A critical review of the probable reasons for the poor variable bioavailability of rifampicin from anti-tubercular fixed-dose combination (FDC) products, and the likely solutions to the problem

Singh, Saranjit; Mariappan, T. Thanga; Shankar, Ravi; Sarda, Nicole; Singh, Baljinder

doi:10.1016/s0378-5173(01)00754-2

Cited by 90 publications

(62 citation statements)

References 16 publications

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“…The more the number of drugs incorporated in a fixed dose combination, the higher is the likelihood of compromised quality, a finding similar to what other researchers reported from the global drug market (Bhutani, 2004;. Previous studies have attributed the frequent occurrence of substandard rifampicin content in four-drug and three-drug FDCs to the presence of ethambutol in the formulations, which creates an environment that causes rifampicin to be degraded in the presence of isoniazid (Singh, 2001;Sankar, 2003). However, bad formulations due to poor manufacturing practice are more likely to be the reason for the poor quality products found in this study.…”

Section: Discussionsupporting

confidence: 82%

Substandard rifampicin based anti-tuberculosis drugs common in Ugandan drug market

Ocan¹

2013

Afr. J. Pharm. Pharmacol.

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Tuberculosis (TB) is an important curable infectious disease in Uganda; its treatment however is facing a challenge of increasing drug resistance. Although rifampicin containing fixed-dose combination (R-FDC) drugs are a mainstay in TB treatment, about one fifth is reportedly substandard in the global drug market. The aim of this study was to determine the quality of R-FDC and rifampicin single formulation anti-TB drugs in Kampala city, Uganda. Eight private and five public pharmacies were randomly selected, the drug samples were purchased and in the latter case obtained free of charge. Drug quality was assessed by visual inspection, weight uniformity, dissolution, and assay. Fifteen batches of anti-TB drugs were collected; 13 R-FDC and two rifampicin single dose formulations. One batch of R-FDC collected from a public pharmacy was not assayed as it had passed its expiry date by the time of analysis. Of the samples analyzed, six batches of R-FDC and two of rifampicin single dose formulations were purchased from private pharmacies. The other six batches of R-FDC were obtained from public pharmacies. Ten samples (10/14: 71.4%) were not in the National Drug Register (NDR), eight of which were R-FDC and two rifampicin single dose formulations. Of the R-FDC drugs, four samples (4/12: 33.3%) failed the assay test and were all not in the NDR. All the R-FDC drug samples passed the dissolution, visual inspection and weight uniformity tests. All rifampicin single dose formulations passed assay, visual, and weight uniformity tests and only one failed the dissolution test. Unregistered and sub-standard rifampicin anti-TB drugs are common in drug outlets on the Ugandan drug market. These substandard drugs pose a risk to patients such as treatment failure that leads to increased cost of treatment and possibly loss of lives.Key words: Rifampicin, fixed-dose combination, post-market quality, drug quality, assay. INTRODUCTIONTuberculosis (TB) is the world's leading curable infectious killer disease (World Health Organization (WHO), 2008). The WHO estimated global TB prevalence as 14.4 million with the incidence of 363/100,000 population and 355/100,000 population in Africa and Uganda, respectively (WHO, 2008). Uganda being one of the most highly TB burdened countries of the world is faced with the challenge of drug resistance to TB treatment. In a previous study by Bertzel (1999), the reported rate of Multi-Drug Resistant TB (MDR-TB) in Uganda was slightly over 4% in *Corresponding author E-mail: ocanmoses@gmail.com. Tel: +256-712-234364. in patients with a history of prior treatment and about 1% in patients with no history of prior treatment. A number of factors contribute to development of resistance to TB medications. Among these factors is use of substandard medications in TB treatment and lack of patient supervision (Pecoul, 1999;Panchagnula, 2004).Rifampicin (3-[4-methyl-1-piperazinyl] iminomethyl rifamycin SV) is a semi synthetic macro cyclic antibiotic derived from Streptomyces mediterranei (Martindale, 2002). It is o...

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Section: Discussionsupporting

confidence: 82%

Substandard rifampicin based anti-tuberculosis drugs common in Ugandan drug market

Ocan¹

2013

Afr. J. Pharm. Pharmacol.

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“…Under alkaline conditions (pH of 7.5 to 9.0) rifampicin will oxidize if oxygen is present, becoming rifampicin-quinone. (Gallo, Radaelli, 1976;Singh et al, 2001). Maximum stability of rifampicin is reached in near-neutral solutions.…”

Section: Introductionmentioning

confidence: 99%

“…These differences in solubility in aqueous media could affect the absorption and bioavailability of the drug when in solid state for oral ingestion (Singh et al, 2001;Agrawal et al, 2004;.…”

Section: Introductionmentioning

confidence: 99%

Thermal behavior and decomposition kinetics of rifampicin polymorphs under isothermal and non-isothermal conditions

Alves

Reis

Silva

et al. 2010

Braz. J. Pharm. Sci.

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The thermal behavior of two polymorphic forms of rifampicin was studied by DSC and TG/DTG. The thermoanalytical results clearly showed the differences between the two crystalline forms. Polymorph I was the most thermally stable form, the DSC curve showed no fusion for this species and the thermal decomposition process occurred around 245 °C. The DSC curve of polymorph II showed two consecutive events, an endothermic event (T peak = 193.9 °C) and one exothermic event (T peak = 209.4 °C), due to a melting process followed by recrystallization, which was attributed to the conversion of form II to form I. Isothermal and non-isothermal thermogravimetric methods were used to determine the kinetic parameters of the thermal decomposition process. For non-isothermal experiments, the activation energy (E a ) was derived from the plot of Log β vs 1/T, yielding values for polymorph form I and II of 154 and 123 kJ mol -1 , respectively. In the isothermal experiments, the E a was obtained from the plot of lnt vs 1/T at a constant conversion level. The mean values found for form I and form II were 137 and 144 kJ mol -1 , respectively. Uniterms: Rifampicin. Tuberculosis. Thermal analysis. Thermal decomposition. Kinetic analysis.O comportamento térmico de duas formas polimórficas da rifampicina foi estudado por DSC e TG/DTG. Os resultados termoanalíticos mostraram claramente as diferenças entre as duas formas cristalinas. O polimorfo I é a forma mais estável termicamente, a curva DSC não mostrou a fusão dessa espécie e o processo de decomposição térmica ocorreu próximo a 245 o C. A curva DSC do Polimorfo II apresentou dois eventos consecutivos, um endotérmico (T pico = 193,9 o C) e outro exotérmico (T pico = 209,4 o C), devido à fusão seguida de recristalização, a qual foi atribuída à conversão da forma II à forma I. Métodos termogravimétricos isotérmicos e não-isotérmicos foram empregados para determinar os parâmetros cinéticos do processo de decomposição térmica. Para experimentos não-isotérmicos, a energia de ativação (E a ) foi obtida a partir do gráfico de Log β vs 1/T, e os valores 154 e 123 kJ mol -1 foram encontrados, respectivamente, para os polimorfos I e II. Para os experimentos isotérmicos, a E a foi obtida a partir do gráfico de lnt vs. 1/T a um nível de conversão constante. O valor médio encontrado foi 137 e 144 kJ mol -1 , respectivamente, para a forma I e forma II.

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“…Rifampicin is one of the first-line drugs recommended by the World Health Organization in the treatment of tuberculosis despite of the drawbacks of poor bioavailability and short biological half-life (5,6). In order to overcome the problems of poor absorption, fast degradation, and adverse side effects of rifampicin, many researchers have concentrated their attention in the development of controlled-release rifampicin formulations (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Rehydrated Lyophilized Rifampicin-Loaded mPEG–DSPE Formulations for Nebulization

2010

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Abstract. Rifampicin-loaded nanoparticles were prepared using two different molecular weights of poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG2000-DSPE and mPEG5000-DSPE) polymers. Particle sizes of all formulations studied were in the range of 162-395 nm. The entrapment efficiency (EE) was not affected by the copolymer's molecular weight, and the highest EE (100%) was obtained with drug to copolymer ratio of 1:5. The differential scanning calorimetry (DSC) thermograms showed Tg of rifampicin-loaded PEG-DSPE nanoparticles that shifted to a lower value, indicating entrapment of rifampicin in polymer matrix. The Fourier transformed infrared spectra revealed no chemical interactions between the drug and both copolymers. The in vitro drug release from the formulations occurred over 3 days and followed first-order release kinetic and Higuchi diffusion model. The nebulization of rehydrated lyophilized rifampicin mPEG-DSPE formulations had mass median aerodynamic diameter of 2.6 µm and fine particle fraction of 42%. The aerodynamic characteristic of the preparations was not influenced by the molecular weight of the copolymers. Therefore, it is suggested that both mPEG-DSPE are promising candidates as rifampicin carrier for pulmonary delivery.

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A critical review of the probable reasons for the poor variable bioavailability of rifampicin from anti-tubercular fixed-dose combination (FDC) products, and the likely solutions to the problem

Cited by 90 publications

References 16 publications

Substandard rifampicin based anti-tuberculosis drugs common in Ugandan drug market

Substandard rifampicin based anti-tuberculosis drugs common in Ugandan drug market

Thermal behavior and decomposition kinetics of rifampicin polymorphs under isothermal and non-isothermal conditions

Rehydrated Lyophilized Rifampicin-Loaded mPEG–DSPE Formulations for Nebulization

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