Pharmaceutical Research

, Volume 29, Issue 10, pp 2912–2925 | Cite as

Optimization of LY545694 Tosylate Controlled Release Tablets Through Pharmacoscintigraphy

  • Evelyn D. Lobo
  • Mark D. Argentine
  • David C. Sperry
  • Alyson Connor
  • John McDermott
  • Lloyd Stevens
  • Ahmad AlmayaEmail author
Research Paper



To optimize a controlled release (CR) matrix formulation with two goals: (1) effectively deliver a prodrug to a preferred absorption region of the upper GI tract, and (2) afford a PK profile similar to a “reference” CR formulation.


A pharmacoscintigraphic clinical study was conducted using a flexible formulation design space. A six-arm, three-prototype study was employed to cover the formulation design space and assess performance against the reference formulation. Pharmacokinetic and scintigraphic data from the first three dosing arms were used to select prototypes to be dosed in subsequent arms.


Of three prototypes tested, the third prototype had an optimal release rate. The in vivo erosion rate was observed via scintigraphy to reach 90% in 3 h. The AUC ratio relative to the reference for the prodrug was 1.25, while the Cmax ratio was 1.07. The ratios for the active moiety were 1.31 (AUC) and 1.01 (Cmax).


A single pharmacoscintigraphic study efficiently investigated a wide formulation design space and precisely optimized the release rate with few formulation iterations. The selected formulation provided the desired exposure at a 30% lower dose. The approach is beneficial when drug absorption is limited to a region of the GI tract.


absorption controlled-release flexible design space pharmacokinetics prodrug 



The authors would like to acknowledge the support from Nick McEntee, Abigail Pedigo, Chad Martinsen and Claudia Jacobs for their formulation development and manufacturing support; Matthew Deverall, for providing analytical in vitro dissolution support; Robert Stratford for providing clinical analytical support; Shobha Reddy, Chris Payne, Harry Haber (i3 Statprobe, Inc., Ann Arbor MI), and Matt Dunn for their support on the clinical study; Matthew Curley, Gaetan Rygaert, and Stacy Nolan for their quality oversight; and Xuan Ding, for her pre-formulation modeling support.

This work was funded by Eli Lilly and Company.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Evelyn D. Lobo
    • 1
  • Mark D. Argentine
    • 1
  • David C. Sperry
    • 1
  • Alyson Connor
    • 2
  • John McDermott
    • 2
  • Lloyd Stevens
    • 2
  • Ahmad Almaya
    • 1
    Email author
  1. 1.Eli Lilly and CompanyIndianapolisUSA
  2. 2.Quotient Clinical LimitedNottinghamUnited Kingdom

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