Formulation Design Issues

The design of a lipid-based system, whether for early pre-clinical investigation or later clinical development of a candidate drug, requires careful and prospective assessment of the likelihood of success. For a lipid-based system to be successful in enhancing drug exposure, it is essential the compound is sufficiently lipophilic to be dissolved within the proposed formulation composition. In many cases, poorly water soluble drugs are not sufficiently soluble within the typical excipients used in lipid-based systems (such as triglycerides and mixed mono/diglycerides, formulation-relevant and miscible surfactants and co-solvents) to provide an adequate unit dose of drug. Hence, such compounds are considered hydrophobic and lipophobic and formulation approaches other than lipid-based systems need to be explored for enhancing their bioavailability after oral administration. In the clinical formulation design environment, unit doses of 25-100 mg of drug are considered a reasonable "drug load" per unit dose of a lipid-based formulation.

There are various formulation approaches that can explored as a means of formulating lipophilic drug candidates and drugs (Pouton, 2000). Although a description of formulation design strategies is beyond the scope this chapter, the following comments briefly highlight some of the key points of difference between the various lipid-based systems. Broadly, there are three types of common lipidic formulation, comprising simple lipid-based solutions self-emulsifying drug delivery systems (so called SEDDS) or microemulsion pre-concentrate formulations. In terms of lipid, there is a choice between triglyceride lipid, and the correspondingly more polar mono/diglyceride lipid blends and for each of these lipid classes, there is the opportunity of using medium chain (e.g. C8-C12) or long chain lipids (e.g. C18) with a further consideration being the degree of unsaturation in the long chain lipids. Typically, co-solvents are also used in the self-emulsifying and microemulsion pre-concentrate formulations in order to facilitate formulation dispersion.

In vitro assessment of prototype lipid-based formulations is a significant area of on-going research as it holds the promise of being able to at least rank order the likely performance of such systems. Studies from our laboratories (Porter and Charman, 2001c; Sek et al, 2002; Kaukonen et al, 2004a,b; Porter et al, 2004a,b) and others (Reymond and Sucker, 1998; Zangenberg et al., 2001a, b) have utilised in vitro lipid digestion methodologies to examine the potential of drugs of varying physicochemical characteristics to: (i) remain associated with the undigested lipid phase of a formulation; (ii) partition into the colloidal species formed on interaction of the lipid formulation or its digestion products with biliary derived lipids, and (iii) precipitate during intestinal processing of the lipid formulation.

Although detailed discussion of these factors is beyond the scope of this chapter, it is clear that avoidance of drug precipitation in vivo and transfer of drug into the colloidal species from which absorption is assumed to occur is paramount for optimal absorption. Depending on the physicochemical characteristics of the particular drug and the formulation excipients, drug precipitation may occur upon initial dispersion of the dosage form in the stomach. This is particularly likely for formulations containing large quantities of water soluble surfactants, co-surfactants and co-solvents (which is most common in the microemulsion pre-concentrate systems) in which dispersion of the water soluble excipients may reduce the overall solubilizing capacity of the formulation. In contrast, formulations containing a larger proportion of poorly water soluble components, such as low HLB surfactants and lipids (e.g. lipid solutions or coarse emulsions) are less likely to be affected by dispersion in the gut contents. However, the performance of these formulations is more susceptible to influence by lipid digestion as demonstrated in our recent studies which highlighted the possibility of drug precipitation following digestion of formulations comprised primarily of medium chain lipids. Since the digestion products of these lipids are considerably more water soluble than those comprised of long chain lipids, digestion may substantially reduce the solubilizing capacity of formulations incorporating medium chain lipid excipients (Porter et al., 2004a,b).

When working in a discovery/early development support area, it is important to consider the extent of formulation "optimization" undertaken in support of the program realising that many of the compounds considered will fail. The authors believe that where possible, minimal formulation optimization work should be undertaken at these early stages as it is important to enable determination of key SAR issues such as potency and selectivity - without the performance of the formulation having too large an effect on the resulting activity profiles. In this regard, DMSO-based solutions have an advantage as a generic 'formulation' during discovery, since the resulting activity data are relatively more uniform as all compounds are administered from the same system and the resulting biological profile of the compounds are less confounded by differences in exposure resulting from different formulations. Whilst this approach has merit, it is important to realise that rapid drug precipitation from a DMSO solution may occur after administration which could limit drug exposure. In this situation, and realising that the biological effects of many highly lipophilic compounds can be beneficially enhanced through the judicious use of a lipid-based system, in our experience, as a second tier approach we have found that relatively robust medium chain lipid or long chain lipid-based systems as described by Khoo et al., (1998) offer a useful starting point once the decision to use a lipid-based system has been made. Although these prototype formulation compositions will not be optimal for all lipophilic drugs, they can be used without any further optimisation assuming that the drug is adequately soluble in the formulation components.

A difficulty working with early stage compounds in pre-clinical species such as mice and rats is the significant limitation regarding the volume of formulation which can be administered. A further issue is the temptation to administer increasingly larger volumes of formulation in the hope that drug exposure may be enhanced - however, in many cases, this will not result as the larger volumes administered are physiologically and pharmaceutically unreasonable thereby confounding the results. For example, in spite of the relatively small sizes of the stomach of the mouse and rat, they are often administered volumes of fluid (including lipid-based systems) as high as 1 mL/kg (excluding any volume used to flush through the oral gavage needle) which equates on a mL/kg basis to approximately 230 mL for a 70 kg human! Hence, these large volumes may swamp the capacity of the stomach to modulate gastric emptying and the capacity of the intestine to digest and absorb the administered lipid. Few studies have formally addressed the effect of increasing liquid (and lipid) volume to rodents and the effects on physiological processing and drug absorption. Consequently, it is difficult to either extrapolate such exposure data to higher species, or to predict whether there would be a "formulation effect" on drug absorption in higher species based on rodent data after administration of physiologically and pharma-ceutically unreasonable volumes.

A further issue associated with assessing rat exposure data after administration of lipid-based formulations is that they do not have a gall bladder. Therefore, as bile flow in the rat is essentially constant in contrast to the typical pre-prandial (fasting) and post-prandial (fed) response observed in higher species such as the dog and humans, it is difficult to extrapolate the likely performance of formulations if bile salt solubilisation is an important process in the enhanced absorption. In contrast, dogs have a gall bladder and their pre- and post-prandial state is reasonably representative of that observed in humans in terms of changing biliary and related secretions. Furthermore, the physical size of the dog makes them well suited to ingest a unit dose human-relevant formulation making them well suited for the extrapolation of bioavailability and exposure data to higher species. Although the permeability of hydrophilic low molecular weights drugs in the dog is higher than observed in humans, there is no such issue when assessing poorly water soluble drugs that are absorbed by the transcellular route making them well suited for studying lipid-based systems of such compounds. As the fasting gastric pH of dogs can be variable, it is important to consider the pre-treatment of dogs with penatgastrin in order to normalise their stomach pH values if it is likely to impact on drug stability, formulation performance or absorption.

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