دانلود رایگان مقاله ارتقای دیسپرسیو جامد آمورف مبتنی بر سلولز

ABSTRACT

Quercetin (Q) is a bioactive flavonol with potential to benefit human health. However, Q bioavailability is relatively low, due to its poor aqueous solubility and extensive phase-II metabolism. Strategies to increase solution concentrations in the small intestinal lumen have the potential to substantially increase Q bioavailability, and by extension, efficacy. We aimed to achieve this by incorporating Q into amorphous solid dispersions (ASDs) with cellulose derivatives. Q was dispersed in matrices of cellulose esters including 6-carboxycellulose acetate butyrate (CCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate suberate (CASub) to afford ASDs that provided stability against crystallization, and pH-triggered release. Blends of CASub and CCAB with the hydrophilic polyvinylpyrrolidone (PVP) further enhanced dissolution. The ASD 10% Q:20% PVP:70% CASub most significantly enhanced Q solution concentration under intestinal pH conditions, increasing area under the concentration/time curve (AUC) 18-fold compared to Q alone. This novel ASD method promises to enhance Q bioavailability in vivo.

4. Conclusions

Overall these results confirm our hypotheses, and significantly illuminate structure-property relationships of ASD polymers. We can term polymer properties like sufficiently high Tg (50 ◦C or more above the highest likely ambient temperature) and solubility parameters within an effective range (hydrophobic enough to interact with hydrophobic drugs, hydrophilic enough to release them) as necessary but clearly not sufficient polymer properties for effectiveness in ASD. This work further confirms the value of the pH-responsive carboxylic acid functional group in providing neutral pH release as well as desirable specific polymer-drug interactions, but this parameter alone is also insufficient to fully predict success or failure. This work also provides a further example of the value of polymer blends for achieving performance levels (in this case both release and crystallization inhibition) that would be diffi- cult to achieve by ASD of drug, in this case Q, with a single polymer. More detailed study of expanded sets of polymers is necessary to further sort out the structural features required for effective ASD. The results ofthis study, particularly with CASub, warrantin vivo investigation of Q ASDs as method for increasing Q bioavailability upon oral administration. They predict that significant supersaturation should be achievable in vivo; it will be of great interest to see whether this results in higher permeation in vivo, and in saturation of metabolic enzymes, thereby providing enhanced bioavailability, particularly of the unmetabolized native Q. If successful, such an ASD approach should enable animal and human in vivo bioavailability enhancement studies, and provide predictable absorbed doses that will enable informative dose-response studies, thus leading to exploration of whether the potential health benefits of Q can be realized in humans.