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Table of Contents
Introduction
Professor Juergen Siepmann, PhD
University of Lille, College of Pharmacy
pages 1-3
pages 4-13
pages 14-19
pages 21-28
Introduction
J. Siepmann1,2
1
2
*correspondence:
Professor Juergen Siepmann, PhD
University of Lille, College of Pharmacy
INSERM U 1008
3 Rue du Prof. Laguesse
59006 Lille, France
Fax: +33-3-20964942
juergen.siepmann@univ-lille2.fr
Nowadays, one of the major hurdles to be faced during the development of innovative drug
products is the limited bioavailability of numerous drug candidates. This is in great part due to
the very low aqueous solubility of these compounds. Consequently, they do not have the time
to dissolve to a sufficient extent upon administration to the living organism. Importantly, only
dissolved drug is able to diffuse and cross major barriers in the human body, e.g. the mucosa
in the gastro intestinal tract. Thus, even if the chemical structure of the drug candidate is ideal
to allow for efficient interaction with its target (and cure the patient), the compound fails in
vivo, since it is not able to reach its site of action. A broad range of formulation approaches
has been proposed to overcome this crucial bottleneck, aiming at increasing the dissolution
rate of poorly water-soluble drugs upon administration into the living body.
In order to quantify the dissolution rate of a drug particle, the famous Noyes-Whitney
equation can be used [1,2]:
= ( )
(1)
where dc/dt is the dissolution rate; K is a constant; cs denotes the solubility of the substance,
and ct is the concentration of dissolved substance in the surrounding bulk fluid at time t. The
basic hypothesis is that the diffusion of individualized drug molecules, ions or atoms through
the liquid unstirred boundary layer surrounding the drug particle is the slowest step in the
Page 1
series of events occurring during drug particle dissolution [3]. Thus, this step (which is
illustrated in Figure 1) is rate limiting and governs the dissolution kinetics.
unstirred
layer
cs
ct
Figure 1: Schematic presentation of the mass transport process, which is often dominant during the
dissolution of a drug particle: The diffusion of individualized drug molecules/atoms/ions through the
unstirred liquid boundary layer surrounding the drug particle (adapted from [3]).
Nernst and Brunner [4,5] used Ficks first law of diffusion to quantify this diffusional mass
transport step and derived the following equation:
dM S D
=
(c s ct )
dt
d
(2)
where dM is amount of substance which dissolves in the time interval dt; S denotes the
surface area available for diffusion/dissolution; D is the diffusion coefficient of the drug
within the liquid unstirred boundary layer; d is the thickness of this layer; cs and ct are the
solubility of the drug in the bulk fluid and the concentration of dissolved drug in the bulk fluid
at time t, respectively.
Looking at the Nernst-Brunner equation (Equation 2), it becomes obvious that different
strategies can be used to increase the dissolution rate of a drug. In particular, one can aim at:
(i) increasing the surface area available for dissolution via a reduction of the particle size;
and/or (ii) increasing the apparent solubility of the drug in the surrounding environment, e.g.
Page 2
via transformation into a physical state with a higher energy. These first two strategies are
very often applied. Eventually, the aim might also be to keep the concentration of dissolved
drug in the surrounding bulk fluid low, e.g. by facilitating the subsequent drug transport away
from its site of dissolution. On the other hand, the thickness of the liquid, unstirred boundary
layer as well as the diffusion coefficient of the drug in this layer are generally very difficult to
alter in practice in the human body.
This ebook is a selection of articles published in the Journal of Drug Delivery Science and
Technology, giving overviews on different types of strategies that are used to increase the
dissolution rates of poorly water-soluble drugs in order to increase their bioavailability. A
variety of practical examples are given and limitations of the different approaches are
discussed. The article of Grohganz et al. reviews the current state of the art in the field of
amorphous drug forms. The basic idea is to provide the drug in a physical form with a high
energy (and, thus, higher apparent solubility). However, recrystallization during long term
storage is a major concern, which needs to be addressed. The review article by Thomas et al.
gives a comprehensive overview on the latest developments in oral lipid-based drug delivery
systems. Briefly, in these cases highly lipophilic drugs are dissolved in lipid dosage forms,
thus, avoiding the drug dissolution step in the human body (or in other words: the apparent
drug solubility in the dosage form is so much increased that the entire drug dose is already
dissolved). Finally, the article by Rodriguez-Aller et al. gives a comprehensive overview on
the broad variety of approaches used to better formulate poorly water-soluble drugs, including
many examples of drug products which are available on the market.
References
[1] Noyes, A.A., Whitney, W.R., 1897. The rate of solution of solid substances in their own
solutions. J. Am. Chem. Soc. 19, 930-934.
[2] Noyes, A.A., Whitney, W.R., 1897. Ueber die Aufloesungsgeschwindigkeit von festen
Stoffen in ihren eigenen Loesungen. Z. Physikal. Chem. 23, 689-692.
[3] Siepmann, J., Siepmann, F., 2013. Mathematical modeling of drug dissolution. Int. J.
Pharm. 453, 12-24.
[4] Nernst, W., 1904. Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen. Z.
Phys. Chem. 47, 52-55.
[5] Brunner, E., 1904. Reaktionsgeschwindigkeit in heterogenen Systemen. Z. Phys. Chem.
47, 56-102.
Page 3
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 March 2015
Received in revised form
12 May 2015
Accepted 12 May 2015
Available online xxx
Water solubility is a key parameter in drug formulation since it highly inuences drug pharmacokinetics
and pharmacodynamics. In the past decades, the challenge with poorly water soluble drugs has been
growing continuously. As a matter of fact, poorly soluble compounds represent 40% of the top 200 oral
drugs marketed in the US, 33% of drugs listed in the US Pharmacopeia, 75% of compounds under
development and 90% of new chemical entities. The present article presents and discusses the pharmaceutical strategies available to overcome poor water solubility in light of nal drug product examples.
First, chemical modications based on the adjustment of the pH and the design of prodrugs are presented and discussed. Physical modications based on modied solid states of the drug, small drug
particles, cosolvents, surfactants, lipids and cyclodextrins are discussed in a second part. Finally, the
option of modifying the route of administration is briey presented.
2015 Elsevier B.V. All rights reserved.
Keywords:
Insoluble drugs
Formulation
Delivery
pH
Pharmaceutical strategies
Alternative administration route
1. Introduction
The water solubility of drugs strongly inuences their pharmacokinetics and pharmacodynamics and is a key parameter for
formulators. Drug solubilization is based on the breaking of some
drugedrug and waterewater interactions for the creation of new
drugewater interactions. The strength of such interactions determines the solubility of a drug in water. Water solubility is one of
the main parameters of the biopharmaceutical classication system
(BCS) of drugs, as illustrated in Fig. 1A [1]. Moreover, Lipinski's rule
of 5 considers the solubility of drug candidates in view of the
rejection of inappropriate candidates at early stages of the drug
discovery process [2].
In the past decades, the challenges linked to poor water solubility have been continuously growing. The surge of combinatorial
chemistry and high throughput miniaturized screening methods
for drug discovery have resulted in an increase in molecular weight
and lipophilicity of drug candidates [3e5]. In addition, the push
towards increasing the potency of drugs often resulted in an increase in their lipophilicity (leading to stronger interactions with
their receptors). Currently, poorly soluble compounds represent
approximately 40% of the top 200 oral drugs marketed in the US
and Europe, as shown in Fig. 1B [6]. In addition, they represent 90%
* Corresponding author.
E-mail address: robert.gurny@unige.ch (R. Gurny).
http://dx.doi.org/10.1016/j.jddst.2015.05.009
1773-2247/ 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 1. A) The biopharmaceutical classication system (BCS) and B) the solubility of the top 200 marketed oral drugs in the US and Europe (adapted from [6]).
drug loading or adsorption. Finally, the surfactant and lipid formulations could include nanoemulsions, micelles, liposomes or
solid lipid nanoparticles.
2.1. Chemical modications
2.1.1. pH adjustment
The pH can inuence the solubility of a drug by affecting its
degree of ionization as a function of its pKa. In its ionized form, a
drug has a higher solubility than at its neutral form. However, drugs
are generally neutral at physiological pH. Thus, the pH of the
formulation can be adjusted with buffering excipients to ensure the
presence of the most soluble form of the poorly water-soluble drug.
For solid dosage forms, the buffering excipients control the pH
of the microenvironment surrounding drug particles during in vivo
dissolution [13]. Kranz and coworkers achieved a constant pHindependent release of the immunosuppressant, ZK811752, by
adding organic acids to the nal composition of the tablets [14].
The pH adjustment is a simple approach and represents a rstline strategy for the formulation of insoluble drugs. It is frequently
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 3. A) Prodrug design categories based on carrier-linked prodrugs and bioprecursors. B) Illustration of a pre-prodrug example combining the carrier-linked and bioprecursor
designs.
one of the most common examples for this group. Telzir and
Lexiva (GlaxoSmithKline, Brentford, UK) contain fosamprenavir,
the phosphate ester prodrug of the HIV protease inhibitor amprenavir. Fosamprenavir displays a water solubility 10 times higher
than amprenavir as well as an increased bioavailability, allowing a
simplication of the dosage regimen. With this prodrug formulation, the treatment went from 8 capsules twice a day to 4 tablets
once a day, which has a direct impact on patient quality of life and
compliance.
Hydrophobic structures can also be used to improve the
aqueous solubility of drugs. Their action is based on the disruption
of some drugedrug interactions (e.g. H-bounds) resulting in a
higher dissolution rate. The levodopa ethyl ester prodrug displayed
a higher solubility and absorption than the parent levodopa,
allowing its administration to Parkinson's disease patients as an
oral solution instead of the conventional tablets with known absorption issues [20]. Interestingly, this levodopa ethyl ester is a
double prodrug, levodopa being itself a prodrug of dopamine that
targets the central nervous system. The development of novel formulations for the anticancer drug 5-uorouracil (5-FU) based on
the prodrug approach has been intensively investigated to increase
its solubility, plasma half-life and selectivity. Xeloda (HoffmannLaRoche, Basel, Switzerland) contains capecitabine, which is a
double prodrug of 5-FU displaying an oral bioavailability close to
100% thanks to its high solubility, high absorption and low afnity
for the intestine thymidine phosphatases [21]. Interestingly, for
capecitabine design, hydrophobic hydrocarbon chains and amides
were covalently linked to the doxiuridine backbone, which is
already a pre-prodrug of 5-FU. After its oral absorption, capecitabine is biotransformed by carboxylesterases, deaminases and
tumor-specic thymidine phosphorylases, releasing the cytotoxic
5-FU specically in the tumor. Capecitabine combines the
advantages of an enhanced oral availability with a tumor-specic
activity [22e25].
The modications with amino acids can simultaneously achieve
two goals: increased water solubility and transporter-mediated
absorption (using amino acid transporters). The diversity in
physical properties of amino acids confers a high versatility to the
approach. An interesting example is valacyclovir, the L-valyl ester
prodrug of acyclovir marketed as Valtex (GlaxoSmithKline,
Brentford, UK). The bioavailability of valacyclovir is two times
higher than acyclovir due to its higher solubility and active transport via amino acid receptors [26]. After intracellular absorption,
valacyclovir is hydrolyzed, generating acyclovir, which requires
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 4. Different drug solid forms that can be used in formulations, including the most stable pure drug crystal, as well as polymorphs, hydrates, salts, cocrystals and amorphous
forms.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
amorphization is higher than that achieved with metastable polymorphs [11]. However, amorphous forms can have a higher hygroscopicity, reactivity and instability.
2.2.2. Small drug particles
A decrease in particle size of poorly water-soluble drugs allows
i) the increase of the drug surface area and its dissolution rate, ii) an
improved bioavailability and iii) a reduced toxicity [58e69]. This
approach can be combined with any of the modied solid states
detailed above, cumulating the advantages of both strategies.
Fine and ultrane drug particles can be obtained using two
types of strategies: reducing the size of preexisting drug particles or
inducing drug solidication into small particles. The methods to
reduce the size of preexisting drug particles are based on cuts,
compression, impact, or attrition, or both impact and attrition [70].
The methods to form small drug particles are: hot-melt extrusion,
hot-melt encapsulation, spray drying and supercritical uid
methods. It is also worth mentioning another approach consisting
of the loading or supercial adsorption of poorly water-soluble
drugs into nanoparticles [12,71].
Small drug particles form a metastable system that needs to be
further stabilized to avoid agglomeration and crystalline growth. A
large number of excipients can be used as stabilizers acting by
electrostatic repulsion or steric stabilization (e.g. surfactants or
polymers) [11,72,73]. Different systems can be formed depending
on the environment surrounding the small particles: suspensions
and nanosuspensions are obtained when drug particles are in a
liquid environment, while solid dispersions are formed when the
drug particles are embedded in a solid matrix.
The advantages of using small drug particles for the formulation of poorly water-soluble actives are illustrated by the number
of marketed products that employ this strategy. Three marketed
formulations of the immunosuppressants sirolimus and everolimus used for the prevention of organ graft rejection can be
cited as examples. Rapamune (Pzer, New York, US) is an oral
tablet containing sirolimus nanocrystals (NanoCrystal technology, Elan Drug Technologies, Dublin, Ireland). Solid dispersion
strategies have been successfully used in the development of the
everolimus formulations Certican and Zortress (Novartis, Basel,
Switzerland).
2.2.3. Cosolvents
A cosolvent is a water-miscible organic solvent used to increase
the solubility of a drug in water. This approach is based on the
theory that the dissolution is enhanced when the solute and solvent have similar physicochemical characteristics. The most
important factor to be considered is the polarity of the mixture (i.e.
its dielectric constant). A large variety of cosolvents such as ethanol,
polyethylene glycol (PEG), propylene glycol (PG), glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethylsolfoxide (DMSO), as well as a number of oils (e.g. peanut, corn,
sesame, olive or peppermint) can be used [73,74]. The cosolvent
approach has been used for VePesid (Bristol-Myers Squibb, New
York, US) where the solubilization of the anticancer agent etoposide
was achieved with a mixture of PEG 400, citric acid, glycerin and
water.
This cosolvent strategy presents some limitations linked to i)
cosolvent taste and stability, ii) adverse physiological effects, iii)
potential modication of the pharmacokinetic prole of the drug
and iv) potential drug precipitation after administration. This
strategy remains a simple option frequently used in combination
with other solubilizing strategies for the formulation of poorly
water-soluble drugs. Nevertheless, the risks of drug instability, drug
precipitation and modication of the pharmacokinetic prole need
to be considered.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 5. Surfactant distribution and self-assembly structures in aqueous environment for the formation of A) a micelle and B) a liposome and C) an emulsion droplet.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 6. A) Structure and characteristics of cyclodextrins (CDs) included in the US Pharmacopeia such as native aCD, bCD and gCD as well as the substituted hydroxypropylbCD
(HPbCD) [93]. B) Potential effect of the use of a CD for the formulation of a drug that has to reach a biological barrier protected by an aqueous layer (such as mucosal secretion or tear
uid). The CD interacts with the drug by: i) forming a complex, ii) caring the drug across the aqueous layer and iii) allowing drug release close to the biological barrier for its
subsequent absorption after complex dissociation. When the drug is formulated alone (upper part of the scheme), the crossing of the aqueous layer is more difcult and potentially a
lower amount of drug can reach the biological barrier for its absorption.
Fig. 7. Pros and cons of the presented strategies for formulating and delivering poorly water-soluble drugs.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
10
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
3. Conclusion
During the last decades, a number of pharmaceutical strategies
have been developed for the formulation and delivery of poorly
water-soluble drugs. In this article, eight of these strategies have
been presented and critically discussed in light of examples of
marketed products. The presented approaches included i) chemical
modications such as the adjustment of the pH and the design of
prodrugs, ii) physical modications such as the use of modied
solid states of the drug, small drug particles, cosolvents, surfactants,
lipids and cyclodextrins and iii) modications of the administration
strategy such as the use of alternative local administration approaches. These strategies can be used alone or in combination and
offer a panel of options for formulators to address the challenges
related to poorly water-soluble drugs. Pros and cons of each strategy are presented in Fig. 7.
Through this article it could be seen that the development of a
generic approach to solve drug solubility issues is not possible for
two main reasons. The rst reason is because each drug presents a
different set of specic challenges. The second reason is related to
the fact that the modication of the solubility of a drug could affect
many drug properties such as its lipophilicity, stability,
permeability, availability or elimination, which can potentially inuence its in vitro and in vivo behavior in a non-predictable manner.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
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Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
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Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
12
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M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
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13
The transformation to an amorphous form is one of the most promising approaches to address the low solubility of drug compounds, the
latter being an increasing challenge in the development of new drug candidates. However, amorphous forms are high energy solids and tend to
recrystallize. New formulation principles are needed to ensure the stability of amorphous drug forms. The formation of solid dispersions is still
the most investigated approach, but additional approaches are desirable to overcome the shortcomings of solid dispersions. Spatial separation by
either coating or the use of micro-containers has shown potential to prevent or delay recrystallization. Another recent approach is the formation
of co-amorphous mixtures between either two drugs or one drug and one low molecular weight excipient. Molecular interactions between the
two molecules provide an energy barrier that has to be overcome before single molecules are available for the formation of crystal nuclei, thus
stabilizing the amorphous form.
Key words: Amorphous Solid dispersion Glass solution Spatial separation Co-amorphous.
through water in the gas phase. The physical stability and especially,
the prediction thereof, is to date still an area of increased research
as currently no method exists, to predict a priori the stability of an
amorphous compound.
Amorphous material above the Tg tends to crystallize fast, as
sufficient mobility exists within the system to allow for nucleation
and crystallisation of the material. It has long been hypothesised that
the amorphous state below Tg does not possess sufficient mobility to
allow for recrystallization, and it was proposed to store amorphous
materials 50 K below its Tg to ensure stability [5]. However, this
rule of thumb has been shown not to hold true as crystallisation
was observed at temperatures well below Tg-50K [6].
14
15
2. Spatial separation
Glass solutions are the most established systems to improve solubility and stabilize amorphous drugs [21-23]. Usually they consist of
a drug and a polymer, often polyvinylpyrrolidone (PVP), polyvinylalcohol, cellulose derivates or polyethyleneglycole (PEG) and they
can be prepared through melt quenching, ball milling, spray drying
or hot melt extrusion [24]. Analytically the existence of a single glass
transition temperature as well as peak shifts in infrared and Raman
spectroscopy due to interactions are taken as indicator for the successful formation of a glass solution [25, 26]. However, it was shown
that amorphous felodipine PVP solid dispersions with different PVP
contents consisted of nano-domains of drug and polymer rather than
being a molecularly dispersed system [27]. In another study a solid
dispersion of a drug and PVP/VA was prepared via hot melt extrusion
with two different sets of processing parameters [28]. While the data
of freshly prepared samples differed neither in DSC nor XRPD, one
sample already started to recrystallize after two months while the other
was still amorphous. Raman microscopy revealed differences in the
drug distribution in the less stable sample being less homogeneous.
But even in a formulation with drug molecularly dissolved into the
polymer, phase separation may occur during storage, especially when
stored at high temperature and/or humidity. The strength of drug
polymer interaction, hygroscopicity and API hydrophobicity were
found to influence phase separation [29].
To be able to predict if a glass solution of a certain drug polymer pair
would be successful and if phase separation would be likely to occur,
the solubility/miscibility of drug and polymer were considered. The
solubility parameters [30] and the Flory Huggins interaction parameter
[31] have been calculated and good correlation to experimental data
was found. In another approach [32] pair distribution functions (PDF)
of single components and the drug (or sugar) polymer mixtures were
compared to each other and differences were attributed to a glass solution formation and confirmed with DSC data (single Tg or two Tgs).
The improved physical stability has not yet been clearly linked to a
stabilisation mechanism, but is probably a complex result of several
factors. In literature the increase of the Tg, antiplastisation, decreased
molecular mobility of the drug molecules by the polymer chains [33],
intermolecular interactions [34], type and ratio of polymer have been
discussed as the main stabilising factors.
In the past few years interest towards the use of amorphous multicomponent mixtures comprising only molecules with a low molecular
weight, instead of the use of large polymers, has increased. The use
of small molecules, such as urea, citric acid, sugars and nicotinamide,
as excipients in binary amorphous blends has been reported [41-44].
A stabilization effect of anhydrous citric acid on the amorphous form
of paracetamol in binary mixtures was observed. The reason for the
increased stability could be later assigned to hydrogen bonding between
paracetamol and citric acid [45].
To further explore this approach using low molecular weight components, Chieng et al. developed co-amorphous drug/drug mixtures.
405
16
The idea behind these systems was first, to create stable amorphous
systems without the use of polymers, and second, developing new
formulations of two drug candidates that could be used in combination
therapy [46], for example a pharmacological relevant pair of drugs. In
addition, the term co-amorphous was introduced for the first time
to differentiate amorphous blends comprising only low molecular
weight components to amorphous drug-polymer mixtures, which are
generally referred to as solid dispersions or glass solutions. In their
study, co-amorphous mixtures of indomethacin (IND) and ranitidine
hydrochloride (RAN) in weight ratios of 2:1, 1:1 and 1:2 were produced
by vibrational ball milling. They could show that the pure drugs alone
were poor glass formers, i.e. it was not possible to transform them into
the amorphous state under similar milling conditions. This changed
drastically when mixtures of two components were processed. Fully
co-amorphous blends were obtained and showed high physical stability
against crystallization. Interestingly, the order of physical stability did
not follow the order of increasing Tg as initially expected, but could
be addressed to molecular interactions between IND and RAN at
molecular and bulk level. These interactions were most distinctive in
the co-amorphous 1:1 mixture. Thus, the 1:1 blend was more stable
than the co-amorphous mixtures at 2:1 and 1:2 even though it had an
intermediate Tg to those of the 2:1 and 1:2 mixtures. However, this
finding could not be related to specific interactions in a 1:1 molar ratio
since weight ratios were used in the study.
In order to further study stability benefits of the 1:1 mixtures
and potential molecular interactions, Alles et. al. investigated coamorphous mixtures of naproxen (NAP) and cimetidine (CIM) at molar
ratios instead of weight ratios [47]. Indeed, the co-amorphous blend at
the molar ratio 1:1 again showed the highest physical stability in spite
of its Tg being in between those of the co-amorphous mixtures at 2:1
and 1:2. The 1:1 blend remained amorphous up to approx. six month
whereas the other mixtures showed recrystallization of the excess
component (Figure 5). In addition, the 1:1 co-amorphous mixture
showed a four-fold and two-fold increase in the intrinsic dissolution
rate of naproxen and cimetidine, respectively, compared to the pure
crystalline compounds. Furthermore, the drugs were released in a
synchronized 1:1 molar fashion which means that with every NAP
molecule one CIM molecule is released into the dissolution medium.
These findings were explained by specific interactions between NAP
and CIM in a pair-wise 1:1 molar fashion.
The concept of co-amorphous drug/drug formulations was further
investigated with respect to the factors influencing dissolution and
stability in studies on co-amorphous IND/NAP [48] and glipizide
17
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
407
18
18.
19.
20.
21.
22.
23.
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31.
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Manuscript
Received 7 March 2013, accepted for publication 30 March 2013.
408
19
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20
Trade
name
Lipid components
Surfactants
Hydrophilic
cosolvents
Alfacalcidol
One-Alpha
Sesame oil
Amprenavir
Agenerase
TPGS
PEG 400,
PG
Ciprofloxacin
Cipro
Mediumchain TAG,
lecithin
Tween 20
Clomethiazole
edisilate
Heminevrin
Fractionated TAG
of coconut
oil
Cyclosporin A
Neoral
MAG, DAG
and TAG of
corn oil
Cremophor
RH 40
Ethanol,
glycerol,
PG
Cyclosporin A
Sandimmune
Corn oil
Labrafil M2125CS
Ethanol,
glycerol
Dronabinol
Marinol
Sesame oil
Fenofibrate
Fenogal
Gelucire
44/14
Lopinavir/
ritonavir
Kaletra
Cremophor
RH 40
Ethanol,
glycerin,
PG
Ritonavir
Norvir
Oleic acid
Cremophor
EL
Ethanol
Saquinavir
Fortovase
Mediumchain MAG
and DAG
are associated with poor and variable absorption [8, 9]. Moreover,
the absorption of poorly water-soluble drugs is often affected by the
consumption of food [10]. In many cases absorption of poorly watersoluble drugs is facilitated by the presence of food. Lipids, in particular,
have been recognized to play a profound role in the solubilization and
absorption of lipophilic drugs. In an attempt to harness the beneficial
Sufficient aqueous solubility along with good intestinal permeability is crucial for adequate drug absorption, ultimately leading to
sufficient bioavailability [8]. Conversely, poorly water-soluble drugs
375
21
studies [22]. However, there is still a considerable lack in the understanding of how the digestion products interact with drugs leading to
enhanced absorption. Many of the current approaches to understand
drug absorption are concerned with the importance of drug solubilization in different biorelevant media using various levels of bile salt
and phospholipids [23, 24]. While this approach appears feasible for
the assessment of those drugs whose solubilities solely depend on the
overall concentration of surfactant, the type of surfactant and the presence of digestion products can cause considerable deviation from the
solubilities for other drugs [25-27]. As an example, danazol solubility
in biorelevant media was not affected by the type of surfactant used,
whereas fenofibrate and cinnarizine showed a substantial increase in
their solubility in media supplemented with oleic acid/monoolein as
model digestion products [27].
In addition to solubilization, several other effects of lipid excipients
in LbDDS may contribute to enhanced drug absorption. For example
highly lipophilic compounds will be directed towards the lymphatic
route when administered with long-chain lipids [28, 29]. In particular,
drugs that demonstrate pharmacological action in the lymphatic system
might benefit from this route, as well as compounds susceptible to a
high first pass metabolism [30, 31].
Moreover, the drug permeability can be elevated by LbDDS and
their digestion products by the opening of tight junctions, inhibitory
effects on efflux transporters and modulation of metabolic enzymes
[30, 32, 33]. As an example, Risovic et al. found that glyceryl monooleate decreased the expression of P-gp protein and stimulated the
intestinal lymphatic uptake of amphotericin B resulting in increased
drug absorption [32].
The presence of lipids can also prolong the residence time of
undissolved drug, for example from normal tablet formulations, in
the gastrointestinal tract, which allows for a longer time for a drug
to dissolve. It has been shown that relatively small amounts of lipids
administered as LbDDS can induce effects comparable to those observed with dietary lipids [34]. Whilst complete dissolution is desirable
for conventional formulations and compounds for which absorption
is limited by dissolution, it is not relevant for LbDDS since the drug
is usually already presented in a dissolved state. However, the importance of presenting the drug in a dissolved state requires further
investigation in light of a recent study that found the same bioavailability of danazol administered either as a solution or as a suspension
administered in the same lipid vehicle [35]. This data demonstrates
that the absence of a dissolution step alone cannot account for the
biopharmaceutical advantages of LbDDS, but that drug dissolution
(in case of a suspension), solubilization and absorption from LbDDS
are highly dynamic and complex. In fact, the underlying mechanisms
determining the absorption of a co-administered drug from LbDDS
are still not completely understood. However, several steps have been
proposed to attain successful drug absorption.
It is necessary that the drug is released from the formulation before
it can be absorbed in the small intestine as neither micelles nor oil
droplets can be absorbed intact through the intestinal epithelium [36].
According to this model, drug release from LbDDS can proceed in
two ways:
- the drug partitions directly from the formulation into the bulk (i.e.
as free drug or solubilized in bile salt micelles) and subsequently into
the enterocyte, or the drug is released from the formulation into the
bulk upon the degradation of the formulation [11]. The first pathway
has also been termed interfacial partition and can be considered
as the only release mechanism for formulations devoid of digestible
excipients [37, 38];
- the second pathway is restricted to formulations containing digestible
excipients. These can be enzymatically degraded by pancreatic lipase
and co-lipase, or other pancreatic esterases [7, 39]. The presence of
exogenous lipids further stimulates the contraction of the gall bladder releasing bile salts and lecithin into the intestine. Together with
22
Water-insoluble excipients
Surfactants
Cosolvents
Beeswax
Corn oil
Glyceryl
monooleate
Ethanol
Oleic acid
Olive oil
Polyoxyl 35
castor oil
Glycerin
Peanut oil
Polyoxyl 40
hydrogenated
castor oil
PEG 300
d--tocopherol
(vitamin E)
Rapeseed oil
PEG 400
caprylic/capric
glycerides
PEG 400
Sesame oil
Polysorbate 20
Propylene
glycol
Medium chain
(C8/C10) monoand di-glycerides
Soybean oil
Polysorbate 80
Propylene glycol
esters of fatty
acids
Hydrogenated
soybean oil
d--tocopheryl
polyethylene
glycol succinate (TPGS)
Caprylic/Capric
triglycerides
derived from coconut oil or palm
seed oil
Cottonseed oil
Sorbitan
monolaurate
377
23
Figure 2 - Illustration of a typical lipolysis set up. The temperaturecontrolled reaction vessel (I) contains the lipolysis medium agitated by
a magnetic stirrer (II). The temperature-sensitive pH-electrode (III) is
connected to the pH-stat unit (IV) controlling the dispensing of sodium
chloride (V) and calcium chloride (VI). The water bath (VII) maintains
the temperature of the lipolysis medium at 37C. Adapted from [66] .
formulation-free lipolysis medium from the sodium hydroxide volume needed for the actual lipolysis experiment. For further chemical
characterization of specific lipid digestion products high performance
thin layer chromatography and evaporative light scattering have
been applied successfully [67, 68]. In addition to the aforementioned
chemical characterization of the lipolysis products several physical
approaches have been used to assess the evolution of the colloidal
phases during in vitro lipolysis. Using cryo transmission electron
microscopy Fatouros et al. observed the presence of oil droplets and
micelles as the prevailing structures before in vitro lipolysis of SNEDDS
was initiated [69]. Over the course of lipid digestion the oil droplets
gradually disappeared, giving rise to unilamellar and multilamellar
vesicles. These findings were confirmed in subsequent studies using
bench top and synchroton small angle x-ray scattering (SAXS) [55,
65, 69, 70].
In the dynamic in vitro lipolysis model employed in Copenhagen
the constant addition of calcium chloride controls the rate and extend
of in vitro lipolysis by the removal of the digestion products from the
lipid surface that would otherwise inhibit further lipolysis [71, 72].
Proceeding lipolytic activity in samples of the medium is inhibited by
the addition of lipase inhibitors such as 4-bromobenzene boronic acid.
This is followed by the quantification of the drug in the aqueous phase
and the pellet obtained after an ultracentrifugation step (Figure3).
LbDDS leading to drug precipitation during dispersion or in vitro
lipolysis have been generally regarded unsuitable for effective drug
delivery [73, 74]. This paradigm is based on the assumption that only
the solubilized drug present in the aqueous phase is available for absorption. Consequently, the general objective of most of the LbDDS
development has been to avoid or retard drug precipitation due to
concerns of re-introducing a dissolution step of solid drug.
A growing body of evidence, however, suggests revision of this
paradigm. Several studies have shown that drug precipitation does not
necessarily correlate with reduced bioavailability [61, 75-77]. In a recent
study investigating the effect of different physicochemical properties
of four different SNEDDS on the in vivo performance, Larsen et al.
observed comparable areas under the plasma curves of cinnarizine
although substantial drug precipitation during in vitro lipolysis was
evident for one of the SNEDDS [61]. Moreover, the authors found
24
Table III - Recent in vivo studies with lipid-based delivery systems carried out in different animal species.
Type and composition of LbDDS*
Drug
Animal species
Ref.
Simvastatin
Beagle dog
[88]
Seocalcitol
Rat
[6, 92]
Seocalcitol
Absolute bioavailability:
MC-SNEDDS = LC-SNEDDS > MCT = LCT
Minipig
[89]
Danazol
Absolute bioavailability:
Solution / suspension in Labrafil M2125CS
(9-fold) > aqueous suspension
Rat
[35]
Probucol
Absolute bioavailability:
Fasted: SNEDDS SEDDS surfactant
solution > oil solution > powder
Fed: SNEDDS = SEDDS, no food effect,
Reduced bioavailability for other formulations with considerable food effect
Minipig
[38]
Danazol
Relative bioavailability:
CrRH 40-SEDDS > CrEL-SEDDS
Beagle dog
[94]
Rabbit
[62]
Albendazol
Relative bioavailability:
SMEDDS (1.6-fold) > commercial suspension
Halofantrine
Absolute bioavailability:
super-SNEDDS SNEDDS
Beagle dog
[77]
Simvastatin
Relative bioavailability:
super-SNEDDS (1.8-fold) > SNEDDS
Beagle dog
[76]
Cinnarizine
Relative bioavailability:
SNEDDS IV > SNEDDS I
Labrador dog
[61]
*Terminology as used by the respective authors, CrEL: Cremophor EL, CrRH40: Cremophor RH 40, MCT: medium chain triglycerides, LCT: long-chain
triglycerides, SNEDDS: self-nanoemulsifying drug delivery system, SMEDDS: self-microemulsifying drug delivery system, MC-SNEDDS/SMEDDS:
formulations containing medium-chain lipids, LC-SNEDDS/SMEDDS: formulations containing long chain lipids, super-SNEDDS: supersaturated SNEDDS.
379
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Received 12 March 2013, accepted for publication 23 April 2013.
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