Relative bioavailability of a paediatric granule formulation of the HIV integrase inhibitor dolutegravir in healthy adult subjects.

BACKGROUND: This study evaluated the pharmacokinetics of a granule formulation of dolutegravir developed as an alternative to tablets for use in paediatric populations. METHODS: A randomized, open-label study in healthy adults was carried out. Subjects received five treatments in a crossover design: a single dose of dolutegravir 50 mg as a tablet and dolutegravir 50 mg in 10 g of granule administered directly to mouth or mixed with purified water, water containing high cation concentrations or milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial pharmacokinetic sampling were done during each treatment period. A non-compartmental pharmacokinetic analysis was performed; geometric least-squares mean ratios and 90% CIs were generated for treatment comparison. Palatability was assessed by questionnaire. RESULTS: Plasma dolutegravir exposures in all granule treatment arms exceeded those of tablet formulation. The mean area under the curve from time 0 to infinity (AUC(0-∞)) and maximum concentrations were 55-83% and 62-102% higher, respectively. Pharmacokinetics were similar when dolutegravir was mixed with purified or cation-containing water. Dolutegravir was well tolerated, with no withdrawals due to adverse events. Taste was rated acceptable for all treatments. CONCLUSIONS: The exposure of dolutegravir after administration of granule formulation alone, with different types of water and with milk formula, exceeded that of the tablet. The similarity of dolutegravir exposure seen with the granule formulation demonstrates that dolutegravir granule can be given without restriction on the type of liquid or can be administered directly to the mouth (for example, when potable water is not available).

Scale-up studies on high shear wet granulation process from mini-scale to commercial scale.

A newly developed mini-scale high shear granulator was used for scale-up study of wet granulation process from 0.2 to 200 L scales. Under various operation conditions and granulation bowl sizes, powder mixture composed of anhydrous caffeine, D-mannitol, dibasic calcium phosphate, pregelatinized starch and corn starch was granulated by adding water. The granules were tabletted, and disintegration time and hardness of the tablets were evaluated to seek correlations of granulation conditions and tablet properties. As the granulation proceeded, disintegration time was prolonged and hardness decreased. When granulation processes were operated under the condition that agitator tip speed was the same, similar relationship between granulation time and tablet properties, such as disintegration time and hardness, between 0.2 L and 11 L scales were observed. Likewise, between 11 L and 200 L scales similar relationship was observed when operated under the condition that the force to the granulation mass was the same. From the above results, the mini-scale high shear granulator should be useful tool to predict operation conditions of large-scale granulation from its mini-scale operation conditions, where similar tablet properties should be obtained.