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Preclinical formulations for pharmacokinetic studies

25 November 2019

When new drug compounds are synthetized, typically as solid powders, at the preclinical stage many properties of the compounds are not known. Apart from biological activity, for example particle size and crystal structure play important roles in further research for the compound. In many in vitro studies, the compound is just fully solubilized in solvent eliminating the issues described above.

For an in vivo study, however, more restrictions apply regarding the solvent selection. Yet it is just as important to either solubilize the compound or, alternatively, try to homogenise the solid compound so that the experiment can be repeated. Dr. Janne Mannila, who has extensive knowledge about preclinical formulation development, gives here a brief introduction to the topic.

The first PK studies are often performed in mice and rats, which sets some limits e.g. to the volumes to be administered. When selecting a vehicle, it should be kept in mind that ideally the vehicle should not affect the PK of the compound. In addition, potential side-effects, such as local irritation caused by the formulation, should be considered. This requires comprehensive understanding not only of the study compound’s physicochemical characteristics but also of the excipients’ properties. Prior proceeding to the first animal studies it is recommendable to screen for the most promising compounds or formulations to reduce the number of animals needed for PK studies. A common approach is to use Caco-2 cell monolayer to investigate the in vitro permeability.

The formulations designed for the first preclinical PK studies should enable acquiring initial information about the in vivo DMPK characteristics of the study compound. Much lower doses are used in these kinds of studies in comparison to toxicity studies, which may facilitate the formulation development. The preclinical formulations are most often administered to rodents via intravenous (i.v.) or per oral (p.o.) routes, which have different requirements for the formulation. Whereas the i.v. formulation should be solution, the p.o. formulation can also be e.g. a suspension.

The more physicochemical characteristics, such as solubility information and pKa, about the study compound is available the better. A solution is the preferred dosage form in PK studies, as it is accurate to dose and suitable for all the administration routes, as long as the pH range, isotonicity and suitable dosing volumes are considered. Therefore, the first formulation development step is to check the solubility of the compound into the most common solvents. Unfortunately, many of the study compounds suffer from limited aqueous solubility. In addition, excessive sonication or high temperatures should be avoided when dissolving the compounds. Therefore, surfactants or co-solvents, such as propylene glycol or DMSO, are often needed to improve the wetting and enhance the solubility, which is the most often used formulation trick in early formulations. Another common approach is to adjust the pH, but it is good to keep in mind that extreme pH values should be avoided and the stability of the compound should be evaluated. Sometimes cyclodextrins, which capture the poorly soluble compound and form a complex with improved solubility, may solve the problem and allow preparing a solution. When it becomes necessary to prepare a suspension, excipients, such as 0-1% w/v hydroxypropylmethyl cellulose, are often used to modify the viscosity and to ease the dosing and redispersion. Dr. Janne Mannila recommends to always prepare a fresh formulation, right before the use, to minimise the risk of chemical and physical instability of the formulation.

Many high-quality CROs are able to help with the preclinical formulation development and experienced formulations scientists are able to find out which one of the formulation tricks should be used. By careful planning and testing, it can be ensured that the used formulation is suitable for the purpose and the results can be confidently used for decision making. This enables the customer just simply to ship the compound and let the CRO scientists take care of the rest.

Written by

Janne Mannila & Miia Kovalainen

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