Yasuhide Horiuchi

Inhibitory Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystal-growth of Nifedipine During Storage: Superior Dissolution and Oral Bioavailability Compared with Polyvinylpyrrolidone K-30

Abstract— To prevent the crystal‐growth of nifedipine during storage, 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐CyD) was employed as a hydrophilic drug carrier and compared with polyvinylpyrrolidone K‐30 (PVP). Amorphous nifedipine powders were prepared by spray‐drying with HP‐β‐CyD or PVP, and their crystal‐growing behaviour at accelerated storage conditions were examined by X‐ray diffraction analysis and microscopy. Although PVP initially retarded the crystallization of nifedipine, it failed to control the increase of crystal size after prolonged storage at 60°C., 75% r.h., resulting in a remarkable decrease in dissolution rate in water. In sharp contrast, a relatively fine and uniform size of nifedipine crystals was maintained in the HP‐β‐CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP‐β‐CyD systems in a dissolution medium containing 0·1% non‐ionic surfactant HCO‐60 were clearly reflected in the in‐vivo absorption of nifedipine following oral administration to dogs. These results suggest that HP‐β‐CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms.

Enhanced dissolution and oral bioavailability of α-tocopheryl esters by dimethyl-β-cyclodextrin complexation

Inclusion complexation of heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD) with α-tocopheryl acetate and α-tocopheryl nicotinate in aqueous solution was studied by the solubility method. The aqueous solubilities of the esters were about 105 times increased by DM-β-CyD complexation. The phase-solubility diagram of the tocopheryl ester-DM-β-CyD systems showed a typicalAp type, and the stability constants (K) of high-order complexes were estimated by analyzing the upward curvature of the diagrams. The solid complex of α-tocopheryl nicotinate with DM-β-CyD in a molar ratio of 1∶2 was prepared by the kneading method. The dissolution rate of the solid complex was much greater than that of the drug itself, and the rapidly dissolving form of α-tocopheryl nicotinate, as an example, showed a markedly increased bioavailability (about 70-fold) after oral administration to fasted dogs.

O-carboxymethyl-O-ethylcyclomalthoheptaose as a delayed-release-type drug carrier: improvement of the oral bioavailability of diltiazem in the dog

The utility of O-carboxymethyl-O-ethylcyclomaltoheptose (carboxymethyl-ethyl-beta-cyclodextrin, CME-beta CD) as a delayed-release-type drug carrier was investigated in vitro and in vivo, using diltiazem hydrochloride as a model drug. The aqueous solubility of CME-beta CD showed a marked dependency on pH, because of the ionization of the carboxyl group (pKa 3.75). The formation of an inclusion complex between diltiazem and CME-beta CD in aqueous solution and in the solid state was assessed by a solubility method and by X-ray diffractometry, respectively. The rate of release of the drug from the compressed tablet containing the complex was significantly retarded in solutions at low pH and increased with increase in pH, and this was reflected in the blood levels in the dog after the oral administration. The results suggested that the use of CME-beta CD could improve the oral bioavailability of diltiazem and release the drug preferentially in the intestinal fluid but only slightly in the gastric fluid.

In vitro and in vivo evaluation of delayed-release behavior of diltiazem from its O-carboxymethyl-O-ethyl-β-cyclodextrin complex

Abstract The objective of this study was to determine whether a correlation exists between in vitro release and oral bioavailability of diltiazem (DTZ) in the delayed-release preparations. O -Carboxymethyl- O -ethyl-β-cyclodextrin (CME-β-CyD) was used as a delayed-release carrier. In vitro release rates were measured by a pH-changeable dissolution testing apparatus controlled by personal computer. Taking into account the physiological pH of gastrointestinal fluids, various release patterns of DTZ were generated by changing pH of the dissolution medium. For in vivo testing animal model, the gastric pH of fasting beagle dogs was controlled to obtain high acidity level (less than pH 2.0) and low acidity level (higher than pH 6.0) by the treatments of tetragastrin and omeprazole, respectively. The in vitro release rate of DTZ from tablets of its CME-β-CyD complex was accelerated with increasing pH of the dissolution medium. The in vivo absorption of DTZ after oral administration of the CME-β-CyD complex was retarded in the high gastric acidity dogs, while the fast absorption of DTZ was observed in the low gastric acidity dogs. In the CME-β-CyD complex, a good in vitro-in vivo correlation was observed for both gastric pH controlled dogs. The present results suggest that CME-β-CyD can serve as delayed-release carrier for water-soluble drugs.

Release control of theophylline by β-cyclodextrin derivatives: hybridizing effect of hydrophilic, hydrophobic and ionizable β-cyclodextrin complexes

Abstract The release control of theophylline from tablets was conducted by hybridizing its hydrophilic, hydrophobic and ionizable cyclodextrin (CyD) complexes, i.e. those with the parent β-CyD, heptakis(2,6-di-O-ethyl)-β-CyD (DE-β-CyD) and carboxymethyl-ethyl-β-CyD (CME-β-CyD), respectively. The rate of release of theophylline from tablets was accelerated by β-CyD, while that from the DE-β-CyD complex was decelerated, both showing pH-independent release. On the other hand, the CME-β-CyD complex showed pH-dependent release, i.e. the rate increased with increase in pH of the medium. The drug release from tablets could be arbitrarily modified by mixing two complexes: a mixture of the DE-β-CyD and CME-β-CyD complexes in a 1:3 molar ratio released the drug above 90% within ca. 8 h in an apparent zero-order fashion. Double-layer tablets consisting of the parent β-CyD complex as a fast-releasing fraction and the mixture of the DE-β-CyD and CME-β-CyD complexes as a slow-releasing fraction released the drug rapidly at the initial stage (within ca. 30 min), followed by slow release. Among various combinations, a double-layer tablet consisting of β-CyD-(DE-β-CyD: CME-β-CyD, 1 : 3) = 1 : 3 was the most suitable to offer a more balanced bioavailability. This formulation gave an initial rapid increase in plasma level of theophylline, followed by a longer maintenance of the relatively constant level, after oral administration to dogs. The mean residence time (MRT) in the systemic circulation increased about 1.5 times for the double-layer tablet compared with the plain tablet of drug alone. The Nimmerfall absolute retarding parameter ( R i ,abs = 83.1%) for the double-layer tablet was higher than the lower limit (75%) for discrimination of a retarding effect. In addition, no appreciable decrease in bioavailability was observed for the double-layer tablet. The results suggest that the release of theophylline from tablets can be arbitrarily modified by hybridizing hydrophilic, hydrophobic and ionizable CyD derivatives in appropriate ratios.

Preparation of heptakis(2,6-di-O-ethyl)-β-cyclodextrin and its nuclear magnetic resonance spectroscopic characterization

Heptakis(2,6-di-O-ethyl)-β-cyclodextrin (DE-β-CyD) was prepared and its 1H and 13C nuclear magnetic resonance (NMR) signals in DMSO-d6 were unequivocally assigned by two-dimensional COSY and ROESY. The results on 1H coupling constants indicated that all ethylated glucose units are in a 4C1 chair conformation. The average spin-lattice relaxation times (T1) of ring carbons of DE-β-CyD were only slightly shorter, and their standard deviations from the mean Tl value were larger, than those of β-cyclodextrin (β-CyD) and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE-β-CyD in DMSO-d6 suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM-β-CyDs is much stronger than that of β-CyD, suggesting the stable macrocyclic ring structure of DE-β-CyD.