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Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility

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Abstract

Purpose

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.

Method

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.

Results

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).

Conclusion

From these findings, MEL/Arg may provide improved oral absorption in severe pain patients.

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Abbreviations

ANOVA:

analysis of variance

Arg:

L-arginine

AUC:

area under the curve of plasma MEL concentration versus time

Cmax :

maximum concentration

DEA:

diethanolamine

DTA:

differential thermal analyses

Gly:

glycine

Lys:

lysine

MEL:

meloxicam

NMR:

nuclear magnetic resonance

NSAID:

non-steroidal anti-inflammatory drug

PLM:

polarized light microscopy

RH:

relative humidity

SD rats:

Sprague-Dawley rats

SEM:

scanning electron microscopy

TEA:

triethanolamine

TGA:

thermogravimetric analysis

Tmax :

time to maximum concentration

Tris:

tris(hydroxymethyl)aminomethane

UPLC/ESI-MS:

ultra-performance liquid chromatography equipped with electrospray ionization mass spectrometry

UV:

ultraviolet

XRPD:

X-ray powder diffraction

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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.

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Authors and Affiliations

  1. Department of Pharmacokinetics and Pharmacodynamics School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Masanori Ochi, Ryo Inoue, Shizuo Yamada & Satomi Onoue

  2. Department of Pharmaceutical Physical Chemistry College of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo, Matsuyama, Ehime, 790-8578, Japan

    Yukinori Yamauchi

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  1. Masanori Ochi
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  2. Ryo Inoue
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  5. Satomi Onoue
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Correspondence to Satomi Onoue.

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Ochi, M., Inoue, R., Yamauchi, Y. et al. Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility. Pharm Res 30, 377–386 (2013). https://doi.org/10.1007/s11095-012-0878-2

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  • DOI: https://doi.org/10.1007/s11095-012-0878-2

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