Norio Ohnishi

Dissolution mechanism and rate of solid dispersion particles of nilvadipine with hydroxypropylmethylcellulose

The dissolution experiments on the solid dispersion particles of nilvadipine with hydroxypropylmethylcellulose were performed in stagnant and stirring water. The particles in stagnant water instantaneously gelatinized to the water content of 84.6% w/w after dipping and those dissolved very slowly through the penetration of water. However the particles in stirring water dissolved quickly at different rates depending on stirring rate, and both components in the solid dispersion dissolved at the same rate. Such experimental results seemed to suggest the important roles of erosion for gelatinized particles and mass transfer rate at the diffusion layer. The high concentrations of nilvadipine obtained after its nucleation and growth depend on complex formation. A new dissolution mechanism and rate equation were proposed on the basis of such experimental results and the availability of the rate equation was confirmed experimentally.

Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-β-CD

AbstractPurpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) for poorly water soluble drugs using a sulfobutyl ether-β-cyclodextrin, (SBE)7m-β-CD or Captisol™, which acted as both a solubilizer and as an osmotic agent. Methods. Prednisolone (PDL) was chosen as a model drug for this study. The release of PDL from osmotic pump devices and tablets was studied. In vivo absorption of PDL from OPT was evaluated in male beagle dogs. Results. PDL release from the osmotic pump tablet with (SBE)7m-β-CD was complete. Another cyclodextrin, hydroxypropyl-β-cyclodextrin (HP-β-CD), and a sugar mixture of lactose and fructose resulted in incomplete release. Although PDL release from the OPT with (SBE)7m-β-CD and the sugar formulation displayed mainly zero-order release characteristics, the tablet utilizing HP-β-CD showed apparent first-order release characteristics. An in vivo absorption study in dogs correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. The present results confirm that (SBE)7m-β-CD can serve as both the solubilizer and the osmotic agent for OPT of PDL, and modify the input rate of PDL without compromising oral bioavailability.

Factors affecting membrane-controlled drug release for an osmotic pump tablet (OPT) utilizing (SBE)(7m)-β-CD as both a solubilizer and osmotic agent

PURPOSE The purpose of this study was to define membrane controlling factors responsible for drug release from a controlled-porosity osmotic pump tablet (OPT) that utilizes a sulfobutyl ether-beta-cyclodextrin, (SBE)(7m)-beta-CD, as both a solubilizing and osmotic agent. METHOD The OPT was spray coated with cellulose acetate solutions varying the amount and size of micronized lactose, the amount of triethyl citrate (TEC) and the composition ratio of dichlormethane to ethanol. Chlorpromazine (CLP) was used as a model drug. The release of CLP from the OPTs was studied using the Japanese Pharmacopoeia dissolution method. The membrane surface area of the OPTs were measured with multi-point analysis by the gas absorption method. RESULTS The release rate of CLP from OPTs containing (SBE)(7m)-beta-CD increased with increasing amounts of micronized lactose and decreasing amounts of TEC and lactose particle size in the membrane. Also, the CLP release rates from the spray-coated OPTs using mixtures of varying ratios of dichlormethane to ethanol were almost identical. The membrane surface area of the OPTs following release of membrane components had a linear relationship to CLP release rates from the OPTs. CONCLUSION The present results confirmed that the membrane controlling factors responsible for the drug release were the amount and size of micronized lactose and the amount of TEC in the membrane.

Design and evaluation of an osmotic pump tablet (OPT) for chlorpromazine using (SBE)7m-β-CD

AbstractPurpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) which exhibits pH-independent release profiles for a basic drug using a sulfobutyl ether-β-cyclodextrin, (SBE)7m-β-CD, which acts as both a solubilizer and as an osmotic agent. Methods. Chlorpromazine free base (CLP) was chosen as a model drug for this study. The release of CLP from osmotic pump tablets was studied in vitro. In vivo absorption of CLP from the OPT was evaluated in male beagle dogs. Results. The CLP release profile from an OPT prepared from a core tablet composed of a 1:10 molar ratio of CLP to (SBE)7m-β-CD was pH-independent, and was controlled by modulating the membrane thickness of the OPT. Another cyclodextrin, hydroxypropyl-β-cyclodextrin (HP-β-CD), and a sugar mixture of lactose and fructose resulted in pH-dependent release at the same molar ratio. An in vivo absorption study in dogs with an OPT containing (SBE)7m-β-CD correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. In addition to serving as a solubilizer and osmotic agent, (SBE)7m-β-CD can also serve as the controlling agent for pH independent release of CLP from OPTs. This system successfully modified the in vivo input rate of CLP without compromising oral bioavailability.

In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs

Abstract In vivo oral absorption study of time-controlled explosion system (TES), using gastrointestinal (GI) physiology regulated dogs, was carried out to predict the feasibility in humans. TES is characterized by rapid drug release with a pre-programmed lag time, which can provide a programmed release system synchronized with circadian rhythm (e.g. asthma attack in the morning), a colon targeting system and a sustained release system with different lag times. In this study, TES containing diclofenac sodium with different lag times of 3 and 6 h (TES-3h and TES-6h) were prepared. TES-3h exhibited good performance in all six GI physiology regulated dogs without remarkable reduction of AUC. In the case of TES-6h, drug absorption was observed ∼6 h after administration in four of six dogs, but plasma level was low. Further, the location of the dosage forms after oral administration was estimated from the gastric emptying time (GET) and the small intestinal transit time (SITT) using a double marker method. As a result, in vivo performance of TES correlated with the intestinal location. It was concluded that TES-3h would perform well in humans and that the environmental water content in the GI tract affected the in vivo dissolution profile of TES when the drug release was initiated after entering the colon.

Quantitative evaluation of tablet sticking by surface roughness measurement

Abstract Effect of lubricant and manufacturing conditions on sticking were investigated by measuring quantitatively surface roughness ( R rms ) of the tablet in two formulations. The R rms values increased in proportion to the number of tablets produced ( N ). At a low concentration of lubricant, there was a good linear relationship between logarithm of R rms / N and magnesium stearate percent. The slopes of the straight line, k s, were about 60 and 3 for the respective two formulations. The k value would become a parameter for the effectiveness of lubricant added against sticking. Because the R rms / N deviated widely in Formulation I with high concentrations of lubricant, it is suggested that there are critical percents of magnesium stearate for sticking.