Toxicology formulation selection

Gad and Cassidy (2006) summarized the comprehensive information of maximum tolerabilities for 65 single component vehicles used in 368 studies across multiple species (e.g., dog, primate, rat, mouse, rabbit, guinea pig, minipig, chick embryo, and cat) by multiple routes. The paper serves as a good reference for excipient selection in the toxicology formulation development. 

Examples of PD, PK, toxicology, and formulation for two selected drugs, Zyprexa (a small molecule drug) and Aranesp (a large molecule drug) are described next. 

The formulation, manufacturing process, analytical development, and long-term toxicology studies in animals are parallel to the clinical investigation (Table 1.1). Clinical trial materials should be developed, manufactured, tested, and released before conducting a phase I clinical trial. Process chemists may redesign the synthetic route for the dmg candidate to meet the requirements of large-scale production in a pilot plant. Preformulation scientists complete the activities of salt selection,... 

Dideoxyinosine (DDI) is a therapeutic agent used in the treatment of AIDS. DDI is known to be easily hydrolyzed in the presence of acid. To aid in the selection of a vehicle for administration of DDI in planned toxicological evaluations, the bioavailability of DDI was determined in B6C3F1 mice of both sexes after intragastric administration in buffered and unbuffered formulations (R. Handy, personal communication, January 11, 1994). The significant effect of vehicle pH on the absorption of DDI was demonstrated by comparison of plasma DDI concentrations from buffered versus unbuffered oral dose formulations. The bioavailability... 

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