In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs

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Abstract

Although several routes of administration can be considered for new drug entities, the most popular remains the oral route. To predict the in vivo performance of a drug after oral administration from in vivo data, it is essential that the limiting factor to absorption can be modelled in vitro. In the case of BCS class II drugs dissolution is rate-limiting to absorption, so the use of biorelevant dissolution tests can be used to predict differences in bioavailability among different formulations and dosing conditions. To achieve an a priori correlation, the composition, volume and hydrodynamics of the contents in the gastrointestinal lumen following administration of the dosage form must be accurately simulated. Four media have been chosen/developed to model composition of the gastric and intestinal contents before and after meal intake. These are SGF, milk, FASSIF and FeSSIF, which model fasted and fed state conditions in the stomach and small intestine respectively. Using these media, excellent correlations have been obtained with the following poorly soluble drugs: danazol, ketoconazole, atovaquone and troglitazone. In all cases, fed vs. fasted state effects can be predicted from dissolution data and, where several formulations were available for testing, dissolution tests could also be used to determine which would have the best in vivo performance.

Introduction

Whether or not a drug will be completely absorbed after oral administration depends on the events depicted in Fig. 1, their importance relative to another and the rate at which they occur. Release and absorption must occur within the available transit time. In this case, the available transit time refers to the time the drug spends in the GI tract before reaching its absorptive sites as well as its residence time at the site of absorption. Also to be considered are the stability of the drug in the luminal fluids and the possibility of first pass metabolism in the gut wall and/or liver.

For immediate release dosage forms, the release rate relative to the transit rate and the permeability profile (including possible exotransport by P-glycoproteins) of the small intestine to the drug are crucial to both the rate and the extent of absorption. The Biopharmaceutics Classification System (Amidon et al., 1995) classifies drugs into four categories (Table 1), depending on their solubility and permeability characteristics. According to this scheme, Class I drugs should be more than 90% absorbed. Class II drugs are those with solubilities too low to be consistent with complete absorption, even though they are highly membrane permeable. Class III is the mirror image of Class II. These drugs have good solubility but are unable to penetrate the gut wall quickly enough for absorption to be complete. Class IV compounds have neither sufficient solubility nor permeability for absorption to be complete. Note, though, that although they certainly do not possess optimal properties, some drugs in this category may still be absorbed well enough to permit oral administration.

Correlation of in vivo results with dissolution tests is likely to be best for Class II drugs, because in this case the dissolution rate is the primary limiting aspect to absorption. The other case where good in vitro/in vivo correlations (IVIVCs) are often obtained is when a Class I drug is formulated as an extended release product, since in this case, too, the release profile controls the rate of absorption.

Section snippets

Which parameters affect the dissolution of Class II drugs?

Factors important to dissolution can be identified from the following modification of the Noyes–Whitney equation:DR=dXdt=A⋅DhCSXdVThe dissolution rate, DR, is a function of: A the surface area of the drug; D the diffusion coefficient of the drug; h the effective boundary layer thickness; Cs the saturation concentration of the drug under the local gastrointestinal conditions; V the volume of the fluid available to dissolve the drug, and Xd the amount of drug already dissolved

As well as the

Media for simulating the upper GI environment

Four suitable media for simulating the composition of proximal GI tract are SGF plus surfactant (fasted state/stomach); longlife milk, 3.5% fat (fed state/stomach); FaSSIF (fasted state/small intestine) and FeSSIF (fed state/small intestine) (e.g. Galia et al., 1998) (Table 3, Table 4).

Typical surface tensions in the stomach in the fasted state are on the order of 35–45 mN/m (e.g. Finholt and Solvang, 1968). In order to simulate these conditions, a suitable surfactant can be added to the

Case examples

Case examples of lipophilic drugs, where substantial differences in dissolution are observed between compendial and biorelevant media include albendazole (Galia et al., 1999), danazol and ketoconazole (Galia et al., 1998), and atovaqone and troglitazone (Nicolaides et al., 1999).

Conclusion

In conclusion, it appears that biorelevant dissolution media can be used to successfully predict the in vivo behavior of poorly soluble, lipophilic drugs and should therefore be especially useful in formulation development.

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    Citation Excerpt :

    Whereas for BCS Class I drugs with MR dosage forms (in vitro drug release rate slower than the gastric emptying) and BCS Class II drugs with IR/ER forms, the limiting factor for absorption is the drug release, which could be simulated through in vitro dissolution profiles. In addition, due to the high permeability of these drugs, the drug’s dissolving location correlates well with its absorption site (Dressman and Reppas, 2000). Therefore, a conventional level A IVIVC is expected to be established (Lu et al., 2011).

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