艾司奥美拉唑钠有关物质的合成

目的合成艾司奥美拉唑钠产品中两个N-吡啶取代杂质,加强其质量控制。方法以奥美拉唑硫醚和2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐为起始原料,经取代反应得到奥美拉唑硫醚N-吡啶取代物(A),再经不对称氧化反应得到N-(4-甲氧基-3,5-二甲基-2-吡啶)甲基艾司奥美拉唑(B)。结果与结论目标化合物的结构经过质谱、核磁确证,纯度均大于98.0%,可用于艾司奥美拉唑钠产品研究质量控制的对照品。本工艺所用原料易得,成本低,纯度高。     

世界畅销药埃索美拉唑的开发应用进展

埃索美拉唑中文又名：艾司奥美拉唑;为5-甲氧基-2-((S)-((4-甲氧基-3,5-二甲基-2-吡啶基)甲基)亚硫酰基)-1H-苯并咪唑【1】。英文名：Esomeprazole ,分子式：C17H19N3O3S。分子结构。     

埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

艾司奥美拉唑钠两种砜类杂质的一锅法合成研究

目的合成艾司奥美拉唑钠两个砜杂质,加强其质量控制。方法以2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐和2-巯基-5-甲氧基苯并咪唑为起始原料,通过一锅法同时合成艾司奥美拉唑钠的两个砜类杂质:5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为49%)和5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-1-氧代-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为46%),总收率为95%。结果与结论两个杂质的结构经质谱、核磁共振氢谱确证,纯度均高于99.8%,可作为艾司奥美拉唑钠原料药和制剂研究质量控制的标准品。本工艺采用一锅法同时合成两种砜类杂质,该法操作简单、条件温和、纯度高、收率高、成本低。     

埃索美拉唑钠合成工艺的改进

目的：优化埃索美拉唑钠大生产制备工艺,使得产品质量和收率符合车间生产需求,解决产品收率低,磺化物高难以处理的问题。方法5－甲氧基－2－（4－甲氧基－3．5二甲基－2－吡啶基）甲基硫代－1H苯并咪唑经过螯合2h在0．5N催化剂的作用下在－10～10℃下,选择1．0～1．1N过氧化氢异丙苯作为氧化剂反应,经过一系列后处理,在10倍乙腈下成盐反应可以得到埃索美拉唑钠。结果本工艺制备得到的埃索美拉唑钠纯度和含量符合质量要求,磺化物小,总摩尔收率达到60％左右。结论该工艺生产的埃索美拉唑钠质量符合产品质量标准,收率大幅提高至总摩尔收率60％,符合车间生产需要。     

2种方案治疗脑外伤和脑出血并发上消化道出血的成本-效果分析

目的:探讨奥美拉唑对比埃索美拉唑治疗脑外伤和脑出血并发上消化道出血的疗效和经济性。方法:回顾性分析110例脑外伤和脑出血并发上消化道出血患者的资料,按用药的不同分为奥美拉唑组(56例)和埃索美拉唑组(54例)。所有患者均给予常规治疗。在此基础上,奥美拉唑组患者给予注射用奥美拉唑钠40 mg静脉滴注,2次/d;埃索美拉唑组患者给予埃索美拉唑注射液40 mg静脉滴注,2次/d。两组患者疗程均为5 d。比较两组患者的疗效和经济性。结果:埃索美拉唑组患者总有效率显著高于奥美拉唑组,埃索美拉唑组患者成本-效果比(1 397.71)显著低于奥美拉唑组(1 512.09),差异有统计学意义(P<0.05),增量成本-效果比为91.52。结论:埃索美拉唑治疗脑外伤和脑出血并发上消化道出血的疗效、安全性、经济性均较好。     

埃索美拉唑与奥美拉唑治疗消化性溃疡132例疗效观察

目的比较埃索美拉唑与奥美拉唑三联疗法治疗幽门螺杆菌(Helicobacter pylori,简称Hp)阳性消化性溃疡的效果。方法将确诊为Hp阳性消化性溃疡132例患者随机分为埃索美拉唑组和奥美拉唑组,每组66例。两组分别给予阿莫西林1g,1日2次,克拉霉素0.5g,1日2次,埃索美拉唑组加用埃索美拉唑20mg,1日2次,奥美拉唑组加用奥美拉唑20mg,1日2次。1周后两组分别单用埃索美拉唑20mg,1日1次,奥美拉唑20mg,1日1次,维持治疗3周。两组患者治疗前和治疗后检测Hp状况。结果埃索美拉唑组溃疡愈合率为94.0%,奥美拉唑组溃疡愈合率为90.9%;埃索美拉唑组Hp根除率为92.4%,奥美拉唑组Hp根除率为84.9%。两组比较溃疡愈合率及Hp根除率差异无统计学意义(P>0.05);第1天和第2天腹痛缓解率埃索美拉唑组为36.4%和60.6%,奥美拉唑组为16.7%和33.3%,两组比较差异有统计学意义(P<0.05)。结论埃索美拉唑、阿莫西林、克拉霉素三联疗法治疗Hp感染消化性溃疡优于奥美拉唑、阿莫西林、克拉霉素三联疗法,腹痛缓解较快。     

莫沙必利与埃索美拉唑或奥美拉唑联用在反流性食管炎中的疗效比较

目的观察莫沙必利联合埃索美拉唑、奥美拉唑治疗反流性食管炎的临床疗效。方法选取116例反流性食管炎患者随机分为埃索美拉唑组和奥美拉唑组,每组58例。2组患者均给予常规治疗和莫沙必利治疗,埃索美拉唑组在此基础上服用埃索美拉唑,奥美拉唑组服用奥美拉唑,2个疗程后比较2组患者的临床疗效和不良反应发生情况。结果埃索美拉唑组的治愈率为58.62%,总有效率为94.83%;奥美拉唑组治愈率为51.72%,总有效率为84.48%,2组治愈率和总有效率比较差异有统计学意义(P<0.05);埃索美拉唑组发生不良反应的患者有2例(3.45%),奥美拉唑组发生不良反应的患者有6例(10.34%),差异有统计学意义(P<0.05)。结论采用莫沙必利与埃索美拉唑治疗反流性食管炎的临床效果优于莫沙必利与奥美拉唑联用,且不良反应发生率较低。     

埃索美拉唑与奥美拉唑治疗胃溃疡的临床分析

目的对比分析埃索美拉唑与奥美拉唑治疗胃溃疡的临床疗效。方法选取我院收治的胃溃疡患者168例,将其按照治疗方式进行分组,分为埃索美拉唑组和奥美拉唑组两组,每组各84例患者。埃索美拉唑组患者给予口服埃索美拉唑进行治疗,奥美拉唑组患者给予口服奥美拉唑进行治疗。结果 埃索美拉唑组患者的临床治疗总有效率为98.81%,显著高于奥美拉唑组的86.90%,比较差异具有统计学意义(P<0.01)。埃索美拉唑组患者的HP转阴率为97.62%显著高于奥美拉唑组患者的80.95%,比较差异具有统计学意义(P<0.01)。两组患者在不良反应发生情况方面的比较差异不具有统计学意义(P>0.05)。随访期间,埃索美拉唑组患者出现2例复发,复发率2.38%,奥美拉唑组患者出现5例复发,复发率为5.95%,比较差异具有统计学意义(P<0.05)。结论埃索美拉唑治疗胃溃疡较奥美拉唑更加安全有效,患者临床治愈率高,没有不良反应。     

埃索美拉唑治疗幽门螺旋杆菌相关性消化性溃疡

目的:观察埃索美拉唑治疗消化性溃疡的临床疗效及对幽门螺杆菌(HP)感染的清除率。方法:98例消化性溃疡患者,其中埃索美拉唑组48例,给埃索美拉唑20mg,Po,bid,共1周,安慰剂3周;奥美拉唑组50例,给奥美拉唑20mg,Po,bid,共3周。疗程结束时,复查胃镜观察溃疡的愈合情况。结果:埃索美拉唑组胃溃疡腹痛消失时间为(2.8±1.2)d,十二指肠溃疡为(1.8±0.5)d;奥美拉唑组分别为(3.8±1.9)d和(2.6±1.0)d,经统计学处理有显著性差异(P<0.01)。溃疡的愈合率和HP清除率,与奥美拉唑组70%和60%相比(P<0.01),埃索美拉唑组分别为95.8%和91.7%。结论:埃索美拉唑能明显缓解消化性溃疡症状,止痛效果快,对溃疡有较高的愈合率及HP清除率。     

右旋佐匹克隆的合成新方法

目的制备右旋佐匹克隆。方法以2,3-吡嗪二酸酐和2-氨基-5-氯吡啶为起始原料,经酯化、环合、不对称还原、成酯和精制反应得到右旋佐匹克隆。结果与结论目标化合物的结构经1H-NMR谱确证。新合成方法操作简便、收率高,适合工业化生产。产品光学纯度大于99.9%,化学纯度大于99.5%。     

Review article: Esomeprazole--enhanced bio-availability,specificity for the proton pump and inhibition of acid secretion

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor available for clinical use as a single isomer. It demonstrates pharmacological and clinical benefits beyond those seen with the racemic omeprazole. Esomeprazole has higher and more consistent bio-availability than omeprazole, which results in a greater area under the plasma concentration-time curve. It is the area under the plasma concentration-time curve of omeprazole and esomeprazole that determines how much of each reaches the parietal cell, and thus the control of gastric acid secretion that is achieved. Esomeprazole, like other proton pump inhibitors, has a high specificity for the acidic environment of the parietal cell, where it is accumulated, activated and covalently inhibits the proton pump. Proton pumps elsewhere in the body do not achieve the level of acidity needed for accumulation and activation. Esomeprazole, 40 mg once daily, provides more effective control of gastric acid secretion than omeprazole, 20 or 40 mg once daily, and all other proton pump inhibitors given at their standard doses. This translates into greater clinical effect compared with omeprazole, 20 mg once daily, and lansoprazole, 30 mg once daily, in the management of reflux disease. Esomeprazole therapy is well tolerated, with a low adverse events profile, similar to that seen with omeprazole.     

Esomeprazole: a review of its use in the management of acid-related disorders in the US

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor to be developed as a single optical isomer. It provides better acid control than current racemic proton pump inhibitors and has a favourable pharmacokinetic profile relative to omeprazole. In large well designed 8-week trials in patients with erosive oesophagitis, esomeprazole recipients achieved significantly higher rates of endoscopically confirmed healed oesophagitis than those receiving omeprazole or lansoprazole. Esomeprazole was effective across all baseline grades of oesophagitis; notably, relative to lansoprazole, as the baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. In two trials, 94% of patients receiving esomeprazole 40mg once daily achieved healed oesophagitis versus 84 to 87% of omeprazole recipients (20mg once daily). In a study in >5000 patients, respective healed oesophagitis rates with once-daily esomeprazole 40mg or lansoprazole 30mg were 92.6 and 88.8%. Resolution of heartburn was also significantly better with esomeprazole than with these racemic proton pump inhibitors. Long-term (up to 12 months) therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole 20 or 40mg once daily for 4 weeks proved effective in patients with symptomatic gastro-oesophageal reflux disease (GORD) without oesophagitis. Eradicating Helicobacter pylori infection is considered pivotal to successfully managing duodenal ulcer disease. Ten days' triple therapy (esomeprazole 40mg once daily, plus twice-daily amoxicillin 1g and clarithromycin 500mg) eradicated H. pylori in 77 to 78% of patients (intention-to-treat) with endoscopically confirmed duodenal ulcer disease. Esomeprazole is generally well tolerated, both as monotherapy and in combination with antimicrobial agents. The tolerability profile is similar to that of other proton pump inhibitors. Few patients discontinued therapy because of treatment-emergent adverse events (<3% of patients) and very few (<1%) drug-related serious adverse events were reported. CONCLUSIONS: Esomeprazole is an effective and well tolerated treatment for managing GORD and for eradicating H. pylori infection in patients with duodenal ulcer disease. In 8-week double-blind trials, esomeprazole effectively healed oesophagitis and resolved symptoms in patients with endoscopically confirmed erosive oesophagitis. Notably, in large (n >1900 patients) double-blind trials, esomeprazole provided significantly better efficacy than omeprazole or lansoprazole in terms of both healing rates and resolution of symptoms. Long-term therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole was also effective in patients with symptomatic GORD. Thus, esomeprazole has emerged as an effective option for first-line therapy in the management of acid-related disorders.     

S-泮托拉唑钠的合成工艺改进

用2-甲基-3、4-二甲氧基吡啶为原料,经氯化亚砜氯化后得2-氯甲基-3、4-二甲氧基吡啶盐酸盐,再和5-二氟甲氧基-2-硫基-1H-苯并咪唑进行缩合反应,再经不对称氧化得S-泮托拉唑,再经氢氧化钠成盐后得S-泮托拉唑钠。     

Esomeprazole: a review of its use in the management of acid-related disorders

Esomeprazole (S-isomer of omeprazole), the first single optical isomer proton pump inhibitor, generally provides better acid control than current racemic proton pump inhibitors and has a favourable pharmacokinetic profile relative to omeprazole. In a large well designed 8-week trial in patients (n >5000) with erosive oesophagitis, esomeprazole recipients achieved significantly higher rates of endoscopically confirmed healed oesophagitis than those receiving lansoprazole. Respective healed oesophagitis rates with once-daily esomeprazole 40mg or lansoprazole 30mg were 92.6 and 88.8%. Overall, esomeprazole was also better than omeprazole, although these differences were not always statistically significance. Ninety-two to 94% of esomeprazole recipients (40mg once daily) achieved healed oesophagitis versus 84 to 90% of omeprazole recipients (20mg once daily). Esomeprazole was effective across all baseline grades of oesophagitis; notably, relative to lansoprazole, as baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. Resolution of heartburn was also significantly better with esomeprazole 40mg than with these racemic proton pump inhibitors. Long-term (up to 12 months) therapy with esomeprazole effectively maintained healing in these patients. Once-daily esomeprazole 20 or 40mg for 4 weeks resolved symptoms in patients with symptomatic gastro-oesophageal reflux disease (GORD) without oesophagitis. Symptoms were effectively managed in the long-term with symptom-driven on-demand esomeprazole (20 or 40mg once daily). Eradicating Helicobacter pylori infection is considered pivotal to successfully managing duodenal ulcer disease. Seven days' treatment (twice-daily esomeprazole 20mg plus amoxicillin 1g and clarithromycin 500mg) eradicated H. pylori in >/=86% of patients (intention-to-treat), a rate that was similar to equivalent omeprazole-based regimens. Esomeprazole is generally well tolerated, both as monotherapy and in combination with antimicrobial agents, with a tolerability profile similar to that of other proton pump inhibitors. Few patients discontinued therapy because of treatment-emergent adverse events (<3% of patients), with very few (<1%) drug-related serious adverse events reported. CONCLUSIONS: Esomeprazole is an effective, well tolerated treatment for managing GORD and for eradicating H. pylori infection in patients with duodenal ulcer disease. In 8-week double-blind trials, esomeprazole healed oesophagitis and resolved symptoms in patients with endoscopically confirmed erosive oesophagitis and overall, provided better efficacy than omeprazole. Notably, in a large (n >5000 patients) double-blind trial, esomeprazole 40mg provided significantly better efficacy than lansoprazole in terms of healing rates and resolution of symptoms. Long-term therapy with esomeprazole maintained healed oesophagitis in these patients. Esomeprazole also proved beneficial in patients with symptomatic GORD without oesophagitis. Thus, esomeprazole has emerged as an option for first-line therapy in the management of acid-related disorders.     

Review of esomeprazole in the treatment of acid disorders

Esomeprazole (Nexium, AstraZeneca) is the (S)-isomer of omeprazole and the first proton pump inhibitor to be developed as an optical isomer. Esomeprazole has an improved pharmacokinetic profile, resulting in increased systemic exposure and less interindividual variability compared with omeprazole, and more effective suppression of gastric acid production compared with other proton pump inhibitors. In several large, double-blind, randomised trials, significantly higher rates of endoscopically-confirmed healing of erosive oesophagitis and resolution of heartburn have been achieved in patients with gastro-oesophageal reflux disease receiving 8 weeks of esomeprazole 40 mg o.d. compared with those receiving omeprazole 20 mg o.d. or lansoprazole 30 mg o.d. In the maintenance of healed erosive oesophagitis, esomeprazole 10, 20 or 40 mg o.d. was significantly more effective than placebo in two 6-month, randomised, double-blind trials. Additionally, esomeprazole 20 mg o.d. was more effective than lansoprazole 15 mg in the maintenance of healed erosive oesophagitis in another 6-month, randomised, double-blind trial. Healing of oesophagitis was also effectively maintained by esomeprazole 40 mg o.d. in a 12-month non-comparative trial. Esomeprazole 20 or 40 mg o.d. effectively relieved heartburn in patients with gastro-oesophageal reflux disease without oesophagitis in two 4-week, placebo-controlled trials. Clinical trials have shown that triple therapy with esomeprazole 40 mg o.d. in combination with amoxicillin and clarithromycin produced Helicobacter pylori eradication rates similar to those obtained using triple therapy involving twice-daily dosing with other proton pump inhibitors. Esomeprazole is well-tolerated, with a spectrum and incidence of adverse events similar to those associated with omeprazole.     

Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators

BACKGROUND: The pharmacologic profile of the new proton pump inhibitor esomeprazole has demonstrated advantages over omeprazole that suggest clinical benefits for patients with acid-related disease. METHODS: 1960 patients with endoscopy-confirmed reflux oesophagitis (RO) were randomized to once daily esomeprazole 40 mg (n=654) or 20 mg (n=656), or omeprazole 20 mg (n=650), the standard recommended dose for RO, for up to 8 weeks in a US, multicentre, double-blind trial. The primary efficacy variable was the proportion of patients healed at week 8. Secondary variables included healing and heartburn resolution at week 4, time to first resolution and sustained resolution of heartburn, and per cent of heartburn-free days and nights. Safety and tolerability were also evaluated. RESULTS: Significantly more patients were healed at week 8 with esomeprazole 40 mg (94.1%) and 20 mg (89.9%) vs. omeprazole 20 mg (86.9%), using cumulative life table estimates, ITT analysis (each P < 0.05). Esomeprazole 40 mg was also significantly more effective than omeprazole for healing at week 4 and for all secondary variables evaluating heartburn resolution. The most common adverse events in all treatment groups were headache, abdominal pain and diarrhoea. CONCLUSION: Esomeprazole was more effective than omeprazole in healing and symptom resolution in GERD patients with reflux oesophagitis, and had a tolerability profile comparable to that of omeprazole.     

Determination of omeprazole, hydroxyomeprazole and omeprazole sulfone using automated solid phase extraction and micellar electrokinetic capillary chromatography

A sensitive method for the determination of omeprazole and its metabolites has been developed. It involves an automated solid phase extraction (SPE) procedure and capillary electrophoresis with UV detection. Omeprazole, hydroxyomeprazole and omeprazole sulfone could be separated by micellar electrokinetic capillary chromatography using a background electrolyte composed of 20 mM borate buffer and 30 mM sodium dodecyl sulfate, pH 9.5. The isolation of omeprazole and its metabolites from plasma was automatically accomplished with an original SPE procedure using surface-modified styrene-divinylbenzene polymer cartridges. Good recovery data and satisfactory precision values were obtained. Responses were linear for the three analytes, from 0.08 to 2.0 microg/mL of plasma. Intra- and inter-day precision values of about 1.6% R.S.D. (n=10) and 2.5% R.S.D. (n=36), respectively, were obtained. The method is highly robust and no breakdown of the current or capillary blockages were observed during several weeks of operation. The validated method was applied to the determination of omeprazole in pharmaceutical preparations and for the analysis of plasma samples obtained from three volunteers who received oral doses of omeprazole.     

埃索美拉唑与奥美拉唑预防性治疗脑血管意外并发应激性溃疡的疗效观察

目的评价埃索美拉唑和奥美拉唑预防性治疗脑血管意外并发应激性溃疡的疗效。方法随机将180例患者分为埃索美拉唑组、奥美拉唑组和对照组,在分别治疗7d后,评价三组应激性溃疡发生的情况。结果埃索美拉唑和奥美拉唑均可有效预防应激性溃疡的发生,且埃索美拉唑组疗效显著高于奥美拉唑组（P〈0.05）。结论埃索美拉唑预防性治疗脑血管意外并发应激性溃疡疗效确切,无明显不良反应,且疗效明显优于奥美拉唑。     

Dissolution Enhancement by Bio-Inspired Mesocrystals: The Study of Racemic (<Emphasis Type="BoldItalic">R</Emphasis>,<Emphasis Type="BoldItalic">S</Emphasis>)-(±)-Sodium Ibuprofen Dihydrate

PURPOSE: The aim of this paper is to enhance the dissolution rate of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate via a bio-inspired method of growing mesocrystals. MATERIALS AND METHODS: Mesocrystals of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate were successfully prepared from a supersaturated aqueous solution of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate having the initial degree of supersaturation, S ( 0 ), of 1.326 and the initial saturated concentration, C*, of 0.986 mol/l at 25 degrees C with sodium dodecyl sulfate (SDS) at a concentration of 0.10 g/l. Dynamic light scattering, scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and optical microscopy with cross polarizers were employed to understand the formation mechanism and to characterize the superstructures of the SDS generated mesocrystals. RESULTS: The SDS generated mesocrystals were the assembly of the oriented attachment of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate nano-sized platelets under the mediation of the side-to-side interaction between SDS and racemic (R,S)-(+/-)-sodium ibuprofen dihydrate. The SDS generated mesocrystals contained a mixture of the racemic compounds in alpha- and beta-forms and the resolved racemic conglomerate in gamma-form with no detectable amount of SDS. The dissolution rate of the SDS generated mesocrystals was more rapid than the one of its counterpart made by conventional crystallization pathway. CONCLUSIONS: The crystallization of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate in the presence of SDS yielded well-faceted, well-separated, but almost perfectly three-dimensionally aligned nano-sized platelets. This kind of bio-inspired mesocrystal superstructure has definitely opened a new doorway for crystal engineering and pre-formulation design in pharmaceutical industry. The future work is to study the mesocrystal formation of some other active pharmaceutical ingredients in organic solvent systems and to develop an efficient method for screening the additives.