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Alphaxalone Reformulated: A Water-Soluble Intravenous Anesthetic Preparation in Sulfobutyl-Ether-β-Cyclodextrin

Goodchild, Colin S. MA, MB, BChir, PhD, FRCA, FANZCA, FFPMANZCA*; Serrao, Juliet M. MB, BS, PhD, FRCA; Kolosov, Anton MSc, PhD*; Boyd, Ben J. PhD

doi: 10.1213/ANE.0000000000000559
Anesthetic Pharmacology: Research Report

BACKGROUND: Alphaxalone is a neuroactive steroid anesthetic that is poorly water soluble. It was formulated in 1972 as Althesin® using Cremophor® EL, a nonionic surfactant additive. The product was a versatile short-acting IV anesthetic used in clinical practice in many countries from 1972 to 1984. It was withdrawn from clinical practice because of hypersensitivity to Cremophor EL. In the investigations reported here, we compared the properties of 3 anesthetics: a new aqueous solution of alphaxalone dissolved in 7-sulfobutyl-ether-β-cyclodextrin (SBECD, a water-soluble molecule with a lipophilic cavity that enables drug solubilization in water); a Cremophor EL preparation of alphaxalone; and propofol.

METHODS: Two solutions of alphaxalone (10 mg/mL) were prepared: one using 13% w/v solution of SBECD in 0.9% saline (PHAX) and the other a solution of alphaxalone prepared as described in the literature using 20% Cremophor EL (ALTH). A solution of propofol (10 mg/mL; PROP) in 10% v/v soya bean oil emulsion was used as a comparator anesthetic. Jugular IV catheters were implanted in male Wistar rats (180–220 g) under halothane anesthesia. Separate groups of 10 implanted rats each were given IV injections of PHAX, ALTH, or PROP from 1.2 mg/kg to lethal doses. Doses of each drug that caused anesthesia (loss of righting reflex and response to tail pinch) and lethality in 50% of rats were calculated by probit analysis. The drugs were also compared for effects on arterial blood pressure and heart rate.

RESULTS: IV PHAX, ALTH, and PROP caused dose-related sedation and anesthesia, with 50% effective dose (ED50) values for loss of righting reflex being 2.8, 3.0, and 4.6 mg/kg, respectively. PROP led to death in 10 of 10 rats at doses >30 mg/kg (50% lethal dose (LD50) = 27.7 mg/kg). A dose of alphaxalone 53 mg/kg as ALTH caused 10 of 10 rats to die (LD50 = 43.6 mg/kg), whereas none died when given the same doses of alphaxalone formulated in SBECD. PHAX caused 20% lethality at the maximal dose tested of 84 mg/kg. PHAX caused less cardiovascular depression than PROP. Control experiments with the 3 drug-free vehicles showed no effects.

CONCLUSIONS: Alphaxalone caused fast-onset anesthesia at the same dose for both formulations (PHAX and ALTH). The use of SBECD as a drug-solubilizing excipient did not alter the anesthetic effect of alphaxalone, but it did increase the therapeutic index of alphaxalone in PHAX compared with ALTH. PHAX has a higher safety margin than the propofol lipid formulation and also the alphaxalone formulation in Cremophor EL (ALTH).

Published ahead of print December 16, 2014

From the *Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia; Drawbridge Pharmaceuticals Pty Ltd, Malvern, Victoria, Australia; and Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.

Colin S. Goodchild, MA, MB BChir, PhD, FRCA, FANZCA, FFPMANZCA, is currently affiliated with the Drawbridge Pharmaceuticals Pty Ltd, Malvern, Victoria, Australia.

Anton Kolosov, MSc, PhD, is currently affiliated with the GlaxoSmithKline Pte Ltd, Gateway West, Singapore.

Accepted for publication October 7, 2014.

Published ahead of print December 16, 2014

Funding: This work was funded entirely by an internal grant from Monash University.

Conflict of Interest: See Disclosures at the end of the article.

This report was presented in part at the 15th World Congress of Anaesthesiologists, Buenos Aires, Argentina, March 2012; and the Annual Meeting of the International Anesthesia Research Society, Boston, MA, May 2012.

Drawbridge Pharmaceuticals Pty Ltd is the startup company set up by 2 of the inventors (C.S. Goodchild and J.M. Serrao) and that has subsumed the intellectual property and the task of development and commercialization of Phaxan.

Reprints will not be available from the authors.

Address correspondence to Colin S. Goodchild, MA, MB, BChir, PhD, FRCA, FANZCA, FFPMANZCA, Drawbridge Pharmaceuticals Pty Ltd, 23 Milton Parade, Malvern, Victoria, Australia 3144. Address e-mail to colin@drawbridgepharmaceuticals.com.au.

© 2015 International Anesthesia Research Society