Present State of New Chiral Drug Development and Review in Japan

Abstract

The current situation of chiral drug development in Japan was investigated. The trend in the Japanese pharmaceutical development is increasingly moving towards the development of single isomers rather than racemates. The development of single-enantiomer drugs was made possible by the current technologies of asymmetric synthesis and chiral separation, and encouraged by the guidelines on the development of chiral drugs worldwide. Japan has not issued specific guidelines on the development of chiral drugs, however, the chiral drug development approached in Japan were essentially consistent with the approaches recommended by the U.S.A. and EU guidelines.

Supercritical fluid chromatography for the enantioseparation of pharmaceuticals

“…Enantioselective identification and quantification methods should be developed for each active pharmaceutical ingredient with chiral properties. In addition pharmacokinetic and toxicological assays should be executed with both pure enantiomers and with the racemate [8][9][10][11]. These requirements made chiral separations a well-recognized and extensively studied topic in today's drug development [7].…”

Separation of Stereoisomeric Mixtures of Nafronyl as a Representative of Compounds Possessing Two Stereogenic Centers By Coupling Crystallization, Diastereoisomeric Conversion and Chromatography

“…[1][2][3][4] This trend emerged as a result of increasing awareness of individual biological properties for opposite enantiomers in racemic drugs. [5][6][7][8] Two approaches can be used to produce single enantiomers, which involve either resolution of racemates or stereoselective synthesis from achiral material.…”

Use of the harmonic mean to the determination of dissociation constants of stereoisomeric mixtures of biologically active compounds

“…The synthesis of these compounds with a particular stereochemistry presents a challenge to chemists as well as to health specialists. Currently, a high fraction of the active principles of pharmaceutical drugs is commercialized as racemates [1][2][3] . Nevertheless, in the last decade there has been a substantial increment in the distribution of enantiomerically pure substances 1 , as it has been shown that there is usually a pharmacokinetic and pharmacodynamic advantage of using only one enantiomer (eutomer) over the other (distomer) [4][5][6] .…”

“…Currently, a high fraction of the active principles of pharmaceutical drugs is commercialized as racemates [1][2][3] . Nevertheless, in the last decade there has been a substantial increment in the distribution of enantiomerically pure substances 1 , as it has been shown that there is usually a pharmacokinetic and pharmacodynamic advantage of using only one enantiomer (eutomer) over the other (distomer) [4][5][6] . On the other hand, the distomer may have a different kind of biological activity, even toxicity 5,7 , or it may have the same activity but different affinity to the receptor.…”