国产固定剂量复合剂治疗肺结核的临床近期效果观察

目的全面评价国产固定剂量复合剂异烟肼利福平吡嗪酰胺／异烟肼利福平(2HRZ／4HR)的抗结核疗效及毒副反应。方法将81例初治菌阳肺结核患者，随机分为治疗组(2HRZ/4HR)和对照组(2HRZ/4HR)观察近期痰菌阴转率、X线病灶改变及不良反应。结果治疗组和对照组2个月痰菌阴转率分别达82．5％和65．7％；满疗程痰菌阴转率各为100．0％和88．6％；胸部X线明显改善，治疗组和对照组病灶吸收分别占92．7％和94.3％，两组空洞闭合率分别为63．2％和62．5％；治疗组和对照组各有2例和4例肝功异常。结论国产固定复合剂是一种安全、高效．易被患者接受、具有推广应用前景的抗结核药物。     

全球市场上抗结核药物固定剂量复合剂的质量控制:体外研究结果报告

目的：评价在国家结核病控制规划中大范围供应使用抗结核药物固定剂量复合剂(FDC)的质量，尤其是FDC中利福平的溶解特性。方法：对4家药厂供应的4种制剂采用不同的溶媒(0．1NHCL及0．01NHCL、磷酸缓冲液(PB)及含20％植物油的PB)、不同振荡强度(USPⅡ型仪)进行溶解度研究。并对FDC进行了4周的催化稳定性研究(40℃／75％相对湿度[RH])，评价其物理、化学和溶解稳定性。结果：根据药典中的质控试验(CQC)对待评价制剂进行检测。利福平的溶解程度不受溶媒影响；有两种产品的利福平溶解速度有轻微降低。75％以上的药物成分在除30rpm外的各种振荡强度下，代表饱食状态的含20％植物油溶媒中45分钟内溶解。在制药厂建议的包装条件下，各制剂至少在4周内性能稳定。结论：所检测的制剂均通过了质量控制试验并证明其性能稳定。虽然有的制剂溶解速度有所降低，但其溶解程度未发生改变，但这就需要胃及肠道不同PH条件下的多点溶解，以保证制剂体内生物利用度的稳定性。     

The physical and chemical stability of anti-tuberculosis fixed-dose combination products under accelerated climatic conditions.

OBJECTIVE: To determine the physical and chemical stability of anti-tuberculosis fixed-dose combinations (FDC) of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) sold on the Indian market. METHODS: The products were stored for 3 months under ICH/WHO accelerated conditions (40 degrees C / 75% RH), with and without the original packaging in the presence and absence of light. RESULTS: The initial RMP, INH and PZA content was found to be within the range of 90-110% of the label claim. However, the products were found to have some chemical instability even initially; one of the tablets also showed physical instability. Under accelerated conditions, the unpackaged products underwent severe changes, whereas both physical and chemical changes were also observed in the packaged formulations. The physical changes were stronger under lighted conditions. A significant finding is that PZA and perhaps EMB may play a catalytic role in the interaction between INH and RMP. CONCLUSION: This study suggests that, unless they are packed in barrier packaging, anti-tuberculosis FDC formulations should be considered unstable, and due consideration should be given to their development pharmaceutics, packaging and stability testing.     

A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products.

A pilot stability study was carried out on four fixed-dose combination anti-tuberculosis products at 40 degrees C and 75% RH. The strip-packed products were stable, while the blister-packed products showed both physical and chemical changes. The products in unpacked conditions showed severe (approximately 60%) decomposition of rifampicin and extensive physical changes. The main decomposition product in the solid state was isonicotinyl hydrazone of 3-formylrifamycin and isoniazid. It is suggested that attention should be paid to the detection and quantitation of this product in the marketed formulations. The packing material used in the manufacture of FDC products should also be of the highest quality.     

Pharmaceutical formulation of a fixed-dose anti-tuberculosis combination.

SETTING: Department of Pharmacy and Pharmacology, University of the Witwatersrand. Despite the availability of highly effective treatment regimens for tuberculosis (TB), the cure rate still remains relatively low. This may be attributed to the high incidence of patient non-compliance, which subsequently leads to the emergence of multidrug-resistant TB (MDR-TB). To avoid the problem of further creation and propagation of MDR-TB, it may be proposed that patients should be given fixed-dose combinations of anti-tuberculosis drugs whenever self-administration is permitted. OBJECTIVE: To optimise an anti-tuberculosis extemporaneous powder formulation for suspension in order to develop a fixed combination of rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as a powder to be reconstituted with water by the patient prior to administration. METHODS: Different suspending agents were evaluated for their influence on powder flow properties, and sediment volume on the powder blends. Sodium starch glycolate was selected as the suspending agent because of its favourable powder flow properties and sediment volume produced. The dissolution characteristics of the extemporaneous powder for suspension were also compared to the dissolution profiles of commercially available anti-tuberculosis tablet dosage forms. RESULTS: The powder for suspension for rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride all compared favourably to the dissolution rate from the commercially available tablet dosage forms.     

抗结核固定复合剂药物不良反应观察

目的观察国产抗结核FDC在治疗初治涂阳肺结核疗程中的不良反应。为临床治疗和不良反应的处理提供一定参考资料。方法从全省的地理环境和经济状况抽取7个点,每个点共纳入120例初治涂阳肺结核病例,分3组:观察组、对照组1和对照组2,每组40例。对3组病人进行药物不良反应发生率及疗程中不良反应变化趋势观察。结果不良反应总发生率:神经系统20.7%。胃肠道系统19.4%。皮肤系统11.8%。肝功能异常37.3%。白细胞降低方面18.5%。结论以上各系统不良反应发生率与国内多家报道基本一致。从发病趋势来看,只有白细胞降低的发生率随着疗程有升高的趋势,其他不良反应发生率都呈下降趋势。     

抗结核固定复合制剂与板式组合药治疗肺结核可行性的对照研究

目的　评价国产抗结核FDC制剂化疗及管理的可行性。方法 自2003年6月1日至2003年12月31日在深圳市6个区就诊的肺结核病人,按往年的病人分布、各个区的经济文化程度等将深圳市6个区分别划分为观察区(FDC制剂组,包括罗湖区、南山区和宝安区)和对照区(组合药组,包括福田区、盐田区和龙岗区)。对2组病人治疗期间的耐受性、管理效果、治疗效果、不良反应进行比较。结果 (1)更多的FDC制剂组病人认为服药方式可以接受,药片大小合适,药片数适中(P＜0.05);(2)2组完成治疗率接近(P＞0.05),但FDC制剂组治愈率高于对照组(P＜0.05);(3)不良反应无显著性差异(P＞0.05);2组病人因肝损害停药率接近,分别为8.9%与5.4%,2组之间均无显著性差异(P＞0.05);(4)更多的FDC制剂组督导管理医生认为发放药物的难度大、药品的量化管理困难、目前药物管治病人不方便、同时说不清能增加病人的依从性(P＜0.05);(5)对照组药物的成本效果分析优于FDC制剂。结论 国产FDC制剂可以改善病人的接受性,提高治愈率;但是由于制作工艺、技术和市场等多方面原因,医务人员的接受性和成本效果方面比组合药差,有待进一步改进。     

提高抗结核药品固定剂量复合剂在省市级结核病定点医院推广使用的实施性研究

目的：评价在国家结核病防治规划实施中,省市级结核病定点医院推广使用抗结核药品固定剂量复合剂(FDC)使用的可行性。方法：按照典型抽样的方法,在全国选择5个省,每省一个省级和一个地市级结核病定点医院作为研究现场,采取观察性研究方法,对新诊断的利福平敏感或无耐药检测结果的肺结核患者,根据 FDC的纳入标准和排除标准进行治疗观察,分析使用抗结核 FDC 患者的纳入和退组情况。结果：2021年4月1日至7月31日,10个机构登记新诊断的利福平敏感或无耐药检测结果的肺结核患者3558例,抗结核 FDC 使用率为71.9%(2559/3558),其中最高为94.5%(346/366),最低为45.6%(215/472);12.1%(431/3558)的患者因禁忌证未使用抗结核 FDC,有禁忌证的患者占登记患者数的比例最高为43.9%(207/472),最低为2.3%(5/215)。使用抗结核 FDC的患者中22.3%(571/2562)在疗程中途停止使用抗结核 FDC,各机构中最高为44.8%(155/346),最低为3.6%(13/365);退组患者中54.5%(311/571)由于发生不良反应...     

Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study.

OBJECTIVE: To determine the quality, and especially the dissolution properties of rifampicin, of fixed-dose combination (FDC) formulations of anti-tuberculosis agents manufactured by major market holders in the anti-tuberculosis sector and supplied for use in national tuberculosis control programmes. METHODS: Dissolution studies were performed for four formulations supplied by four different manufacturers in four dissolution media (0.1N and 0.01N HCl, phosphate buffer [PB] and 20% vegetable oil in PB), at four different agitation rates using USP apparatus II. The formulations were subjected to 4-week accelerated stability studies (40 degrees C / 75% RH) and evaluated for physical, chemical and dissolution stability. RESULTS: The formulations tested complied with pharmacopeial quality control (QC) tests. The extent of rifampicin release was independent of dissolution medium; however, a slight decrease in the dissolution rate was observed in two products. More than 75% of drug was released in 45 min at all agitation intensities except 30 rpm, and 20% oil in the medium reflected fed state. Formulations were stable in the packaging conditions recommended by the manufacturer for at least 4 weeks. CONCLUSIONS: The formulations tested passed the QC tests and were found to be stable. A decrease in the rate, although not the extent, of dissolution necessitated multiple point dissolution in gastric and intestinal pH conditions to ensure consistency in in vivo bioavailability.     

国产抗结核固定剂量复合剂的药效学和药代动力学研究

目的 研究国产固定剂量复合剂的药效学和药代动力学，评价其抗结核作用及产品质量。方法 采用二倍稀释法测定最低抑菌浓度（MIC），以半数动物存活时间为指标比较药物对实验性结核病的疗效。高效液相色谱法测定健康志愿者口服同剂量国产及进口三药复方片剂（卫非特）的血药浓度，求出各组分的主要药代动力学参数及相对生物利用度，并用双单侧t检验分析药物等效性。结果 复方制剂各成分对结核分枝杆菌的MIC均低于单独应用时各自的MIC；对小鼠试验性结核病均显著优于三者相应剂量单独应用的效果，与国外相应产品卫非特比较未见显著性；国产与进口片剂的主要药代动力学参数t1/2、Cmax、AUC、tmax未见显著性差异，相对生物利用度生物等效性检验合格。结论 三药复方的抗结核作用具有协同作用；国产与进口片剂为等效制剂。