The project's goal is to develop age-appropriate fast disintegrating, fast dissolving (FDFD) granules and tablets of fixed dose combination antiretroviral (ARV) drugs - zidovudine, lamivudine and nevirapine for the pediatric population. The ultimate goal is to facilitate access of ARV drugs in a dispersible solid dosage form that does not need refrigeration for children suffering from HIV/AIDS, especially in resource poor countries that also have high prevalence of the disease. The hypotheses are that optimal FDFD granules and tablets with acceptable potencies will be developed using a stability-indicating method.
In Specific Aim 1, interaction of drugs with excipients such as sweeteners (e.g., saccharin, sucralose, sucrose) and diluents/binder (e.g., microcrystalline cellulose, dicalcium phosphate) will be examined. The methodologies that will be used to examine the solid state properties such as crystallinity, and state of hydration of the drug include powder X- Ray diffraction, differential scanning calorimetry, thermogravimetry and particle size analysis. These properties could affect the solubility, disintegration and dissolution of the final product. Stability-indicating high performance liquid chromatography (HPLC) will be used to assay the drug as well as monitor stability monitoring in Aim 3.
In Specific Aim 2, wet granulation method will be used to develop fast disintegrating fast dissolving granules. The formulation variables will be optimized using full factorial statistical design of experiment. The goal is to select the best formulation using the screened excipients and combinations. The optimized granules will be divided into 2 batches, one to be developed as such (FDFD granules) for younger children and the other to be further developed into compressed FDFD tablets, suitable for older children. Performance of the products will be evaluated techniques such as particle size distribution, flowability, compactibility, tensile strength and dissolution.
In Aim 3, the short-term (3-month) physical and chemical stability of the optimized formulation will be investigated using ICH Q1FC conditions for climactic zones III and IV. A lot of countries in many resource-poor countries in sub-Sahara Africa and Asia fall under these climactic conditions. The stability will be such that the expected potencies of 90-110% range will be achieved over the storage period. Methodologies and data from these studies could be adapted for other fixed dose combination products. The data obtained in this project will serve as a basis for future grant proposal submission. This will facilitate future manufacturing scale up and pilot clinical trials on limited number of children for examination of bioavailability, increased CD4 count decreased viral load. PUBLIC HEALTH NARRATIVE: HIV-infected infants frequently show clinical symptoms in the first year of life, and by one year of age an estimated one-third of infected infants would have died, and about half by 2 years of age. There is thus a critical need to provide antiretroviral therapy (ART) for infants and children who become infected. Developing robust and stable age- appropriate fast dispersible fast dissolving granules or tablet formulations for infected perinatal (0-6 months) and pediatric children (6 months - 12 years) respectively will fill the void of appropriate formulations for the target populations and reduce mortality and morbidity.
| Esseku, Frederick; Joshi, Anjali; Oyegbile, Yemisi et al. (2013) A randomized pahse I bioequivalence clinincal trial of a paediatric fixed-dose combination antiretroviral reconstitutable suspension in healthy adult volunteers. Antivir Ther 18:205-12 |
| Esseku, Fredrick; Joshi, Anjali; Oyegbile, Yemisi et al. (2013) A randomized Phase I bioequivalence clinical trial of a paediatric fixed-dose combination antiretroviral reconstitutable suspension in healthy adult volunteers. Antivir Ther 18:205-12 |
