Dissolution Behavior of an Amorphous Solid Dispersion in Surfactant Containing Media

The present study aimed to develop an amorphous solid dispersion of nobiletin (ASD/NOB) using hydroxypropyl cellulose-SSL (HPC-SSL) to improve the pharmacokinetic properties and hypouricemic effect of NOB. ASD/NOB was prepared by the freeze-drying method (ASD/NOB). ASD/NOB was characterized with a focus on crystallinity, dissolution, pharmacokinetic behavior, and hypouricemic action in a rat model of hyperuricemia. ASD/NOB showed significant improvement in dissolution behavior, as evidenced by a 4.4-fold higher dissolved NOB concentration than crystalline NOB at 2 h in distilled water. After the oral administration of ASD/NOB (50 mg NOB/kg) in rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the Tmax value of orally administered ASD/NOB was 60% shorter than that of orally administered crystalline NOB. In a rat model of hyperuricemia, orally dosed ASD/NOB showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline NOB. Based on these findings, ASD/NOB may be an efficacious dosage option to improve the nutraceutical potential of NOB for the treatment of hyperuricemia.

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Impact of Drug-Polymer Interaction in Amorphous Solid Dispersion Aiming for the Supersaturation of Poorly Soluble Drug in Biorelevant Medium

AAPS PharmSciTech ◽

10.1208/s12249-020-01737-6 ◽

2020 ◽

Vol 21 (5) ◽

Author(s):

Cassiana Mendes ◽

Rafael G. Andrzejewski ◽

Juliana M. O. Pinto ◽

Leice M. R. de Novais ◽

Andersson Barison ◽

...

Keyword(s):

Solid Dispersion ◽

Amorphous Solid ◽

Amorphous Solid Dispersion ◽

Poorly Soluble ◽

Poorly Soluble Drug ◽

Drug Polymer Interaction ◽

Biorelevant Medium ◽

Polymer Interaction

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Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs

Pharmaceutics ◽

10.3390/pharmaceutics13040557 ◽

2021 ◽

Vol 13 (4) ◽

pp. 557

Author(s):

Deanna M. Mudie ◽

Aaron M. Stewart ◽

Jesus A. Rosales ◽

Nishant Biswas ◽

Molly S. Adam ◽

...

Keyword(s):

Solid Dispersion ◽

Drug Exposure ◽

Ph Effect ◽

Hydroxypropyl Methylcellulose ◽

Amorphous Solid ◽

Gastric Ph ◽

Patient Treatment ◽

Oral Exposure ◽

Amorphous Solid Dispersion ◽

Plasma Drug

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

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Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

Pharmaceutics ◽

10.3390/pharmaceutics13060889 ◽

2021 ◽

Vol 13 (6) ◽

pp. 889

Author(s):

Kaijie Qian ◽

Lorenzo Stella ◽

David S. Jones ◽

Gavin P. Andrews ◽

Huachuan Du ◽

...

Keyword(s):

Solid Dispersion ◽

Oral Drug Delivery ◽

Drug Product ◽

Amorphous Solid ◽

Water Soluble ◽

Nucleation Theory ◽

Product Development Process ◽

Classical Nucleation Theory ◽

Oral Drug ◽

Amorphous Solid Dispersion

Among many methods to mitigate the solubility limitations of drug compounds, amorphous solid dispersion (ASD) is considered to be one of the most promising strategies to enhance the dissolution and bioavailability of poorly water-soluble drugs. The enhancement of ASD in the oral absorption of drugs has been mainly attributed to the high apparent drug solubility during the dissolution. In the last decade, with the implementations of new knowledge and advanced analytical techniques, a drug-rich transient metastable phase was frequently highlighted within the supersaturation stage of the ASD dissolution. The extended drug absorption and bioavailability enhancement may be attributed to the metastability of such drug-rich phases. In this paper, we have reviewed (i) the possible theory behind the formation and stabilization of such metastable drug-rich phases, with a focus on non-classical nucleation; (ii) the additional benefits of the ASD-induced drug-rich phases for bioavailability enhancements. It is envisaged that a greater understanding of the non-classical nucleation theory and its application on the ASD design might accelerate the drug product development process in the future.

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