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Abstract
The field of nanoparticle delivery systems for nutrients and nutraceuticals with poor water solubility has been expanding, almost exponentially,
over the last five years, and some of these technologies are now in the process of being incorporated in food products. The market projections for
these technologies suggest a multifold increase in their commercial potential over the next five years. The interest in the pharmaceutical and foodrelated applications of these technologies has sparked tremendous developments in mechanical (top-down) and chemical (bottom-up) processes to
obtain such nanoparticle systems. Mechanical approaches are capable of producing nanoparticles, typically in the 1001000 nm range, whereas
chemical methods tend to produce 10100 nm particles. Despite these technological developments, there is a lack of information regarding the
basis of design for such nanoparticle systems. Fundamental thermodynamic and mass transfer equations reveal that, in order to generate a broad
spectrum delivery system, nanoparticles with 100 nm diameter (or less) should be produced. However, experimental data reveal that, in some
cases, even nanoparticles in the 1001000 nm range are capable of producing substantial improvement in the bioavailability of the active
ingredients. In most cases, this improvement in bioavailability seems to be linked to the direct uptake of the nanoparticle. Furthermore, direct
nanoparticle uptake is controlled by the size and surface chemistry of the nanoparticle system. The use of this direct nanoparticle uptake, in
particular for soluble but poorly absorbed ingredients, is one of the areas that needs to be explored in the future, as well as the potential side effects
of these nanoparticle carriers.
2008 Elsevier Ltd. All rights reserved.
Keywords: Lipid nanoparticles; Bioavailability; Dissolution; Uptake; Peyer's patches; BCS dissolution models; Vitamins; Minerals; Food fortification
1. Introduction
The field of food nanotechnology has experienced significant growth over the last five years. Such growth has been
fuelled by the potential of harnessing the large surface area to
volume ratio of these materials to improve the bioavailability of
active ingredients, introduce controlled/target release, improve
sensory aspects, and others [1,2,3,4,5]. The growth of the
field is partially quantified in Fig. 1, where the cumulative
number of articles and patents containing the keywords food
and nanoparticles in their abstract or the claims (in the case of
patents) is presented as a function of year of publication. As
indicated by the trends in Fig. 1, most of the growth in the food
Department of Chemical Engineering and Applied Chemistry, The
University of Toronto, 200 College Street, room 131, Toronto, Ontario, Canada
M5S3E5. Tel.: +1 416 946 0742; fax: +1 416 978 8605.
E-mail address: acosta@chem-eng.utoronto.ca.
1359-0294/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cocis.2008.01.002
The term mechanical process, in this article, refers to processes that use shear or particle collisions as the energy source
to break down larger entities into smaller nano-scale aggregates.
Such mechanical processes could be considered as part of the
top-down approach mentioned above. The potential advantage of mechanical processes over chemical processes is that
mechanical processes require minimal use of chemical additives, which mitigates the concerns regarding the regulations
imposed on such formulation ingredients. There are two types
of mechanical processes mills for the nanonization (as
opposed to micronization) of solid particles, and microfluidic
processes for the nanonization of liquids or melts. Fig. 2
presents selected examples of mills and microfluidic processes.
As expected, there are challenges in the production of
nanoparticle systems with mechanical processes. These challenges include creating high energy density bursts to break
down the particle, preventing the re-aggregation of the particles,
Fig. 3. Schematic of chemical processes used to produce nanoparticle formulations based on the classification of Horn and Rieger [12].
system to less than 100 nm [51,52]. SMEDDS have been recently used to deliver Isoflavones extracted from Pueraria
Lobata (a traditional Chinese medicinal herb), finding that this
form of delivery increased the bioavailability (absorption) of this
active ingredient by 2.5 folds when compared to a tablet formula
[53]. Microemulsion aggregates have also been stabilized
(against phase changes) through the use of complex coacervation. According to this approach, an oil-in-water microemulsion
was coated with a coacervate phase formed after combining gum
Arabic and gelatin [54]. The encapsulation efficiency of this
complex was 60%, and the size of the coated aggregates ranged
between 30 and 100 nm.
3. Bioavailability enhancement with nanoparticles
The term bioavailability refers to the fraction of a dose that is
available at the site of action in the body. For most oral doses
this definition is interpreted as the fraction of the dose that
enters the bloodstream. Uptake (or intestinal absorption), on the
other hand, refers to fraction of the dose that is absorbed through
the intestinal walls. Although both definitions are related, the
entire dose that is absorbed through the intestine (uptake) may
not be bioavailable due to the various processes involved in the
absorption of nutrients. To design effective nanoparticle delivery systems for nutrients, nutraceuticals and related active
ingredients, it is necessary to understand the biological processes that regulate uptake and bioavailability.
The schematic of Fig. 4 illustrates some of the main processes involved in the absorption of nutrients and active ingredients. After the food/dose has been partially digested
(mainly by mastication) in the oral cavity, the food goes through
a dissolution process in the stomach at acidic conditions (pH ~ 1
to 2) during a period of time that ranges from 1 to 3 h. Various
enzymes (pepsin and others) are released in the stomach to help
break down some of the proteins and carbohydrates. Dissolution
in the stomach of the nanoparticle may or may not be desirable
depending on the stability of the active ingredients in the acidic
pH. If the nanoparticles require protection against the acidic
environment of the stomach, they can be microencapsulated
using enteric coatings [55]. As the digested food (now in the
form of a suspension) leaves the stomach and enters the duodenum, it mixes with the bile salts (such as sodium glycocholate, sodium taurocholate, and lecithin) released by the
gall bladder. These bile salts emulsify the fats and other
hydrophobic compounds present in the suspension.
The average size of bile salt aggregates ranges from 4 nm
(for bile salt micelles) to 60 nm (for bile salt vesicles) [56]. In
some ways, bile salts micelles and vesicles are nature's own
nanoparticle delivery system. In fact, the need for manufactured
nanoparticle delivery systems is questionable in certain cases.
For example, Faulks and Southon indicate that the solubility of
most carotenoids in triglycerides is 100200 mg/g and that
up to 70 mg of apolar and 44 mg of polar carotenoids could
be absorbed in a single meal without the use of nanoparticle
delivery systems [57]. However, these authors indicate that
carotenoids (as nutraceutical extracts without a delivery formulations) are not bioavailable if they are not consumed with
Fig. 4. Schematic of the mechanisms of active ingredient uptake using nanoparticle systems.
food. This observation reflects the fact that bile salts can
emulsify (and serve as nanocarriers) carotenoids dissolved in
triglycerides, but that bile salt micelles cannot solubilize pure
carotenoids.
In addition to the release of bile salts, a bicarbonate solution
containing a cocktail of enzymes (trypsin among others) is
also released in the duodenum, increasing the pH of the solution to
67. The suspension then enters the largest part of the small
intestine (47 m) where it resides for about 3 to 5 h before entering
the large intestine. The inner surface of the small intestine is
covered with small finger-like protuberances called vili. Each
epithelial cell is covered with even smaller protuberances called
microvilli that helps increase the area for nutrient absorption.
A mucous layer of an anionic glycoprotein (mucin) typically
covers the surface of the microvili and represents a key factor in
the uptake of nanoparticles. The microvili and the mucous
(mucin-rich) layer are illustrated in Fig. 4.
The absorption of nutrients through the small intestine occurs
through two main mechanisms, active and passive transport.
Active transport involves the uptake of the active ingredient
through specific channels on the surface of the epithelial cells.
The cells use their own energy to capture and absorb nutrients
even when the concentration of the nutrient inside the cell is
higher than the concentration outside the cell. Active transport
is the main mechanism by which cell captures and absorb
highly soluble minerals like calcium and iron. This active uptake
is controlled by hormones that regulate the concentration of
minerals and other nutrients in the body. Fig. 4 also presents a
simplified schematic of the control systems that regulate the
absorption of nutrients and nutraceuticals. These control systems
maintain a certain homeostatic level of substances in the blood,
in a way that, if there is any excess of the active ingredient in the
the value at a given particle size by the maximum uptake/bioavailability obtained in each study. Out of these five systems,
there are three groups that studied the plasma concentration of the
active ingredient and obtained the bioavailability from the area
under the curve (AUC) for their systems [12,65,66] and two
groups that studied the uptake of polymeric nanoparticles by the
surface of the small intestine [63,67].
In the study described by Horn and Rieger, the concentration
of -carotene in calve's blood is reported as a function of time,
after a dosage of -carotene nanoparticles prepared by the
amphiphilic (internal) solvent method [12]. This data was
integrated to obtain the AUC value, and the AUC values were
normalized according to the criteria indicated above. Wu et al.
presented the data of AUC for the absorption of the poorly
soluble drug MK-0869 prepared using three different milling
procedures Nanocrystals (120 nm), wet-milled particles
(480 nm) and jet-milled particles (1850 nm) [65]. Luo et al.
reported the AUC of vinpocetine prepared using solid lipid
nanoparticles (SLN) [66]. From the nanoparticle uptake series,
the data from Desai et al. presents the uptake of poly(lactic-coglycolic) acid particles produced by four different methods
sonication (100 nm), microfluidization (500 nm), high pressure
homogenization (1000 nm) and simple vortex mixing
(10000 nm) [63]. These researchers used an in-situ rat model
to load the particles in a section of the intestine, and determine
the number of particles absorbed per unit of area of the intestinal
tissue, and the fraction of particles absorbed was calculated
based on the initial dosage. The work of Jani et al. was conducted in a similar way, but they used a continuous (chronic)
Cs
Cso
2Mw g 1
qRT r
Fig. 5. Relative bioavailability of the active ingredient delivered using nanoparticle formulations and relative uptake of polymeric nanoparticles as a function of particle
size. The right abscissa presents the relative solubility of an example compound (molecular weight of 500 g/mol, surface tension of 50 dyn/cm and density 1 g/cm3)
calculated using the OstwaldFrendlich equation (Eq. (1)).
10
dr
Dn 1 C
dz
3
r
Fig. 6. Left schematic of the mechanism of dissolutionabsorption used by Oh and Amidon to setup the mass balance equations (Eqs. (2)(7)) to determine the
fraction of active ingredient absorbed. Right threshold solubility of the active ingredient for absorption as a function of particle size calculated using Eq. (3), and a
critical dissolution number Dn = 3.3. A diffusion coefficient of the active ingredient of 1 10 5 cm2/s, and a residence time of 3 h were assumed in these calculations.
The corrected solubility values were calculated on the basis of Eq. (1) (same basis used in Fig. 5).
Mo 1
Vo CS
Peff k R L
Q
Using the total mass balance of the active ingredient, the fraction absorbed (F) is:
F 1 r43
C
:
Do
11
12
13
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