Triglyceride-based microemulsion for intravenous administration of sparingly soluble substances.
A pharmaceutically acceptable microemulsion system composed of a medium-chain triglyceride (MCT), soybean phosphatidylcholine and poly(ethylene glycol)(660)-12-hydroxystearate (12-HSA-EO15) as amphiphiles, and poly(ethylene glycol) 400 (PEG 400) and ethanol as cosolvents is presented and characterized in terms of phase behavior, microstructure, solubilization capacity and in vivo effects after intravenous administration to conscious rats. At a total concentration of 11.9 wt % of soybean phosphatidylcholine and 12-HSA-EO15, a microemulsion region was formed over a wide range of alpha, where alpha is the weight fraction of MCT/(MCT + water + PEG 400 + ethanol). The microstructure of the microemulsion was of a bicontinuous nature even at high oil concentrations. The mean droplet diameter of the oil-in-water emulsion formed after dilution of microemulsions prepared at different alpha within the one-phase region was between 60 and 200 nm. It was concluded that it is possible to administer up to 0.5 mL/kg of the microemulsion (alpha = 0.5) without producing any significant effect on acid-base balance, blood gases, plasma electrolytes, mean arterial blood pressure (MAP), heart rate (HR), and PQ time (the time between depolarization of atrium and chamber). At a dose of 1.5 mL/kg, a temporary increase in MAP, a decrease in HR, and a prolongation of the PQ time were observed.
von Corswant
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C
Astra Hässle AB, Mölndal, Sweden. christian.corswant@hassle.se.astra.com
Thorén
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Engström
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S
D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004553:Electric Conductivity; D004562:Electrocardiography / Q000187:drug effects; D004655:Emulsions / Q000008:administration & dosage* / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology; D015736:Felodipine / Q000737:chemistry; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012996:Solutions; D013024:Soybean Oil / Q000494:pharmacology; D013696:Temperature; D014280:Triglycerides / Q000008:administration & dosage* / Q000737:chemistry*
D000975:Antioxidants; D002121:Calcium Channel Blockers; D004655:Emulsions; D005079:Excipients; D012996:Solutions; D014280:Triglycerides; D011092:Polyethylene Glycols; D013024:Soybean Oil; D015736:Felodipine