Page 346 - Chiral Separation Techniques

13.6 The Effect of Regulatory Guidelines 339

and 1985, the proportion was about 60 %, and between 1986 and 1991 it was about
25 %, whereas from 1992 to 1999 it appeared to increase from 30 % to 40 %, thus
making any conclusions about trends rather difficult.

1
Table 13-3. New chemical entities (NCEs) categorized according to their origin and chirality.
Drugs in NCEs NCEs Drugs in NCEs NCEs
use 1982 approved approved use 1991 approved assessed
1983–85 in Japan in Japan by MCA
1986–89 1992–93 1996–99
[19] [19] [17] [20] [18]
Natural/Semi-synthetic 475 39 53 147 – 17
Racemate 8 0 5 8 – 1
Single enantiomer 461 39 47 119 – 14
Achiral 6 0 1 8 – 2
Synthetic 1200 91 47 521 47 61
Racemate 422 36 29 140 22 13
(88 %) (95 %) (80 %) (56 %) (67 %) (35 %)
Single enantiomer 58 2 7 110 11 24
(12 %) (5 %) (20 %) (44 %) (33 %) (65 %)
Achiral 720 53 11 140 14 24
Total 1675 130 100 668 78
1 In the US, NCEs are referred to as new molecular entities (NMEs).

The area of “racemic switches” where a single enantiomer is developed subse-
quently to a corresponding racemate which is already on the market has attracted
much interest [7, 8]. A description of the preclinical and clinical development of
dexketoprofen provides a detailed example of one of these racemic switches [21].
The regulations in Europe and the US both allow for the development of a single
enantiomer from a racemate by the use of bridging studies between the old and new
applications. One problem to be considered is how a company which was not
responsible for the original development can provide equivalent data.
Apart from any intrinsically beneficial effects to patients from the administration
of pure enantiomers, it has been speculated that such switches may provide a mech-
anism for extending the patentable period of a new drug. While this may have been
attempted, the theoretical advantages of single enantiomers have not always been
realized in practice. Examples of drugs which were first marketed as racemates
where the single enantiomer is now available are dexfenfluramine, levofloxacin, lev-
obupivacaine, dexketoprofen and dexibuprofen (in a limited number of countries).
Others are either in development or in the process of registration. Inspection of the
indications and precautions granted for such compounds reveals that the claimed
advantages of the single enantiomer are not necessarily borne out by the clinical
studies. Some of the pitfalls in developing chiral drugs from the clinical point of
view have been outlined previously [12]. One problem is interconversion of
stereoisomers which can offset any differences in pharmacological effect. For exam-
ple, the inactive form of ibuprofen, the R(–)-isomer, is incompletely converted to the