title: Alphaxalone Reformulated: A Water-Soluble Intravenous Anesthetic Preparation in Sulfobutyl-Ether-β-Cyclodextrin.
abstract: 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 It was withdrawn from clinical practice because of hypersensitivity to Cremophor EL.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).
authors.affiliation: 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.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Goodchild
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Serrao
authors.forename: Anton
authors.initials: A
authors.lastname: Kolosov
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
mesh_terms: D018686:Anesthetics, Intravenous / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000737:chemistry*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D011277:Pregnanediones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015742:Propofol / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D018570:Risk Assessment; D012890:Sleep / Q000187:drug effects; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D013997:Time Factors; D014867:Water / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D018686:Anesthetics, Intravenous; D005079:Excipients; D011277:Pregnanediones; D047392:beta-Cyclodextrins; D014867:Water; C093196:SBE4-beta-cyclodextrin; C000515:cremophor EL; D013024:Soybean Oil; C006477:alphaxalone; D005990:Glycerol; D015742:Propofol