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Source: From Ref. 1.

Source: From Ref. 1.

in the gastrointestinal fluids will result not only in a fine emulsion but that a micel-lar phase will be formed either initially or as the dispersion comes in contact with the lipases, bile salts and lecithin secreted into the duodenum from the pancreas and gall bladder, respectively. Here too, attempts to better understand the dispersion process in vivo by diluting the formulation with biorelevant media may aid development of systems which behave robustly under gastrointestinal conditions (see p. 243). Since at least part of the API will initially be located in the emulsion phase, centrifugation and subsequent analysis of the oily and aqueous phases for the API will give some indications of the relative importance of the various phase transfer mechanisms to the overall release rate. If most of the API resides in the emulsion initially, obviously bulk partitioning is going to be more important than if the API has already partly transferred into the aqueous phase as a result of the dilution procedure. A third point to consider is whether the API has remained in solution during the dilution: this can be investigated by comparing turbidometric measurements in formulations with and without API present, in both the oily and aqueous phases obtained after centrifugation.

The Dosage Form Is Already an Emulsion

Sometimes the API is presented in an emulsion, rather than a self-emulsifying formulation. In this case, the question of whether the droplet size of the emulsion will be changed when the formulation comes in contact with the gastrointestinal fluids may well be important to the rate of phase transfer. Interestingly, the motility pattern in the stomach comes into play here. Studies in the food industry indicate that, regardless of the initial droplet size of an emulsion, the droplet size will be adjusted to 15 to 20 ^m by the time it is emptied through the pylorus. This phenomenon is observed both with coarse emulsions (>20 ^m) and fine emulsions like processed milk, which has a droplet size of about 1 ^m (3,4). To study release from ready-made emulsion products with droplet sizes greater than 20 ^m under intestinal conditions, shearing the emulsion to produce an appropriate droplet size may improve predictions of in vivo release behaviour. However, for physical stability reasons, most pharmaceutical emulsions aim to have a fine droplet size, far less than

15-20 ^m. For such products, one could contemplate breaking the emulsion, though admittedly this might be difficult to achieve with any degree of reproducibility.

Partitioning of the API From the Dosage Form into the Aqueous Phase

The Drug Is in Solution in the Lipid-Based Formulation

If the drug is truly in solution in the lipophilic phase of the dosage form, and the lipid is digested by the gastric and intestinal lipases, release of the API may be governed by the kinetics of lipolysis. Pancreatic juice contains at least three lipolytic enzymes (5).

The first enzyme, usually referred to as lipase, is a glycerol-ester hydrolase that hydrolyses a wide variety of insoluble esters of glycerol at an oil-water interface; it requires the cooperation of surface active agents such as bile salts and of co-lipase which is also secreted by the pancreas. Its pH optimum depends on the substrate and ranges from pH 7 to 9. The rate of reaction will depend on the lipids that are used in the formulation. For example, triglycerides with chain lengths of 16 to 20 are good substrates for lipolysis, but those with longer chain lengths are only slowly, if at all, digested. Long chain triglycerides (C16 and C18) often form the basis for lipophilic formulations, but medium chain triglycerides are being increasingly used for formulation, as well.

The second enzyme hydrolyses esters of secondary and other alcohols, such as those of cholesterol, at an optimal pH of 8.0 and also requires the presence of bile salts. The third enzyme hydrolyzes water-soluble esters.

In addition to hydrolyzing triglycerides, lipase can also remove one of the esterified fatty acid molecules from di-glycerides to form mono-glycerides and the reaction can proceed further, resulting in the formation of free fatty acids and glyc-erol. Many commercial lipid vehicles contain a mixture of glycerides with varying fatty acid chain length and/or degree of glycerol substitution. For example, soybean oil is a long chain triglyceride, whereas Peceol® consists of long chain mono- and diglycerides, and Capmul® of medium chain mono- and di-glycerides. The mono-glycerides, in particular, enjoy some water solubility. For example, glycerol monooleate is soluble in water up to a maximum concentration of about 8-10 mM. Monoglycerides also act as water-in-oil emulsifiers and thus promote generation of interfacial area, which will facilitate both API partitioning into the aqueous phase and hydrolysis of the triglycerides. Thus, their presence will encourage faster release of the API from the lipid vehicle. In addition, many formulations contain one or more additional surfactants such as Labrasol and Softigen 767 [principally macrogol-C8/C10-(partial)glycerides], Gelucire 44/14 (Lauryl macrogol 32 glyceride containing a range of C10 to C18 fatty acid chains), Tweens (e.g., POE-sorbitan-monolaurate and -monooleate) and Vit E TPGS. These additional surfactants can improve the dispersability of the formulation in aqueous systems substantially. This in turn will increase the interface available for both API partitioning and digestion, although the question remains as to whether interactions of the surfactants with co-lipase, lecithin and bile salts favour or hinder the digestive process.

Nondigestible oils for example, paraffin oil, appear not to release lipophilic APIs readily into the aqueous phase. In fact, their continued use has been shown to lead to deficiencies in fat-soluble vitamins. This is a strong indication that digestion of the lipid vehicle is a key factor in the release of the dissolved API from the vehicle.

The Drug Is Suspended in the Lipid-Based Formulation

If the API is suspended rather than dissolved in the lipid vehicle, the slowest of the various processes involved in release from the vehicle will determine the overall rate. Thus, digestion of the lipid vehicle, which enables contact of the solid API with the aqueous medium or dissolution of the API in the aqueous medium after digestion of the lipid surrounding it may determine the overall rate of release. On the other hand, if the drug is very poorly soluble, the particle size of the suspended material may be crucial to the overall rate of release.

APPROACHES TO RELEASE TESTING OF LIPID-BASED DOSAGE FORMS Compendial Approaches

One approach to release testing of lipid-based dosage forms is to argue that the formulation should be as robust to the gastrointestinal physiology as possible. Following this line of reasoning, the best formulations in terms of reproducibility of performance will be the ones that can release the API into even simple, aqueous media. Common pharmacopieal media such as those described in the United States Pharmacopeia (USP) and International Pharmacopeia (Ph.Int.) of the World Health Organisation (WHO) would be applicable for formulations developed in this context.

Simulated Gastric Fluid

Typically used media for testing robustness of release are simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Recipes for these vary among the different pharmacopeia, but generally speaking SGF contains a dilute hydrochloric acid solution (mimicking normal gastric pH, although the pH of SGF is a bit on the low side—see the formula for FaSSGF in the tables), some sodium chloride to adjust the osmolarity to a value close to that of gastric aspirates and pepsin, the main digestive enzyme in the stomach. For the purposes of studying release from lipid-based vehicles, the addition of pepsin offers few advantages since it is a protease, not a lipase. Additionally, the amounts of pepsin suggested by the USP are very high compared to those recovered in gastric aspirates from healthy volunteers (6).

Simulated Intestinal Fluid

SIF consists of a phosphate buffer to adjust the pH to 6.8 (a value typical of the mid-jejunum) (7) and pancreatin, which is an extract of the pancreas rich in amylase, proteases and lipase. For lipid-based dosage forms it could obviously be quite important to include the pancreatin in the medium. However, at the USP

suggested concentration of 2000 lipase Units/mL, the concentration exceeds, by far, the concentration that would be expected in the fasted state in the intestine of healthy human volunteers.

It should also be taken into consideration that the lipase levels in the fed human small intestine exceed by far the concentration actually required to complete lipolysis, and for release testing purposes it is not necessary to use the fed state physiological concentration. One only needs to make sure there is enough pancreatic lipase added to digest the modest concentrations of lipid in the dosage form to be tested. Moreover, at 2000 Units/mL lipase, the equivalent concentration of pancreatin will not dissolve completely and this can lead to analytical difficulties.

How much lipase is necessary? Assuming that the formulation contributes about one gram of fat/oil, and assuming a density of about 0.9 g/mL, this would correspond to about 900 mg of digestible lipid. Using a molecular weight of just under 900 (e.g., triolein), this corresponds to a concentration of about 1 mMole, which would require 1000 Units of lipase for digestion. Assuming a media volume of 500 mL per vessel in a Biodis (Type III) dissolution apparatus, this will require the addition of about 10 Units/mL. To be on the safe side, a lipase concentration of 100 Units/mL is suggested, which corresponds to one-twentieth of the concentration of pancreatin recommended by the USP for use in SIF.

Addition of Surfactants to Compendial Media

For APIs that have low solubility in aqueous media, it may be useful to consider adding a surfactant to the medium for quality control (QC) testing. Sodium laurylsulphate and Tween 80 are two surfactants that are often used to boost release rates for QC testing. This approach is discussed and elaborated in the new General Chapter on dissolution testing of the USP (8).

Case Example

In some cases, it has been possible to generate in vitro-in vivo correlations (IVIVC) using modified compendial methods. A case example has been described by Schamp et al., who studied a variety of lipid formulations of an experimental Merck API (9). In these studies, lipid semisolid formulations of EMD 50733, a poorly soluble, neutral drug candidate were developed using Gelucire 44/14 and Vitamin E TPGS as the lipid vehicles, and tested both in vitro and in a dog model. The media used in vitro were SGF with a surfactant added to lower the surface tension to physiologically relevant levels (SGF+, the forerunner of FaSSGF), FaSSIF and FeSSIF. Results clearly indicated that the release for the Gelucire formulations is robust—maximum concentrations achieved in SGF+ were similar to those obtained in the biorelevant intestinal media and a supersaturated concentration of the API was sustained for more than an hour. The results in SGF+ also predicted that the API would be better absorbed from the Gelucire than from the other formulations studied (Table 4). The bioavailability of the various formulations in dogs were measured and compared to that of a standard formulation consisting of

Table 4 Solubilities of EMD 57033 in Different Dissolution Media and Maximum Concentrations Resulting from Dissolution of Different Formulations

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