Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility
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Because of its poor solubility in acidic solution, oral absorption and efficacy of meloxicam (MEL) may be reduced in severe pain patients with impaired gastric motility. The present study aimed to develop salt forms to overcome these drawbacks.
Upon MEL salt screening with eight counterions, five MEL salts were obtained. The physicochemical properties of these MEL salts were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and chemical/photo-stability. Pharmacokinetic profiling of an orally administered MEL salt was also carried out in both normal rats and rats treated with propantheline for the suppression of gastric motility.
Dissolution behaviors for all obtained MEL salts were markedly better than that of crystalline MEL; in particular, the initial dissolution rate of arginine MEL dihydrate (MEL/Arg) was ca. 14-fold higher than that of crystalline MEL. MEL/Arg was found to be chemically and physically stable. There was ca. 18-fold reduction of AUC0–4 for orally dosed crystalline MEL (1.0 mg-MEL/kg) in propantheline-treated rats compared with that in normal rats. In contrast, there was only a ca. 3-fold difference in AUC0–4 between normal and propantheline-treated rats after oral administration of MEL/Arg (1.0 mg-MEL/kg).
From these findings, MEL/Arg may provide improved oral absorption in severe pain patients.
KeywordsAbsorption dissolution meloxicam salt screening stability
analysis of variance
area under the curve of plasma MEL concentration versus time
differential thermal analyses
nuclear magnetic resonance
non-steroidal anti-inflammatory drug
polarized light microscopy
- SD rats
scanning electron microscopy
time to maximum concentration
ultra-performance liquid chromatography equipped with electrospray ionization mass spectrometry
X-ray powder diffraction
Acknowledgments and Disclosures
The authors are grateful to Boehringer Ingelheim Japan (Kobe, Japan) for kindly providing MEL. This work was supported in part by a Grant-in-Aid for Scientific Research (No. 24590200; S. Onoue) from the Ministry of Education, Culture, Sports, Science, and Technology.
- 4.Ghorab MM, Abdel-Salam HM, El-Sayad MA, Mekhel MM (2004) Tablet formulation containing meloxicam and beta-cyclodextrin: mechanical characterization and bioavailability evaluation. AAPS PharmSciTech 5: article 59Google Scholar
- 6.Kulmatycki KM, Jamali F. Drug disease interactions: role of inflammatory mediators in pain and variability in analgesic drug response. Int J Pharm Pharm Sci. 2007;10:554–66.Google Scholar
- 13.NationalToxicologyProgram. NTP toxicology and carcinogenesis studies of diethanolamine (CAS No. 111-42-2) in F344/N rats and B6C3F1 mice (dermal studies). Natl Toxicol Program Tech Rep Ser. 1999;478:1–212.Google Scholar
- 14.NationalToxicologyProgram. NTP toxicology and carcinogenesis studies of triethanolamine (Cas No. 102-71-6) in B6C3F1 mice (dermal studies). Natl Toxicol Program Tech Rep Ser. 2004;449:1–298.Google Scholar
- 28.Sachs-Barrable K, Thamboo A, Lee SD, Wasan KM. Lipid excipients peceol and gelucire 44/14 decrease P-glycoprotein mediated efflux of rhodamine 123 partially due to modifying P-glycoprotein protein expression within caco-2 cells. Int J Pharm Pharm Sci. 2007;10:319–31.Google Scholar
- 29.Schleier P, Prochnau A, Schmidt-Westhausen AM, Peters H, Becker J, Latz T, Jackowski J, Peters EU, Romanos GE, Zahn B, Ludemann J, Maares J, Petersen B. Ibuprofen sodium dihydrate, an ibuprofen formulation with improved absorption characteristics, provides faster and greater pain relief than ibuprofen acid. Int J Clin Pharmacol Ther. 2007;45:89–97.PubMedGoogle Scholar