Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction.
Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.
Lee
Jung-Mi
JM
College of Pharmacy, Seoul National University, Kwanak-Gu, Korea.
Park
Kyung-Mi
KM
Lim
Soo-Jeong
SJ
Lee
Mi-Kyung
MK
Kim
Chong-Kook
CK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003002:Clonixin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004655:Emulsions; D006207:Half-Life; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004655:Emulsions; D003002:Clonixin