swallowing and gastrointestinal absorption (e.g.
rizatriptan wafer). Benzocaine lozenges are
intended for the same purpose but to dissolve
more slowly, thus batheing the esophagus as a
symptomatic treatment (for example) for radiation
esophagitis; a similar approach is used with anti-
fungal drugs.
Bioequivalence and generic products
Although the subject of their own chapter in this
book, it should be emphasized here that there is no
regulatory requirement for innovative and generic
drugs to have identical excipients. Exemption from
demonstration of efficacy for generic products is
obtained only when bioequivalence with a proto-
type, approved product is demonstrated.
The standards for bioequivalence are similar
worldwide, but as a specimen we can use the
Code of Federal Regulations, Title 21 (21CFR),
parts 320.1–320.63) in the United States. The
regulation states that bioequivalence is ‘...demon-
demonstrated if the product’s rate and extent of
absorption, as determined by comparison of mea-
sured parameters, for example concentration of
active drug ingredient in the blood, urinary excre-
tion rates, or pharmacological effects, do not indi-
cate a significant difference from the reference
material’s rate and extent of absorption’.
The data that have traditionally been most per-
suasive have been a pharmacokinetic comparison
of the generic and reference drugs in humans. The
commonest study design is to compare two oral
formulations with the following optimal design
features (21CFR, part 320.26):
Normal volunteers in the fasting state.
Single-dose, randomized, crossover with well-
defined reference material.
Collection of blood samples for at least three half
times of elimination and at a frequency that
captures distribution phase,CmaxandTmax, all
at identical times post-dose for each formulation
being compared.
When there are major metabolites, then collec-
tions should accommodate at least three half
times of their elimination.In this case, theTmax,Cmax, AUC and the half
time of elimination for parent drug and principal
metabolites become the end-points of the study.
For combination therapies, these end points have to
be measured and fulfilled for all active compo-
nents, and the therapies should not be administered
separately.
The regulation does not define what a significant
difference might be, although a commonly applied
standard seems to be a formulation whose mean
Tmax,Cmaxand AUC is within 20% of the reference
material and is also within the 95% confidence
interval. However, these limits are tightened
whenthe therapeutic ratio of the drug is low;the solubility of the drug is<5mgml^1 ;tablet dissolutionin vitrois slower than 50% in
30 min.;the absolute bioavailability is<50%;there is extensive first pass metabolism that
makes rate of absorption, as well as extent, a
factor governing exposure;there are special physicochemical constraints
such as chelation, complex formation or crystal-
lization to consider (see 21CFR, part 320.33).There are also alternative ways to demonstrate
bioequivalence. It may be possible to demonstrate
bioequivalence using well-validatedin vitroor
animal methods, and these appear at 21CFR, part
320.24(ii)–(iii). For example, two oral formula-
tions can be compared with an intravenous dose
of equal or unequal size. If the drug is concentrated
in the urine but has negligible concentration in
the blood (e.g. nitrofurantoin antibiotics), then
urine sampling with a frequency that matches the
blood samples could be employed. Multiple-dose54 CH5 PHARMACEUTICS