The combination of real-time Raman spectroscopy and mathematical modeling provided insights into the kinetics of lipolysis-triggered drug crystallization. This knowledge allows a better biopharmaceutical understanding and will, ultimately, lead to the improved development of lipid-based drug formulations.

The first aim of this study was to characterize the luminal contents and their micellar phase after the administration of a heterogeneous liquid meal to healthy adults. The second aim was to evaluate the impact of micellar lipids and coarse lipid particles on danazol flux through intestinal monolayers. A third aim was to compare the micellar composition in the upper small intestine with the composition of fed state simulating intestinal fluid (FeSSIF-V2), a medium that has been proposed for investigating dissolution of poorly soluble drugs in the fed state. Danazol (150 mg), predissolved in the olive oil portion of the meal, was administered via the gastric port of a two-lumen tube to the antrum of eight adults. Aspirates from the ligament of Treitz [collected up to 4 h postdosing (~15 mL every 30 min)] were characterized physicochemically. Comparison of these characteristics with FeSSIF-V2 indicates that FeSSIF-V2 is an appropriate medium for evaluating drug solubilization in the luminal micellar phase in the fed state. Individual aspirates and their corresponding micellar phases were also diluted with aqueous transport medium and subjected to Caco-2 cell permeation experiments. Permeability coefficients for danazol in the diluted aspirates were smaller than those for the diluted micellar phases, which in turn were similar to those for aqueous transport medium. The high danazol concentrations overcompensated the reduced permeability coefficient values in the diluted aspirates in terms of total drug flux. We conclude that drug dissolved in the coarse lipid particles formed after administration of a triglyceride solution can directly contribute to the flux of lipophilic drugs across the intestinal mucosa.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Nasal application of midazolam has been studied for a variety of indications. Due to the limited application volume, highly concentrated formulations are required to reach clinically relevant concentrations in adult patients. No data on the pharmacokinetics and pharmacodynamics of nasal midazolam formulations based on cyclodextrin and chitosan are available. WHAT THIS STUDY ADDS• Clinically effective midazolam concentrations can be reached within less than 10 min after nasal administration of highly concentrated formulations containing an equimolar amount of the solubilizer randomly methylatedb-cyclodextrin combined with the absorption enhancer chitosan. Immediate non-invasive application of such formulations in emergency treatment of seizure patients by lay persons could offer clinical benefits in situations where intravenous access cannot be quickly established. AIMSTo investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml METHODSAn open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. RESULTSMean bioavailability of midazolam after nasal administration ranged from 76 Ϯ 12% to 92 Ϯ 15%. With formulations delivering 1 mg midazolam, mean Cmax values between 28.1 Ϯ 9.1 and 30.1 Ϯ 6.6 ng ml -1 were reached after 9.4 Ϯ 3.2-11.3 Ϯ 4.4 min. With formulations delivering 3 mg midazolam, mean Cmax values were between 68.9 Ϯ 19.8 and 80.6 Ϯ 15.2 ng ml -1 after 7.2 Ϯ 0.7-13.0 Ϯ 4.3 min. Chitosan significantly increased Cmax and reduced tmax of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 Ϯ 0.15 and 1.06 Ϯ 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 Ϯ 78 ms and 19 Ϯ 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. CONCLUSIONSEffective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMbCD combined with the absorption enhancer chitosan.

Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.

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