Formulation development of sustained release Zidovudine-lamivudine fixed dose combination paediatric mini matrices by hot melt extrusion

Abstract

HIV/AIDS has become one of the major and deadliest pandemics in the world today. Besides concerns about cost and accessibility, a major concern for current therapies in most developing countries is the lack of age appropriate antiretroviral formulations which might expose children to "homemade" formulations with significant risks of variable dosing, poor and erratic absorption and inappropriate pharmacokinetic profiles. In this light and with the several campaigns driven by the World Health Organisation (WHO), UNICEF and the European Medicines Agency (EMA) in mind, the potential for developing alternative presentations for paedratic use has been raised. Flexible options such as granules, pellets, mini- matrices which children are able to swallow or which can be dispersed on the tongue or in water have been identified as the presentations of choice in some of these WHO led discussions. It is therefore critical that feasibility assessments are undertaken to demonstrate the likelihood of administrating essential medicines in this manner. In this regard, two antiretroviral drugs have been identified for this study. Oral zidovudine (AZT) and lamivudine (3TC) are soluble drugs with short elimination half-lives and moderate bioavailability. Free high doses are therefore required to achieve and maintain therapeutic blood. As a result, dose-dependent toxic side effects are frequently observed. One way to avoid dependent side effects is by formulating the dosage forms as sustained release formulations intended to optimize a therapeutic regimen by providing slow and continued service delivery over the entire dosing giving reduced side effects, whilst also providing compliance and convenience. To have access and availability of paediatric fixc : iSC bination mini matrices at low cost, a fast, flexible and efficient manufacturing process which can be adapted by local manufacturers in HIV/AIDS endemic regions such .: ; 'an African is required. One-such process that could be adapted and scaled up for: .ctic .isily is hot melt extrusion (HME).

This study was therefore designed to investigate the physicochemical properties of zidovudine and lamivudine and their influence on interactions with matrix forming polymers such as ethylcellulose, Polyvinylpyrrolidone/Vinyl acetate (Kollidon® SR) and polyethylene oxide (PEG) during hot melt extrusion. Furthermore, mini-matrix formulations of fixed dose combinations of zidovudine and lamivudine were developed followed by evaluation of key quality attributes including in-vitro dissolution and accelerated stability studies. The dissolution data were used to make estimations of in-vivo performance using a method described in the literature. The results showed that Zidovudine and Lamivudine were thermally stable and miscible (Van Krevelen's solubility parameter calculations) with polymers such as ethylcellulose, Kollidon® SR and PEG enabling extrusion by hot melt extrusion. Thermal and crystalline characteristics were studied using Differential Scanning Calorimetry (DSC) and X-ray powder diffraction studies (XRPD) which showed that the drugs were transformed from the crystalline to the amorphous state. Rheological studies showed that addition of Zidovudine decreased the melt viscosity with all the polymers while Lamivudine seemed to saturate the polymer at 40%w/w concentration at which point there was a marked increase in melt viscosity. Triethyl citrate (TEC) was used as plasticizer during hot melt extrusion, whilst polyethylene oxide (PEG) was added to modulate the drug release profile. For some formulation variants, extensive drug release (98%) was observed over a period of .24 hrs, particularly for mini-matrices of zidovidine and lamivudine formulated with Kollidon® SR. The release was related to the increases in percentage of plasticizer TEC which may have caused strong coalescence between the drug and polymer particles. Accelerated stability studies done using mini matrices in open and closed high density polyethylene (HDPE) bottles for a period of three month in a hot oven chamber at 40° C and 75% Relative Humidity (RH) as well as at 60°C in Humidity (RR) as well as at 60°C in closed HDPE bottles for 15 days and the results showed that the both zidovudine and lamivudine did not recrystallized and the matrices were stable after 3 months. The data obtained from the predicted in vivo drug blood concentration profiles for ethylcellulose and Kollidon® SR formulations showed that both zidovudine and lamivudine not only sustained drug release for over 16 hrs but also maintained drug concentration within the effective drug concentrations (therapeutic window) over the same period which suggests that side effects caused by frequent dosing of the drugs could be avoided. In conclusion, it is feasible to produce stable fixed dose combination sustained release mini matrices of zidovudine/lamivudine using HME with ethylcellulose, Kollidon® SR and PEO. This platform therefore provides potential to be used a standard method for producing sustained release formulations of antiretroviral drugs for use in the paediatric population.