Improvement in the water solubility of drugs with a solid dispersion system by spray drying and hot-melt extrusion with using the amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and d-mannitol.

The aim of this study was to prepare and characterize solid dispersion particles with a novel amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, as a water-soluble carrier. Solid dispersion particles were prepared by hot-melt extrusion and spray drying. Indomethacin (IMC) was used as a model comprising drugs with low solubility in water and d-mannitol (MAN) was used as an excipient. The physicochemical properties of prepared particles were characterized by scanning electron microscopy, thermal analysis, powder X-ray diffraction (PXRD) analysis, FTIR spectra analysis, and drug release studies. Stability studies were also conducted under stress conditions at 40°C, 75% relative humidity. We found that dissolution behavior of the original drug crystal could be improved by solid dispersion with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The PXRD pattern and thermal analysis indicated that the solid dispersion prepared with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC was in an amorphous state. FTIR spectra analysis indicated that the interaction manner between the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC may differ with the preparation method and formulation of solid dispersions. Stability studies proved that the amorphous state of IMC in solid dispersion particles was preserved under stress conditions for more than two weeks.

Imaging of (13)C-labeled glucose and sorbitol in bovine lens by (1)H-detected (13)C nuclear magnetic resonance spectroscopy.

Bovine lenses were incubated in a solution containing [1-(13)C]glucose (50 mM) for 1, 2 and 4 days. Spectroscopic images of [1-(13)C]glucose and [1-(13)C]sorbitol were constructed using (1)H-detected gradient-enhanced heteronuclear multiple-quantum coherence (GE-HMQC) in a 2.0-tesla magnetic field. Accumulations of [1-(13)C]glucose and [1-(13)C]sorbitol were mainly observed at the periphery of the lens. Their distributions corresponded to the cortex. (1)H-detected (13)C nuclear magnetic resonance (NMR) spectroscopic imaging by GE-HMQC successfully demonstrated the distribution of [1-(13)C]glucose and [1-(13)C]sorbitol at the periphery of bovine lenses.

[Localization of glucose and sorbitol in incubated bovine lenses using chemical shift imaging].

PURPOSE: To use chemical shift imaging (CSI) to measure the metabolic changes in glucose metabolites in bovine lenses incubated in tissue culture medium 199(TCM 199) with a high concentration of glucose and to evaluate the viability of this method. METHODS: We detected an accumulation of 13C-labeled glucose and sorbitol in the bovine lenses incubated in TCM 199 containing 50 mM glucose-1-13C for 1, 2, 4, or 6 days using a 2 T CSI Omega system. 1H-13C gradient-selected heteronuclear multiple-quantum coherence (GH-HMQC) in nuclear magnetic resonance (NMR), an indirect method of detecting nuclei in low sensitivity by 1H NMR, was used to observe 13C-enriched metabolites in the bovine lens in vivo. RESULTS: We found an accumulation of 13C-labeled glucose and sorbitol using the 2 T CSI Omega system. The level of glucose increased rapidly in the posterior segment of the lens as well as the anterior segment at one day after the beginning of incubation. Then it diminished gradually, and could no longer be detected on the 6th day after the start of incubation possibly because of the breakdown of the cell membrane. The levels of sorbitol increased in the anterior area and the equator of the lens one day after the beginning of incubation, and remained unchanged for 6 days. CONCLUSION: We encountered many problems especially with the imaging resolution (consequently the time for measurement was prolonged), but this approach may be useful for non-invasive monitoring of 13C-labeled compounds. We believe this method will be especially useful for detecting various metabolites in vivo.

Sex-differences in adrenocortical responsiveness during development in rats.

It is known that the stress hyporesponsive period (SHRP), which seems to be related to an immature hypothalamo-pituitary-adrenal (HPA) regulatory system, occurs during the first 2 weeks after birth in rats. In the present study, we investigated the effects of sex-steroid hormones on adrenocortical responsiveness to adrenocorticotropic hormone (ACTH) in neonatal rats. The levels of cyclic adenosine 3',5'-monophosphate (cAMP), corticosterone, and adenylate cyclase activity increased with the dose of ACTH in adrenal cells of males and females in vitro. The ACTH responsiveness in adrenal cells increased with age (7-35 days of age), that is, the loss in responsiveness to ACTH just after birth began to recover in 14-35-day-old rats, but the responsiveness in 14-day-old rats was attenuated in males compared with females. Although castration markedly augmented the responsiveness in male rats, testosterone-replacement in the castrated male rats inhibited the enhancement. Furthermore, the responsiveness in 14-day-intact female rats was suppressed by treatment with testosterone. Expression levels of ACTH receptor mRNA in adrenals increased with age in the female rat, but not in the male. Castration enhanced the level of ACTH receptor mRNA to three-fold of that in intact male rats at 14 days of age, but replacement treatment with testosterone in castrated male rats lowered the elevated levels. Testicular androgens are thought to evoke a gender-specific response in neonates, and the temporal decrease of adrenal ACTH-responsiveness might be due to the topically immature adrenal system as well as the central nervous system in mammals.