Mini Review Publication

Lipid-based Dosage Forms - An emerging platform for drug delivery

Dr. Hassan Benameur, Ph.D

Senior Director, Global Pharmaceutical Sciences
Capsugel, Inc
Introduction
New chemical entities (NCEs) in modern discovery libraries and development programs have an everincreasing number of unconventional physical and chemical properties. In particular, up to 70% of
discovery compounds and 40% of pipeline candidates are insoluble in water. [1] These promising
molecules present unique formulation and development challenges and often suffer from poor
bioavailability. [1] Therefore, conventional formulation systems cannot be employed.[2] Techniques
available for scientists to increase the bioavailability of poorly soluble drugs are either increasing their
solubility in biological media of choice, or increasing their dissolution kinetics.
The use of advanced lipid-based drug delivery systems (LBDDS) is a strategy to design pharmaceutical
dosage forms with improved therapeutic benefits[3] [4]. A list of commercially available lipid-based
formulations has been published by Strickley in Hauss book [2], and another recent study published by
Chakraborty [5] has demonstrated that LBDDS show better
results than traditional oral formulations [6] [7] [8]. Good examples of successful bioavailability
enhancements are cyclosporine A (Neoral), HIV protease inhibitor ritonavir (Norvir) or saquinavir
(Fortovase).
This article will provide a background and review the recent advances and updates on Lipid-based Drug
Delivery Systems with a primarily focus on those designed for their projected use in the oral route.
Regulatory perspectives regarding their applications will also be discussed.
Wide application of LBDDS
The use of lipids in drug delivery is by no means a new phenomenon. Old lipid dosage forms such as
suppositories, creams or emulsions have been on the market for a long time, and some of them in use

since Egyptian times. However, over the last decade, approaches in new designs of lipid carriers have
considerably evolved for the delivery of poorly soluble drugs.
If we consider the number of articles referenced in Pub med and published on Lipid-based Drug Delivery
Systems in the last 10 years, we can infer that these new types of formulations have gained increasing
interest.
Evolution of literature issued in Pubmed during the last 10 years
250

number

200

150
Number of publications on LBDDS
100

50

0
2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

years

LBDDS can be used to deliver various types of drugs from new chemical entities to more recent new
developments for proteins and peptides, nucleic acids (DNA, siRNA), cellular site-specific delivery.[9]
[10] [11]
Lipid-based Dosage forms are administered through many routes: oral, parenteral, ocular, intranasal,
dermal/transdermal, vaginal.[12] [13]. There have been recent developments in pulmonary drug delivery.
In the inhalation field, excipients considered as GRAS (generally recognized as safe) can comprise
materials that are endogenous to the lungs and locally present in large quantities, such as
phosphatidylcholine. [14]. However, oral remains the preferred route because it is non-invasive, less
expensive, and is less prone for side effects, such as injection-site reactions. It is also the easiest and the
most convenient method of drug delivery for chronic therapies. Nevertheless, at a very early stage of
development, formulation strategies based on a rational and systematic approach need to be developed to
avoid erratic and poor in vitro/in vivo correlations, and thus increase the chances of success in formulation
development. Some useful guidelines have been published by several authors [15] [16] [17] [18] .
Advantages of Lipids
Lipids are a large class of materials that includes fatty acids, glycerides, phospholipids, sphingolipids,
waxes and sterols to name a few [19] They may be insoluble in water, amphiphilic, and often identified
by their fatty acid composition, melting point, Hydrophilic-Lipophilic Balance (HLB), and solubility in
organic solvents. Vegetable oils and their derivatives are the primary source for the manufacture of
hundreds of lipid-based excipients intended for the development of solid, semi-solid or liquid lipid-based
formulations. [20] Gibson provides a detailed list of the most used excipients for oral administration [2].
A normal diet includes a daily intake of 60-80g of lipid, mostly composed of triglycerides. A normal
adults digestive system is powerful enough to hydrolyze around 100 -140g of lipid every day. Due to

their resemblance to in vivo components, lipids used in LBDDS are well tolerated in the organism, and
less cytotoxic. Their presence in the gastrointestinal (GI) tract mimics the fed state, which in turn
stimulates the secretion of bile salts. [5]
Two parameters are of interest if we consider oral drug delivery: the solubilisation of the drug in GI tract
digestive phase and the absorption phase through the intestinal barrier followed by circulatory uptake of
the drug to allow its therapeutic action.
The poor aqueous solubility of a drug leads to poor solubilisation in gastrointestinal fluids, low and/or
variable bioavailability and poor in vitro/in vivo correlation[21]. Lipids and lipophilic excipients can have
a significant positive effect on the absorption of poorly soluble drugs after oral delivery. There are three
mechanisms by which lipids and lipophilic excipients can improve the bioavailability after oral
administration:
-

alteration of the composition and character of gastro-intestinal milieu; the stimulation of bile salts
secretion causes emulsification of the poorly soluble drug in the gastrointestinal fluid and thus
enhances its in vivo solubility
interaction with enterocyte-based transport and influence on drug uptake and efflux,
recruitment of lymphatic drug transport, avoiding hepatic first pass drug metabolism.[17]

In 2006, Pouton proposed the Lipid Formulation Classification System (LFCS) to help predict the fate of
a formulated drug based on the criteria of dispersion and digestion, and to optimize the choice of
formulation for a specific drug.[22] Due to their stability at varying pH and moisture levels, lipids provide
adequate protection from gastric or environmental conditions for certain sensitive actives. They also
provide a hydrophobic environment to delay the release of the loaded drug. This property has been widely
used in the design of sustained release beads, tablets, suspensions, implants or microcapsules. Their
hydrophobic properties may also be used for masking the bitter or generally bad taste of certain drugs by
hot melt coating [23], or inclusion in solid lipid pellets. Moreover, lipids offer advantages for
manufacturing. Drugs with low melting points or poor compression properties, or low dosage forms are
all difficult to process using conventional approaches, especially when the drug is liquid at ambient
temperature. Lipid-based formulations can be filled into hard or soft capsules[24].
Design of Lipid-based DDS
Several LBDDS have been developed over the years, most of them for oral delivery. Hauss has given a
comprehensive summary of the development, characterization and use of oral lipid based formulations
from both physicochemical and biopharmaceutical perspectives.[25] Fricker has provided/described good
examples of different types of lipid-based formulations using phospholipids. [26]. Approaches in the
design can be separated in 2 categories: lipid-based formulations, and lipid carriers as particulate systems
(liposomes, solid lipid nanoparticles, lipid implants, lipid microtubules and microcylinders, lipid
microbubbles, lipospheres, microspheres, pellets, nanostructure lipid carriers).[5, 26-30]
Formulations can be classified as:

Liquid lipid-based formulations

o Emulsions or microemulsions (oil/water; water/oil, bicontinuous structures)

An emulsion is a blend of two immiscible phases wherein a surfactant is added to stabilize the
dispersed droplets. The proper choice of surfactants and manufacturing conditions is important
to stabilize the mixture. A microemulsion is a thermodynamically stable system composed of
at least water, oil and surfactant/co-surfactant producing a transparent and thermodynamically
stable system whose droplet size is 10-140 nm [31]. Drugs will partition between the aqueous
and hydrophobic phases depending on their lipophilicity. Oral, ocular pulmonary, nasal
vaginal and intravenous routes are the main routes of administration.
o Self-Emulsifying Drug Delivery Systems (SEDDS) and related systems SEDDS can be binary
systems made of oil and surfactant. Their dispersions have a turbid appearance because lipid
droplet sizes are between 200nm to 5m. Self-Micro-Emulsifying DDS( SMEDDS) or SelfNano-Emulsifying DDS (SNEDDS) is an isotropic mixture of lipid, surfactant, co-surfactant
and sometimes co-solvents and drug substance that can spontaneously form fine oil-in-water
microemulsions (particle size less than 100nm) under mild agitation following dilution with an
aqueous phase.
The choice between a SEDDS or a SMEDDS often depends of the intrinsic drug properties,
and its solubility and dissolution profile during in vitro screening with a number of
excipients[32] [33].[34] SMEDDS have demonstrated to have a high solubilisation capacity,
and excellent stability. They can substantially provide reproducible and increased oral
bioavailability as they enhance the permeation across the intestinal membrane and eliminate
food effects.[35]
o Solid-in-oil (S/O) suspension is an alternative LBDDS: Piao et al. reported that Diclofenac
sodium, a non-steroid anti-inflammatory drug (NSAID), can be orally and successfully
delivered in S/O suspension without serious GI injuries and side effect.[4]

Solid lipid-based formulations

Recently, increasing research has focused on this area. Techniques to obtain diverse solid or
semi-solid lipid-based formulations have been described by several authors Jannin et al. [36]
Canon et al [37]
A solid state microemulsion of cyclosporine was prepared by coating a microemulsion with
enteric coating material. Solid SEDDS can be used for several dosage forms (dry emulsions,
self emulsifying capsules, implants, sustained/controlled release tablets or pellets, beads,
microspheres, nanoparticles, suppositories and can provide flexible solutions for oral and
parenteral administration[32].

Lipid as particulate drug carriers

o Liposomes
Liposomes are vesicles comprising a phospholipid bilayer surrounding an aqueous
compartment. In the lipid domain of the bilayer membrane, lipophilic drug can be included.
Despite the poor stability of vesicles in the GI tract, studies indicate the potential of liposomes
to offer a dynamic technology for enhancing the oral bioavailability of poorly soluble drugs,
including peptides and proteins. Several studies indicate that blood glucose levels can be
decreased by orally administered liposomal insulin. They can be suitable for oral vaccination
systems.[26]. The therapeutic index of vincristine can be significantly enhanced through the
use of liposomal delivery system in the treatment of human carcinoma [38]. Liposomal

formulations are often regarded as safe due to the GRAS status of the phospholipid
constituents. They are mostly used for parenteral applications or injectable dosage forms (e.g.
Doxil).
o Solid Lipid Nanoparticles (SLNs),
SLNs are particulate systems with particle diameters ranging 50-1000nm. They are derived
from oil-in-water emulsions, by replacing the liquid oil by a solid lipid. They present several
advantages: the lipid matrix is generally made from physiologically well-tolerated lipid
components, which decreases the toxicity; they combine physical integrity of particle shape
and physical protection capacities of sensitive compounds. They have a stability of around 3
years and can easily be manufactured at industrial scales[39]. SLNs have been reported to
increase the bioavailability of several drugs after oral administration, such as piribedil,
cyclosporine A and vinpocetin. [40]
Solid lipid particulate systems such as SLNs, lipid micro particles and lipospheres have been
sought as alternative carriers for therapeutic peptides, proteins and antigens. Formulation as
SLNs confers improved protein stability, avoids proteolysis, as well as providing sustained
release of the incorporated molecules. Well-known peptides such as cyclosporine A, insulin,
calcitonin and somatostatin have been incorporated into solid lipid particles and are currently
under investigation.[10]
o Squalene
Squalene is a natural lipid belonging to the terpenoid family, and a precursor of cholesterol
biosynthesis. Because of its significant dietary benefits, biocompatibility, inertness, and other
advantageous properties, squalene is extensively used as an excipient in pharmaceutical
formulations for disease management and therapy. In addition, squalene acts as a protective
agent, has been shown to decrease chemotherapy-induced side-effects and exhibits
chemopreventive activity. Although it is a weak inhibitor of tumor cell proliferation, it
contributes either directly or indirectly to the treatment of cancer due to its potentiating effect.
In addition, squalene enhances the immune response to various associated antigens, and it is
therefore being investigated for vaccine delivery applications. Since this triterpene is well
absorbed orally, it has been used to improve the oral delivery of therapeutic molecules. All of
these properties have made squalene a potential excipient for pharmaceutical applications,
especially for the delivery of vaccines, drugs, genes, and other biological substances. [41]
Challenges
Lipid oxidation
One of the challenges faced by lipids is their sensitivity to oxidation, especially for unsaturated
triglycerides and fatty acids. It occurs during storage or processing, and leads to a loss in
product quality. When lipids are exposed to environmental factors such as light, air or
temperature, autoxidation may occur, and can produce change of texture, color, rancid flavor
or, generally, loss of quality and even the generation of toxic compounds with health risks for
patients. Other degradation pathways are catalyzed by lipoxygenases enzymes. Trace of metals
(eg iron, copper, cobalt) can have a significant impact in promoting oxidation. Autoxidation
seems to be a key and complex mechanism in lipid oxidation. It mainly generates

hydroperoxides and volatile compounds, generally through a three-phase process (initiation,

propagation and termination).
o The initiation phase involves homolytic breakdown of hydrogen in -position relative to
the LH fatty acid chain double bond. The reaction can, however, be initiated via external
physical agents such as heat, ionizing radiation or a photonic impact in the ultraviolet
spectrum, and also by chemical agents such as metal ions, free radicals and
metalloproteins. This results in the formation of (L). free radicals, i.e. chemical species
with an unpaired electron. These are highly unstable, short-lived intermediates that
stabilize by abstracting an hydrogen from another chemical species. The oxidation process
remains slow during this phase.
o Propagation: In aerobic environments, the (L). radical centered on the carbon molecule
and formed during the initiation phase reacts very quickly with triplet oxygen to generate
different radical species, including (LOO)_peroxyradicals. The peroxyradical then
abstracts a hydrogen atom from another unsaturated lipid molecule to form hydroperoxide
(primary oxidation compound) and another L radical, thus replenishing reaction. This is a
rapidly peaking irreversible reaction. Hydroperoxide formation from unsaturated fatty
acids is generally accompanied by stabilization of the radical state via double- bond
rearrangement (electron delocalization), which gives rise to conjugated dienes and trienes
o Termination: The oxidation process then continues with the transformation of
hydroperoxides into secondary nonradical oxidation compounds. The main hydroperoxide
decomposition mechanism involves scission of the double bond adjacent to the
hydroperoxyl group, leading to the formation of hydrocarbons, aldehydes, alcohols and
volatile ketones. Other nonvolatile secondary compounds are also formed, including
nonvolatile aldehydes, oxidized triacylglycerols and their polymers. [42]
Nitrogen flushing can be a means of preventing oxidation in closed systems such as capsules.
[43] To avoid metal-based catalysis, the use of chelators (EDTA or citric acid) is an
alternative. The use of antioxidants can prevent oxidation reaction by different mechanisms
that have been described by several authors and reported by Karabulut [44].
As an example, alpha-tocopherol is a primary antioxidant responsible of terminating freeradical chain reactions by donating hydrogen or electrons to free radicals, and converting them
to more stable products. The pathways mainly used to inhibit oxidation with antioxidants are
singlet oxygen deactivation (ascorbic acid), free radical scavenging (ascorbyl palmitate) and
chain-breaking reactions (-Carotene).
Blends of antioxidants can be used to combine the effects.
To assess the effects of antioxidants on oxidative stability, several analytical methods can be
used, such as peroxide value for primary oxidation value and p-anisidine value for secondary
oxidation products, scanning calorimetry[45], and thermogravimetry [46]. Cyclic voltammetry
is a rapid method used for identifying excipients in which the drug is more sensitive to
oxidation, and for screening antioxidants. [47]
Regulatory aspects

From a regulatory point of view, quality and safety issues related to preclinical and clinical
studies are the main difficulties likely to be encountered in launching a lipid-based dosage
form on the market, and above all the demonstration of the therapeutic efficacy. The overall
drug stability and absence of immunological reactions to the oils or lipid excipients has to be
demonstrated. Sufficient details explaining the use of lipid excipients and the types of dosage
form, the drug release mechanism and their manufacture should be provided to convince the
regulatory authorities of their acceptability.[48] Safety assessment and the potential influence
of biopharmaceutical factors on the drug or lipid excipients need to be explored. It may be
difficult to predict in vivo performances of a lipid dosage form based on in vitro results
obtained with conventional dissolution methods in view of the convoluted GI processing of
lipid formulations. More mechanistic studies should be conducted to facilitate a better
understanding of the pharmaceutical characteristics of lipid formulations and interactions
between lipid excipients, drug and physiological environment. The lack of predictability for
product quality and performance may be due to the nature of empirical and iterative processes
traditionally employed.[49]
With the aim of rationalizing the design of lipid formulation, and to better understand the fate
of a drug after oral administration in a lipid-based formulation, a Consortium, composed of
academics and industrial scientists, has been created (www.lfcsconsortium.org). The
Consortium sponsors and conducts research to develop in vitro methods to assess the
performance of LBDDS during dispersion and digestion, which are critical parameters. The
primary objective is to develop guidelines that rationalize and accelerate the development of
drug candidates through the identification of key performance criteria, and the validation and
eventual publication of universal standard tests and operating procedures. In order to establish
approved guidelines, appropriate dialogue with pharmaceutical regulatory bodies (FDA,
EMEA) is also foreseen.
Conclusion
Lipid-based drug delivery systems, a physiologically well-tolerated class of formulations, provide
a vast array of possibilities to formulate and potentially increase the bioavailability of an evergrowing number of poorly soluble drugs. In recent years, progressive elucidation of the various
mechanisms through which lipids can increase bioavailability a unique combination of
solubilisation, dispersion or encapsulation, and stimulation of the digestive process, potential
inhibition of receptor-mediated efflux or pre-systemic metabolism, or (even if poorly understood),
passage through the lymphatic system have all contributed, and will continue to contribute to a
greater number of products in preclinical and clinical development, and in the market.
Investigational initiatives such as the Lipid Formulation Classification System Consortium will
further advance our understanding of key criteria dictating the performance of LBDDS, and
generate universally acceptable methods to evaluate the same. However, the progress of these
innovative systems remains more challenging than that of traditional dosage forms, in particular
due to the as yet limited toxicological data even if some excipient suppliers have taken on the
task of generating such data , and the lack of widespread awareness at the regulatory level even
if, again, collective efforts progressively address the issue.

Acknowledgement
The author would like to gratefully acknowledge the support provided by Francine Gartner who
assisted in preparation of the manuscript.

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