Intravenous and Oral Pharmacokinetic Evaluation of a 2-Hydroxypropyl-β-cyclodextrin-Based Formulation of Carbamazepine in the Dog: Comparison with Commercially Available Tablets and Suspensions

Abstract

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

Cyclodextrins

“…Many of these drugs are excreted only to a small extent in the urine, a few percent, but this can be increased by the presence of the CDs. For example, when given IV with HP-β-CD, the renal excretion of both unchanged carbamazepine (Brewster et al, 1997) and dexamethasone (Dietzel et al, 1990) is increased. However, this is insufficient to alter their plasma PK properties, as the renal excretion only increases from about 0.75% to about 2.3% for carbamazepine.…”

Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes

“…With the growing acceptance of CDs as excipients and the presence of CD in formulations rapidly approaching regulatory approval, these pharmacokinetic and pharmacodynamic studies might be beneficial in generating dosage forms not only for TBM but also for a variety of other drugs (Brewster et al, 1997). …”

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

“…Dabei war die Konzentration von AZT im Gehirn nicht signifikant erhçht; weil AZT-CDS aber die AZT-Konzentration im Blut absenkt, resultiert daraus ein hçheres Konzentrationsverhältnis zwischen Gehirn und Blut als bei der Gabe von AZT allein. [38] Das CDS-Verfahren wurde auch verwendet, um verschiedene Neuropeptide wie Enkephalin, TRH [39][40][41] Dihydropyridine wurden auch mit Erfolg zur hirnspezifischen Freisetzung verschiedener Verbindungen wie Dopamin, [32] verschiedener Östrogene [42] und 4-Aminobuttersäure (GABA) eingesetzt.…”