Method development and stability of pheroid-based anti-retroviral formulations
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Southern Africa is the worst affected sub region in the world, with South Africa continuing to have the highest number of people living with HIV in the world. It is estimated that 5.3 million people in South Africa were living with HIV at the end of 2003. According to the WHO the total number of people living with HIV in 2004 was 39.4 million. The estimated total for children with HIV under 15 years was 2.2 million. From a total of 3.1 million AIDS deaths in 2004, 510 000 were children under 15 years. Combination antiretroviral therapy has proven to be the most effective approach in treating HIV positive patients. This triple cocktail treatment is also known as highly active antiretroviral therapy (HAART). The key to its success lies in the drug combination's ability to disrupt HIV at different stages in its replication. Reverse transcriptase inhibitors, which usually make up two drugs in the HAART regimen, restrain an enzyme crucial to an early stage of HIV duplication. Protease inhibitors hold back another enzyme that functions near the end of the HIV replication process. This combination therapy leaves us with a major patient compliance problem for children and babies. It would be difficult for children and babies to swallow large amount of tablets. Therefore an alternative dosage form to the conventional fix dose combination tablets is desired and would be of importance for paediatric HIV patients, and for those like the elderly, who cannot swallow other oral dosage forms such as capsules and tablets. According to the WHO should paediatric formulations consist of the following actives: Zidovudine/Lamivudine/Abacavir. The triple combination containing zidovudine, was omitted because of the toxicity and adverse effects, which is cardiomyopathy in children. The aim of this study was therefore, to formulate a triple combination formulation containing stavudine/lamivudine/nevirapine in the pheroidTM delivery system; to develop and validate a HPLC method for all the actives and preservatives; and to evaluate the physical and chemical stability of these products over a period of three months (12 weeks) at three conditions, namely 25OC /60%RH, 30°C /65%RH and 40°C /70%RH. Two types of pheroidTM formulations were used in this study i.e., Formulation A which contains the water and oily phase of the pheroidTM and Formulation B which consists of only the oil phase. The active ingredients, together with the preservatives and the anti-oxidants are entrapped in each of these formulations. After the formulations were made, initial assays were done as well as pH and viscosity tests, and then these samples were kept in climate rooms for accelerated stability studies of three months. A HPLC method were successful develop and validated which is suitable to analyse lamivudine, stavudine, nevirapine, sodium methyl hydroxybenzoate and propyl hydroxybenzoate simultaneously in the pheroid or the pro-pheroid solution for stability testing, quality control and batch release purposes. This method could be regarded as being stability indicating. The development of an HPLC method for the anti-oxidants, BHT, BHA and Vitamin E simultaneously in the pheroid or the pro-pheroid were successful and can also be regarded as being stability indicating. A pH test as well as a viscosity test were done on formulation A. The results for the pH and viscosity tests indicate that no significant changes took place during the accelerated stability testing. Viscosity and pH tests were not performed on formulation B, due to the high viscosity of the formulation. The results for the microbial limit tests for formulation A and formulation B indicated the absence of micro-organisms for all practical purposes. There was however, a change in the physical appearance of the product in formulation A and B. The product became a darker yellow at the higher temperatures. This could be due to the breakdown of stavudine or due to the free radicals present in the formulation. Results during the assay yielded a wide variation in the concentrations of the actives, and this indicated a major problem in the formulation/active combination. Nevirapine is highly insoluble in aqueous media and stavudine had stability problems. The assay values of lamivudine remain stable throughout the study. Due to the variations in the assay results, this pilot study showed some critical formulation problems, but the pheroid and pro-pheroid formulations has definite marketing possibilities and could become an essential part in the fight against AIDS.
- ETD@PUK