Abstract
This study aimed to develop a novel sustained release pellet of loxoprofen sodium (LXP) by coating a dissolution-rate controlling sub-layer containing hydroxypropyl methyl cellulose (HPMC) and citric acid, and a second diffusion-rate controlling layer containing aqueous dispersion of ethyl cellulose (ADEC) on the surface of a LXP conventional pellet, and to compare its performance in vivo with an immediate release tablet (Loxinon®). A three-level, three-factor Box-Behnken design and the response surface model (RSM) were used to investigate and optimize the effects of the citric acid content in the sub-layer, the sub-layer coating level, and the outer ADEC coating level on the in vitro release profiles of LXP sustained release pellets. The pharmacokinetic studies of the optimal sustained release pellets were performed in fasted beagle dogs using an immediate release tablet as a reference. The results illustrated that both the citric acid (CA) and ADEC as the dissolution- and diffusion-rate controlling materials significantly decreased the drug release rate. The optimal formulation showed a pH-independent drug release in media at pH above 4.5 and a slightly slow release in acid medium. The pharmacokinetic studies revealed that a more stable and prolonged plasma drug concentration profile of the optimal pellets was achieved, with a relative bioavaibility of 87.16% compared with the conventional tablets. This article provided a novel concept of two-step control of the release rate of LXP, which showed a sustained release both in vitro and in vivo.
Highlights
Pellets, as multiple unit preparations, offer a lot of clinical benefits compared with single unit dosage forms, such as reduced intra- and inter-subject variability on drug plasma, decreased local irritations, less dose dumping risk, and stable plasma concentrations [1,2]
In order to reduce the usage of pH-modifiers and maintain an appropriate pHM in the dosage form, citric acid (CA) as the pH-modifier was first proposed to be incorporated into the dissolution-rate controlling layer to decrease the dissolution rate of Loxoprofen sodium (LXP)
In order to better understand the impact of CA on the drug release rate, simultaneous release profiles of CA and LXP in formulations with different CA concentrations were conducted
Summary
As multiple unit preparations, offer a lot of clinical benefits compared with single unit dosage forms, such as reduced intra- and inter-subject variability on drug plasma, decreased local irritations, less dose dumping risk, and stable plasma concentrations [1,2]. Incorporation of pH-modifiers into the preparation was a common approach in matrix or coating systems These pH modifiers could significantly modify the micro-environmental pH (pHM) inside the systems, and result in a decrease or increase of the drug solubility, leading to a modified drug dissolution rate [22,23,24]. In order to reduce the usage of pH-modifiers and maintain an appropriate pHM in the dosage form, citric acid (CA) as the pH-modifier was first proposed to be incorporated into the dissolution-rate controlling layer to decrease the dissolution rate of LXP. In this system, the first-step control was to reduce the dissolution rate of LXP by creating a sub-coating layer containing pH-modifier CA, while the second-step control was to decrease the diffusion rate of LXP by creating a non-soluble polymeric film.
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