration in comparison with the standard formulation. Based on these results, it was found that powdered cellulose is a useful and functional excipient if added to the formulation in proper quantities.

A rapidly disintegrating tablet is known to be a form that can be swallowed easily because it is deformed by sputum in the human oral cavity. In this study, the tablet was prepared by the dry granulation and compression method using powdered cellulose (PC) as the main excipient. Powdered cellulose is expected to be good for not only compressibility but also disintegration due to its swelling property. It also has the advantage of lower cost compared with other excipients such as microcrystalline cellulose. Batches containing some model drugs, PC, lactose (Lac) and L-HPC as excipients were compacted to flakes by a Roller Compactor, then the flakes were crushed and sieved to granules. The granules were mixed with sucrose fatty acid esters (SE) as a lubricant and AEROSIL (AERO) as a fluidized ingredient then compressed to tablets by a rotary tableting machine. The tablets were evaluated mainly by tensile strength and disintegration time. Consequently, the rapidly disintegrating tablets containing PC were successfully prepared by the dry granulation and compression method. Fluidity of the granules and tensile strength of the tablets were improved by using 0.1% AERO. As the amounts of SE were increased, the tensile strength became lower and the disintegration time became longer, but from the pressure transmission ratio, the optimal amounts were 1-2%. PC had very good compressibility and disintegrated more rapidly after blending with L-HPC than using L-HPC alone. Although the evaluations on sensory test worsened as the amounts of PC increased, it was improved by using saccharides such as Lac. Optimal proportions of PC, Lac and L-HPC could be determined by Artificial Neural Network.

A rapidly disintegrating tablet is known to be a form that can be swallowed easily because it is disintegrated by saliva in the mouth. In this study, the roller compactor and the rotary tableting machine, production equipment generally used, were employed in the manufacture of granules and tablets. Ethenzamide, a water-insoluble drug, and ascorbic acid, a water-soluble drug, were used as model drugs, and tablets containing these drugs at a rate of 70% in the formulation were prepared. In the case of 70% ethenzamide tablets, the addition of a superior disintegrant was needed since the disintegration time of the tablet was long. As a result of examining five disintegrants, tablets prepared with Kollidon CL disintegrated the most rapidly. The amount of water adsorbed by Kollidon CL was large, and its maximum swelling speed was marked. Therefore, it was found that Kollidon CL adsorbed water the fastest compared with the other disintegrants. On the other hand, although the subjects described a gritty texture when ethenzamide tablets disintegrated in the mouth, the texture was improved on using a combination of Kollidon CL with its superior swelling power and fine-grade Kollidon CL-M with a superior distribution. In the case of 70% ascorbic acid tablets, the addition of a superior binder was needed since the tablet could not be formed well. As a result of examining three sorts of binders, water-soluble polymers, saccharides, and water-insoluble polymers, the disintegration time was very long in the case of water-soluble polymers, and tablets failed to form in the case of saccharides. Regarding water-insoluble polymers, the tensile strength and disintegration time were good, but subjects reported a powdery texture in the mouth. The texture was improved on using a combination of water-insoluble polymers and saccharides. The combination of PC-F and EMDEX reduced the required amount of PC-F causing the powdery texture to a 5% minimum.

Direct tableting is the easiest method of pharmaceutical compacting processes. The standard formulation, defined in the lactose/corn starch in a 7/3 mixture with 20% binder, was adopted in this process. Four direct compression lactose powders, DCL11, DCL14, Lactopress Spray-dried, Dilactose S, were examined as a lactose in this formulation. Acetaminophen (drug content 1%) was used as a model drug.The bulk density of lactose powders were higher than that of mixtures with other excipients. On the other hand, the tap density of mixtures was much higher than that of lactose. The four lactose mixtures showed the same level of flowability in spite of the differences in flowability of the bulk lactose powders. The shearing property of these powders was also measured in order to evaluate the flowability. The tablets from these mixtures had a low friability ( 90N) and a short disintegration time (<220s).

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. In previous papers, a combination of the square-root time law and cube-root law equations was confirmed to be a useful equation for qualitative treatment. It was also confirmed that the combination equation could analyze the release properties of layered granules as well as matrix granules. The drug release property from layered granules is different from that of matrix granules. A time lag occurs before release, and the entire release property of layered granules was analyzed using the combination of the square-root time law and cube-root law equations. It is considered that the analysis method is very useful and efficient for both matrix and layered granules. Comparing the granulation methods, it is easier to control the manufacturing process by tumbling granulation (method B) than by tumbling-fluidized bed granulation (method C). Ethylcellulose (EC) layered granulation by a fluidized bed granulator might be convenient for the preparation of controlled release dosage forms as compared with a tumbling granulator, because the layered granules prepared by the fluidized bed granulator can granulate and dry at the same time. The time required for drying by the fluidized bed granulator is shorter than that by the tumbling granulator, so the fluidized bed granulator is convenient for preparation of granules in handling and shorter processing time than the tumbling granulator. It was also suggested that the EC layered granules prepared by the fluidized bed granulator were suitable for a controlled release system as well as the EC matrix granules.

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. The dissolution test is a very important and useful method for understanding and predicting drug-release properties. It was readily confirmed in the previous paper that the release process could be assessed quantitatively by a combination of the square-root time law and cube-root law equations for ethylcellulose (EC) matrix granules of phenylpropanolamine hydrochloride (PPA). In this paper EC layered granules were used in addition to EC matrix. The relationship between release property and the concentration of PPA in plasma after administration using beagle dogs were examined. Then it was confirmed that the correlativity for EC layered granules and EC matrix were similar each other. Therefore, it was considered that the dissolution test is useful for prediction of changes in concentration of PPA in the blood with time. And it was suggested that EC layered granules were suitable as a controlled release system as well as EC matrix.

We investigated the effects of binder particle size on high shear and extrusion granulation using the wet granulation method by evaluating the properties of granules and tablets. Ethenzamide was used as a model drug at a concentration of 1% with lactose/corn starch in a 7/3 mixture, with 3.5% hydroxypropylcellulose and 0.5% magnesiuu stearate as the standard formulation, as recommended by the Standard Formulation Research Association. Hydroxypropylcellulose, as the binder, was classified into three particle size grades with the sieving method and used by the powder and solution addition method. In conclusion, although an effect of differences in the binder particle size on the particle size and its distribution in high shear granulation granules was observed, it was not an important parameter in the product properties. Accordingly, it was thought that standardization of the binder particle size was useful to control the granule particle size.

Crude drug powders are very useful for health and therapeutics, but these powders have various particle shapes and properties, leading to poor fluidity and strong adhesiveness and these properties make handling during processing of the powders and controlling the qualities of products difficult. The granulation of the crude drug seems to be an appropriate procedure to solve the problem. In our last study we examined pharmaceutical manufacture of crude drug powder using the dry compacting method, and we achieved our goal of tablet hardness of about 2.0 kg and disintegration time of less than 1,000 s. In this study, senna powder was chosen and we studied the surface-modifying method. We prepared tablets from surface modified senna powder, surface modified and dry granulated senna powder, and granules by unmodified and dry granulated senna powder and surface modifying agents added at the time of tableting. Their physical properties such as tablet hardness and disintegration time were evaluated. As a result, we achieved our goal of a more than 4.0 kg tablet hardness and less than 600 s disintegration time, when the tablet was made of granules of senna powder modified with 2% surface modification agents and dry granulated, and a disintegrant and more surface modification agents whose total content was 5% in the tablet, and tableting at 200 MPa.