利伐沙班片自研制剂和参比制剂鼻饲条件下体外评价

目的 评价利伐沙班自研制剂与参比制剂鼻饲条件下的体外一致性。方法 采用鼻胃管和胃造口管进行鼻饲实验,以沉降体积、粒度分布和回收率为指标进行利伐沙班自研制剂和参比制剂的体外研究。结果 自研制剂在沉降体积、粒度分布和回收率方面均与参比制剂相似。结论 自研制剂与参比制剂经鼻胃管给药条件下体外特性一致,消除给药方式所带来的影响。     

碳酸锂片的制备及其体内外评价研究

目的 制备碳酸锂片并考察体内外释药特性。方法 采用体外溶出评价筛选碳酸锂片中原料粒径、马铃薯淀粉用量、硬脂酸镁用量;采用生物等效性试验比较自制制剂与参比制剂在健康受试者体内的药动学行为。结果 碳酸锂片处方为碳酸锂250 mg、小麦淀粉75 mg、马铃薯淀粉5 mg、硬脂酸镁3 mg。自制制剂与参比制剂的溶出曲线f₂因子均大于50;两种制剂在健康受试者体内的药动学参数均无显著性差异,自制碳酸锂片相对生物利用度为(103.67±7.54)%。结论 成功制备碳酸锂片,其体外溶出和体内药动学行为与参比制剂相似。     

吗替麦考酚酯胶囊的制备工艺研究

目的：探讨吗替麦考酚酯胶囊的制备工艺。方法：吗替麦考酚酯由瑞士罗氏（Roche）公司开发,商品名为骁悉（CellCept）。选用原研胶囊剂作为参比制剂,经文献调研,获得与参比制剂溶出相似的处方,成功开发出与参比制剂质量一致的仿制药。结果 ：自制吗替麦考酚酯胶囊溶出曲线与参比制剂相似,有关物质在制剂加速试验过程中稳定可控,且制备方法工艺简单,流化床干燥所得颗粒粒度均匀、流动性好。结论 ：自制吗替麦考酚酯胶囊与参比制剂质量一致。     

纳米注射剂仿制药的药学技术要求

纳米注射剂是近年来高端制剂研发的热点,我国纳米注射剂仿制药研发水平尚在起步阶段,缺少相应的技术要求,此类制剂的研发和监管面临极大的挑战。本文对纳米注射剂仿制药与参比制剂药学一致性考察的要点进行了总结,重点讨论了粒径表征技术以及对相关参数进行体外群体生物等效性研究的方法及方法的科学性和可行性。纳米注射剂仿制药与参比制剂的药学等效性研究对我国纳米注射剂仿制产品的研发、规模化生产和质量控制具有重要的借鉴意义。     

美乐托宁缓释片在不同介质中的释放试验

目的:制备美乐托宁缓释片,以国外上市制剂美乐托宁缓释片为参比制剂,考察自研制剂和参比制剂在不同pH释放介质中体外释放行为的相似性及体外释药机制。方法:采用释放度测定法转篮法的装置进行体外释放实验,用HPLC法测定释放度,采用f2相似因子对2种制剂释放曲线的相似度进行评价,并进行释放行为模型的拟合。结果:在不同pH的释放介质中,自制制剂释放度曲线与参比制剂比较,f2相似因子均大于50;美乐托宁缓释片在4种释放介质中体外释药拟合模型更接近一级方程、Higuchi方程和Peppas方程。结论:参比制剂与自制制剂在不同pH释放介质中的体外释放一致,释放机制为扩散释药。     

小儿清热利肺口服液联合头孢曲松钠治疗小儿急性支气管炎的临床研究

经肠内饲管给药的口服药品的需求增多,但以往对此研究不够深入细致,监管力度也不大。为确保这种给药方式安全有效,美国食品药品管理局（FDA）于2021年6月发布了“经肠内饲管给药的口服药品：体外试验和说明书建议”供企业用的指导原则。提出了临床前体外试验的具体而详细的建议,建议的试验类型包括回收率试验、沉降量和再分散性试验、在指定分散介质中的使用稳定性试验、粒度分布研究、肠溶衣药品的耐酸性试验和缓释制剂溶出度试验。还提出了这类给药方式药品说明书的撰写建议,特别是给药说明的详细建议并列举了示例。我国目前还没有类似的指导原则,详细介绍FDA该指导原则,供我国这方面的研究和监管人员参考。以期将经肠内饲管给药的口服药品的体外试验和说明书的撰写落到实处。     

临床药师对住院患者特殊剂型药品经鼻饲给药的持续药学监护效果评价

目的 评估临床药师对住院患者鼻饲特殊剂型药品（本文特指缓释固体制剂、肠溶固体制剂）的持续药学监护的效果。方法 纳入2018年1月～2019年6月在住院期间使用特殊剂型鼻饲给药的591例患者作为对照组,2019年7月～2020年12月使用特殊剂型鼻饲给药的621例患者作为干预组,通过日常查房、药物宣教以及处方点评实行药学监护作为干预措施。对特殊剂型药物的使用率、特殊剂型鼻饲处方合理率进行统计分析。结果 临床药师持续干预,提高了鼻饲给药的合理率,差异有统计学意义（P <0.01）;可鼻饲的特殊剂型药物的使用率也有所提高。结论缓释制剂与肠溶制剂这类特殊的药物制剂,如果选择正确的药物预处理方式是可以经鼻饲给药的,这需要临床药师掌握更加全面的药学相关理论知识给临床提供药学帮助,这样可以增加鼻饲的药品选择度,提高鼻饲给药的合理性;同时,临床药师积极参与临床药物治疗过程,并持续随访疗效与不良反应,才能体现临床药师的价值。     

不同介质中头孢地尼干混悬剂溶出曲线相似性比较的研究

目的：评价自制头孢地尼干混悬剂与市售原研品头孢地尼胶囊体外溶出行为的相似性,同时为难溶性药物制剂质量判断提供参考.方法：分别考查自制试验制剂头孢地尼干混悬和参比制剂头孢地尼胶囊在纯水、pH 1.2人工胃液、pH 4.0与pH 6.8磷酸盐缓冲液4种溶出介质中的体外溶出行为,以紫外-可见分光光度法进行测定,并采用f2相似因子法评价受试制剂和市售参比制剂溶出曲线的相似性.结果：在4种介质中,自制样品与参比制剂相似因子f2均大于50.结论：在这4种介质中,自制试验制剂与参比制剂溶出行为相似,说明受试制剂的处方工艺合理.     

包衣药物经鼻饲给药的风险控制及合理使用

包衣药物在鼻饲患者中的合理使用是临床用药的盲区,也是药学服务的空缺之处。包衣药物能否用于鼻饲患者,以及如何保证药物治疗的安全性、有效性,需引起医务人员重视。鼻饲给药时制剂状态或给药部位发生变化,会影响体内药动学过程,导致药物疗效难以保证。包衣药物有其特定包衣目的,鼻饲给药会破坏包衣材料,故而需要评估包衣药物能否经鼻饲给药。针对不同类型包衣药物,首先从制剂基本组成、释药原理及临床常用药物进行总结,其次分析包衣药物经鼻饲给药时的风险控制点,而后提出规范化操作建议及注意事项,最后以常用鼻饲药品——质子泵抑制剂为例,总结其鼻饲用法及体内外评价方式,为其他包衣制剂经鼻饲给药提供方法指导,推动鼻饲用药临床实践规范化、合理化。     

特殊制剂体外群体生物等效性研究案例分析

目的：采用体外群体生物等效性评价方法评估4种特殊制剂的等效性。方法：对国内外指南中关于群体生物等效性的内容进行总结,选择混合标度法,针对不同制剂,主要考察粒径参数、给药装置等体外测量数据参数,将指南中的公式和方程运用于2种吸入制剂（吸入用布地奈德混悬液和左沙丁胺醇雾化吸入溶液）以及2种脂质纳米注射剂（阿扎胞苷注射剂和注射用白蛋白结合型紫杉醇）的等效性研究。结果：该文的体外群体生物等效性研究取得良好的实践结果,除了阿扎胞苷注射剂的受试制剂与参比制剂不等效,需要对粒径继续加以改进外,其他3种制剂有95%的把握度说明受试制剂与参比制剂等效。结论：该研究成功将指南中的公式运用在实际案例中,对特殊制剂体外群体生物等效性在制剂研发中的应用有指导意义。     

<Emphasis Type="Italic">In vitro</Emphasis> Approaches to Support Bioequivalence and Substitutability of Generic Proton Pump Inhibitors via Nasogastric Tube Administration

Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products.     

In vitro evaluation of nasogastric administration methods for phenytoin

The effect on phenytoin recovery of various methods of nasogastric administration of phenytoin suspension was studied. Phenytoin acid suspension 4 mL (100 mg) was administered through a nasogastric (NG) tube using 10 methods designed to simulate clinical situations. The suspension was given either undiluted or diluted, with or without irrigation of the NG tube. Solutions of 5% dextrose injection, 0.9% sodium chloride injection, sterile water for irrigation, and lactated Ringer's injection were used as diluents or irrigants. After each administration, 40 mL of air was forced through the NG tube to expel any remaining suspension. Phenytoin concentration was assayed by high-performance liquid chromatography before and after administration through the NG tube. In the method that used no diluent or irrigation, 75.5 +/- 5.3% of the initial dose volume was lost, significantly more loss than with any of the other methods. The mean dose volume lost for all of the other nine methods was 6.4 +/- 3.4%. The type of fluid used for dilution or irrigation had little influence on phenytoin recovery. Until other methods can be evaluated, phenytoin suspension should be diluted and irrigated with at least 20 mL of fluid when given by nasogastric tube. Evacuation of the tube with 40 mL of air after phenytoin administration is also recommended.     

Delivery of esomeprazole magnesium through nasogastric and gastrostomy tubes using an oral liquid vehicle as a suspending agent in vitro.

PURPOSE: The optimal delivery medium for esomeprazole magnesium enteric-coated pellets dispersed in various concentrations of Ora-Plus suspension through commonly used nasogastric and gastrostomy tubes using a previously used standardized in vitro protocol was studied. METHODS: The study was conducted in two phases. In phase A, 60 size 14 French nasogastric tubes were used to compare esomeprazole pellet delivery via tap water or 30, 50, or 70% Ora-Plus concentrations (15 tubes for each). In phase B, tap water and the concentration that yielded the best pellet delivery from phase A were used with the narrower size 8 and shorter size 20 French tubes. In both phases, the appropriate volume of water was added. All capsules were assumed to have 1,240 pellets. At the end of each administration, pellet retention counts were performed. RESULTS: The results showed excellent delivery of esomeprazole pellets using water as a medium for tube delivery. When compared with tap water as a delivery medium, no differences in pellet retention were observed when 30% and 50% Ora-Plus were used; thus, these Ora-Plus concentrations are feasible alternatives to tap water for nasogastric tube delivery of esomeprazole pellets. CONCLUSION: Administration of esomeprazole magnesium enteric-coated pellets dispersed in tap water or Ora-Plus through size 14 French nasogastric tubes in vitro delivered over 99% of capsule contents, regardless of the Ora-Plus concentration used. For immediate bedside administration, Ora-Plus at 50% concentration is a feasible alternative to water when delivering the pellets through size 14 French tubes, while 30% Ora-Plus is an alternative to water for all tubes studied.     

Loss of carbamazepine suspension through nasogastric feeding tubes

The apparent loss of carbamazepine suspension during administration through polyvinyl chloride nasogastric feeding tubes in vitro was studied. Twelve methods of administering carbamazepine suspension (100 mg/5 mL) were tested; the methods differed with respect to nasogastric tube size, presence and type of diluent, and type of flush solution. Undiluted or 50% diluted carbamazepine suspension 200 mg was drawn up in a syringe and forced through adult or pediatric nasogastric feeding tubes. The tubes were immediately flushed twice with 50 mL of sterile water, 0.9% sodium chloride solution, or 5% dextrose solution, by using the same syringe used to administer the suspension. Samples were collected and analyzed for carbamazepine concentration by high-performance liquid chromatography. Each administration method was tested six times, and the results were subjected to analysis of variance. Significant loss of carbamazepine was noted for four of the six methods in which undiluted suspension was administered. In these methods, adult and pediatric tubes were flushed with sterile water or 0.9% sodium chloride. No significant loss of drug occurred for any of the methods involving the use of diluent. Significant losses were associated with diluent and flush solution but not nasogastric tube size. Carbamazepine suspension should be mixed with an equal volume of diluent before being administered through nasogastric feeding tubes.     

临床药师参与颅脑损伤患者鼻饲给予丙戊酸钠的药学监护

目的 通过血药浓度监测,探讨临床药师对颅脑损伤患者鼻饲给予丙戊酸钠的药学监护模式。方法 利用HPLC检测颅脑损伤患者鼻饲给予及静脉给予丙戊酸钠后丙戊酸的血药浓度,研究不同给药方式对丙戊酸血药浓度的影响,探讨临床药师药学监护的作用。结果 丙戊酸钠鼻饲给药严重影响血浆药物浓度,其血药浓度均达不到有效参考范围。经临床药师建议后,丙戊酸钠改为静脉给药,血药浓度较鼻饲给药升高,达窗率提高,差异有统计学意义（P<0.01）。结论 临床药师在临床治疗团队中充分运用血药浓度监测方法及扎实的药学知识,在临床药物治疗过程中起到重要作用。     

改良鼻胃管置入法的效果观察

目的减少鼻胃管置入患者在置管过程中的不适感及提高置管的一次性成功率,指导临床工作。方法选择住院的普通外科需进行鼻胃管置入的神志清醒的成年患者随机分为两组,A组为常规法,B组为改良置管法,观察两组患者的不适症状、一次性置管成功率及患者对置管操作的接受程度。结果两组患者在不舒适症状、一次性置管成功率及患者对置管操作的接受程度上有统计学意义(P<0.05)。结论改良置管法可以减少患者在置管过程中的不适感及提高置管的一次性成功率,使患者容易接受。     

Effects of enteral feeding on the oral bioavailability of moxifloxacin in healthy volunteers

BACKGROUND AND OBJECTIVE: Moxifloxacin is a new generation fluoroquinolone antimicrobial agent used worldwide. In clinical practice in intensive care units, moxifloxacin may be frequently administered through a nasogastric feeding tube. In the absence of an oral liquid formulation and since the multivalent cations contained in enteral feeds may potentially impair absorption of moxifloxacin administered via this route, we studied the effect of concomitant enteral feeding on the pharmacokinetics and tolerability of moxifloxacin administered as a crushed tablet through the nasogastric tube. PARTICIPANTS AND METHODS: This was a single-centre, open-label, randomised, controlled, nonblinded, three-way crossover study. Twelve young healthy volunteers (nine females and three males) aged 20-42 years were included in the study. Each participant received three separate treatment regimens in a randomised fashion: an intact moxifloxacin 400 mg tablet (regimen A, reference treatment), a crushed moxifloxacin 400 mg tablet as a suspension through a nasogastric tube with water (regimen B) and a crushed moxifloxacin 400 mg tablet as a suspension through a nasogastric tube with enteral feeding (regimen C). A washout period of 1-week followed each treatment. Concentrations of moxifloxacin in serum were measured by a validated high-performance liquid chromatography method. Pharmacokinetic parameters were calculated by noncompartmental methods. Additionally, the primary parameters indicative for changes in absorption (area under the serum concentration-time curve from time zero to infinity [AUC(infinity)] and peak serum concentration [C(max)]), were tested for bioequivalence, assuming log-normally distributed data using ANOVA. RESULTS: All moxifloxacin treatment regimens were well tolerated. The AUC(infinity) was slightly, but not statistically significantly, decreased in treatments with regimens B and C. AUC(infinity) (geometric means 39.6 [regimen A] vs 36.1 [regimen B] vs 36.1 mg.h/L [regimen C] and point estimates 91% for B : A and C : A) indicated bioequivalence of the treatments. Bioequivalence criteria of AUC(infinity) and C(max) were met upon retrospective statistical analysis. Likewise C(max) after moxifloxacin administration through nasogastric tube with water (regimen B) and with tube feed (regimen C) were slightly decreased (geometric means 3.20 [regimen A] vs 3.05 [regimen B] vs 2.83 mg/L [regimen C]; point estimates 88% for B : A, and 95% for C : A). They were within the range seen in other studies conducted with oral administration of the drug. No statistically significant differences were observed in time to reach C(max) (t(max); median 1.75 [regimen A] vs 1.00 [regimen B] vs 1.75 hours [regimen C]). Thus, the rate of absorption of moxifloxacin was not affected by administration through a nasogastric tube. This route of ingestion seems to be associated with a slight loss of bioavailability independent of the carrier medium used (water vs enteral feed); no clinically relevant interaction with the multivalent cations contained in the enteral feed was observed, indicating that moxifloxacin and enteral nutrition can be administered concomitantly. CONCLUSION: There was no clinically relevant effect of enteral feeding on the pharmacokinetics of oral moxifloxacin in healthy volunteers. This result has to be evaluated in patients, particularly those from the intensive care unit, who are characterised by severe infectious and/or concomitant diseases that might influence absorption of moxifloxacin.     

临床药师对低体质量慢性血栓栓塞性肺动脉高压患者应用利伐沙班的药学监护及文献复习

目的:探讨低体质量慢性血栓栓塞性肺动脉高压患者服用利伐沙班后凝血异常的原因及剂量选择。方法:临床药师深入临床,对1例低体质量慢性血栓栓塞性肺动脉高压患者实施药学监护。临床药师计算机检索各数据库,结合相关文献,分析患者出现凝血异常的原因,评定患者使用利伐沙班的剂量,提出个体化给药建议。结果与结论:极端体质量患者使用常规剂量的利伐沙班,凝血酶原时间变化有一定的意义,必要时进行血药浓度监测是最佳选择。     

Stability of Crushed Tedizolid Phosphate Tablets for Nasogastric Tube Administration

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections. To determine whether the expected dose of tedizolid phosphate can be delivered via nasogastric tube in patients who have difficulty swallowing and in whom venous access is not suitable, this in vitro study evaluated the recovery of tedizolid phosphate 200-mg tablets after crushing, dispersion in water, and passage through a nasogastric tube. To analyze the chemical stability of the crushed tablet dispersed in water, the aqueous preparation was assayed initially after dispersion and again after 4 h at room temperature. Recovery of tedizolid phosphate after the crushed tablets were dispersed in water and passed through nasogastric tubes ranged from 92.5 to 97.1 %, which is within the specified acceptance criteria of 90 to 110 %. There was no significant change in recovery values after 4 h of storage at room temperature (93.9 % initially and 94.7 % after 4 h). The stability and recovery findings support the feasibility of administering an aqueous dispersion of crushed tedizolid phosphate tablets through a nasogastric tube in patients who have difficulty swallowing and in whom intravenous administration is not possible.