Polymer–Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole

Abstract

The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer–surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0–24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer–surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…through API partitioning into micelles. This partitioning can reduce the fraction of molecularly dissolved API, known as a true supersaturation, and therefore thermodynamically stabilize the drug solution (Feng et al, 2018). Furthermore, a more detailed systematic study on the effects of surfactants on API stabilization below and above of the CMC was conducted by Zhang et al (2019).…”

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

“…Surfactants at high concentrations in ASDs have been used to increase the solubility of the drug (see, e.g., the references cited in Table 1). Moreover, the presence of a surfactant in the ASD formulation could increase wettability of the relatively hydrophobic drug [17,18], while it can also inhibit drug precipitation in the aqueous medium [19,20]. On the contrary, other studies [21][22][23][24] have suggested that surfactants negatively affected drug release from ASDs due to the competitive interaction between the drug-polymer-surfactant, resulting in drug recrystallization promotion from the supersaturated solutions.…”

“…On the other hand, a significant improvement in the performance of drug ASDs has been reported with ternary systems, such as the drug-binary polymers [11] and drug-polymer-surfactant [12]. Several studies have suggested improvement in processability, dissolution performance, and storage stability owing to incorporation of a surfactant in ASDs over those without a surfactant [12][13][14][15][16][17]. Surfactants at high concentrations in ASDs have been used to increase the solubility of the drug (see, e.g., the references cited in Table 1).…”

“…Formulation composition of drug amorphous solid dispersion (ASDs) with sodium dodecyl sulfate (SDS) in various studies and survey of the use of wettability and desupersaturation tests. Table 1 also shows that the effects of SDS on drug supersaturation maintenance have not been routinely examined in separate desupersaturation-recrystallization kinetic studies, unlike in recent studies such as Chen et al [35], Deshpande et al [24], and Feng et al [17]. Moreover, several studies have indicated that SDS had a deleterious impact on drug supersaturation maintenance as it promoted drug recrystallization in the presence of polyvinyl pyrrolidone-vinyl acetate (PVP-VA) [22] and crystal growth in the presence of PVP [38].…”

Supersaturable organic-inorganic hybrid matrix based on well-ordered mesoporous silica to improve the bioavailability of water insoluble drugs

“…In principle, high drug concentration exposed to the gastrointestinal (GI) tract leads to an increased oral adsorption (Strindberg et al., 2020 ). However, the supersaturated state is inherently thermodynamically unstable, which will gradually lead to precipitation of the water insoluble drugs prior to absorption, subsequently resulting in unsatisfactory bioavailability (Ilevbare et al., 2013 ; Feng et al., 2018 ). Therefore, the prolonged maintenance of supersaturated state in the GI tract would be beneficial for better absorption.…”