Ann: Anagrelide Project Update, page-44

Good news this...

1. 3 formulations tried - 2 demonstrate increased blood concentration compared to the capsule, one didn't. There is no indication of whether hydrotropes IP was used.
2. Increase in blood concentrations statistically significant for SS-101 (and I expect that the >25% increase of EF-164 is also statistically significant).
3. No evidence of tachycardia although one needs to ask whether the cardio-stimulatory effects occur in canines.
4. No irritation to the oral mucosa
5. SS-101, increase the blood concentration of the active (platelet reducing) compound by 42%
6. This formulation increases the concentration of the (nasty) metabolite by 28%.

So the question begs, how is it that the 101 formulation produces 28% more of the metabolite than the capsule. I reckon for a few reasons:

1. Whilst the formulation was sprayed into the dogs mouth, bowser is not going to be a good dog and let it sit there for 3.5 minutes until the active passes the oro-mucosal membrane.
2. So, Bowser swallows the load and it almost all ends up in the Gastro-intestinal tract and subsequent exposure to first pass metabolism in the liver.
3. The formulation has permeation enhancers (that's the business that SUD does) so chances are if it is going to increase permeation of an active ingredient over the oral mucosa then presumably it will do the same for any other mucosa, like in the GI tract.
4. And perhaps most importantly (and from the Patent)  in clinical practice plasma concentrations of this metabolite typically exceed those of the parent drug by 2-3 -fold (Martinez-Selles et al, 2013).

• Finally, more work is required on formulation stability so the human clinical trial ain't gunna happen this year.

Dunno what all the long faces are about.