ITRACONAZOLE-A VERY LOW BIOAVAILABILITY BCS CLASS II DRUG

Summary

KinetiSol was able to formulate itraconazole, a very difficult drug, and achieve 6-fold enhanced bioavailability over the marketed Sporanox® product.

Furthermore, showcasing the flexibility of KinetiSol, compositions can also be tuned down to match the pharmacokinetic profile of Sporanox, a drug which years after coming off-patent still only has two generics on market. This study established the unique ability of KinetiSol to process thermally sensitive, highly viscous polymers without use of a plasticizer with a resulting improvement in physical stability of the amorphous dispersion end product.

Finally, KinetiSol was able to homogenously process a highly viscous, cross-linked polymer into an amorphous dispersion without use of a plasticizer opening new possibilities for the use of cross-linked materials for solubility enhancement applications.

Introduction

Itraconazole is a broad spectrum anti-fungal BCS II compound with a melting point of 170°C. The solubility in 0.1N HCl is approximately 4-6 µg/mL and in water is 1-4 ng/mL. Itraconazole exhibits very poor oral bioavailability owing to its insolubility in intestinal fluids.

Itraconazole: Physicochemical Properties
IndicationAnti-fungal
Melting Point170°C
Solubility – 0.1 N HCl4 – 6 μg/mL
Solubility – Water1 – 4 ng/mL
LogP5.66
pKa3.7
BCS ClassII

ITZ-HPMC-DSC-and-Disso

ITZ-HPMC-DSC-and-Disso (1)

Result

Single-Phase Amorphous Dispersions of Itraconazole and HPMC by KinetiSol

In a study conducted by DiNunzio et al., thermal processing of ITZ and HPMC by both hot-melt extrusion (HME) and KinetiSol was investigated. These researchers found that ITZ:HPMC E5 (1:2) amorphous solid dispersions produced by HME were two-phase systems; whereas, the same composition processed by KinetiSol yielded a single-phase amorphous dispersion. These findings are presented in the figure below which shows a single glass transition temperature at 86.02°C for the KinetiSol product and two distinct Tgs for the melt extruded product.

The more homogenous, single-phase KinetiSol system was also determined to produce more rapid and extensive supersaturation of ITZ in simulated gastric fluid versus the HME system (shown above, right). The dissolution result correlated with the results of mDSC in that the dissolution rate of the more homogenous KinetiSol system would be governed primarily by the hydrophilic polymer, while the heterogeneous HME system containing drug rich, hydrophobic domains would dissolve more slowly.

CASE STUDIES

Read about exciting new breakthroughs

KinetiSol® has been the subject of numerous research articles published in top peer-reviewed journals in recent years. These papers demonstrate unique capabilities of the KinetiSol®process and its benefits for amorphous solid dispersion processing. Key advantages of the KinetiSol® process are illustrated in these case studies.

 

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