Design of novel tacrolimus formulations with chemically synthesized oils for oral lymphatic delivery.

High consumption of oil formulations has been reported to reduce the blood exposure of drugs like tacrolimus. Consumption of oil formulations has also been shown to inhibit T-cell production of interleukin-2 (IL-2) compared to solid dispersion formulations (SDFs). However, a large amount of oil causes gastrointestinal side effects such as diarrhea and low compliance. Here, we investigated the feasibility of reducing the amount of oil and substitution of chemically synthetized oils for natural oils in these formulations. Reducing the amount of sunflower oil increased blood tacrolimus exposure despite sufficient suppression of IL-2 production. While medium-chain triglyceride (MCT) increased tacrolimus blood exposure, addition of 10% glyceryl monostearate (GMS) to MCT significantly decreased drug blood exposure without requiring a large amount of oil (p < .05). Effects of the contents of GMS in the MCT/GMS formulations, and fatty acid composition in GMS on drug blood exposure were also investigated. The results indicated that both the amount and type of oil were important for maintaining a good balance between a reduction in blood exposure and sufficient IL-2 suppression. The ratio of drug concentration in lymphocytes to that in whole blood after dosing with an oil formulation was significantly higher than that after administration of the SDF (p < .01). These results indicate the feasibility of developing oral oil tacrolimus formulations to reduce systemic side effects and maintain high efficacy for practical use in patients.

Crystal Structures of Flavone C-Glycosides from Oolong Tea Leaves: Chafuroside A Dihydrate and Chafuroside B Monohydrate.

Chafuroside A and chafuroside B are flavone C-glycosides isolated from oolong tea leaves. They have a number of beneficial pharmacological activities related to antiinflammation at various concentrations. However, no crystallographic study of chafurosides has yet been reported. In the present study, the crystal structures of chafuroside A and chafuroside B were investigated using single-crystal X-ray diffraction. The asymmetric unit of the chafuroside A crystal consists of one chafuroside A and two water molecules, and that of chafuroside B contains one chafuroside B and one water molecule. The flavone moiety of chafuroside A is curved, i.e., the angle between the best-fit planes of the chromene and phenyl rings is 18.9°, whereas the chafuroside B flavone moiety is relatively flat. A comparison of the curvatures of the flavone moieties of various C-glycosides showed that the curvature of chafuroside A is significantly larger than those of the others. This structural feature might contribute to the differences between the strengths of the pharmacological activities of chafurosides A and B.

Oral tacrolimus oil formulations for enhanced lymphatic delivery and efficient inhibition of T-cell's interleukin-2 production.

Oral oil formulations have been reported to deliver drugs into the lymph. Lymphatic delivery of immunomodulatory drugs can more efficiently expose the drugs to T-cells in lymph, consequently induce higher efficacy and lower side effects. In this study, effects of tacrolimus oral oil formulations on drug blood exposure, and on inhibition of T-cell's interleukin-2 (IL-2) production were investigated in rats. Oil formulations (sunflower oil, cacao butter, medium chain triglyceride, and palm oil) dissolving tacrolimus showed lower drug blood concentration than a solid dispersion formulation (SDF). The sunflower oil, and cacao butter formulations suppressed drug blood exposure to 50% of the SDF, and inhibited T-cell's IL-2 production similar to the SDF. In vitro digestion tests indicated that slower digestion of the oils might reduce amount and rate of tacrolimus blood absorption. The cacao butter formulations showed 3.0 times more rapid tacrolimus absorption to lymphatic fluid than the SDF. Ratio of the rate constants of absorption into lymph to that into blood was higher in oil formulations (15 times in cacao butter, 15 times sunflower oil, and 3.5 times palm oil) than in the SDF. These results indicated that the oral oil formulations might be suitable for reduced tacrolimus blood concentration for low systemic side effects, and keep high lymph concentration for high efficacy in organ transplantation patients.

Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation.

To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt.

Time-release compression-coated core tablet containing nifedipine for chronopharmacotherapy.

Compression-coated time-release tablets (CC tablets) containing nifedipine, dihydropyridine Ca channel blocker, in the core tablet were prepared by dry coating with different polyethylene oxide-polyethylene glycol mixtures. Each formulation showed a clear lag period before nifedipine release initiation, followed by sustained drug release lasting up to 24 h. The lag time of nifedipine release increased as the amount of polyethylene oxide in the outer layer increased. To investigate the applicability of such CC-tablets for chronopharmacotherapy, the pharmacokinetics of CC-1 and CC-2 tablets, with different in vitro lag times before drug release, were compared with the pharmacokinetics of a sustained-release (SR) tablet in dogs. The times of first nifedipine appearance (TFA) in plasma were 0.7 +/- 0.3 h for SR, 2.5 +/- 1.2 h for CC-1, and 5.3 +/- 1.0 h for CC-2. These data show a significant difference in in vivo lag time (P < 0.01) among the three formulations that correlates with the in vitro lag times. Thus, the in vivo lag time could be predicted from the in vitro lag time. Additionally, higher plasma nifedipine concentrations were observed at 8 h after administration of the CC-2 than that observed for the SR-tablet. These results indicate that a CC-tablet with a lag time before drug release is a potentially useful formulation for chronopharmacotherapy that can control the time and duration of plasma drug concentration better than existing SR technologies.

Characteristics of the gastric pH profiles of unfed and fed cynomolgus monkeys as pharmaceutical product development subjects.

Gastric pH is an important factor which significantly affects the dissolution of drugs, and therefore their bioavailability. In this study, the gastric pHs were measured directly with a miniature pH electrode inserted through the nostril into the body of the stomach of cynomolgus monkeys. Results from three separate sets of measurements using the same male monkeys indicated that the median gastric pH profiles of unfed monkeys were low, fluctuating between pH 1 and pH 3. However, the median gastric pHs in fed monkeys given about 108 g of a biscuit-type solid food, which are commonly provided, shifted toward a more neutral range between pH 5 and pH 7, and remained in this range for about 9 h. This result contrasted with reported results for humans after eating a standard meal, which showed a neutral range between pH 5 and pH 7 for a brief period. Consequently, these results indicate that although the gastric pH of unfed cynomolgus monkeys is similar to that of fasting humans, there is a great difference in the gastric pH profiles between humans and monkeys after eating, which suggests that further studies are needed to establish optimal feeding conditions for bioavailability studies in monkeys.