Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 426

Table 1 Nanocrystal products on the pharmaceutical market: trade name, drug, producer,
nanoparticle technol ogy

Nanoparticle
technology

Product Drug Company

Rapamune ® Sirolimus Wyeth Elan nanocrystals ®

Emend ® Aprepitant Merck Elan nanocrystals ®

Tricor ® Fenofibrate Abbott Elan nanocrystals ®

Megace ® ES Megestrol acetate PAR pharmaceutical Elan nanocrystals ®

Invega ® Sustenna™ Paliperidone palmitate Janssen Elan nanocrystals ®

Triglide™ Fenofibrate Shionogi pharma SkyePharma IDD ® -P

technology

the barrier gut wall. In addition, the nanocrystals provide a fast replacement of
molecules permeated. Therefore nanocrystals are a suitable formulation for class II
drugs of the biopharmaceutical classification system (BCS). Class II drugs pene-
trate well (similar to lipophilic rutin), but dissolve slowly, the dissolution velocity
is the rate limiting step for oral bioavailability.
The first product on the market was Rapamune (sirolimus) (Müller and
Junghanns 2006 ). The nanocrystals in a tablet have a higher bioavailability than a
solution of sirolimus. In addition the solution is less patient friendly, also required
special storage conditions (fridge) and complicated reconstitution. The tablet can
be stored at room temperature. The second product was Emend (aprepitant, pellets
in a capsule). The drug aprepitant is absorbed within an absorption window in
the upper intestinal tract. The nanocrystals provide a sufficiently high dissolution
velocity to exploit this absorption window for efficient oral delivery of this drug,
not achievable with a classical formulation. The most successful nanocrystal
product is Tricor (fenofibrate, tablet) launched by Abbott. Fenofibrate shows a 35%
higher absorption in the fed state. The nanocrystal formulation removed the big
difference in bioavailability between fed and non-fed state. In addition the dose
could be reduced from 54/160 mg to 48/145 mg. Sales are meanwhile more than
one billion USD per year, a nano block buster. Triglide is the competitive product
of fenofibrate, but produced with high pressure homogenization.
Remarkable is the product Megace ES ( E nhanced S tability), a formulation of
megestrol acetate. It is a suspension with the shelf life of a pharmaceutical product.
It demonstrates nicely that physically long-term stable nanosuspension can be
produced - despite their state of high dispersitivity, high interfacial energy and risk
of Ostwald ripening. The previous oral suspension showed a food effect on the
bioavailability. The nanosuspension reduced the difference between fed and
non-fed, in addition the nanosuspension is less viscous and requires only ¼ of the
administration volume - three patient convenient factors increasing compliance.
Invega ® Sustenna ® is the first injectable nanocrystal product, approved in 2009.
As once-a-month release formulation of the drug paliperidone palmitate, it is injected
intramuscularly, thus avoiding the problems of i.v. injected nanosuspensions. The
aqueous nanosuspension delivers the drug in a small volume, conveniently to inject.