Ryuzo ISHINO’s research while affiliated with Meijo University and other places

In order to elucidate the influence of the particle size of water-soluble ingredients in a wax matrix and the solubility of drugs on the drug dissolution rate from a dosage form, reservoir devices were prepared from a wax matrix layer consisting of hydrogenated caster oil (HCO) and lactose, a drug reservoir and a water non-permeable layer of HCO, and dissolution tests were then carried out. Drug permeability and water penetrability of the wax matrix layer were affected by the particle size of lactose incorporated into the wax matrix layer. Drug permeability and water penetrability could be decreased by using smaller lactose particles. Tortuosity in the wax matrix layer after the dissolution of lactose could be increased inversely proportional to the particle size. Permeability of the wax matrix layer differed depending on the kinds of drugs forming the drug reservoir, which was attributed to differences in the solubility and viscosity of the drug saturated solution formed in the drug reservoir.

In order to elucidate individually the influence of drug solubility and the matrix structure on the drug release rate from a wax matrix tablet, the intrinsic dissolution rates of drugs and the release rates of several matrix tablets consisting of various proportions of drug and hydrogenated castor oil were measured for five drugs differing in solubility. From the theoretical modification of Higuchi's equation, the boundary retreat rate of the matrix tablet was expressed with two parameters : one parameter was a constant consisting of three physical quantities (diffusivity, solubility and density), and the other was the tortuosity representing the matrix structure. As the constant term in the modified Higuchi's equation was related to the intrinsic dissolution rate constant for every drig, it was found to be an index of the drug solubility in the matrix system. From this study, therefore, it is clear that boundary retreat rate constant, namely, the drug release rate constant form the matrix tablet, was in proportion to the solubility and in inverse proportion to the square root of tortuosity. The relation between the tortuosity and the void space (porosity) was well expressed by the proposed equation derived on the basis of the free volume theory (H. Yasuda and C. E. Lamaze, J. Polymer Sic., Part A-2, 9, 1537 (1971)). It was found that the tortuosity in the matrix tablets varied with the drug species even though the porosity was the same, and also the dependency of tortuosity on porosity varied. Further, it was determined that the dependency of tortuosity on porosity could be controlled by the addition of other materials.

In order to examine the function of a wax matrix system as a barrier for the controlled release of oral dosage forms, reservoir devices were prepared and dissolution tests were conducted. The permeability coefficients of isoniazid through wax matrix layers consisting of various proportions of α-lactose monohydrate and hydrogenated castor oil were determined coincidently with the penetration rate constants of water into the wax matrix layers. To elucidate the barrier function relating to control of the drug release rate, dry-coated tablets in which the outer shell was formed with the wax matrix system were prepared. The dissolution behavior of isoniazid from the dry-coated tablets coincided with the simulation result calculated using the obtained permeability coefficient and penetration rate constant.

An orally applicable pulsatile drug delivery system in dry-coated tablet form was prepared using diltiazem hydrochloride as the model drug, and a polyvinyl chloride-hydrogenated castor oil-polyethyleneglycol mixture as the outer shell of the tablet. In vitro drug release from the prepared tablet exhibited a typical pulsatile pattern with a 7 h lag phase (non-drug release period). This dosage form was orally administered to three beagle dogs under non-fasting and fasting conditions, and the plasma concentration level of diltiazem was determined according to time after administration. The result of the in vivo study in non-fasting dogs suggested that the drug could be released in the gastrointestinal tract as in the in vitro test. However, under the fasting condition, a large difference in the plasma concentration profile was found, suggesting that the disintegration time of the tablet tended to be influenced by the feeding condition of subject.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.

To examine the influence of the internal structure of a wax matrix tablet on in vitro drug release, the release rates of several tablets consisting of various proportions of drug and wax were compared with the water penetration rates from the compressed and lateral surfaces of the tablets. The penetration rates from the lateral surface were found to be much faster than those from the compressed surface in all cases. A theoretical equation involving a two-dissolving-direction was derived on the basis of the boundary retreating concept. The retreating rate constants deduced from the dissolution results were well coincident with the values directly determined by the needle penetration method, suggesting good applicability of the proposed equation. The results suggest that the tortuosity of the water channels created in a tablet during dissolution is generally smaller in the horizontal direction than that in the vertical direction. This would be caused by the drug particles or granules being elongated in the horizontal direction by compression.

In order to characterize the force-dependence of the consolidation behavior and drug release properties of wax matrix tablets, granules consisting of isoniazid and hydrogenated castor oil (80 : 20) were compressed at various compression force, then the compacts obtained were tested for various properties including tablet density, crushing force and dissolution rate. The packing fraction increased with increasing compression force and reached a constant level (0.973) at a force above 1273 kg/cm2. The tensile strength of the compacts increased with the increase of the packing fraction, but it continued to increase slightly even after the packing fraction held at an almost constant value. Although the matrix structure became tighter with increasing compression force, the drug release rate from the tablet noticeably increased. Theoretical analysis of this seemingly extraordinary phenomenon provides a reasonable explanation in which the void space left after compression could not work as an effective water channel during dissolution due to the poor wettability of the matrix material. Also, the force-dependence of the disorder in the internal structure of the tablets was examined on the basis of the two-direction dissolution rate analysis. As a result, it was found that the internal disorder increased with increasing compression force, and when the compression force exceeded 1273 kg/cm2, the disorder was considerably extended.

To examine the influence of tabletting speed on compactibility and compressibility under high speed compression, two direct compressible powders, alpha-lactose monohydrate and microcrystalline cellulose of different particle size ranges were compressed using an instrumented rotary press with varying tabletting speed and compression force. The maximum applied force and total time during compression (contact time) were determined from a time-force profile, and the relation between these parameters and properties of compacts was examined. For all lactose tablets, the porosity and tensile strength of compacts were less affected by compression rate though they depended on the applied force. However, the properties of microcrystalline cellulose tablets were varied depending on the tabletting speed in addition to the applied force. In an attempt to quantitatively evaluate the effect of compression rate on the compactibility, an empirical equation was derived from the numerical analysis of the experimental data. The compactibility parameters deduced from the equation well elucidated the effect of tabletting speed on the properties of microcrystalline cellulose tablets and lactose tablets made of various particle size powders.