Combination antiretroviral therapy : formulation of a powder for oral suspension containing Lamivudine, Zidovudine and Nevirapine

Abstract

The human race has had to endure a variety of disabling and life threatening diseases which include leprosy, plaque, Black Death and numerous other infamous viruses, none of which awaken terror like the Human Immunodeficiency Virus (HIV). HIV infection has produced one of the most dreaded epidemics of the twentieth century, or rather, of all time, leaving no country or race untouched. Until this time, no cure for this disease has been discovered, and sufferers have to tolerate the frustrating adverse effects of the numerous Antiretroviral (ARV) drugs that have to be taken in order to live an average life. Whilst combination antiretroviral therapy has proven to be the most effective approach in treating HIV positive patients, Fixed Dose Combination (FDC) therapy seem to assure better patient adherence. An oral liquid dosage formulation is desired for paediatric HIV patients, and for those who cannot swallow other oral dosage forms such as capsules and tablets. The focus of this study was to combine lamivudine, zidovudine and nevirapine into a powder for oral suspension, and to identify incompatibilities and other factors that could possible affect the physical arid chemical stability of the formulation. Formulations were designed according to the UNICEF/WHO (2004) dosage suggestions. The first step in the product development was an investigative literature study into the stability and possible interactions between the three active pharmaceutical ingredients (APIs) and excipients. Compatibility was confirmed by means of DSC and High Performance Liquid Chromatography (HPLC) -studies. The optimal mixing time for the powders for suspension was determined before formulation of the bulk formulae began. Six suspension formulations according to patient mass were formulated containing the dosage regime for one month as suggested by WHO. Sodium propyl hydroxybenzoate and sodium methyl hydroxybenzoate were added as preservatives. The physical and chemical stability of pharmaceutical substances do play a vital role in the success of a specific product. Stability tests, physical and chemical. and preservative efficacy studies were therefore performed on all six formulations over a period of twelve weeks, at three temperature conditions, namely 25oC+60%RH, 30°+65%RH and 40°C+75%RH. In that period, in-use stability testing, to ensure the stability during patient use, was also conducted. Results obtained for pH, relative density, viscosity and moisture content indicated that no significant changes took place during the accelerated stability testing. as well as the in-use test period. 'There was a change in the physical appearance, especially the colour, with time at the 3O0C+6S%RH and 40°C+75%RH storage conditions, as well as during in-use testing after 12 weeks. Dissolution results showed that larnivudine, zidovudine and nevirapine were immediately dissolved, with 100% dissolution after 10 minutes. The assay results for lamivudine, zidovudine and nevirapine remained within the specification of 90-110%, but a downward trend in lamivudine assay was observed in the 300 ml and 900 ml formulation, where a result of 89.3% was measured after 12 weeks at 40oC+75%RH. Results for sodium methyl hydroxybenzoate were all within the 90-110% limit. Results higher than the upper limit of 110% were calculated for sodium propyl hydroxybenzoate in some samples. This could be due to integration inconsistencies during assay due to the very mall peak. Preservative Efficacy Test (PET) results were all within the USP 28 specifications, even during in-use studies, and confirmed the effectiveness of the preservative system. In conclusion it can be said that lamivudine, zidovudine and nevirapine were successfully combined in a FDC for use in paediatric, adult and geriatric AIDS patients. The powder for suspension formulations have definite marketing possibilities and could become an essential part in the fight against AIDS.