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.     

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。     

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。     

Modification to improve efficiency of sampling schedules for BA/BE testing of FDC anti-tuberculosis drugs.

SETTING: The assessment of rifampicin (RMP) containing fixed-dose combination (FDC) formulations using in vivo bioequivalence testing is widely accepted. It would be advantageous for both the drug regulatory authorities and drug manufacturers, for optimum minimum blood testing time intervals that encompass all anti-tuberculosis active constituents in the FDC to be established. OBJECTIVE: To determine the optimum blood sampling schedule for testing novel FDC anti-tuberculosis drugs, isoniazid, RMP, pyrazinamide and ethambutol DESIGN: The results of 12 different single-dose, two-way cross-over designs are presented. The studies determined the bioavailability and bioequivalence of RMP-containing FDCs, and conformed with the requirements of the South African national drug regulatory authority for each of the active constituents. RESULTS: The pharmacokinetic parameters to determine bioavailability and the Hauschke method to determine bioequivalence revealed that a six-point time protocol, namely 0, 1, 2, 4, 6 and 8 h, provides a good approximation of the area under the curve, and that an 11-point time protocol of 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h provided information comparable to the conventional 15 time-points for FDCs containing up to four drugs. CONCLUSION: The findings provide concrete economic benefit and convenience for quality assurance testing of existing and novel FDCs.     

Minimum sample size and sampling time requirements for assessment of rifampicin bioequivalence from FDC formulations.

SETTING: The WHO- and IUATLD-recommended protocol for rifampicin (RMP) bioequivalence utilises 20-22 volunteers and 8 h, whereas the requirement of other regulatory authorities is 12 volunteers with a 24 h sampling schedule. Differing sampling size and time requirements may change the outcome of RMP bioequivalence. OBJECTIVE: To determine the minimal sample size and time required to assess RMP bioequivalence from FDC formulations. DESIGN: Bioequivalence studies were conducted that fulfilled the criteria of the WHO and Indian regulatory protocols. From earlier studies, retrospective pharmacokinetic evaluation, power of the test and bioequivalence limits were also calculated using 8-22 volunteers and sampling points of 8-24 h. Pharmacokinetic and statistical evaluations from three representative studies showing low, moderate and high intra-subject variability are given to determine minimum requirements for RMP bioequivalence. RESULT: It was found that a sampling schedule up to 8 h was sufficient to compare the absorption process of RMP. There was no influence of reduced sample size on bioequivalence estimates of RMP that showed low or moderate variability. However, in a study showing higher variation, a sample size of 14-16 subjects was found to be optimal. CONCLUSION: It is possible to reduce the sample size requirement for determination of RMP bioequivalence using the WHO protocol.     

The potential use of urinary excretion data for assessing the relative bioavailability of rifampicin in fixed dose combination anti-tuberculosis formulations.

SETTING: The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations. OBJECTIVE: To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations. DESIGN: A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6 and 8 hours after each drug administration using a high performance liquid chromatography (HPLC) method. The rifampicin and desacetylrifampicin content of complete urinary collections made from 0-4 and 4-8 hours after dosage were determined using both the HPLC and a much simpler colorimetric procedure. RESULTS: There was good agreement between the relative bioavailability of the formulations using plasma and urinary excretion data, although the precision of the urinary-based estimates was slightly less than those derived from the plasma findings. There was also good agreement between the HPLC and colorimetric estimates of the combined urinary excretion of rifampicin plus desacetylrifampicin. CONCLUSIONS: Urinary excretion data may be used for ongoing quality control to confirm that commercial combined rifampicin-containing formulations that were initially shown to be satisfactory continue to be so.     

Current issues in global tuberculosis control.

Despite attempts to standardize tuberculosis (TB) control strategies, there remains wide variation in the selection and implementation of control strategies within and among nations. Some of this variation is appropriate; based on wide variations in the available resources, the prevalence of TB infection, the incidence of TB disease, the relative contribution of reactivation versus recent transmission to incident cases, and the rate of HIV co-infection. This review will discuss three controversial questions relevant to global TB control: (1) What is the role of the treatment of latent TB infection in global TB control? (2) What are successful strategies to control immigrant TB in low incidence countries? (3) What are successful strategies to control TB in persons with HIV infection?     

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.     

Substandard tuberculosis drugs on the global market and their simple detection.

SETTING: The prevalence of substandard anti-tuberculosis drugs is unknown. To maximize the effectiveness of tuberculosis (TB) control efforts, simple, inexpensive drug quality screening methods are needed. DESIGN: Isoniazid (INH) and rifampin (RMP) single- and fixed-dose combination (FDC) formulations were collected from selected TB programs and pharmacies in Colombia, Estonia, India, Latvia, Russia and Vietnam. Samples were screened using a recently developed thin-layer chromatography (TLC) kit. All abnormal samples and a 40% random sample of normal formulations were further analyzed using confirmatory techniques. Samples outside of 85% to 115% of stated content, and/or containing compounds other than the stated drug, were defined as being substandard. RESULTS: Overall, 10% (4/40) of all samples, including 13% (4/30) RMP samples, contained <85% of stated content. More FDCs (5/24, 21%) than single-drug samples (2/16, 13%) were substandard. A comparison of TLC with the confirmatory analysis for RMP analysis showed a sensitivity of 100% (4/4), a specificity of 92% (24/26), a positive predictive value (PPV) of 67% (4/6), and a negative predictive value (NPV) of 100% (24/24). An analysis of INH showed a specificity of 90% (9/10). However, sensitivity, PPV, and NVP could not be determined. CONCLUSION: A substantial number of anti-tuberculosis drugs from several countries, in particular FDCs, were found to be substandard. Such drugs may contribute to the creation of drug-resistant TB. TLC is an effective, convenient, and inexpensive method for the detection of substandard drugs.     

Morphologic studies of the erythropoietic part of bone marrow in myeloid leukaemias.

The erythropoietic part of the bone marrow has been morphologically analyzed in 147 patients with various forms of myeloid leukaemias and in 20 healthy controls. In all the patients the percentage of basophilic erythroblasts was abnormally high and correlated to elevated mitotic indices. Megaloblastic changes were found to be relatively common in the patients. All these findings are compatible with an ineffective erythropoiesis where the normal differentiation towards more mature erythroblasts becomes in creasingly blocked during the course of the disease regardless of the type of myeloid leukaemia.     

Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies.

Pediatric pulmonary tuberculosis (PPTB) remains a major cause of morbidity and mortality worldwide, particularly in less developed countries. Current techniques are inadequate for diagnosing PPTB. This is an impediment not only for the diagnosis and treatment of PPTB cases, but also for epidemiological investigations assessing PPTB burden and disease transmission. Causes of misdiagnosis of PPTB include non-specific signs/symptoms, low bacillary load, recovery methods (sputum or gastric aspirate) for obtaining a clinical sample with low bacillary yield, and the inherent low sensitivities of the diagnostic tests themselves. New diagnostic and recovery methods have recently been evaluated which may provide a means of overcoming some of these obstacles. Unfortunately, progress in developing and implementing improved diagnostic tests for PPTB has been partially impeded by the very low priority of PPTB in global TB control programs based on cost-effective strategies. Regardless of the cost-effectiveness of diagnosing and treating PPTB, our moral obligation to provide access to health care demands that we evaluate and deal with this neglected group of patients. Furthermore, recent evidence indicates that PPTB may actually be responsible for more disease transmission than previously thought. In this review, we present compelling evidence that research agendas and TB control programs should be reassessed and possibly revised to deal with the global disease caused by PPTB.