Hans-Ulrich Schulz

New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation

Summary: The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2‐hydroxypropyl‐β‐cyclodextrin(HPβCD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HPβCD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol‐based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally Infusion of CBZ:HPβCD solutions or HPbCD “placebo” formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ: glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardio‐vascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by de‐creasing formation of the major CBZ metabolite CBZ‐10,11‐epoxide (CBZ‐E). With infusion of CBZ:HPβCD 10 ml/min for 12–15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of −3.6 pgl μmCl were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half‐life (t/2) <1 h]. Comparison of peak plasma levels determined after p.0. administration of CBZ to dogs with peak CBZ levels previously determined after p.0. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans. In view of previous experimental data showing rapid penetration of CBZ into brain, our results indicate that aqueous CBZ:HPPCD solutions might be ideally suited for parenteral use in acute clinical conditions such as status epilepticus (SE), particularly because CBZ is a drug with only minor respiratory or cardiovascular effects.

Tramadol SR Formulations : Pharmacokinetic Comparison of a Multiple-Units Dose (Capsule) versus a Single-Unit Dose (Tablet).

AbstractIntroduction: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet). Methods: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC12) and maximum concentration (Cmax), as well as the mean AUC12 and CPmax for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC12 of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment. Results: The two formulations were equivalent in the area under the curve (AUC∞: 2411 vs 2527 μg · h/L). However, capsules led to a lower Cmax (148.6 vs 183.2 μg/L), to a later time to reach Cmax (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC12 was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05). Conclusion: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.

Bioavailability of β-aescin from horse chestnut seed extract: Comparative clinical studies of two galenic formulations

The bioavailability of β-aescin—the main active constituent of horse chestnut seed extract—in a nonretarded test medication in comparison with that in a retarded reference formulation was evaluated in 2 randomized crossover clinical trials involving 18 healthy volunteers each. Serum concentration/time curves derived under steady-state conditions and pharmacokinetic parameters measured during both studies showed no significant difference between absorption rates for the retarded versus nonretarded preparation. In the first study, investigators found a test-to-reference ratio of 1.06 (90% confidence interval [CI] range: 99–113) for the area under the curve (AUC; the primary outcome measure). Absorption rates were diminished during the night compared with daytime rates for both study preparations. In the second study, using AUC and maximum concentration (Cmax) as the primary characteristics, investigators analyzed bioavailability based on the mean of 2 consecutive daytime periods and obtained estimates of 1.07 for AUC (90% CI range: 0.96–1.19) and 1.05 for Cmax (90% CI range: 0.90–1.21). Bioequivalence of the test and reference drug preparations was thus established according to theNote for Guidance on the Investigation of Bioavaiiability and Bioequivalence. Both treatments were equally well tolerated.

Simultaneous determination of spirapril and spiraprilat in plasma by capillary gas chromatography-mass spectrometry

A specific, sensitive and precise method for the simultaneous determination of spirapril (CAS 94841-17-5) and spiraprilat (CAS 83602-05-5) in human plasma is described. The method involves the use of enalapril as internal standard, solid-phase extraction, derivatization and capillary gas chromatography with mass sensitive detection. The working range is from 2.5 to 500 micrograms/l for spirapril and spiraprilat, respectively. Data demonstrating the precision and accuracy of the analytical method are given. Moreover, data concerning freeze-thaw stability, long-term stability of frozen samples, short-term stability of thawed samples, and stability of the extracts in the autosampler are given.