9α-氟-6α-甲基氢化泼尼松的合成研究

以6α-甲基氢化泼尼松为起始原料,经酯化、脱水、溴化、环合、二次酯化、加成6步反应合成了目标化合物9α-氟-6α-甲基氢化泼尼松,总收率13%。该合成路线反应步骤较少,反应条件温和,操作简单,对工业生产具有较好的参考价值。     

Bioconversion of hydrocortisone to prednisolone by immobilized bacterial cells in a two-liquid-phase system

Bioconversion of hydrocortisone to prednisolone by free, immobilized and reused immobilized cells of three bacterial strains (Bacillus sphaericus ATCC 13805, Bacillus sphaericus SRP III and Arthrobacter simplex 6946) in an aqueous and a two-liquid-phase system using different organic solvents was investigated. The experiments were carried out in a 125 cm³ shake flask at 27±2°C, 220 rpm for 96 h. The contents of prednisolone and hydrocortisone in samples taken at 0, 3, 6, 24, 48, 72, 96 and 144 h were determined by HPLC analysis. The immobilized bacterial cells showed higher prednisolone yield than the free form in an aqueous system. In the two-phase systems, the butyl acetate to aqueous media ratio of 1: 30 for all three bacterial strains in immobilized forms gave the highest prednisolone yields, at an incubation time of 144 h, of 87·6, 70·6 and 88·3% respectively. For an n-decane to aqueous ratio of 1: 6, moderate prednisolone yields of 81·8, 47·9 and 71·4% were obtained with shorter incubation times of 72, 96 and 6 h respectively. For cyclohexane and other alcohols, the organisms produced low yields of prednisolone (0–30%). Single reuse of all three immobilized bacterial cells gave a 3–20% lower yield of prednisolone than the non-reused cells. The increase in hydrocortisone concentration decreased the prednisolone production whereas increasing the n-decane to aqueous ratio from 1: 6 to 1: 3 caused no significant change in the productivity. © 1998 Society of Chemical Industry     

Investigation of the presence of prednisolone in bovine urine

Over the past two years low levels of prednisolone have been reported in bovine urine by a number of laboratories in European Union member states. Concentrations vary, but are reported to be below approximately 3 µg l^–1. Forty per cent of bovine urine samples from the Dutch national control plan had concentrations of prednisolone between 0.11 and 2.04 µg l^–1. In this study the mechanism of formation of prednisolone was investigated. In vitro conversion of cortisol by bacteria from faeces and soil, bovine liver enzymes and stability at elevated temperatures were studied. In vitro bovine liver S9 incubation experiments showed a significant 20% decrease of cortisol within 6 h, and formation of prednisolone was observed from 0.2 g l^–1 at t = 0 to 0.5 g l^–1 at t = 6. Under the influence of faeces, the stability of cortisol in urine is reduced and cortisol breaks down within 50 h. Prednisolone is formed up to 4 µg l^–1 at 70°C after 15 h. However, this decreases again to zero after 50 h. With soil bacteria, a slower decrease of cortisol was observed, but slightly higher overall formation of prednisolone, up to 7 µg l^–1 at 20°C. As opposed to incurred urine, in fortified urine incubated with faeces or soil bacteria no prednisolone was detected. This difference may be explained by the presence of natural corticosteroids in the incurred sample. With UPLC-QToF-MS experiments, in urine and water samples incubated with faeces, metabolites known from the literature could be (tentatively) identified as 20β-hydroxy-prednisolone, cortisol-21-sulfate, oxydianiline, tetrahydrocortisone-3-glucuronide and cortexolone, but for all compounds except 20β-hydroxy-prednisolone no standards were available for confirmation. Based on the results of this study and literature data, for regulatory purposes a threshold of 5 µg l^–1 for prednisolone in bovine urine is proposed. Findings of prednisolone in concentrations up to 5 µg l^–1 in bovine urine can, most likely, originate from other sources than illegal treatment with growth promoters.     

Eudragit S100 coated microsponges for Colon targeting of prednisolone

Context: Microsponge is a novel approach for targeting the drug to the colon for the management of colon ailments such as inflammatory bowel disease.

Objective: Prednisolone loaded microsponges (PLMs) were prepared and coated with Eudragit S 100 (ES) and evaluated for colon-specific drug delivery.

Materials and methods: PLMs were prepared using quasi emulsion solvent diffusion technique using ethyl cellulose, triethylcitrate (1% v/v, plasticizer) and polyvinyl alcohol (Mol. Wt. 72?kDa, emulsifying agent). The developed microsponges were compressed into tablets via direct compression technique using sodium carboxymethyl cellulose (Na CMC) and magnesium stearate as super-disintegrant and lubricant, respectively. The tablets were then coated with ES to provide protection against harsh gastric environment and manifest colon-specific drug release.

Results: PLMs were found to be nano-porous spherical microstructures with size around 35?µm and 86% drug encapsulation efficiency. Finally, they were compressed into tablets which were coated with Eudragit S 100 In vitro drug release from ES coated tablets was carried out at various simulated gastrointestinal fluids i.e. 1?hr in SGF (pH 1.2), 2 to 3?h in SIF (pH 4.6), 4–5?h in SIF (pH 6.8), and 6–24?h in SCF (pH 7.4) and the results showed the biphasic release pattern indicating prolonged release for about 24?h.

Discussion and conclusion: In vitro drug release studies revealed that drug starts releasing after 5?h by the time PLMs may enter into the proximal colon. Hence maximum amount of drug could be released in the colon that may result in reduction in dose and dose frequency as well as side effects of drug as observed with the conventional dosage form of prednisolone.     

HPLC-ESI-MS/MS assessment of the tetrahydro-metabolites of cortisol and cortisone in bovine urine: promising markers of dexamethasone and prednisolone treatment

The effects of long-term administration of low doses of dexamethasone (DX) and prednisolone (PL) on the metabolism of endogenous corticosteroids were investigated in veal calves. In addition to cortisol (F) and cortisone (E), whose interconversion is regulated by 11β-hydroxysteroid dehydrogenases (11βHSDs), special attention was paid to tetrahydrocortisol (THF), allo-tetrahydrocortisol (aTHF), tetrahydrocortisone (THE) and allo-tetrahydrocortisone (aTHE), which are produced from F and E by catalytic activity of 5α and 5β-reductases. A specifically developed HPLC-ESI-MS/MS method achieved the complete chromatographic separation of two pairs of diastereoisomers (THF/aTHF and THE/aTHE), which, with appropriate mass fragmentation patterns, provided an unambiguous conformation. The method was linear (r² > 0.9905; 0.5–25 ng ml^?1), with LOQQ of 0.5 ng ml^?1. Recoveries were in range 75–114%, while matrix effects were minimal. The experimental study was carried out on three groups of male Friesian veal calves: group PL (n = 6, PL acetate 15 mg day^–1 p.o. for 31 days); group DX (n = 5, 5 mg of estradiol (E2) i.m., weekly, and 0.4 mg day^–1 of DX p.o. for 31 days) and a control group (n = 8). Urine was collected before, during (twice) and at the end of treatment. During PL administration, the tetrahydro-metabolite levels decreased gradually and remained low after the suspension of treatment. DX reduced urinary THF that persisted after the treatment, while THE levels decreased during the experiment, but rebounded substantially after the DX was withdrawn. Both DX and PL significantly interfered with the production of F and E, leading to their complete depletion. Taken together, the results demonstrate the influence of DX and PL administration on 11βHSD activity and their impact on dysfunction of the 5-reductase pathway. In conclusion, profiling tetrahydro-metabolites of F and E might serve as an alternative, indirect but reliable, non-invasive procedure for assessing the impact of synthetic glucocorticosteroids administration.     

Drug‐release behavior of chitosan‐g‐poly(vinyl alcohol) copolymer matrix

Chitosan‐g‐poly(vinyl alcohol) (PVA) copolymers with different grafting percent were prepared by grafting water‐soluble PVA onto chitosan. The drug‐release behavior was studied using the chitosan‐g‐PVA copolymer matrix containing prednisolone in a drug‐delivery system under various conditions. The relationship between the amount of the released drug and the square root of time was linear. From this result, the drug‐release behavior through the chitosan‐g‐PVA copolymer matrix is shown to be consistent with Higuchi's diffusion model. The drug‐release apparent constant (K_H) was slightly decreased at pH 1.2, but increased at pH 7.4 and 10 according to the increasing PVA grafting percent. Also, K_H was decreased by heat treatment and crosslinking. The drug release behavior of the chitosan‐g‐PVA copolymer matrix was able to be controlled by the PVA grafting percent, heat treatment, or crosslinking and was also less affected by the pH values than was the chitosan matrix. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 458–464, 1999     

新型抗哮喘药物环索奈德的合成

使用新的方法合成了环索奈德。以泼尼松龙为原料,用新的催化剂改进了17α羟基的酯化方法,优化了产品的重结晶方法。降低了成本易于工业化生产。     

Nano-carrier mediated co-delivery of methyl prednisolone and minocycline for improved post-traumatic spinal cord injury conditions in rats

Objective: The objective of this study is to investigate the fate of albumin coupled nanoparticulate system over non-targeted drug carrier in the treatment of hemisectioned spinal cord injury (SCI).

Significance: Targeted delivery of methyl prednisolone (MP) and minocycline (MC) portrayed improved therapeutic efficacy as compared with non-targeted nanoparticles (NPS).

Methods: Albumin coupled, chitosan stabilized, and cationic NPS (albumin-MP?+?MC???NPS) of poly-(lactide-co-glycolic acid) were prepared using the emulsion solvent evaporation method. Prepared NPS were characterized for drug entrapment efficiency, particle size, poly-dispersity index (PDI), zeta potential, and morphological characteristics. Their evaluation was done based on the pharmaceutical, toxicological, and pharmacological parameters.

Results and discussion: In vitro release of MP?+?MC from albumin-MP?+?MC???NPS and MP?+?MC???NPS was observed to be very controlled for the period of eight days. Cell viability study portrayed non-toxic nature of the developed NPS. Albumin-MP?+?MC???NPS showed prominent anti-inflammatory potential as compared with non-targeted NPS (MP?+?MC???NPS) when studied in LPS-induced inflamed astrocytes. Albumin-MP?+?MC???NPS reduced lesional volume and improved behavioral outcomes significantly in rats with SCI (hemisectioned injury model) when compared with that of MP?+?MC???NPS.

Conclusions: Albumin-coupled NPS carrier offered an effective method of SCI treatment following safe co-administration of MP and MC. The in vitro and in vivo effectiveness of MP?+?MC was improved tremendously when compared with the effectiveness showed by MP?+?MC???NPS. That could be attributed to the site specific, controlled release of MP?+?MC to the inflammatory site.     

Drug dispersion degree and drug dissolution rate in Hybrane S1200-based instant-release matricial particles prepared by hot melt extrusion

The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from <250 to >1500?µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45?°C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250?µm.