Preserving Anti-Platelet Activity of Aspirin by Preventing Hydrolysis

John C. Somberg*, Vasant V. Ranade*, Imran Qadeer*, Jackie Coleman**, Janos Molnar***

Rush University, Chicago, IL*Accumetrics, San Diego, CA**

Academic Pharmaceuticals, Lake Bluff, IL***

Purpose of the Study

Hydrolysis of aspirin markedly reduces the

anti-platelet activity of aspirin (ASA) preventing the

development of an effective IV formulation.

This study evaluates a new IV formulation

that prevents hydrolysis and preserves platelet

inhibition.

Benefits of ASAISIS-2: Second International Study of Infarct Survival

Reduction in odds of vascular death in days 0–35, by time from pain onset

Odds ratio and 95%CI*

0–1 2 3 4 Subtotal for 0–4

5–12 13–24 Subtotal for 5–24

Total for 0–24

The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.

* Size of squares indicates how muchinformation available; lines anddiamonds indicate 95% CIs

0.5 1.0 1.5 0.5 1.0 1.5

Time of randomization(hours from pain onset)

SKbetter

Placebobetter

Aspirinbetter

Placebobetter

SK; Streptokinase

Benefits of ASA

Kong et al, AJC 90:622, 2002

Feldman and Cryer, AJC 84: 404, 1999

Kotake et al. JCPT 31:237, 2006

Methods

• Hydrolysis was determined by HPLC using a Luna column (5µ, 100x46 mm), a constant flow pump (Thermo-Finnigan Spectra System P2000) and a Spectra 200 programmable UV wavelength detector.

• Platelet function was evaluated ex vivo using the “Verify Now” assay developed by Accumetrics that employs a method that is based upon the principle that agonist (arachidonic acid) -induced activated platelets bind to fibrinogen-coated polystyrene beads that agglutinate in whole-blood. Infrared-light transmittance through the chamber increases as the agglutinated platelets and beads fall out of the solution.

Rate of Hydrolysis

Percent not hydrolyzed

Fresh 1 Day 1 month 6 months 40°C 40°C 40 °C

New formulation ASA 99.8 99 99 99

Aqueous ASA 97.9 70 56 11

The Effect of ASA Solutions on Platelet Inhibition

Percent Inhibition Platelets

Fresh 1 month 6 months

Aqueous ASA 26 0 0

New ASA Formulation 37 37 39

Vehicle Solution 0 0 0

Conclusions

Aqueous solutions of ASA hydrolyzes and this correlates with a diminished ex vivo ASA effect on platelet function

A new formulation of ASA for IV administration shows no hydrolysis at 1 & 6 months of storage at 40°C

This lack of hydrolysis of the new formulation correlates with ex vivo measured platelet inhibition by ASA

Availability of an IV formulation of ASA may be useful in the treatment of acute coronary syndromes