Linking the concentrations of itraconazole and 2-hydroxypropyl-β-cyclodextrin in human intestinal fluids after oral intake of Sporanox®

Abstract

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (A-type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution.

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

“…In addition, adequately capturing the bio-enabling nature of the itraconazole formulations was challenging. In the case of the OS, the mean maximum cyclodextrin concentration in the duodenum in the PBPK model (18.87 mg/mL) was close to the reported in vivo value (20.5 mg/mL) [46] The cyclodextrin binding was represented by a 1:2 model (1 API molecule to 2 cyclodextrin molecules) as a 1:3 binding model is not yet available in the software. However, considering the concentration range of cyclodextrin in the GI tract, the assessment of the difference in the solubility of itraconazole using the 1:2 or 1:3 binding model was minor.…”

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

“…For this reason, many BCS Class II drugs have traditionally failed due to the difficulty in formulating products that achieve efficacious exposures in vivo with these compounds . However, with the development of modern supersaturating drug delivery systems (SDDS) such as cocrystals, − inclusion complexes, − lipid formulations, , and amorphous solid dispersions, − it is possible to increase the overall amount of drug dissolved in solution and consequently enhance bioavailability. As a result, there has been a shift in industry perspective from avoiding such risky development candidates toward acceptance.…”

Assessing the Impact of Endogenously Derived Crystalline Drug on the in Vivo Performance of Amorphous Formulations

“…The maximum supersaturation is dictated by the amorphous-to-crystalline solubility ratio, which in the case of tacrolimus is approximately 33 . However, just because a formulation consists of amorphous drug, reaching the amorphous solubility is not guaranteed, and it is very hard to estimate the actual supersaturation achieved in vivo, although this has been attempted by removing samples from the small intestine in several studies by Augustijns and co-authors. , Factors that impact the extent of supersaturation include the ratio of the dose to the fluid volume, the dissolution rate and extent, the solubility of the drug in the dissolution fluid, and any phase transitions such as crystallization, which will deplete the supersaturation. − …”