Advanced Drug Delivery Reviews 59 (2007) 667 – 676

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Oral lipid-based formulations ☆

David J. Hauss ⁎
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, USA
Received 27 February 2007; accepted 10 May 2007
Available online 26 May 2007

Abstract

Poor drug solubility remains a significant and frequently encountered problem for pharmaceutical scientists. The ability of lipid-based
formulations to facilitate gastrointestinal absorption of many poorly soluble drug candidates has been thoroughly documented in the published
literature. However, a considerable gap exists between our knowledge of this technology and the know-how required for its application. This
commentary provides a comprehensive summary of the development, characterization, and utilization of oral lipid-based formulations, from both
physicochemical and biopharmaceutical perspectives. The characteristics of currently available lipid excipients are reviewed in context of their
application to the basic lipid-based formulation modalities. The fundamental concepts of in vitro and in vivo evaluation of lipid-based
formulations are summarized followed by a forward-looking summary of unrealized opportunities and potential limitations to more widespread
use of this technology.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Lipid-based formulations; Drug solubility; Lipid excipients; Lipid digestion; Drug absorption; Surfactant; Drug delivery

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
2. Currently marketed oral lipid-based formulation products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
3. Excipient classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
3.1. Natural product oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
3.2. Semi-synthetic lipid excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
3.3. Fully-synthetic excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
3.4. Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
4. Formulation modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
4.1. Single-component lipid solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
4.2. Self-emulsifying formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
4.3. Self-emulsifying solid dispersion formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
4.4. Melt pelletization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
5. Formulation development and characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
5.1. Candidate compound selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
5.1.1. Excipient compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
5.2. Selection of a formulation modality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
5.2.1. Physicochemical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671

☆
This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug solubility: How to measure it, how to improve it”.
⁎ Tel.: +1 609 252 6304; fax: +1 609 252 3315.
E-mail address: [email protected].

0169-409X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2007.05.006
668 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676

5.2.2. Biopharmaceutical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672

5.3. In vitro characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
5.3.1. In vitro dissolution testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
5.3.2. Role of simulated lipolysis in release testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
5.4. In vivo characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
5.4.1. Nonclinical evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
6. Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

1. Introduction facilities and the associated clean-up procedures required for

highly-potent drug substances is minimized.
It has been estimated that anywhere from 40 to as much as 70 This review will provide a high-level summary of the
percent of all new chemical entities (NCE) entering drug development, characterization, and utilization of oral lipid-
development programs possess insufficient aqueous solubility based formulations, from both physicochemical and biophar-
to allow consistent gastrointestinal absorption of a magnitude maceutical perspectives.
sufficient to ensure therapeutic efficacy [1]. The poor and
variable absorption afforded these compounds by conventional 2. Currently marketed oral lipid-based formulation products
formulations can be complicated by a significant, positive food
effect, potentially resulting in unexpected toxicity while making As determined in a recently published survey by Strickley,
development more costly and difficult [2–4]. Solubilization of a oral lipid-based formulations have been marketed for over 2
drug in the gastrointestinal tract (GIT) is dependent upon the decades and currently comprise an estimated 2–4% of the
complex interplay of multiple factors, including the presence of commercially available drug products surveyed in 3 markets
food, and thus is an inherently variable phenomenon often worldwide [11,12]. These products accounted for approximate-
resulting in erratic absorption of poorly soluble drugs [5]. By ly 2% (21 products total) of marketed drug products in the
eliminating the variables of pre-absorptive gastrointestinal (GI) United Kingdom, 3% (27 products total) in the United States of
solubilization and the effects of dietary status from the equation, America, and 4% (8 products total) in Japan. Strickley's survey
lipid-based formulations not only improve but normalize drug revealed that the most frequently chosen excipients for
absorption, which is particularly beneficial for low therapeutic preparing oral lipid-based formulations were dietary oils
index drugs [3]. These formulations can also enhance drug composed of medium- (e.g., coconut or palm seed oil) or
absorption by a number of ancillary mechanisms, including long-chain triglycerides (e.g., corn, olive, peanut, rapeseed,
inhibition of P-glycoprotein-mediated drug efflux and pre- sesame, or soybean oils, including hydrogenated soybean or
absorptive metabolism by gut membrane-bound cytochrome vegetable oils), lipid soluble solvents (e.g., polyethylene glycol
enzymes [6,7], promotion of lymphatic transport, which 400, ethanol, propylene glycol, glycerin), and various pharma-
delivers drug directly to the systemic circulation while avoiding ceutically-acceptable surfactants (e.g., Cremophor® EL, RH40,
hepatic first-pass metabolism [8,9], and by increasing GI or RH60; polysorbate 20 or 80; D-α-tocopherol polyethylene
membrane permeability [10]. Although the manufacturing glycol 1000 succinate (TPGS®); Span 20; various Labrafils®,
processes used for lipid-based formulation products are Labrasol®, and Gelucires®). These formulations, which took
considerably slower than those of conventional tablets or the form of either bulk oral solutions or liquid-filled hard or soft
capsules, this disadvantage is offset by the minimization of gelatin capsules, were applied in instances where conventional
other process support activities required to develop and approaches (i.e., solid wet or dry granulation, or water-miscible
manufacture conventional dosage forms. For example, hard solution in a capsule) did not provide sufficient bioavailability,
gelatin or HPMC encapsulated lipid formulations are prepared or in instances in which the drug substance itself was an oil
from a single bulk solution that can be filled, sealed and (e.g., dronabinol, ethyl icosapentate, indometacin farnesil,
converted into the package-ready, final dosage form in as little teprenone, and tocopherol nicotinate). The total daily drug
as 10 min. And there is no need for coating to address product dose administered in these formulations, which range in
appearance or to provide taste-masking properties, thus complexity from simple solutions of the drug in a dietary oil
eliminating the need for a complex series of additional up to multi-excipient, self-emulsifying drug delivery systems
operations. In comparison, development of conventional solid (SEDDS), range from less than 0.25 μg to greater than 2000 mg.
dosage forms requires the identification of a stable, crystalline The amount of drug contained in a unit-dose capsule product
form of the drug substance which often necessitates lengthy and ranges from 0.25 μg to 500 mg and for oral solution products,
sometimes fruitless searches for salts or developable crystalline from 1 μg/mL to 100 mg/mL. The total amount of lipid
forms of the drug. Finally, since the liquid-filling process used excipient administered in a single dose of a capsule formulation
to prepare lipid-based dosage forms is essentially dust-free after ranges from 0.5 to 5 grams, but can range from as low as 0.1 mL
the initial preparation of the bulk filling solution, the need for to as high as 20 mL for oral solution products. Some of these
the installation, running and maintenance of costly containment products tolerate room temperature storage for only brief
 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676 669

periods of time and require long-term storage at 2–8 °C due to enhancement. A few examples of the most commonly applied
chemical and/or physical stability issues. excipients in this class and their applications follows.
Among the polymeric glycol-based excipients finding
3. Excipient classes pharmaceutical application, the polyethylene glycols (PEGs)
are a versatile, well-characterized and widely applied class of
3.1. Natural product oils solubilizers which are available as both liquids and thermo-
softening semi-solids. The physical state of these excipients at
A number of natural product oils, derived primarily from ambient room temperature is determined by their molecular
plant sources and processed to remove impurities or to isolate weights [16]. PEGs ranging from 200 to 600 in molecular
various fractions of the original product, are available and weight are liquid at ambient room temperature whereas those
suitable for use in encapsulated oral formulation products. possessing molecular weights of 1000 or greater exist as
Naturally occurring oils and fats are comprised of mixtures of thermo-softening semi-solids. In comparison to natural product
triglycerides which contain fatty acids of varying chain lengths oils, PEGs have the following disadvantages: they tend to be
and degrees of unsaturation. The melting point of a particular oil more chemically reactive; they can be more irritating to the GI
increases in proportion to the fatty acid chain lengths and mucosa than oils. PEGs are also known to contain varying
decreases with increasing degree of unsaturation, which also levels of peroxide impurities and secondary products formed by
increases the relative susceptibility to oxidation. Triglycerides auto-oxidation, which can contribute to chemical instability of
are classified as short (b5 carbons), medium (6–12 carbons), or the incorporated drug substance. These excipients are widely
long chain (N 12 carbons) and may be synthetically hydroge- used in soft gelatin capsule formulations but find limited use in
nated to decrease the degree of unsaturation, thereby conferring conjunction with hard gelatin capsules due to their hygroscop-
resistance to oxidative degradation. Separation of natural icity and resultant effects on gelatin moisture content, which can
product oils into their component glyceride fractions is used compromise capsule physical integrity.
to prepare excipients that maximize desirable physical and drug Propylene glycol, a pharmaceutically-acceptable, monomer-
absorption-promoting properties [13,14] while minimizing such ic solvent possessing humectant and plasticizing properties,
issues as susceptibility to oxidation. finds application for soft gelatin capsule formulations of poorly
water-soluble drugs [17].
3.2. Semi-synthetic lipid excipients The poloxamers, which are co-polymers of polyoxyethylene
and polyoxypropylene, possess both solvent and surfactant
Several semi-synthetic liquid and thermo-softening (semi- properties and thus find application in the oral delivery of
solid) excipients, most commonly prepared by chemically poorly water-soluble drugs [18]. As with the PEGs, they are
combining medium-chain saturated fatty acids or glycerides available in a range of molecular weights which control the
derived from natural product plant oils, with one or more physical state of the excipient at room temperature. In addition
hydrophilic chemical entities are currently available as to improving the bioavailability of poorly water-soluble drugs,
pharmaceutical excipients for oral formulation development they have found application in modified release formulations
[15]. These excipients find application as drug-solubilizing [19].
vehicles, surfactants and wetting agents and as emulsifiers and
co-emulsifiers in SEDDS and self-microemulsifying drug 3.4. Surfactants
delivery systems (SMEDDS). They are generally well-suited
for filling into both soft and hard gelatin or into HPMC Various non-ionic surfactants such as the polysorbates (e.g.,
capsules. Thermo-softening excipients, which melt in the range Tween® 80) and polyoxyls (e.g., Cremophor® EL), which cover
of 26–70 °C and exist as waxy semi-solids at ambient room the HLB range from 2 to 18, may be used in combination with
temperatures, are typically filled into capsules in the molten lipid excipients to promote self-emulsification or microemulsi-
state, with the excipient melting temperature limiting their use fication [15]. Due to their relatively low toxicity, the acceptable
to hard gelatin capsules. quantities for use of these surfactants are limited primarily by
their tendency, at high concentrations, to cause brittleness of
3.3. Fully-synthetic excipients hard and soft gelatin capsules due to their dehydrating effects on
capsule gelatin.
A number of fully-synthetic, monomeric and polymeric
liquid and semi-solid excipients, most of which are glycolic in 4. Formulation modalities
nature and relatively non-toxic, are used as solvents for
formulating poorly water-soluble drugs. These excipients can 4.1. Single-component lipid solutions
be used alone or in combination with other lipid excipients to
improve the overall solubilizing power of the formulation. The simplest lipid-based formulations consist of the drug
However, their pronounced water miscibility can compromise substance solubilized in a single excipient, such as a plant oil, a
formulation performance due to uncontrolled precipitation of fractionated glyceride, or a PEG. The obvious advantage of this
the drug substance following dilution in the aqueous contents of formulation approach is its relative simplicity. With the
the GIT. This typically results in dose-dependent bioavailability exception of the PEGs, which function primarily as water-
670 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676

miscible solvents, these formulations depend solely on the solubilized state until it can be absorbed from the GIT [25,26].
gastrointestinal lipid handling pathways to promote emulsifi- Indeed, the amount of water-miscible surfactant necessary to
cation which is essential for facile drug release and absorption promote the self-emulsification of these formulations can
[20]. As such, drug absorption may be less than optimal in occasionally be problematic in that it results in drug
patients for whom lipid digestion has been compromised by age precipitation upon dilution in vivo [27]. In some instances,
or disease [21]. While single-component PEG solutions often SMEDDS formulations have proven useful in mitigating the
have high solubilizing power for poorly water-soluble drugs, enhancing effect that food can have on the absorption of poorly
they are water miscible which can result in precipitation of the water-soluble drugs, as was the case for the Neoral®
drug subsequent to solubilization in the aqueous contents of the formulation of cyclosporine [21,28].
GI tract. Thus, the degree of bioavailability enhancement is
dose-dependent, which renders PEG solution formulations 4.3. Self-emulsifying solid dispersion formulations
poorly effective for high-dose drugs [22]. There are at least
10 commercially available single-component lipid solution Liquid self-emulsifying formulations rely on micellar or
formulations. All are marketed in soft gelatin capsules, with solvent/cosolvent systems to fully solubilize the drug dose,
most relying on the use of PEGs or medium-chain triglycerides which helps to ensure optimal absorption. However, the
as the primary or sole excipient [11]. usefulness of these formulations can be limited by their inability
to solubilize the entire drug dose in the volume of a single oral
4.2. Self-emulsifying formulations capsule. In these instances, solid dispersion formulations, which
may not fully solubilize the drug in the excipient matrix, can
Self-emulsifying drug delivery systems (SEDDS) are provide a viable, although not necessarily as effective,
physically stable, isotropic mixtures of oil, surfactant, co- alternative oral formulation. These formulations consist of a
surfactant and solubilized drug substance that are suitable for dispersion of the drug in an inert excipient matrix, where the
oral delivery in soft and hard gelatin (or hard hydroxypropyl- drug could exist in either the finely divided crystalline,
methylcellulose) capsules. Depending on the excipient selection solubilized or amorphous states or a mixture thereof. This can
and relative composition of the formulation, aqueous dilution increase the dissolution rate of the drug in, and subsequent
will result in spontaneous formation of lipid droplets ranging in absorption from, the GI tract relative to the stable crystalline
size from approximately 100 nm (SEDDS) to less than 50 nm drug substance [29–31]. A review of these formulations was
(SMEDDS) [1]. The optimum concentrations, or concentration published by Serajuddin, who discussed how various issues that
ranges, of oil, surfactant and co-surfactant necessary to promote had previously impeded the commercial development of solid
self-emulsification are determined by construction of a pseudo- dispersions can be surmounted by the use of newer thermo-
ternary phase diagram, which should also assess the effect of softening, surface-active and self-emulsifying excipients (Fig. 2)
drug loading on the efficiency of self-emulsification (Fig. 1) [32]. These excipients have the potential to further increase the
[23]. Since droplet surface area is inversely proportional to absorption of poorly water-soluble drugs relative to previously
diameter, smaller lipid droplets with their associated, greater used PEG solid dispersions and may also be filled directly into
surface area are thought to facilitate digestion, resulting in more hard gelatin capsules in the molten state, thus obviating the
rapid and uniform drug release and absorption [24]. The former requirement for milling and blending prior to filling. In
improved drug absorption provided by self-emulsifying for- addition, more recently introduced hot-melt extrusion technol-
mulations is contingent upon the maintenance of the drug in the ogy has proven to be of value in resolving some of the remaining
manufacturing issues associated with solid dispersions [33].

4.4. Melt pelletization

Melt pelletization is a novel process in which a thermo-

softening binder (e.g., PEGs, fatty acids, fatty alcohols, or
polyglycolized glycerides) is mixed with the drug substance and
other excipients under high shear to produce pellets or granules
of a desired particle size [34–36]. Using melt pelletization, solid
dispersions of diazepam were prepared with either PEG 3000 or
Gelucire 50/13 as the thermo-softening binder [37]. It was
found that the dissolution rate of diazepam from pellets
containing either binder was significantly greater than that of
neat diazepam, with Gelucire 50/13 resulting in a higher
Fig. 1. A pseudo-ternary phase diagram for a SEDDS formulation prepared from dissolution rate than PEG 3000, presumably due to the
peanut oil, Labrafac CM-10 (surfactant) and a model drug (Ro 15-0778) surfactant properties of the former [38,39]. Melt pelletization
illustrates regions describing combinations of drug, surfactant and oil which
produce good (A), intermediate (C) and poor (B) SEDDS formulations with has been used not only to enhance, but also to retard the release
permission, from: N.H., Shah, Self-Emulsifying Drug Delivery Systems. Int. J. rate of incorporated drugs. Although this technique is well-
Pharm. Sci. 1 (1994) 15–23. suited for process scale-up, it is critical to define the processing
 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676 671

Fig. 2. Advantages of self-emulsifying semi-solid dispersion formulations as compared to those prepared from excipients devoid of self-emulsifying properties.

parameters to ensure consistent product quality and perfor- the use of unsaturated lipids, by inclusion of appropriate
mance [40–42]. antioxidants, or through the use of sealed hard gelatin capsule
shells, which are relatively impermeable to oxygen [47].
5. Formulation development and characterization
5.2. Selection of a formulation modality
5.1. Candidate compound selection
Choosing a particular lipid-based formulation modality for a
For compounds in which the primary limitation to absorption poorly water-soluble drug requires careful consideration of the
is poor aqueous solubility and slow dissolution rate, and where objectives that the formulator wishes to achieve. First, and
intestinal permeability is not a limiting factor, (e.g., Biophar- usually foremost, the main reason for selecting a lipid-based
maceutical Classification System (BCS) Type II drugs) and for formulation is the need to improve the GI absorption of a drug
which conventional formulation approaches (e.g. salt or crystal candidate that suffers from poor aqueous solubility and an
form selection, particle size reduction, solid dispersions or the associated, slow dissolution rate. Beyond this initial objective,
addition of surfactants) have failed, a lipid-based formulation the formulation selection and development activities will be
should be considered. driven by the physicochemical properties of the drug substance
A preliminary indication of the potential utility of this and the interaction of the formulation with the GIT.
approach can be obtained by assessing the drug lipophilicity
(e.g. octanol:water Log P) and particularly, its solubility in 5.2.1. Physicochemical considerations
pharmaceutically-acceptable lipid excipients, which should be The initial consideration in developing a lipid-based
sufficient to allow the entire dose of drug to be administered in a formulation will be to identify an excipient, or excipient
single dosage unit. Another indicator of the potential for success blend, that will fully solubilize the entire drug dose, preferably
of a lipid-based formulation is the observance of a strong, in a volume that does not exceed that of a single oral capsule.
positive food effect when the drug is administered with a fatty Furthermore, the formulation must maintain the drug in the
meal as opposed to dosing in the fasted state [43,2,44]. In solubilized state in the GIT until absorption has occurred.
addition, the foregoing observation may indicate the potential Useful methods for assessing this parameter in vitro are
usefulness of a properly designed lipid-based formulation for described in this review in Section 5.3 In vitro characterization.
mitigating food effect [3]. An additional choice the formulator must make is whether
the formulation should be liquid or semi-solid, which will
5.1.1. Excipient compatibility influence the options available for encapsulation. Unlike
A thorough and methodical evaluation of the various thermo-softening semi-solid formulations, which are filled
chemical incompatibilities that could exist between lipid into hard capsules in the molten state and promptly solidify
excipients and drug substances has not been published. upon cooling to ambient temperature, liquid formulations
However, it is well recognized that a number of lipid and usually require an additional capsule sealing operation. This
some surfactant excipients are vulnerable to oxidation, with the can be problematic from the standpoint of potential leakage of
attendant formation of highly-reactive peroxide species [45]. the capsule contents. However, liquid formulations are more
Peroxide formation can be detrimental not only to the stability a suited to thermolabile drugs, which may not tolerate the
formulated drug substance, but has been shown to cause gelatin extended exposures to elevated temperatures required during
cross-linking, resulting in delayed disintegration of the capsule bulk filling of molten thermo-softening formulations into
shell which in turn, may adversely affect drug release [46]. hard capsules. While hard capsules are suitable for use with
Lipid oxidation can be controlled by limiting (when possible) either liquid or thermo-softening formulations, soft gelatin
672 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676

encapsulation is frequently limited to liquid formulations due to systemic toxicity, particularly when it is necessary to administer
the lower melting point of the capsule shell which is multiple dosage units for a single dose [1].
incompatible with the relatively high temperatures encountered
during filling of most thermo-softening formulations. Finally, 5.3. In vitro characterization
stability of the drug (both chemical and physical) will be a
critical parallel concern to be addressed in identifying a For a number of reasons, it is highly desirable to identify an
prototype formulation. efficient in vitro means for assessing drug release from a
formulation. Such tests, provided they are biorelevant, can be
5.2.2. Biopharmaceutical considerations useful for guiding preliminary formulation development efforts
Beyond the initial and essential physicochemical considera- prior to more costly and time-consuming in vivo evaluation of
tions discussed above are those pertaining to the biopharma- prototypes. Subsequent to the decision to proceed into initial
ceutical characteristics of the formulation, which relate largely clinical trials and beyond with a particular formulation, in vitro
to the degree and reproducibility of drug absorption achievable. tests serve to assess batch-to-batch consistency and to ensure
Self-emulsifying formulations have been most heavily studied that formulation performance is maintained throughout the
with regard to their reported abilities to provide greater drug product shelf-life.
absorption, with less variability, than lipid formulations that
depend on the GIT for pre-absorptive emulsification. While 5.3.1. In vitro dissolution testing
some self-emulsifying formulations have shown superior The seminal work of Dressman et al. has identified a number
performance relative to their non-self-emulsifying counterparts, of biorelevant dissolution test media and experimental meth-
a number have failed to do so. This emphasizes the needs for odologies that have found application in assessing drug release
careful nonclinical evaluation prior to testing in man and further from both lipid-based and conventional oral formulations
research aimed at providing a better understanding of the [50,51]. Unlike conventional dosage forms, from which the
mechanisms by which self-emulsification influences drug drug substance simply dissolves in the aqueous dissolution test
absorption [48,49]. In addition, the high concentrations of media, lipid-based formulations release the drug from an oily
incorporated surfactant necessary to promote self-emulsifica- solution which is often immiscible with water. In evaluating
tion can occasionally be problematic with regard to local or drug release from a lipid-based formulation, quantification of

Fig. 3. Release and absorption of a drug in vivo when administered as an oily dispersion. Formulation-mediated mechanisms of enhanced drug absorption include:
(A) Increased membrane fluidity facilitating transcellular absorption, (B) opening of tight junctions to allow paracellular transport, (C) inhibition of P-glycoprotein-
mediated drug efflux and/or metabolism by gut membrane-bound CYP450 enzymes (D) Enhanced lymphatic drug transport occurring in conjunction with stimulation
of lipoprotein/chylomicron production. Key: ABL, aqueous boundary layer; D, drug; D-, ionized drug substance; FA, fatty acid; MG, monoglyceride; LCFA, long-
chain fatty acid; ME, microemulsion; SEDDS, self-emulsifying drug delivery system; TG, triglyceride; TJ, tight junction (with permission, from: O'Driscoll, C.M.,
2002. Lipid-based formulations for intestinal lymphatic delivery. Eur J Pharm Sci, 15, 405–415).
 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676 673

the surface area of the dispersed oil droplets is deemed more solubilization and release from lipid-based formulations
critical in assessing formulation performance than is solubili- [53,54]. The model has also proven useful in assessing the
zation of drug in the aqueous test media which, if it occurs at all, ability of lipid-based formulations to reduce the positive food
is unlikely to be reflective of in vivo formulation performance. effect seen with many poorly water-soluble drugs [55].
Release and absorption of drugs from oily dispersions in vivo is Dynamic lipolysis experiments are conducted in a continu-
thought to occur subsequent to lipid digestion and micellization ously agitated dissolution vessel, maintained at 37 °C, contain-
or possibly, via direct transfer from the oil droplets to the intestinal ing dissolution medium consisting of a mixture of bile salts,
epithelia, the efficiency of both processes being proportional to phospholipid, and a dietary lipid dispersed in a buffered
the total oil droplet surface area (Fig. 3). In the case of formu- aqueous solution (Fig. 4). Lipolysis is initiated by addition of
lations which incorporate large amounts of surfactant (e.g., self- pancrelipase. The pH and free calcium concentration of the
emulsifying formulations), evaluation of the oil droplet size medium, which controls the rate of lipolysis, is maintained by a
formed in a biorelevant aqueous test medium could prove of value computer-controlled pump. Serial samples of the dissolution
in anticipating drug release in vivo. However, in instances where medium are withdrawn over time, lipolysis is terminated by
the formulation depends on gastrointestinal processing for addition of a lipase inhibitor, and the samples are centrifuged to
emulsification (e.g., a simple oily solution of drug), design of yield 3 distinct fractions, which include a pellet comprised
a meaningful release test will require evaluation of drug release largely of insoluble calcium soaps of fatty acids; an intermediate
from the formulation in the presence of lipolytic enzymes that aqueous layer, consisting of bile salt mixed-micelles and
catalyze GI lipid digestion in vivo. various lipid vesicles; and an upper-most, oily layer comprised
of diglycerides and unhydrolyzed triglyceride. During lipolysis,
5.3.2. Role of simulated lipolysis in release testing a drug dissolved in a lipid-based formulation will either: (1)
Perhaps one of the most complex and poorly understood remain in the lipid (2) be solubilized in the aqueous phase in
aspects of oral lipid-based formulations is their interaction with combination with lipolysis products (3) precipitate as the
the gastrointestinal lipid digestion processes and the influence insoluble drug substance. The partitioning of the drug between
that these interactions have on formulation performance. It is these various phases, which is not completely understood but
widely recognized that lipid digestibility is an essential thought to be influenced in part by the drug lipophilicity, which
determinant of the ability of a lipid to enhance hydrophobic in turn drives the affinity for a particular lipolytic phase, is
drug absorption. Indigestible lipids, such as paraffin oil, are not believed to be a critical determinant in drug absorption [56,57].
only ineffective at promoting drug absorption but have even The aqueous layer, which contains various lipolysis products as
been reported to inhibit the process, presumably by providing a well as a diverse mixture of micellar and vesicular entities
non-absorbable, lipophilic reservoir from which drug release [58,59], has been extensively characterized and is of greatest
cannot efficiently occur [52]. interest in studying the basic mechanisms controlling the GI
Mullertz et al. have published a number of highly useful absorption of hydrophobic drugs [60]. The lipolysis model has
articles detailing their development and application of a proven useful in selecting and optimizing both drug absorption
physiologically-relevant, in vitro dynamic lipolysis model for and the resistance to food effect associated with a particular oral
studying the effects of simulated lipid digestion on drug lipid-based formulation [55].

Fig. 4. Schematic diagram of the in vitro dynamic lipolysis model, as described in Section 5.3.2 Role of simulated lipolysis in release testing [53,54] (with permission
from Dr. Anette Mullertz).
674 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676

5.4. In vivo characterization 5.4.1.2. Lymphatic transport. While the primary physiolog-
ical purpose of the intestinal lymphatic system is to assimilate
5.4.1. Nonclinical evaluation dietary lipid from the gut, lymphatic transport can be
While a number of dispersion tests and models of lipid responsible for a portion of the total uptake of hydrophobic
digestion are being developed as methods for optimizing lipid- drugs, as well. These drugs are transported to the systemic
based formulations [56,57,61], proof-of-concept testing invari- circulation in association with chylomicrons and very low
ably requires administration of the formulated drug to an animal density lipoproteins (VLDL) [4,8,9,67,8,9,68,69,70] and by-
prior to clinical application, due to the complex and pass the liver and any potential for hepatic first-pass
incompletely understood dynamics of the interaction of these metabolism, which provides a further boost to bioavailability.
formulations with the gastrointestinal milieu. In designing these The process by which lipophilic drugs associate with chylomi-
studies, a number of factors should be borne in mind by the crons is far from clear, but appears to be controlled, at least in
formulator, including animal species, use of anaesthesia, dosing part, by relative drug hydrophobicity (e.g. octanol:water Log P)
volume and route, and the number and types of biological fluid and solubility in triglyceride [71], which constitutes 95% of the
samples to be collected [62,63]. The relative consideration chylomicron bulk [8]. Since chylomicron synthesis is driven by
given to these factors will be determined, in part, by the exogenously derived triglyceride, knowledge that lymphatic
developmental stage of the drug. transport plays a significant role in the absorption of a drug
should direct the formulator toward the use of excipients
5.4.1.1. Choice of non-human test species. Rats and dogs are containing triglyceride, or suitable components thereof (e.g.
the most frequently utilized animal species for evaluating the long-chain mono- or di-glycerides and fatty acids). Although
performance of oral lipid-based formulations. During early lymphatic drug transport remains relatively unexplored, recent
development, rats are generally suitable for initial proof-of- investigations are providing some very interesting findings with
concept studies provided the formulation is a syringeable liquid regard to the mechanistic aspects of chylomicron transport of
which can be administered via oral gavage and provided that the xenobiotics [72]. Methods for assessing lymphatic drug
study does not require administration of a human-sized dosage transport in animals have been developed and described in
form. Some investigators, however, have questioned the use of detail for both rats [62] and dogs [73], with both models
the rat for evaluating oral lipid-based formulation performance allowing for the simultaneous assessment of blood absorption,
due to a species-specific difference in bile secretion. Bile flow in thus permitting determination of the relative significance of
the rat, which lacks a gallbladder, is continuous and substantially lymphatic transport to overall drug absorption.
more dilute than man or other species which have gallbladders
that release bile in response to the presence of food or a sufficient 6. Summary and outlook
amount of lipid in the GIT (probably more than that contained in
a unit-dose oral lipid-based formulation) [65,64]. By comparison, Among the benefits which oral lipid-based formulations can
bile flow in the dog is more similar to that of man, suggesting that provide are included:
this species may be more relevant for projecting clinical
performance of oral lipid-based formulations. Given that the • Improvement and reduction in the variability of GI
primary objective of a lipid-based formulation is to maintain the absorption of poorly water-soluble, lipophilic drugs
drug in solution in the GIT, it is conceivable that the phys- • Possible reduction in, or elimination of, a number of devel-
iological differences in the rat GIT, particularly in the fasted state, opment and processing steps (e.g., salt selection or identifica-
could influence formulation performance in a manner that results tion of a stable crystalline form of the drug, coating, taste-
in the generation of clinically irrelevant data. However, when or masking, and reduced need for containment and clean-up
even whether this concern is valid has yet to be conclusively requirements during manufacture of highly-potent or cytotoxic
determined. Indeed, other investigators have suggested that the drug products)
rat [65], in comparison to the dog [66], is a more appropriate • Reduction or elimination of positive food effect
model for predicting drug absorption in man, which would • Relative ease of manufacture using readily available equipment.
reasonably be expected to influence the relevance of these
species with regard to projecting drug absorption from lipid- However, a considerable gap exists between the need for this
based formulations. technology, as justified by the preponderance of poorly water-
In summary, choice of an animal species for preclinical soluble compounds filling drug discovery pipelines, and its
evaluation of a lipid-based formulation is probably best dictated application, as evidenced by the low number of marketed drug
by the stage of drug development and the specific questions that products relying on oral lipid-based formulations. A carefully
the formulator wishes to address. Due to lower cost and greater planned study aimed at explaining this paradox has not yet been
ease of handling, small animals (e.g., rats) usually represent the executed. However, a growing opinion in the scientific
best choice for most early stage proof-of-concept investigations, community has suggested that lack of a clearly defined process
while a larger animal, such as the dog, is most appropriately for developing a lipid-based formulation which, among other
utilized for the final stages of testing which require evaluation things, involves selecting excipients from a list of hundreds of
of a prototype dosage form intended for administration to possibilities, has contributed substantially to the reluctance to
humans. use these formulations [27]. An equally plausible reason is that
 D.J. Hauss / Advanced Drug Delivery Reviews 59 (2007) 667–676 675

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